Lack of utility of arteriojugular venous differences of lactate as a reliable indicator of increased brain anaerobic metabolism in traumatic brain injury.

PubMed

Poca, Maria A; Sahuquillo, Juan; Vilalta, Anna; Garnacho, Angel

2007-04-01

Ischemic lesions are highly prevalent in patients with traumatic brain injuries (TBIs) and are the single most important cause of secondary brain damage. The prevention and early treatment of these lesions is the primary aim in the modem treatment of these patients. One of the most widely used monitoring techniques at the bedside is quantification of brain extracellular level of lactate by using arteriojugular venous differences of lactate (AVDL). The purpose of this study was to determine the sensitivity, specificity, and predictive value of AVDL as an indicator of increases in brain lactate production in patients with TBIs. Arteriojugular venous differences of lactate were calculated every 6 hours using samples obtained though a catheter placed in the jugular bulb in 45 patients with diffuse head injuries (57.8%) or evacuated brain lesions (42.2%). Cerebral lactate concentration obtained with a 20-kD microdialysis catheter implanted in undamaged tissue was used as the de facto gold standard. Six hundred seventy-three AVDL determinations and cerebral microdialysis samples were obtained simultaneously; 543 microdialysis samples (81%) showed lactate values greater than 2 mmol/L, but only 21 AVDL determinations (3.1%) showed an increase in brain lactate. No correlation was found between AVDL and cerebral lactate concentration (p = 0.014, p = 0.719). Arteriojugular venous differences of lactate had a sensitivity and specificity of 3.3 and 97.7%, respectively, with a false-negative rate of 96.7% and a false-positive rate of 2.3%. Arteriojugular venous differences of lactate do not reliably reflect increased cerebral lactate production and consequently are not reliable in ruling out brain ischemia in patients with TBIs. The clinical use of this monitoring method in neurocritical care should be reconsidered.

Response of lactate metabolism in brain glucosensing areas of rainbow trout (Oncorhynchus mykiss) to changes in glucose levels.

PubMed

Otero-Rodiño, Cristina; Librán-Pérez, Marta; Velasco, Cristina; Álvarez-Otero, Rosa; López-Patiño, Marcos A; Míguez, Jesús M; Soengas, José L

2015-12-01

There is no evidence in fish brain demonstrating the existence of changes in lactate metabolism in response to alterations in glucose levels. We induced in rainbow trout through intraperitoneal (IP) treatments, hypoglycaemic or hyperglycaemic changes to assess the response of parameters involved in lactate metabolism in glucosensing areas like hypothalamus and hindbrain. To distinguish those effects from those induced by peripheral changes in the levels of metabolites or hormones, we also carried out intracerebroventricular (ICV) treatments with 2-deoxy-D-glucose (2-DG, a non-metabolizable glucose analogue thus inducing local glucopenia) or glucose. Finally, we also incubated hypothalamus and hindbrain in vitro in the presence of increased glucose concentrations. The changes in glucose availability were in general correlated to changes in the amount of lactate in both areas. However, when we assessed in these areas the response of parameters related to lactate metabolism, the results obtained were contradictory. The increase in glucose levels did not produce in general the expected changes in those pathways with only a minor increase in their capacity of lactate production. The decrease in glucose levels was, however, more clearly related to a decreased capacity of the pathways involved in the production and use of lactate, and this was especially evident after ICV treatment with 2-DG in both areas. In conclusion, the present results while addressing the existence of changes in lactate metabolism after inducing changes in glucose levels in brain glucosensing areas only partially support the possible existence of an astrocyte-neuron lactate shuttle in hypothalamus and hindbrain of rainbow trout relating glucose availability to lactate production and use.

Lactate shuttling and lactate use as fuel after traumatic brain injury: metabolic considerations

PubMed Central

Dienel, Gerald A

2014-01-01

Lactate is proposed to be generated by astrocytes during glutamatergic neurotransmission and shuttled to neurons as ‘preferred' oxidative fuel. However, a large body of evidence demonstrates that metabolic changes during activation of living brain disprove essential components of the astrocyte–neuron lactate shuttle model. For example, some glutamate is oxidized to generate ATP after its uptake into astrocytes and neuronal glucose phosphorylation rises during activation and provides pyruvate for oxidation. Extension of the notion that lactate is a preferential fuel into the traumatic brain injury (TBI) field has important clinical implications, and the concept must, therefore, be carefully evaluated before implementation into patient care. Microdialysis studies in TBI patients demonstrate that lactate and pyruvate levels and lactate/pyruvate ratios, along with other data, have important diagnostic value to distinguish between ischemia and mitochondrial dysfunction. Results show that lactate release from human brain to blood predominates over its uptake after TBI, and strong evidence for lactate metabolism is lacking; mitochondrial dysfunction may inhibit lactate oxidation. Claims that exogenous lactate infusion is energetically beneficial for TBI patients are not based on metabolic assays and data are incorrectly interpreted. PMID:25204393

Dorsal Anterior Cingulate Lactate and Glutathione Levels in Euthymic Bipolar I Disorder: 1H-MRS Study.

PubMed

Soeiro-de-Souza, Márcio Gerhardt; Pastorello, Bruno F; Leite, Cláudia da Costa; Henning, Anke; Moreno, Ricardo A; Garcia Otaduy, Maria Concepción

2016-08-01

Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls. Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm(3)) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program. Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed. This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Dorsal Anterior Cingulate Lactate and Glutathione Levels in Euthymic Bipolar I Disorder: 1H-MRS Study

PubMed Central

Pastorello, Bruno F.; Leite, Cláudia da Costa; Henning, Anke; Moreno, Ricardo A.; Garcia Otaduy, Maria Concepción

2016-01-01

Objective: Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls. Methods: Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm3) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program. Results: Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed. Conclusion: This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis. PMID:27207914

MRS of brain metabolite levels demonstrates the ability of scavenging of excess brain glutamate to protect against nerve agent induced seizures.

PubMed

Ruban, Angela; Biton, Inbal E; Markovich, Arik; Mirelman, David

2015-02-02

This study describes the use of in vivo magnetic resonance spectrocopy (MRS) to monitor brain glutamate and lactate levels in a paraoxon (PO) intoxication model. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces the brain-accumulated levels of glutamate. Previously we have shown that the treatment causes a rapid decrease of blood glutamate levels and creates a gradient between the brain and blood glutamate levels which leads to the efflux of excess brain glutamate into the blood stream thereby reducing its potential to cause neurological damage. The fact that this treatment significantly decreased the brain glutamate and lactate levels following PO intoxication suggests that it could become a new effective neuroprotective agent.

Lactate transport and receptor actions in cerebral malaria

PubMed Central

Mariga, Shelton T.; Kolko, Miriam; Gjedde, Albert; Bergersen, Linda H.

2014-01-01

Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood–brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM. PMID:24904266

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

PubMed Central

Hagihara, Hideo; Catts, Vibeke S; Katayama, Yuta; Shoji, Hirotaka; Takagi, Tsuyoshi; Huang, Freesia L; Nakao, Akito; Mori, Yasuo; Huang, Kuo-Ping; Ishii, Shunsuke; Graef, Isabella A; Nakayama, Keiichi I; Shannon Weickert, Cynthia; Miyakawa, Tsuyoshi

2018-01-01

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder. PMID:28776581

Microdialysis Monitoring of CSF Parameters in Severe Traumatic Brain Injury Patients: A Novel Approach

PubMed Central

Thelin, Eric P.; Nelson, David W.; Ghatan, Per Hamid; Bellander, Bo-Michael

2014-01-01

Background: Neuro-intensive care following traumatic brain injury (TBI) is focused on preventing secondary insults that may lead to irreversible brain damage. Microdialysis (MD) is used to detect deranged cerebral metabolism. The clinical usefulness of the MD is dependent on the regional localization of the MD catheter. The aim of this study was to analyze a new method of continuous cerebrospinal fluid (CSF) monitoring using the MD technique. The method was validated using conventional laboratory analysis of CSF samples. MD-CSF and regional MD-Brain samples were correlated to patient outcome. Materials and Methods: A total of 14 patients suffering from severe TBI were analyzed. They were monitored using (1) a MD catheter (CMA64-iView, n = 7448 MD samples) located in a CSF-pump connected to the ventricular drain and (2) an intraparenchymal MD catheter (CMA70, n = 8358 MD samples). CSF-lactate and CSF-glucose levels were monitored and were compared to MD-CSF samples. MD-CSF and MD-Brain parameters were correlated to favorable (Glasgow Outcome Score extended, GOSe 6–8) and unfavorable (GOSe 1–5) outcome. Results: Levels of glucose and lactate acquired with the CSF-MD technique could be correlated to conventional levels. The median MD recovery using the CMA64 catheter in CSF was 0.98 and 0.97 for glucose and lactate, respectively. Median MD-CSF (CMA 64) lactate (p = 0.0057) and pyruvate (p = 0.0011) levels were significantly lower in the favorable outcome group compared to the unfavorable group. No significant difference in outcome was found using the lactate:pyruvate ratio (LPR), or any of the regional MD-Brain monitoring in our analyzed cohort. Conclusion: This new technique of global MD-CSF monitoring correlates with conventional CSF levels of glucose and lactate, and the MD recovery is higher than previously described. Increase in lactate and pyruvate, without any effect on the LPR, correlates to unfavorable outcome, perhaps related to the presence of erythrocytes in the CSF. PMID:25228896

Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease.

PubMed

Lin, Doris D M; Crawford, Thomas O; Barker, Peter B

2003-01-01

Mitochondrial diseases are a group of inherited disorders caused by a derangement of mitochondrial respiration. The clinical manifestations are heterogeneous, and the diagnosis is often based on information acquired from multiple levels of inquiry. MR spectroscopy has previously been shown to help detect an abnormal accumulation of lactate in brain parenchyma and CSF in association with mitochondrial disorders, but the frequency of detection is largely unknown. We sought to examine the frequency of detectable elevations of CNS lactate by proton MR spectroscopy in a population of children and young adults with suspected mitochondrial disease. MR spectroscopy data evaluated for the presence or absence of abnormal brain or CSF lactate were compared with other clinical indicators of mitochondrial dysfunction for 29 patients with suspected mitochondrial disease during the years 1990 to 2000. Based on an independent review of the final diagnoses, the patients were divided into groups based on the probability of mitochondrial disorder. A total of 32 scans from 29 patients were reviewed. Of eight patients thought to have a definitive mitochondrial disorder on the basis of genetic, biochemical, or pathologic features, five were found to have abnormal brain or CSF lactate levels revealed by MR spectroscopy (for one patient in whom two images were acquired, one was negative and the other positive). Among the studies conducted using a multisection spectroscopic imaging technique, five of six showed elevated lactate in the brain parenchyma, six of six showed elevated lactate in the CSF, and five of six showed elevated lactate in both brain and CSF. Of 16 patients who were highly suspected of having mitochondrial disorders on the basis of clinical grounds alone but who were lacking genetic, biochemical, or pathologic confirmation, four had abnormal lactate levels shown by MR spectroscopy. Mitochondrial disorder was excluded for five patients, none of whom had CNS lactate shown by MR spectroscopy. Detection of CNS lactate by MR spectroscopy is useful in the diagnosis of mitochondrial disease. In our series of patients with confirmed mitochondrial disease, a high level of lactate shown by MR spectroscopy correlated well with other markers of mitochondrial disease. As with all other means used to diagnose mitochondrial disorders, MR spectroscopy does not depict elevated lactate in all cases. Abnormal CNS concentrations of lactate may be undetected by MR spectroscopy because of differences in the type of mitochondrial disorder, timing, severity, or location of the affected tissues and the site of interrogation.

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

PubMed Central

Morland, Cecilie; Andersson, Krister A.; Haugen, Øyvind P.; Hadzic, Alena; Kleppa, Liv; Gille, Andreas; Rinholm, Johanne E.; Palibrk, Vuk; Diget, Elisabeth H.; Kennedy, Lauritz H.; Stølen, Tomas; Hennestad, Eivind; Moldestad, Olve; Cai, Yiqing; Puchades, Maja; Offermanns, Stefan; Vervaeke, Koen; Bjørås, Magnar; Wisløff, Ulrik; Storm-Mathisen, Jon; Bergersen, Linda H.

2017-01-01

Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor. PMID:28534495

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1.

PubMed

Morland, Cecilie; Andersson, Krister A; Haugen, Øyvind P; Hadzic, Alena; Kleppa, Liv; Gille, Andreas; Rinholm, Johanne E; Palibrk, Vuk; Diget, Elisabeth H; Kennedy, Lauritz H; Stølen, Tomas; Hennestad, Eivind; Moldestad, Olve; Cai, Yiqing; Puchades, Maja; Offermanns, Stefan; Vervaeke, Koen; Bjørås, Magnar; Wisløff, Ulrik; Storm-Mathisen, Jon; Bergersen, Linda H

2017-05-23

Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.

Proton MRS of the peritumoral brain.

PubMed

Chernov, Mikhail F; Kubo, Osami; Hayashi, Motohiro; Izawa, Masahiro; Maruyama, Takashi; Usukura, Masao; Ono, Yuko; Hori, Tomokatsu; Takakura, Kintomo

2005-02-15

Long-echo (TR: 2000 ms, TE: 136 ms) proton MRS of the cerebral tissue in the vicinity to intracranial lesion was done in 15 patients, mainly with parenchymal brain tumors. Significant decrease of N-acetylaspartate (NAA) (P<0.001) and more frequent presence of lactate (P<0.01) comparing with distant normal white matter were found in the perilesional brain tissue. The level of NAA in the perilesional brain tissue had negative associations with presence of lactate in the lesion (P<0.05), excess of lactate in the lesion compared to perilesional brain (P<0.01), grade of the perilesional edema (P<0.01) and patient's age (P<0.05). Multivariate analysis disclosed that identification of lactate in the lesion is associated with lower relative NAA content in the perilesional brain tissue, independently on the presence or absence of any other factor, including brain edema (P<0.001). In patients with lobar lesions who had at least one epileptic seizure during course of their disease the relative NAA content in the perilesional brain was significantly lower, comparing with those who were seizure-free (P<0.05). Therefore, lactate diffused from the tumor, or other metabolites secreted by lactate-producing neoplasm, should be considered as important contributors to the neuronal dysfunction in the surrounding brain. Decrease of NAA in the vicinity to intracranial lesions may reflect neuronal alteration responsible for associated epilepsy.

Fueling and imaging brain activation

PubMed Central

Dienel, Gerald A

2012-01-01

Metabolic signals are used for imaging and spectroscopic studies of brain function and disease and to elucidate the cellular basis of neuroenergetics. The major fuel for activated neurons and the models for neuron–astrocyte interactions have been controversial because discordant results are obtained in different experimental systems, some of which do not correspond to adult brain. In rats, the infrastructure to support the high energetic demands of adult brain is acquired during postnatal development and matures after weaning. The brain's capacity to supply and metabolize glucose and oxygen exceeds demand over a wide range of rates, and the hyperaemic response to functional activation is rapid. Oxidative metabolism provides most ATP, but glycolysis is frequently preferentially up-regulated during activation. Underestimation of glucose utilization rates with labelled glucose arises from increased lactate production, lactate diffusion via transporters and astrocytic gap junctions, and lactate release to blood and perivascular drainage. Increased pentose shunt pathway flux also causes label loss from C1 of glucose. Glucose analogues are used to assay cellular activities, but interpretation of results is uncertain due to insufficient characterization of transport and phosphorylation kinetics. Brain activation in subjects with low blood-lactate levels causes a brain-to-blood lactate gradient, with rapid lactate release. In contrast, lactate flooding of brain during physical activity or infusion provides an opportunistic, supplemental fuel. Available evidence indicates that lactate shuttling coupled to its local oxidation during activation is a small fraction of glucose oxidation. Developmental, experimental, and physiological context is critical for interpretation of metabolic studies in terms of theoretical models. PMID:22612861

The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain.

PubMed

Morland, Cecilie; Lauritzen, Knut Husø; Puchades, Maja; Holm-Hansen, Signe; Andersson, Krister; Gjedde, Albert; Attramadal, Håvard; Storm-Mathisen, Jon; Bergersen, Linda Hildegard

2015-07-01

We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippocampus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce cAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the blood-brain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucose- and glycogen-saving response. HCAR1 may contribute to optimizing the cAMP concentration. For instance, in the prefrontal cortex, excessively high cAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells. © 2015 Wiley Periodicals, Inc.

Carbohydrate management, anaerobic metabolism, and adenosine levels in the armoured catfish, Liposarcus pardalis (castelnau), during hypoxia.

PubMed

Maccormack, Tyson James; Lewis, Johanne Mari; Almeida-Val, Vera Maria Fonseca; Val, Adalberto Luis; Driedzic, William Robert

2006-04-01

The armoured catfish, Liposarcus pardalis, tolerates severe hypoxia at high temperatures. Although this species can breathe air, it also has a strong anaerobic metabolism. We assessed tissue to plasma glucose ratios and glycogen and lactate in a number of tissues under "natural" pond hypoxia, and severe aquarium hypoxia without aerial respiration. Armour lactate content and adenosine in brain and heart were also investigated. During normoxia, tissue to plasma glucose ratios in gill, brain, and heart were close to one. Hypoxia increased plasma glucose and decreased tissue to plasma ratios to less than one, suggesting glucose phosphorylation is activated more than uptake. High normoxic white muscle glucose relative to plasma suggests gluconeogenesis or active glucose uptake. Excess muscle glucose may serve as a metabolic reserve since hypoxia decreased muscle to plasma glucose ratios. Mild pond hypoxia changed glucose management in the absence of lactate accumulation. Lactate was elevated in all tissues except armour following aquarium hypoxia; however, confinement in aquaria increased armour lactate, even under normoxia. A stress-associated acidosis may contribute to armour lactate sequestration. High plasma lactate levels were associated with brain adenosine accumulation. An increase in heart adenosine was triggered by confinement in aquaria, although not by hypoxia alone.

Regional analyses of CNS microdialysate glucose and lactate in seizure patients.

PubMed

Cornford, Eain M; Shamsa, Kamran; Zeitzer, Jamie M; Enriquez, Cathleen M; Wilson, Charles L; Behnke, Eric J; Fried, Itzhak; Engel, Jerome

2002-11-01

To correlate glucose (and lactate) results obtained from microdialysate to recent studies suggesting that glucose transporter activity may be significantly altered in seizures. We used a fluorometric technique to quantify glucose and lactate levels in microdialysates collected from two to four depth electrodes implanted per patient in the temporal and frontal lobes of a series of four patients. Hour-by-hour and day-to-day changes in brain glucose and lactate levels at the same site were recorded. Additionally we compared regional variations in lactate/glucose ratios around the predicted epileptogenic region. Lactate/glucose ratios in the range of 1-2:1 were the most commonly seen. When the lactate/glucose ratio was <1:1, we typically observed a relative increase in local glucose concentration (rather than decreased lactate), suggesting increased transport, perhaps without increased glycolysis. In some sites, lactate/glucose ratios of 3:1-15:1 were seen, suggesting that a circumscribed zone of inhibition of tricarboxylic acid cycle activity may have been locally induced. In these dialysates, collected from probes closer to the epileptogenic region, the large increase in lactate/glucose ratios was a result of both increased lactate and reduced glucose levels. We conclude that regional variations in brain extracellular glucose concentrations may be of greater magnitude than previously believed and become even more accentuated in partial seizure patients. Data from concomitant assays of microdialysate lactate and glucose may aid in understanding cerebral metabolism.

Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis

PubMed Central

Martin, Neil A.; McArthur, David L.; Hovda, David A.; Vespa, Paul; Johnson, Matthew L.; Horning, Michael A.; Brooks, George A.

2015-01-01

Abstract We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-2H2]glucose, i.e., D2-glucose, and [3-13C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2–10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain. PMID:25279664

Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis.

PubMed

Glenn, Thomas C; Martin, Neil A; McArthur, David L; Hovda, David A; Vespa, Paul; Johnson, Matthew L; Horning, Michael A; Brooks, George A

2015-06-01

We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2-10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain.

ARALAR/AGC1 deficiency, a neurodevelopmental disorder with severe impairment of neuronal mitochondrial respiration, does not produce a primary increase in brain lactate.

PubMed

Juaristi, Inés; García-Martín, María L; Rodrigues, Tiago B; Satrústegui, Jorgina; Llorente-Folch, Irene; Pardo, Beatriz

2017-07-01

ARALAR/AGC1 (aspartate-glutamate mitochondrial carrier 1) is an important component of the NADH malate-aspartate shuttle (MAS). AGC1-deficiency is a rare disease causing global cerebral hypomyelination, developmental arrest, hypotonia, and epilepsy (OMIM ID #612949); the aralar-KO mouse recapitulates the major findings in humans. This study was aimed at understanding the impact of ARALAR-deficiency in brain lactate levels as a biomarker. We report that lactate was equally abundant in wild-type and aralar-KO mouse brain in vivo at postnatal day 17. We find that lactate production upon mitochondrial blockade depends on up-regulation of lactate formation in astrocytes rather than in neurons. However, ARALAR-deficiency decreased cell respiration in neurons, not astrocytes, which maintained unchanged respiration and lactate production. As the primary site of ARALAR-deficiency is neuronal, this explains the lack of accumulation of brain lactate in ARALAR-deficiency in humans and mice. On the other hand, we find that the cytosolic and mitochondrial components of the glycerol phosphate shuttle are present in astrocytes with similar activities. This suggests that glycerol phosphate shuttle is the main NADH shuttle in astrocytes and explains the absence of effects of ARALAR-deficiency in these cells. © 2017 International Society for Neurochemistry.

Glymphatic clearance controls state-dependent changes in brain lactate concentration.

PubMed

Lundgaard, Iben; Lu, Minh Lon; Yang, Ezra; Peng, Weiguo; Mestre, Humberto; Hitomi, Emi; Deane, Rashid; Nedergaard, Maiken

2017-06-01

Brain lactate concentration is higher during wakefulness than in sleep. However, it is unknown why arousal is linked to an increase in brain lactate and why lactate declines within minutes of sleep. Here, we show that the glymphatic system is responsible for state-dependent changes in brain lactate concentration. Suppression of glymphatic function via acetazolamide treatment, cisterna magna puncture, aquaporin 4 deletion, or changes in body position reduced the decline in brain lactate normally observed when awake mice transition into sleep or anesthesia. Concurrently, the same manipulations diminished accumulation of lactate in cervical, but not in inguinal lymph nodes when mice were anesthetized. Thus, our study suggests that brain lactate is an excellent biomarker of the sleep-wake cycle and increases further during sleep deprivation, because brain lactate is inversely correlated with glymphatic-lymphatic clearance. This analysis provides fundamental new insight into brain energy metabolism by demonstrating that glucose that is not fully oxidized can be exported as lactate via glymphatic-lymphatic fluid transport.

Glymphatic clearance controls state-dependent changes in brain lactate concentration

PubMed Central

Lu, Minh Lon; Yang, Ezra; Peng, Weiguo; Mestre, Humberto; Hitomi, Emi; Deane, Rashid; Nedergaard, Maiken

2016-01-01

Brain lactate concentration is higher during wakefulness than in sleep. However, it is unknown why arousal is linked to an increase in brain lactate and why lactate declines within minutes of sleep. Here, we show that the glymphatic system is responsible for state-dependent changes in brain lactate concentration. Suppression of glymphatic function via acetazolamide treatment, cisterna magna puncture, aquaporin 4 deletion, or changes in body position reduced the decline in brain lactate normally observed when awake mice transition into sleep or anesthesia. Concurrently, the same manipulations diminished accumulation of lactate in cervical, but not in inguinal lymph nodes when mice were anesthetized. Thus, our study suggests that brain lactate is an excellent biomarker of the sleep–wake cycle and increases further during sleep deprivation, because brain lactate is inversely correlated with glymphatic-lymphatic clearance. This analysis provides fundamental new insight into brain energy metabolism by demonstrating that glucose that is not fully oxidized can be exported as lactate via glymphatic-lymphatic fluid transport. PMID:27481936

Energy and glucose pathways in thiamine deficient primary rat brain microvascular endothelial cells.

PubMed

Ham, D; Karska-Wysocki, B

2005-12-01

Thiamine deficiency (TD) results in lactate acidosis, which is associated with neurodegeneration. The aim of this study was to investigate this alteration in primary rat brain endothelia. Spectrophotometric analysis of culture media revealed that only a higher concentration of pyrithiamine, which accelerates the intracellular blocking of thiamine, significantly elevated the lactate level and lactate dehydrogenase activity within 7 days. The medium without pyrithiamine and with a thiamine concentration comparable to pathophysiological plasma levels mildly reduced only the activity of transketolase. This suggests that significant metabolic changes may not occur at the early phase of TD in cerebral capillary cells, while anaerobic glycolysis in capillaries may be mediated during late stage/chronic TD.

Long-Term Effect of Docosahexaenoic Acid Feeding on Lipid Composition and Brain Fatty Acid-Binding Protein Expression in Rats

PubMed Central

Elsherbiny, Marwa E.; Goruk, Susan; Monckton, Elizabeth A.; Richard, Caroline; Brun, Miranda; Emara, Marwan; Field, Catherine J.; Godbout, Roseline

2015-01-01

Arachidonic (AA) and docosahexaenoic acid (DHA) brain accretion is essential for brain development. The impact of DHA-rich maternal diets on offspring brain fatty acid composition has previously been studied up to the weanling stage; however, there has been no follow-up at later stages. Here, we examine the impact of DHA-rich maternal and weaning diets on brain fatty acid composition at weaning and three weeks post-weaning. We report that DHA supplementation during lactation maintains high DHA levels in the brains of pups even when they are fed a DHA-deficient diet for three weeks after weaning. We show that boosting dietary DHA levels for three weeks after weaning compensates for a maternal DHA-deficient diet during lactation. Finally, our data indicate that brain fatty acid binding protein (FABP7), a marker of neural stem cells, is down-regulated in the brains of six-week pups with a high DHA:AA ratio. We propose that elevated levels of DHA in developing brain accelerate brain maturation relative to DHA-deficient brains. PMID:26506385

Measurement of Lactate Content and Amide Proton Transfer Values in the Basal Ganglia of a Neonatal Piglet Hypoxic-Ischemic Brain Injury Model Using MRI.

PubMed

Zheng, Y; Wang, X-M

2017-04-01

As amide proton transfer imaging is sensitive to protein content and intracellular pH, it has been widely used in the nervous system, including brain tumors and stroke. This work aimed to measure the lactate content and amide proton transfer values in the basal ganglia of a neonatal piglet hypoxic-ischemic brain injury model by using MR spectroscopy and amide proton transfer imaging. From 58 healthy neonatal piglets (3-5 days after birth; weight, 1-1.5 kg) selected initially, 9 piglets remained in the control group and 43 piglets, in the hypoxic-ischemic brain injury group. Single-section amide proton transfer imaging was performed at the coronal level of the basal ganglia. Amide proton transfer values of the bilateral basal ganglia were measured in all piglets. The ROI of MR spectroscopy imaging was the right basal ganglia, and the postprocessing was completed with LCModel software. After hypoxic-ischemic insult, the amide proton transfer values immediately decreased, and at 0-2 hours, they remained at their lowest level. Thereafter, they gradually increased and finally exceeded those of the control group at 48-72 hours. After hypoxic-ischemic insult, the lactate content increased immediately, was maximal at 2-6 hours, and then gradually decreased to the level of the control group. The amide proton transfer values were negatively correlated with lactate content ( r = -0.79, P < .05). This observation suggests that after hypoxic-ischemic insult, the recovery of pH was faster than that of lactate homeostasis. © 2017 by American Journal of Neuroradiology.

Cerebral metabolism following traumatic brain injury: new discoveries with implications for treatment

PubMed Central

Brooks, George A.; Martin, Neil A.

2015-01-01

Because it is the product of glycolysis and main substrate for mitochondrial respiration, lactate is the central metabolic intermediate in cerebral energy substrate delivery. Our recent studies on healthy controls and patients following traumatic brain injury (TBI) using [6,6-2H2]glucose and [3-13C]lactate, along with cerebral blood flow (CBF) and arterial-venous (jugular bulb) difference measurements for oxygen, metabolite levels, isotopic enrichments and 13CO2 show a massive and previously unrecognized mobilization of lactate from corporeal (muscle, skin, and other) glycogen reserves in TBI patients who were studied 5.7 ± 2.2 days after injury at which time brain oxygen consumption and glucose uptake (CMRO2 and CMRgluc, respectively) were depressed. By tracking the incorporation of the 13C from lactate tracer we found that gluconeogenesis (GNG) from lactate accounted for 67.1 ± 6.9%, of whole-body glucose appearance rate (Ra) in TBI, which was compared to 15.2 ± 2.8% (mean ± SD, respectively) in healthy, well-nourished controls. Standard of care treatment of TBI patients in state-of-the-art facilities by talented and dedicated heath care professionals reveals presence of a catabolic Body Energy State (BES). Results are interpreted to mean that additional nutritive support is required to fuel the body and brain following TBI. Use of a diagnostic to monitor BES to provide health care professionals with actionable data in providing nutritive formulations to fuel the body and brain and achieve exquisite glycemic control are discussed. In particular, the advantages of using inorganic and organic lactate salts, esters and other compounds are examined. To date, several investigations on brain-injured patients with intact hepatic and renal functions show that compared to dextrose + insulin treatment, exogenous lactate infusion results in normal glycemia. PMID:25709562

Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury.

PubMed

Carteron, Laurent; Solari, Daria; Patet, Camille; Quintard, Hervé; Miroz, John-Paul; Bloch, Jocelyne; Daniel, Roy T; Hirt, Lorenz; Eckert, Philippe; Magistretti, Pierre J; Oddo, Mauro

2018-06-19

Lactate promotes cerebral blood flow and is an efficient substrate for the brain, particularly at times of glucose shortage. Hypertonic lactate is neuroprotective after experimental brain injury; however, human data are limited. Prospective study (clinicaltrials.gov NCT01573507). Academic ICU. Twenty-three brain-injured subjects (13 traumatic brain injury/10 subarachnoid hemorrhage; median age, 59 yr [41-65 yr]; median Glasgow Coma Scale, 6 [3-7]). Three-hour IV infusion of hypertonic lactate (sodium lactate, 1,000 mmol/L; concentration, 30 µmol/kg/min) administered 39 hours (26-49 hr) from injury. We examined the effect of hypertonic lactate on cerebral perfusion (using transcranial Doppler) and brain energy metabolism (using cerebral microdialysis). The majority of subjects (13/23 = 57%) had reduced brain glucose availability (baseline pretreatment cerebral microdialysis glucose, < 1 mmol/L) despite normal baseline intracranial pressure (10 [7-15] mm Hg). Hypertonic lactate was associated with increased cerebral microdialysis lactate (+55% [31-80%]) that was paralleled by an increase in middle cerebral artery mean cerebral blood flow velocities (+36% [21-66%]) and a decrease in pulsatility index (-21% [13-26%]; all p < 0.001). Cerebral microdialysis glucose increased above normal range during hypertonic lactate (+42% [30-78%]; p < 0.05); reduced brain glucose availability correlated with a greater improvement of cerebral microdialysis glucose (Spearman r = -0.53; p = 0.009). No significant changes in cerebral perfusion pressure, mean arterial pressure, systemic carbon dioxide, and blood glucose were observed during hypertonic lactate (all p > 0.1). This is the first clinical demonstration that hypertonic lactate resuscitation improves both cerebral perfusion and brain glucose availability after brain injury. These cerebral vascular and metabolic effects appeared related to brain lactate supplementation rather than to systemic effects.

Increased brain lactate is central to the development of brain edema in rats with chronic liver disease.

PubMed

Bosoi, Cristina R; Zwingmann, Claudia; Marin, Helen; Parent-Robitaille, Christian; Huynh, Jimmy; Tremblay, Mélanie; Rose, Christopher F

2014-03-01

The pathogenesis of brain edema in patients with chronic liver disease (CLD) and minimal hepatic encephalopathy (HE) remains undefined. This study evaluated the role of brain lactate, glutamine and organic osmolytes, including myo-inositol and taurine, in the development of brain edema in a rat model of cirrhosis. Six-week bile-duct ligated (BDL) rats were injected with (13)C-glucose and de novo synthesis of lactate, and glutamine in the brain was quantified using (13)C nuclear magnetic resonance spectroscopy (NMR). Total brain lactate, glutamine, and osmolytes were measured using (1)H NMR or high performance liquid chromatography. To further define the interplay between lactate, glutamine and brain edema, BDL rats were treated with AST-120 (engineered activated carbon microspheres) and dichloroacetate (DCA: lactate synthesis inhibitor). Significant increases in de novo synthesis of lactate (1.6-fold, p<0.001) and glutamine (2.2-fold, p<0.01) were demonstrated in the brains of BDL rats vs. SHAM-operated controls. Moreover, a decrease in cerebral myo-inositol (p<0.001), with no change in taurine, was found in the presence of brain edema in BDL rats vs. controls. BDL rats treated with either AST-120 or DCA showed attenuation in brain edema and brain lactate. These two treatments did not lead to similar reductions in brain glutamine. Increased brain lactate, and not glutamine, is a primary player in the pathogenesis of brain edema in CLD. In addition, alterations in the osmoregulatory response may also be contributing factors. Our results suggest that inhibiting lactate synthesis is a new potential target for the treatment of HE. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Lactate is oxidized outside of the mitochondrial matrix in rodent brain.

PubMed

Herbst, Eric A F; George, Mitchell A J; Brebner, Karen; Holloway, Graham P; Kane, Daniel A

2018-05-01

The nature and existence of mitochondrial lactate oxidation is debated in the literature. Obscuring the issue are disparate findings in isolated mitochondria, as well as relatively low rates of lactate oxidation observed in permeabilized muscle fibres. However, respiration with lactate has yet to be directly assessed in brain tissue with the mitochondrial reticulum intact. To determine if lactate is oxidized in the matrix of brain mitochondria, oxygen consumption was measured in saponin-permeabilized mouse brain cortex samples, and rat prefrontal cortex and hippocampus (dorsal) subregions. While respiration in the presence of ADP and malate increased with the addition of lactate, respiration was maximized following the addition of exogenous NAD + , suggesting maximal lactate metabolism involves extra-matrix lactate dehydrogenase. This was further supported when NAD + -dependent lactate oxidation was significantly decreased with the addition of either low-concentration α-cyano-4-hydroxycinnamate or UK-5099, inhibitors of mitochondrial pyruvate transport. Mitochondrial respiration was comparable between glutamate, pyruvate, and NAD + -dependent lactate oxidation. Results from the current study demonstrate that permeabilized brain is a feasible model for assessing lactate oxidation, and support the interpretation that lactate oxidation occurs outside the mitochondrial matrix in rodent brain.

Enhancement of Astroglial Aerobic Glycolysis by Extracellular Lactate-Mediated Increase in cAMP

PubMed Central

Vardjan, Nina; Chowdhury, Helena H.; Horvat, Anemari; Velebit, Jelena; Malnar, Maja; Muhič, Marko; Kreft, Marko; Krivec, Špela G.; Bobnar, Saša T.; Miš, Katarina; Pirkmajer, Sergej; Offermanns, Stefan; Henriksen, Gjermund; Storm-Mathisen, Jon; Bergersen, Linda H.; Zorec, Robert

2018-01-01

Besides being a neuronal fuel, L-lactate is also a signal in the brain. Whether extracellular L-lactate affects brain metabolism, in particular astrocytes, abundant neuroglial cells, which produce L-lactate in aerobic glycolysis, is unclear. Recent studies suggested that astrocytes express low levels of the L-lactate GPR81 receptor (EC50 ≈ 5 mM) that is in fat cells part of an autocrine loop, in which the Gi-protein mediates reduction of cytosolic cyclic adenosine monophosphate (cAMP). To study whether a similar signaling loop is present in astrocytes, affecting aerobic glycolysis, we measured the cytosolic levels of cAMP, D-glucose and L-lactate in single astrocytes using fluorescence resonance energy transfer (FRET)-based nanosensors. In contrast to the situation in fat cells, stimulation by extracellular L-lactate and the selective GPR81 agonists, 3-chloro-5-hydroxybenzoic acid (3Cl-5OH-BA) or 4-methyl-N-(5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-4-(2-thienyl)-1,3-thiazol-2-yl)cyclohexanecarboxamide (Compound 2), like adrenergic stimulation, elevated intracellular cAMP and L-lactate in astrocytes, which was reduced by the inhibition of adenylate cyclase. Surprisingly, 3Cl-5OH-BA and Compound 2 increased cytosolic cAMP also in GPR81-knock out astrocytes, indicating that the effect is GPR81-independent and mediated by a novel, yet unidentified, excitatory L-lactate receptor-like mechanism in astrocytes that enhances aerobic glycolysis and L-lactate production via a positive feedback mechanism. PMID:29867342

Secondary Increase of Lactate Levels in Asphyxiated Newborns during Hypothermia Treatment: Reflect of Suboptimal Hemodynamics (A Case Series and Review of the Literature)

PubMed Central

Al Balushi, Asim; Guilbault, Marie-Pier; Wintermark, Pia

2015-01-01

Objective To evaluate whether a secondary increase of serum lactate levels in asphyxiated newborns during hypothermia treatment may reflect suboptimal dynamics. Methods–Retrospective case series and review of the literature. We present the clinical course of four asphyxiated newborns treated with hypothermia who presented with hypotension requiring inotropic support, and who displayed a secondary increase of serum lactate levels during hypothermia treatment. Serial serum lactate levels are correlated with blood pressure and inotropic support within the first 96 hours of life. Results Lactate levels initially decreased in the four patients. However, each of them started to present lower blood pressure, and lactate levels started to increase again. Inotropic support was started to raise blood pressure. The introduction of an epinephrine drip consistently worsened the increase of lactate levels in these newborns, whereas dopamine and dobutamine enabled the clearance of lactate in addition to raising the blood pressure. Rewarming was associated with hemodynamics perturbations (a decrease of blood pressure and/or an increase of lactate levels) in the three newborns who survived. Conclusions Lactate levels during the first 4 days of life should be followed as a potential marker for suboptimal hemodynamic status in term asphyxiated newborns treated with hypothermia, for whom the maintenance of homeostasis during hypothermia treatment is of utmost importance to alleviate brain injury. PMID:26929870

13C-labelled microdialysis studies of cerebral metabolism in TBI patients☆

PubMed Central

Carpenter, Keri L.H.; Jalloh, Ibrahim; Gallagher, Clare N.; Grice, Peter; Howe, Duncan J.; Mason, Andrew; Timofeev, Ivan; Helmy, Adel; Murphy, Michael P.; Menon, David K.; Kirkpatrick, Peter J.; Carpenter, T. Adrian; Sutherland, Garnette R.; Pickard, John D.; Hutchinson, Peter J.

2014-01-01

Human brain chemistry is incompletely understood and better methodologies are needed. Traumatic brain injury (TBI) causes metabolic perturbations, one result of which includes increased brain lactate levels. Attention has largely focussed on glycolysis, whereby glucose is converted to pyruvate and lactate, and is proposed to act as an energy source by feeding into neurons’ tricarboxylic acid (TCA) cycle, generating ATP. Also reportedly upregulated by TBI is the pentose phosphate pathway (PPP) that does not generate ATP but produces various molecules that are putatively neuroprotective, antioxidant and reparative, in addition to lactate among the end products. We have developed a novel combination of 13C-labelled cerebral microdialysis both to deliver 13C-labelled substrates into brains of TBI patients and recover the 13C-labelled metabolites, with high-resolution 13C NMR analysis of the microdialysates. This methodology has enabled us to achieve the first direct demonstration in humans that the brain can utilise lactate via the TCA cycle. We are currently using this methodology to make the first direct comparison of glycolysis and the PPP in human brain. In this article, we consider the application of 13C-labelled cerebral microdialysis for studying brain energy metabolism in patients. We set this methodology within the context of metabolic pathways in the brain, and 13C research modalities addressing them. PMID:24361470

Metabolic changes in rat striatum following convulsive seizures.

PubMed

Darbin, Olivier; Risso, Jean Jacque; Carre, Emily; Lonjon, Michel; Naritoku, Dean K

2005-07-19

Generalized convulsive seizures increase glucose utilization within the brain but their impact on metabolism is not well known. The striatum receives excitatory input from widespread sources in the brain and could potentially reflect energy depletion in the brain resulting from generalized seizures. We utilized multiprobe microdialysis in freely moving rats subjected to maximal electroshock to simultaneously measure glucose, lactate, and pyruvate levels in the interstitial space within striatum and in peripheral subcutaneous tissue. A brief convulsive seizure was associated with marked changes in striatal and peripheral metabolism during the post-ictal state that lasted up to 1 h. There were significant central and peripheral elevations of glucose, pyruvate, and lactate, reflecting increased glucose metabolism. Interestingly, the lactate-to-pyruvate ratio increased significantly in the periphery but remained unchanged in the striatum. Thus, there appears to be brain mechanisms that maintain adequate energy sources and prevent anaerobic shift during the post-ictal state.

Influence of acute and chronic treadmill exercise on rat plasma lactate and brain NPY, L-ENK, DYN A1-13.

PubMed

Chen, Jia-Xu; Zhao, Xin; Yue, Guang-Xin; Wang, Zhu-Feng

2007-02-01

This study was designed to investigate the effect of acute and chronic high-intensity treadmill exercise on changes in plasma lactate and brain neuropeptide (NPY), leucine-enkephalin (L-ENK), and dynorphin A(1-13) (DYN A(1-13)). Avidin-biotin complex (ABC) immunohistochemistry and image pattern analysis were used to observe the effect of chronic (total 7 weeks) and acute treadmill exercise (an initial speed of 15 m min(-1) gradually increased to 35 m min(-1) with 0 degrees, 20-25 min per day duration) on the changes of NPY, L-ENK, and DYN A(1-13) in different areas of rat brain. Plasma lactate was also measured in response to such exercise. Compared with preexercise control (P < 0.01), plasma lactate concentration significantly increased in the immediate postexercise; but it returned to the normal level soon after the 30 min postexercise. The content of NPY in paraventricular (PVN), dorsomedial (DMN), and ventromedial (VMN) hypothalamic nuclei continued to increase in 0, 30, and 180 min postexercise compared with preexercise control (P < 0.01). The content of L-ENK in caudate-putamen (CPu) significantly increased in the immediate postexercise compared with preexercise control (P < 0.01), but it gradually returned to the normal level after the 180 min postexercise. However, the content of DYN A(1-13) in PVN rose substantially only in 30 min postexercise in comparison with the preexercise control (P < 0.01). Thus, different changes of NPY, L-ENK, and DYN A(1-13) in response to such high-intensity exercise depend on the brain region and the time examined, especially, the contents of NPY in different brain regions continuously remain at a high level after such high-intensity exercise. And this high level might reduce energy expenditure and thus contribute to the stimulation of brain NPY neurons.

Neuroenergetic Response to Prolonged Cerebral Glucose Depletion after Severe Brain Injury and the Role of Lactate.

PubMed

Patet, Camille; Quintard, Hervé; Suys, Tamarah; Bloch, Jocelyne; Daniel, Roy T; Pellerin, Luc; Magistretti, Pierre J; Oddo, Mauro

2015-10-15

Lactate may represent a supplemental fuel for the brain. We examined cerebral lactate metabolism during prolonged brain glucose depletion (GD) in acute brain injury (ABI) patients monitored with cerebral microdialysis (CMD). Sixty episodes of GD (defined as spontaneous decreases of CMD glucose from normal to low [<1.0 mmol/L] for at least 2 h) were identified among 26 patients. During GD, we found a significant increase of CMD lactate (from 4 ± 2.3 to 5.4 ± 2.9 mmol/L), pyruvate (126.9 ± 65.1 to 172.3 ± 74.1 μmol/L), and lactate/pyruvate ratio (LPR; 27 ± 6 to 35 ± 9; all, p < 0.005), while brain oxygen and blood lactate remained normal. Dynamics of lactate and glucose supply during GD were further studied by analyzing the relationships between blood and CMD samples. There was a strong correlation between blood and brain lactate when LPR was normal (r = 0.56; p < 0.0001), while an inverse correlation (r = -0.11; p = 0.04) was observed at elevated LPR >25. The correlation between blood and brain glucose also decreased from r = 0.62 to r = 0.45. These findings in ABI patients suggest increased cerebral lactate delivery in the absence of brain hypoxia when glucose availability is limited and support the concept that lactate acts as alternative fuel.

Reproducibility of proton MR spectroscopic imaging (PEPSI): comparison of dyslexic and normal-reading children and effects of treatment on brain lactate levels during language tasks.

PubMed

Richards, Todd L; Berninger, Virginia W; Aylward, Elizabeth H; Richards, Anne L; Thomson, Jennifer B; Nagy, William E; Carlisle, Joanne F; Dager, Stephen R; Abbott, Robert D

2002-01-01

We repeated a proton echo-planar spectroscopic imaging (PEPSI) study to test the hypothesis that children with dyslexia and good readers differ in brain lactate activation during a phonologic judgment task before but not after instructional treatment. We measured PEPSI brain lactate activation (TR/TE, 4000/144; 1.5 T) at two points 1-2 months apart during two language tasks (phonologic and lexical) and a control task (passive listening). Dyslexic participants (n = 10) and control participants (n = 8) (boys and girls aged 9-12 years) were matched in age, verbal intelligence quotients, and valid PEPSI voxels. In contrast to patients in past studies who received combined treatment, our patients were randomly assigned to either phonologic or morphologic (meaning-based) intervention between the scanning sessions. Before treatment, the patients showed significantly greater lactate elevation in the left frontal regions (including the inferior frontal gyrus) during the phonologic task. Both patients and control subjects differed significantly in the right parietal and occipital regions during both tasks. After treatment, the two groups did not significantly differ in any brain region during either task, but individuals given morphologic treatment were significantly more likely to have reduced left frontal lactate activation during the phonologic task. The previous finding of greater left frontal lactate elevation in children with dyslexia during a phonologic judgment task was replicated, and brain activation changed as a result of treatment. However, the treatment effect was due to the morphologic component rather than the phonologic component.

SUPPLY AND DEMAND IN CEREBRAL ENERGY METABOLISM: THE ROLE OF NUTRIENT TRANSPORTERS

PubMed Central

Simpson, Ian A.; Carruthers, Anthony; Vannucci, Susan J.

2007-01-01

Glucose is the obligate energetic fuel for the mammalian brain and most studies of cerebral energy metabolism assume that the vast majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state. Glucose transporter proteins (GLUTs) deliver glucose from the circulation to the brain: GLUT1 in the microvascular endothelial cells of the blood brain barrier (BBB) and glia; GLUT3 in neurons. Lactate, the glycolytic product of glucose metabolism, is transported into and out of neural cells by the monocarboxylate transporters: MCT1 in the BBB and astrocytes and MCT2 in neurons. The proposal of the astrocyte-neuron lactate shuttle hypothesis (Pellerin and Magistretti, 1994) suggested that astrocytes play the primary role in cerebral glucose utilization and generate lactate for neuronal energetics, especially during activation. Since the identification of the GLUTs and MCTs in brain, much has been learned about their transport properties, i.e. capacity and affinity for substrate, which must be considered in any model of cerebral glucose uptake and utilization. Using concentrations and kinetic parameters of GLUT1 and GLUT3 in BBB endothelial cells, astrocytes and neurons, along with the corresponding kinetic properties of the monocarboxylate transporters, we have successfully modeled brain glucose and lactate levels as well as lactate transients in response to neuronal stimulation. Simulations based on these parameters suggest that glucose readily diffuses through the basal lamina and interstitium to neurons, which are primarily responsible for glucose uptake, metabolism, and the generation of the lactate transients observed upon neuronal activation. PMID:17579656

A Comparison of Oxidative Lactate Metabolism in Traumatically Injured Brain and Control Brain.

PubMed

Jalloh, Ibrahim; Helmy, Adel; Howe, Duncan J; Shannon, Richard J; Grice, Peter; Mason, Andrew; Gallagher, Clare N; Murphy, Michael P; Pickard, John D; Menon, David K; Carpenter, T Adrian; Hutchinson, Peter J; Carpenter, Keri L H

2018-05-18

Metabolic abnormalities occur after traumatic brain injury (TBI). Glucose is conventionally regarded as the major energy substrate, although lactate can also be an energy source. We compared 3- 13 C lactate metabolism in TBI with "normal" control brain and muscle, measuring 13 C-glutamine enrichment to assess tricarboxylic acid (TCA) cycle metabolism. Microdialysis catheters in brains of nine patients with severe TBI, five non-TBI brain surgical patients, and five resting muscle (non-TBI) patients were perfused (24 h in brain, 8 h in muscle) with 8 mmol/L sodium 3- 13 C lactate. Microdialysate analysis employed ISCUS and nuclear magnetic resonance. In TBI, with 3- 13 C lactate perfusion, microdialysate glucose concentration increased nonsignificantly (mean +11.9%, p = 0.463), with significant increases (p = 0.028) for lactate (+174%), pyruvate (+35.8%), and lactate/pyruvate ratio (+101.8%). Microdialysate 13 C-glutamine fractional enrichments (median, interquartile range) were: for C4 5.1 (0-11.1) % in TBI and 5.7 (4.6-6.8) % in control brain, for C3 0 (0-5.0) % in TBI and 0 (0-0) % in control brain, and for C2 2.9 (0-5.7) % in TBI and 1.8 (0-3.4) % in control brain. 13 C-enrichments were not statistically different between TBI and control brain, showing both metabolize 3- 13 C lactate via TCA cycle, in contrast to muscle. Several patients with TBI exhibited 13 C-glutamine enrichment above the non-TBI control range, suggesting lactate oxidative metabolism as a TBI "emergency option."

Hypertonic sodium lactate reverses brain oxygenation and metabolism dysfunction after traumatic brain injury.

PubMed

Millet, A; Cuisinier, A; Bouzat, P; Batandier, C; Lemasson, B; Stupar, V; Pernet-Gallay, K; Crespy, T; Barbier, E L; Payen, J F

2018-06-01

The mechanisms by which hypertonic sodium lactate (HSL) solution act in injured brain are unclear. We investigated the effects of HSL on brain metabolism, oxygenation, and perfusion in a rodent model of diffuse traumatic brain injury (TBI). Thirty minutes after trauma, anaesthetised adult rats were randomly assigned to receive a 3 h infusion of either a saline solution (TBI-saline group) or HSL (TBI-HSL group). The sham-saline and sham-HSL groups received no insult. Three series of experiments were conducted up to 4 h after TBI (or equivalent) to investigate: 1) brain oedema using diffusion-weighted magnetic resonance imaging and brain metabolism using localized 1 H-magnetic resonance spectroscopy (n = 10 rats per group). The respiratory control ratio was then determined using oxygraphic analysis of extracted mitochondria, 2) brain oxygenation and perfusion using quantitative blood-oxygenation-level-dependent magnetic resonance approach (n = 10 rats per group), and 3) mitochondrial ultrastructural changes (n = 1 rat per group). Compared with the TBI-saline group, the TBI-HSL and the sham-operated groups had reduced brain oedema. Concomitantly, the TBI-HSL group had lower intracellular lactate/creatine ratio [0.049 (0.047-0.098) vs 0.097 (0.079-0.157); P < 0.05], higher mitochondrial respiratory control ratio, higher tissue oxygen saturation [77% (71-79) vs 66% (55-73); P < 0.05], and reduced mitochondrial cristae thickness in astrocytes [27.5 (22.5-38.4) nm vs 38.4 (31.0-47.5) nm; P < 0.01] compared with the TBI-saline group. Serum sodium and lactate concentrations and serum osmolality were higher in the TBI-HSL than in the TBI-saline group. These findings indicate that the hypertonic sodium lactate solution can reverse brain oxygenation and metabolism dysfunction after traumatic brain injury through vasodilatory, mitochondrial, and anti-oedema effects. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism.

PubMed

Dienel, Gerald A; Cruz, Nancy F

2016-07-01

Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas β-receptor blockade 're-balances' the stoichiometry of oxygen-glucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential non-oxidative glucose utilization and glycogen turnover during brain activation. Aerobic glycolysis, the preferential up-regulation of glucose utilization (CMRglc ) compared with oxygen consumption (CMRO2 ) during brain activation, is blocked by propranolol. Epinephrine release from the adrenal gland stimulates vagus nerve signaling to the locus coeruleus, enhancing norepinephrine release in the brain, and regulation of astrocytic and neuronal metabolism to stimulate CMRglc more than CMRO2 . Propranolol suppresses CMRglc more than CMRO2 . © 2016 International Society for Neurochemistry.

Regulation of Brain Glucose Metabolic Patterns by Protein Phosphorlyation and Drug Therapy

DTIC Science & Technology

2007-03-30

chlorpromazine and haloperidol revolutionized the treatment of mental illness the sedating and neuroleptic side effects produced by "typical...demonstrated in rodents chronically treated with haloperidol and clozapine. We also demonstrate significantly higher levels of lactate in the postmortem...lactate levels in the cerebellum of patients with schizophrenia (n = 35) and control subjects (n = 42) and in rats chronically treated with haloperidol

Association of brain metabolites with blood lactate and glucose levels with respect to neurological outcomes after out-of-hospital cardiac arrest: A preliminary microdialysis study.

PubMed

Hifumi, Toru; Kawakita, Kenya; Yoda, Takeshi; Okazaki, Tomoya; Kuroda, Yasuhiro

2017-01-01

Out-of-hospital cardiac arrest (OHCA) is associated with poor prognosis. Cerebral microdialysis (CMD) is an efficient sampling technique to detect neurochemical changes in brain interstitial tissue. In this retrospective study, we hypothesised that there are different CMD levels between patients with favourable and unfavourable neurological outcomes. Data of patients with OHCA admitted to Kagawa University Hospital and administered therapeutic hypothermia (TH) were collected. Using a CMD probe, extracellular glucose, lactate and pyruvate levels were measured hourly along with intracranial perfusion pressure (ICP) and cerebral perfusion pressure (CPP) for the initial 72h during TH. The lactate/pyruvate (LP) ratio was calculated. Patients were divided into favourable [Glasgow-Pittsburgh cerebral performance category 1-2 at 30days after cardiac arrest] or unfavourable neurological outcome groups. CMD biochemical markers and blood lactate and glucose levels were compared between two groups. Ten patients were included. ICP was significantly higher in the unfavourable than in the favourable neurological outcome group; there were no significant differences with respect to CPP. The CMD LP ratio in the unfavourable outcome group progressively increased; significant differences were observed on days 2, 3 and 4 (p<0.01). Significant differences in blood lactate levels were observed between the groups only on day 3.5. CMD and blood glucose levels were higher in the unfavourable than in the favourable outcome group during TH. The association of CMD levels with long-term outcomes would be better defined in a large randomised prospective study. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Lactate: Brain Fuel in Human Traumatic Brain Injury: A Comparison with Normal Healthy Control Subjects

PubMed Central

Martin, Neil A.; Horning, Michael A.; McArthur, David L.; Hovda, David A.; Vespa, Paul; Brooks, George A.

2015-01-01

Abstract We evaluated the hypothesis that lactate shuttling helps support the nutritive needs of injured brains. To that end, we utilized dual isotope tracer [6,6-2H2]glucose, that is, D2-glucose, and [3-13C]lactate techniques involving arm vein tracer infusion along with simultaneous cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Traumatic brain injury (TBI) patients with nonpenetrating brain injuries (n=12) were entered into the study following consent of patients' legal representatives. Written and informed consent was obtained from control volunteers (n=6). Patients were studied 5.7±2.2 (mean±SD) days post-injury; during periods when arterial glucose concentration tended to be higher in TBI patients. As in previous investigations, the cerebral metabolic rate for glucose (CMRgluc, i.e., net glucose uptake) was significantly suppressed following TBI (p<0.001). However, lactate fractional extraction, an index of cerebral lactate uptake related to systemic lactate supply, approximated 11% in both healthy control subjects and TBI patients. Further, neither the CMR for lactate (CMRlac, i.e., net lactate release), nor the tracer-measured cerebral lactate uptake differed between healthy controls and TBI patients. The percentages of lactate tracer taken up and released as 13CO2 into the JB accounted for 92% and 91% for control and TBI conditions, respectively, suggesting that most cerebral lactate uptake was oxidized following TBI. Comparisons of isotopic enrichments of lactate oxidation from infused [3-13C]lactate tracer and 13C-glucose produced during hepatic and renal gluconeogenesis (GNG) showed that 75–80% of 13CO2 released into the JB was from lactate and that the remainder was from the oxidation of glucose secondarily labeled from lactate. Hence, either directly as lactate uptake, or indirectly via GNG, peripheral lactate production accounted for ∼70% of carbohydrate (direct lactate uptake+uptake of glucose from lactate) consumed by the injured brain. Undiminished cerebral lactate fractional extraction and uptake suggest that arterial lactate supplementation may be used to compensate for decreased CMRgluc following TBI. PMID:25594628

Cerebrospinal fluid lactate and pyruvate concentrations and their ratio.

PubMed

Zhang, Wan-Ming; Natowicz, Marvin R

2013-05-01

Determinations of cerebrospinal fluid (CSF) lactate and pyruvate concentrations and CSF lactate:pyruvate (L/P) ratios are important in several clinical settings, yet published normative data have significant limitations. We sought to determine a large dataset of stringently-defined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios. We evaluated data from 627 patients who had determinations of CSF lactate and/or CSF pyruvate from 2001 to 2011 at the Cleveland Clinic. Inclusion in the normal reference population required normal CSF cell counts, glucose and protein and routine serum chemistries and absence of progressive brain disorder, epilepsy, or seizure within 24h. Brain MRI, if done, showed no evidence of tumor, acute changes or basal ganglia abnormality. CSF cytology, CSF alanine and immunoglobulin levels, and oligoclonal band analysis were required to be normal, if done. Various inclusion/exclusion criteria were compared. 92 patients fulfilled inclusion/exclusion criteria for a reference population. The 95% central intervals (2.5%-97.5%) for CSF lactate and pyruvate levels were 1.01-2.09mM and 0.03-0.15mM, respectively, and 9.05-26.37 for CSF L/P. There were no significant gender-related differences of CSF lactate or pyruvate concentrations or of CSF L/P. Weak positive correlations between the concentration of CSF lactate or pyruvate and age were noted. Using stringent inclusion/exclusion criteria, we determined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios in a large, well-characterized reference population. Normalcy of routine CSF and blood analytes are the most important parameters in determining reference intervals for CSF lactate and pyruvate. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Use of a rapid brain-sampling technique in a physiologic preparation: effects of morphine, ketamine, and halothane on tissue energy intermediates.

PubMed

Dedrick, D F; Sherer, Y D; Biebuyck, J F

1975-06-01

A new method of rapid sampling of brain tissue, "freeze-blowing," has been used to compare the neurochemistry of the brain during anesthesia with that in the awake state. The method avoids anoxia associated with the sampling process. Physiologic variables, including body temperature, blood-gas tensions and blood pressure, were carefully monitored and controlled in the experimental animals. None of the agents tested (halothane, morphine, and ketamine) reduced the brain tissue high-energy phosphate reserved. All three drugs doubled glucose levels. Morphine lowered both lactate and the lactate/pyruvate ratio. Uniformly, the three anesthetic agents led to twofold increases of brain cyclic 3'-5' adenosine monophosphate concentrations. These changes suggest a possible role for cyclic nucleotides in central neurotransmission.

Lactate in the brain of the freely moving rat: voltammetric monitoring of the changes related to the sleep-wake states.

PubMed

Shram, Nataliya; Netchiporouk, Larissa; Cespuglio, Raymond

2002-08-01

Cortical lactate was monitored voltammetrically in freely moving rats equipped with polygraphic electrodes. Differential normal pulse voltammetric measurements were carried out using a lactate biosensor coated with lactate oxidase and cellulose acetate. Changes occurring in lactate level were in keeping with sleep-wake states. During slow wave sleep (SWS), the lactate level decreased significantly (-16.2%) vs. the spontaneous waking state (W) referenced to as 100%. During paradoxical sleep (PS), and still vs. W, it remained low (-9.0%) but this variation was not statistically significant. However, when this PS change was compared to the SWS variation, a significant increase in lactate level was then revealed (+8.5%). Finally, during the active waking (aW) triggered by a water puff stress, lactate level rose significantly in accordance with the animal activity (+53% compared to W). Long-term monitoring also allowed the determination of a circadian component in lactate production, the lowest and highest values being monitored during light and dark periods, respectively. The acrophasis of the circadian change occurred during the dark period, about 3 h after the light-off (+89%). It is suggested that during wakefulness astrocyte metabolism allows the transformation of the blood-borne glucose into lactate. The increase in this substrate observed during PS may fulfil the oxidative phosphorylation in order to supply the important ATP need of PS.

[Power metabolism from neurons and a glia to the whole brain: norm, pathology and correction].

PubMed

Zil'berter, Iu I; Zil'berter, T M

2012-01-01

The review outlines current state of the thepretical, methodological and applies aspects of brain's energy homeostasis. Authors suggest reconsidering the exclusive role of glucose as an energy substrate (ES) at both neuronal and systemic levels discussing recent research data on qualitative composition of ES pool in the brain. The role of ES alternative to glucose, e.g., lactate and ketone bodies, is examined. The hypotheses of intracellular and astrocyte-neuron lactate shuttles are discussed along with the hypotheses of astrocyte-neuron shuttle of ketone bodies, the selfish brain theory and suppositions on homeostatic versus non-homeostatic ES supply chains. In conclusion, authors argue that exogenous native ES may be used for prevention and treatment of neurodegenerative diseases.

The metabolism of [3-(13)C]lactate in the rat brain is specific of a pyruvate carboxylase-deprived compartment.

PubMed

Bouzier, A K; Thiaudiere, E; Biran, M; Rouland, R; Canioni, P; Merle, M

2000-08-01

Lactate metabolism in the adult rat brain was investigated in relation with the concept of lactate trafficking between astrocytes and neurons. Wistar rats were infused intravenously with a solution containing either [3-(13)C]lactate (534 mM) or both glucose (750 mM) and [3-(13)C]lactate (534 mM). The time courses of both the concentration and (13)C enrichment of blood glucose and lactate were determined. The data indicated the occurrence of [3-(13)C]lactate recycling through liver gluconeogenesis. The yield of glucose labeling was, however, reduced when using the glucose-containing infusate. After a 20-min or 1-h infusion, perchloric acid extracts of the brain tissue were prepared and subsequently analyzed by (13)C- and (1)H-observed/(13)C-edited NMR spectroscopy. The (13)C labeling of amino acids indicated that [3-(13)C]lactate was metabolized in the brain. Based on the alanine C3 enrichment, lactate contribution to brain metabolism amounted to 35% under the most favorable conditions used. By contrast with what happens with [1-(13)C]glucose metabolism, no difference in glutamine C2 and C3 labeling was evidenced, indicating that lactate was metabolized in a compartment deprived of pyruvate carboxylase activity. This result confirms, for the first time from an in vivo study, that lactate is more specifically a neuronal substrate.

Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte-neuron lactate shuttle in brain.

PubMed

Dienel, Gerald A

2017-11-01

Glutamate-stimulated aerobic glycolysis in astrocytes coupled with lactate shuttling to neurons where it can be oxidized was proposed as a mechanism to couple excitatory neuronal activity with glucose utilization (CMR glc ) during brain activation. From the outset, this model was not viable because it did not fulfill critical stoichiometric requirements: (i) Calculated glycolytic rates and measured lactate release rates were discordant in cultured astrocytes. (ii) Lactate oxidation requires oxygen consumption, but the oxygen-glucose index (OGI, calculated as CMR O2 /CMR glc ) fell during activation in human brain, and the small rise in CMR O2 could not fully support oxidation of lactate produced by disproportionate increases in CMR glc . (iii) Labeled products of glucose metabolism are not retained in activated rat brain, indicating rapid release of a highly labeled, diffusible metabolite identified as lactate, thereby explaining the CMR glc -CMR O2 mismatch. Additional independent lines of evidence against lactate shuttling include the following: astrocytic oxidation of glutamate after its uptake can help "pay" for its uptake without stimulating glycolysis; blockade of glutamate receptors during activation in vivo prevents upregulation of metabolism and lactate release without impairing glutamate uptake; blockade of β-adrenergic receptors prevents the fall in OGI in activated human and rat brain while allowing glutamate uptake; and neurons upregulate glucose utilization in vivo and in vitro under many stimulatory conditions. Studies in immature cultured cells are not appropriate models for lactate shuttling in adult brain because of their incomplete development of metabolic capability and astrocyte-neuron interactions. Astrocyte-neuron lactate shuttling does not make large, metabolically significant contributions to energetics of brain activation. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: a proton magnetic resonance spectroscopy study at 1.5 Tesla.

PubMed

Maddock, Richard J; Buonocore, Michael H; Lavoie, Shawn P; Copeland, Linda E; Kile, Shawn J; Richards, Anne L; Ryan, John M

2006-11-22

Proton magnetic resonance spectroscopy ((1)H-MRS) studies showing increased lactate during neural activation support a broader role for lactate in brain energy metabolism than was traditionally recognized. Proton MRS measures of brain lactate responses have been used to study regional brain metabolism in clinical populations. This study examined whether variations in blood glucose influence the lactate response to visual stimulation in the visual cortex. Six subjects were scanned twice, receiving either saline or 21% glucose intravenously. Using (1)H-MRS at 1.5 Tesla with a long echo time (TE=288 ms), the lactate doublet was visible at 1.32 ppm in the visual cortex of all subjects. Lactate increased significantly from resting to visual stimulation. Hyperglycemia had no effect on this increase. The order of the slice-selective gradients for defining the spectroscopy voxel had a pronounced effect on the extent of contamination by signal originating outside the voxel. The results of this preliminary study demonstrate a method for observing a consistent activity-stimulated increase in brain lactate at 1.5 T and show that variations in blood glucose across the normal range have little effect on this response.

Monocarboxylate transporters in temporal lobe epilepsy: roles of lactate and ketogenic diet.

PubMed

Lauritzen, Fredrik; Eid, Tore; Bergersen, Linda H

2015-01-01

Epilepsy is a serious neurological disorder that affects approximately 1 % of the general population, making it one of the most common disorders of the central nervous system. Furthermore, up to 40 % of all patients with epilepsy cannot control their seizures with current medications. More efficacious treatments for medication refractory epilepsy are therefore needed. A better understanding of the mechanisms that cause this disorder is likely to facilitate the discovery of such treatments. Impairment in cerebral energy metabolism has been proposed as a possible causative factor in the pathogenesis of temporal lobe epilepsy (TLE), which is one of the most common types of medication-refractory epilepsies in adults. In this review, we will discuss some of the current hypotheses regarding the possible causal relationship between brain energy metabolism and TLE. Emphasis will be placed on the role of energy substrates (lactate and ketone bodies) and their transporter molecules, particularly monocarboxylate transporters 1 and 2 (MCT1 and MCT2). We recently reported that the cellular distribution of MCT1 and MCT2 is perturbed in the hippocampus in patients with TLE. The changes may be an adaptive response aimed at keeping high levels of lactate in the epileptic tissue, which may serve to counteract epileptic activity by downregulating cAMP levels through the lactate receptor GPR81, newly discovered in hippocampus. We propose that the perturbation of MCTs may be further involved in the pathophysiology of TLE by influencing brain energy homeostasis, mitochondrial function, GABA-ergic and glutamatergic neurotransmission, and flux of lactate through the brain.

Lactate overrides central nervous but not beta-cell glucose sensing in humans.

PubMed

Schmid, Sebastian M; Jauch-Chara, Kamila; Hallschmid, Manfred; Oltmanns, Kerstin M; Peters, Achim; Born, Jan; Schultes, Bernd

2008-12-01

Lactate has been shown to serve as an alternative energy substrate in the central nervous system and to interact with hypothalamic glucose sensors. On the background of marked similarities between central nervous and beta-cell glucose sensing, we examined whether lactate also interacts with pancreatic glucose-sensing mechanisms in vivo. The effects of intravenously infused lactate vs placebo (saline) on central nervous and pancreatic glucose sensing were assessed during euglycemic and hypoglycemic clamp experiments in 10 healthy men. The release of neuroendocrine counterregulatory hormones during hypoglycemia was considered to reflect central nervous glucose sensing, whereas endogenous insulin secretion as assessed by serum C-peptide levels served as an indicator of pancreatic beta-cell glucose sensing. Lactate infusion blunted the counterregulatory hormonal responses to hypoglycemia, in particular, the release of epinephrine (P = .007) and growth hormone (P = .004), so that higher glucose infusion rates (P = .012) were required to maintain the target blood glucose levels. In contrast, the decrease in C-peptide concentrations during the hypoglycemic clamp remained completely unaffected by lactate (P = .60). During euglycemic clamp conditions, lactate infusion did not affect the concentrations of C-peptide and of counterregulatory hormones, with the exception of norepinephrine levels that were lower during lactate than saline infusion (P = .049) independently of the glycemic condition. Data indicate that glucose sensing of beta-cells is specific to glucose, whereas glucose sensing at the central nervous level can be overridden by lactate, reflecting the brain's ability to rely on lactate as an alternative major energy source.

In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons.

PubMed

Mächler, Philipp; Wyss, Matthias T; Elsayed, Maha; Stobart, Jillian; Gutierrez, Robin; von Faber-Castell, Alexandra; Kaelin, Vincens; Zuend, Marc; San Martín, Alejandro; Romero-Gómez, Ignacio; Baeza-Lehnert, Felipe; Lengacher, Sylvain; Schneider, Bernard L; Aebischer, Patrick; Magistretti, Pierre J; Barros, L Felipe; Weber, Bruno

2016-01-12

Investigating lactate dynamics in brain tissue is challenging, partly because in vivo data at cellular resolution are not available. We monitored lactate in cortical astrocytes and neurons of mice using the genetically encoded FRET sensor Laconic in combination with two-photon microscopy. An intravenous lactate injection rapidly increased the Laconic signal in both astrocytes and neurons, demonstrating high lactate permeability across tissue. The signal increase was significantly smaller in astrocytes, pointing to higher basal lactate levels in these cells, confirmed by a one-point calibration protocol. Trans-acceleration of the monocarboxylate transporter with pyruvate was able to reduce intracellular lactate in astrocytes but not in neurons. Collectively, these data provide in vivo evidence for a lactate gradient from astrocytes to neurons. This gradient is a prerequisite for a carrier-mediated lactate flux from astrocytes to neurons and thus supports the astrocyte-neuron lactate shuttle model, in which astrocyte-derived lactate acts as an energy substrate for neurons. Copyright © 2016 Elsevier Inc. All rights reserved.

Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-13C2 glucose

PubMed Central

Jalloh, Ibrahim; Carpenter, Keri L H; Grice, Peter; Howe, Duncan J; Mason, Andrew; Gallagher, Clare N; Helmy, Adel; Murphy, Michael P; Menon, David K; Carpenter, T Adrian; Pickard, John D; Hutchinson, Peter J

2015-01-01

Increased ‘anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-13C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. 13C enrichment for glycolytic 2,3-13C2 lactate was the median 5.4% (interquartile range (IQR) 4.6–7.5%) in TBI brain and 4.2% (2.4–4.4%) in ‘normal' brain (P<0.01). The ratio of PPP-derived 3-13C lactate to glycolytic 2,3-13C2 lactate was median 4.9% (3.6–8.2%) in TBI brain and 6.7% (6.3–8.9%) in ‘normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=−0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than ‘normal' brain. Several TBI patients exhibited PPP–lactate elevation above the ‘normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain. PMID:25335801

Lactate storm marks cerebral metabolism following brain trauma.

PubMed

Lama, Sanju; Auer, Roland N; Tyson, Randy; Gallagher, Clare N; Tomanek, Boguslaw; Sutherland, Garnette R

2014-07-18

Brain metabolism is thought to be maintained by neuronal-glial metabolic coupling. Glia take up glutamate from the synaptic cleft for conversion into glutamine, triggering glial glycolysis and lactate production. This lactate is shuttled into neurons and further metabolized. The origin and role of lactate in severe traumatic brain injury (TBI) remains controversial. Using a modified weight drop model of severe TBI and magnetic resonance (MR) spectroscopy with infusion of (13)C-labeled glucose, lactate, and acetate, the present study investigated the possibility that neuronal-glial metabolism is uncoupled following severe TBI. Histopathology of the model showed severe brain injury with subarachnoid and hemorrhage together with glial cell activation and positive staining for Tau at 90 min post-trauma. High resolution MR spectroscopy of brain metabolites revealed significant labeling of lactate at C-3 and C-2 irrespective of the infused substrates. Increased (13)C-labeled lactate in all study groups in the absence of ischemia implied activated astrocytic glycolysis and production of lactate with failure of neuronal uptake (i.e. a loss of glial sensing for glutamate). The early increase in extracellular lactate in severe TBI with the injured neurons rendered unable to pick it up probably contributes to a rapid progression toward irreversible injury and pan-necrosis. Hence, a method to detect and scavenge the excess extracellular lactate on site or early following severe TBI may be a potential primary therapeutic measure. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Combination of Acute Physiology and Chronic Health Evaluation II score, early lactate area, and N-terminal prohormone of brain natriuretic peptide levels as a predictor of mortality in geriatric patients with septic shock.

PubMed

Wang, Hao; Li, Zhong; Yin, Mei; Chen, Xiao-Mei; Ding, Shi-Fang; Li, Chen; Zhai, Qian; Li, Yuan; Liu, Han; Wu, Da-Wei

2015-04-01

Given the high mortality rates in elderly patients with septic shock, the early recognition of patients at greatest risk of death is crucial for the implementation of early intervention strategies. Serum lactate and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels are often elevated in elderly patients with septic shock and are therefore important biomarkers of metabolic and cardiac dysfunction. We hypothesized that a risk stratification system that incorporates the Acute Physiology and Chronic Health Evaluation (APACHE) II score and lactate and NT-proBNP biomarkers would better predict mortality in geriatric patients with septic shock than the APACHE II score alone. A single-center prospective study was conducted from January 2012 to December 2013 in a 30-bed intensive care unit of a triservice hospital. The lactate area score was defined as the sum of the area under the curve of serial lactate levels measured during the 24 hours following admission divided by 24. The NT-proBNP score was assigned based on NT-proBNP levels measured at admission. The combined score was calculated by adding the lactate area and NT-proBNP scores to the APACHE II score. Multivariate logistic regression analyses and receiver operating characteristic curves were used to evaluate which variables and scoring systems served as the best predictors of mortality in elderly septic patients. A total of 115 patients with septic shock were included in the study. The overall 28-day mortality rate was 67.0%. When compared to survivors, nonsurvivors had significantly higher lactate area scores, NT-proBNP scores, APACHE II scores, and combined scores. In the multivariate regression model, the combined score, lactate area score, and mechanical ventilation were independent risk factors associated with death. Receiver operating characteristic curves indicated that the combined score had significantly greater predictive power when compared to the APACHE II score or the NT-proBNP score (P < .05). A combined score that incorporates the APACHE II score with early lactate area and NT-proBNP levels is a useful method for risk stratification in geriatric patients with septic shock. Copyright © 2014 Elsevier Inc. All rights reserved.

Evaluation of passive avoidance learning and spatial memory in rats exposed to low levels of lead during specific periods of early brain development.

PubMed

Rao Barkur, Rajashekar; Bairy, Laxminarayana K

2015-01-01

Widespread use of heavy metal lead (Pb) for various commercial purposes has resulted in the environmental contamination caused by this metal. The studies have shown a definite relationship between low level lead exposure during early brain development and deficit in children's cognitive functions. This study investigated the passive avoidance learning and spatial learning in male rat pups exposed to lead through their mothers during specific periods of early brain development. Experimental male rats were divided into 5 groups: i) the normal control group (NC) (N = 12) consisted of rat offspring born to mothers who were given normal drinking water throughout gestation and lactation, ii) the pre-gestation lead exposed group (PG) (N = 12) consisted of rat offspring, mothers of these rats had been exposed to 0.2% lead acetate in the drinking water for 1 month before conception, iii) the gestation lead exposed group (G) (N = 12) contained rat offspring born to mothers who had been exposed to 0.2% lead acetate in the drinking water throughout gestation, iv) the lactation lead exposed group (L) (N = 12) had rat offspring, mothers of these rats exposed to 0.2% lead acetate in the drinking water throughout lactation and v) the gestation and lactation lead exposed group (GL) (N = 12) contained rat offspring, mothers of these rats were exposed to 0.2% lead acetate throughout gestation and lactation. The study found deficit in passive avoidance learning in the G, L and GL groups of rats. Impairment in spatial learning was found in the PG, G, L and GL groups of rats. Interestingly, the study found that gestation period only and lactation period only lead exposure was sufficient to cause deficit in learning and memory in rats. The extent of memory impairment in the L group of rats was comparable with the GL group of rats. So it can be said that postnatal period of brain development is more sensitive to neurotoxicity compared to prenatal exposure. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case without elevated white matter lactate.

PubMed

Sharma, Suvasini; Sankhyan, Naveen; Kumar, Atin; Scheper, Gert C; van der Knaap, Marjo S; Gulati, Sheffali

2011-06-01

A 17-year-old Indian boy with gradually progressive ataxia with onset at 12 years of age is described. Magnetic resonance imaging (MRI) of the brain revealed extensive, inhomogeneous signal abnormalities in the cerebral white matter, with involvement of selected tracts in the brain stem and spinal cord. The imaging findings were characteristic of leukoencephalopathy with brain stem and spinal cord involvement and high lactate, a recently described leukodystrophy. Interestingly, magnetic resonance spectroscopy of the abnormal white matter did not reveal elevated lactate. The patient was compound heterozygous for 2 new mutations in DARS2, genetically confirming the diagnosis.

Cerebral glycolysis: a century of persistent misunderstanding and misconception

PubMed Central

Schurr, Avital

2014-01-01

Since its discovery in 1780, lactate (lactic acid) has been blamed for almost any illness outcome in which its levels are elevated. Beginning in the mid-1980s, studies on both muscle and brain tissues, have suggested that lactate plays a role in bioenergetics. However, great skepticism and, at times, outright antagonism has been exhibited by many to any perceived role for this monocarboxylate in energy metabolism. The present review attempts to trace the negative attitudes about lactate to the first four or five decades of research on carbohydrate metabolism and its dogma according to which lactate is a useless anaerobic end-product of glycolysis. The main thrust here is the review of dozens of scientific publications, many by the leading scientists of their times, through the first half of the twentieth century. Consequently, it is concluded that there exists a barrier, described by Howard Margolis as “habit of mind,” that many scientists find impossible to cross. The term suggests “entrenched responses that ordinarily occur without conscious attention and that, even if noticed, are hard to change.” Habit of mind has undoubtedly played a major role in the above mentioned negative attitudes toward lactate. As early as the 1920s, scientists investigating brain carbohydrate metabolism had discovered that lactate can be oxidized by brain tissue preparations, yet their own habit of mind redirected them to believe that such an oxidation is simply a disposal mechanism of this “poisonous” compound. The last section of the review invites the reader to consider a postulated alternative glycolytic pathway in cerebral and, possibly, in most other tissues, where no distinction is being made between aerobic and anaerobic glycolysis; lactate is always the glycolytic end product. Aerobically, lactate is readily shuttled and transported into the mitochondrion, where it is converted to pyruvate via a mitochondrial lactate dehydrogenase (mLDH) and then is entered the tricarboxylic acid (TCA) cycle. PMID:25477776

Extracellular metabolites in the cortex and hippocampus of epileptic patients.

PubMed

Cavus, Idil; Kasoff, Willard S; Cassaday, Michael P; Jacob, Ralph; Gueorguieva, Ralitza; Sherwin, Robert S; Krystal, John H; Spencer, Dennis D; Abi-Saab, Walid M

2005-02-01

Interictal brain energy metabolism and glutamate-glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero-flow microdialysis method to measure the extracellular levels of glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepileptogenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization. The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energetic deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate-glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies.

1H Magnetic resonance spectroscopy of the internal capsule in human brain: a feasibility study to detect lactate following contralateral motor activity.

PubMed

Mostert, Jop P; Sijens, Paul E; Oudkerk, Matthijs; De Keyser, Jacques

2005-07-01

Animal experiments suggest that astrocytic glycogen may act as an energy source for axons especially during heightened activity. In this model astrocytic glycogen breaks down to lactate that is shuttled to axons where it is metabolized oxidatively to generate ATP. The aim of this study was to investigate whether (1)H-magnetic resonance spectroscopy could be used to detect a rise in lactate levels in human white matter during enhanced axonal activation. Six healthy volunteers (four women and two men; age range 21-38 years) participated in the study. We were unable to detect any significant MR spectral change, i.e. neither in the peak areas of inositol, choline, creatine, glutamate and N-acetylaspartate nor in the lactate level, in the contralateral posterior limb of the internal capsule during intense motor activation of the hand (four successive episodes of squeezing a soft ball for 7 min followed by 7 min rest). Possible explanations are that the technique is not sensitive enough to detect a small rise in lactate, or lactate turnover is too fast to be detected, or that another monocarboxylate different from lactate may be involved in axonal energy metabolism.

Effect of alternate energy substrates on mammalian brain metabolism during ischemic events.

PubMed

Koppaka, S S; Puchowicz; LaManna, J C; Gatica, J E

2008-01-01

Regulation of brain metabolism and cerebral blood flow involves complex control systems with several interacting variables at both cellular and organ levels. Quantitative understanding of the spatially and temporally heterogeneous brain control mechanisms during internal and external stimuli requires the development and validation of a computational (mathematical) model of metabolic processes in brain. This paper describes a computational model of cellular metabolism in blood-perfused brain tissue, which considers the astrocyte-neuron lactate-shuttle (ANLS) hypothesis. The model structure consists of neurons, astrocytes, extra-cellular space, and a surrounding capillary network. Each cell is further compartmentalized into cytosol and mitochondria. Inter-compartment interaction is accounted in the form of passive and carrier-mediated transport. Our model was validated against experimental data reported by Crumrine and LaManna, who studied the effect of ischemia and its recovery on various intra-cellular tissue substrates under standard diet conditions. The effect of ketone bodies on brain metabolism was also examined under ischemic conditions following cardiac resuscitation through our model simulations. The influence of ketone bodies on lactate dynamics on mammalian brain following ischemia is studied incorporating experimental data.

CSF lactate level: a useful diagnostic tool to differentiate acute bacterial and viral meningitis.

PubMed

Abro, Ali Hassan; Abdou, Ahmed Saheh; Ustadi, Abdulla M; Saleh, Ahmed Alhaj; Younis, Nadeem Javeed; Doleh, Wafa F

2009-08-01

To evaluate the potential role of CSF lactate level in the diagnosis of acute bacterial meningitis and in the differentiation between viral and bacterial meningitis. This was a hospital based observational study, conducted at Infectious Diseases Unit, Rashid Hospital Dubai, United Arab Emirates, from July 2004 to June 2007. The patients with clinical diagnosis of acute bacterial meningitis and who had CSF Gram stain/culture positive, CSF analysis suggestive of bacterial meningitis with negative Gram stain and culture but blood culture positive for bacteria and patients with clinical diagnosis suggestive of viral meningitis supported by CSF chemical analysis with negative Gram stain and culture as well as negative blood culture for bacteria were included in the study. CT scan brain was done for all patients before lumber puncture and CSF and blood samples were collected immediately after admission. CSF chemical analysis including lactate level was done on first spinal tap. The CSF lactate level was tested by Enzymatic Colorimetric method. A total 95 adult patients of acute meningitis (53 bacterial and 42 viral) fulfilled the inclusion criteria. Among 53 bacterial meningitis patients, Neisseria meningitides were isolated in 29 (54.7%), Strept. Pneumoniae in 18 (33.96%), Staph. Aureus in 2 (3.77%), Klebsiell Pneumoniae in 2 (3.77%), Strept. Agalactiae in 1 (1.8%) and E. Coli in 1 (1.8%). All the patients with bacterial meningitis had CSF lactate > 3.8 mmol/l except one, whereas none of the patients with viral meningitis had lactate level > 3.8 mmol/l. The mean CSF lactate level in bacterial meningitis cases amounted to 16.51 +/- 6.14 mmol/l, whereas it was significantly lower in viral group 2.36 +/- 0.6 mmol/l, p < .0001. CSF lactate level was significantly high in bacterial than viral meningitis and it can provide pertinent, rapid and reliable diagnostic information. Furthermore, CSF lactate level can also differentiate bacterial meningitis from viral one in a quick and better way.

Effective and safe mannitol administration in patients undergoing supratentorial tumor surgery: A prospective, randomized and double blind study.

PubMed

Akcil, Eren Fatma; Dilmen, Ozlem Korkmaz; Karabulut, Esra Sultan; Koksal, Serdar Selcuk; Altindas, Fatis; Tunali, Yusuf

2017-08-01

Although osmotic diuresis with mannitol is commonly used to provide brain relaxation, there is no consensus regarding its optimal dose and combination with loop diuretics. The aim of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity in patients undergoing supratentorial tumor surgery. This prospective, randomized, double blind, placebo-controlled study included 51 patients (ASA I-III) scheduled for elective supratentorial craniotomy. Different doses and combinations of diuretics were administered after the bone flap removal. The Group 1 received mannitol at 0.5gkg -1 and furosemide at 0.5mgkg -1 , the Group 2 received mannitol at 1gkg -1 and furosemide at 0.5mgkg -1 , and the Group 3 received mannitol at 0.5gkg -1 and placebo. The primary end-point of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and the secondary end-points are to evaluate their effects on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity. This study shows that mannitol alone (0.5gkg -1 ), and the combinations of furosemide (0.5mgkg -1 ) with different doses of mannitol (0.5gkg -1 -1gkg -1 ) provides adequate brain relaxation. However, administration of furosemide with low or high doses of mannitol may cause reduction in the sodium and chloride levels as well as rise in the lactate level. Moreover it may cause high urine output and negative intra-operative fluid balance. Administration of 0.5gkg -1 mannitol provides adequate brain relaxation without causing systemic side effects in patients undergoing supratentorial tumor surgery. This study is registered to clinical trials (Clinical Trials.gov identifier NCT02712476). Copyright © 2017 Elsevier B.V. All rights reserved.

Implementation of 3 T Lactate-Edited 3D 1H MR Spectroscopic Imaging with Flyback Echo-Planar Readout for Gliomas Patients

PubMed Central

Chen, Albert P.; Zierhut, Matthew L.; Ozturk-Isik, Esin; Vigneron, Daniel B.; Nelson, Sarah J.

2010-01-01

The purpose of this study was to implement a new lactate-edited 3D 1H magnetic resonance spectroscopic imaging (MRSI) sequence at 3 T and demonstrate the feasibility of using this sequence for measuring lactate in patients with gliomas. A 3D PRESS MRSI sequence incorporating shortened, high bandwidth 180° pulses, new dual BASING lactate-editing pulses, high bandwidth very selective suppression (VSS) pulses and a flyback echo-planar readout was implemented at 3 T. Over-prescription factor of PRESS voxels was optimized using phantom to minimize chemical shift artifacts. The lactate-edited flyback sequence was compared with lactate-edited MRSI using conventional elliptical k-space sampling in a phantom and volunteers, and then applied to patients with gliomas. The results demonstrated the feasibility of detecting lactate within a short scan time of 9.5 min in both phantoms and patients. Over-prescription of voxels gave less chemical shift artifacts allowing detection of lactate on the majority of the selected volume. The normalized SNR of brain metabolites using the flyback encoding were comparable to the SNR of brain metabolites using conventional phase encoding MRSI. The specialized lactate-edited 3D MRSI sequence was able to detect lactate in brain tumor patients at 3 T. The implementation of this technique means that brain lactate can be evaluated in a routine clinical setting to study its potential as a marker for prognosis and response to therapy. PMID:20652745

Maternal nurturing is dependent on her innate anxiety: the behavioral roles of brain oxytocin and vasopressin.

PubMed

Bosch, Oliver J

2011-02-01

The maternal brain undergoes remarkable physiological and behavioral changes in the peripartum period to meet the demands of the offspring. Here, the brain neuropeptides oxytocin and vasopressin, together with prolactin, play important roles. These neuropeptides are critically involved in the regulation of maternal behavior. Furthermore, reduced anxiety in lactation is another adaptation of the maternal brain. Therefore, a link between maternal behavior and maternal anxiety has been repeatedly postulated. This is supported by our studies in rats bred for high (HAB) and low (LAB) anxiety-related behavior. While female HAB rats become less anxious in lactation, their anxiety level is still four times higher compared with LAB dams. Interestingly, HAB dams display an intense and protective mothering style including increased arched back nursing and pup retrieval whereas LAB dams display only low levels of maternal care. The amount of maternal care directed towards the pups correlates with the mother's innate anxiety. In addition to differences in maternal care, HAB dams are also more protective as they show heightened aggression against a virgin intruder compared with the less aggressive LAB dams. The level of maternal aggression correlates with both their innate anxiety level as well as with the release of oxytocin and vasopressin in hypothalamic and limbic brain areas. Importantly, manipulations of the brain oxytocin and vasopressin systems alter maternal behavior and - depending on the brain region - can also alter the dam's anxiety. Thus, the mother's innate anxiety determines her maternal performance and oxytocin and vasopressin are involved in both parameters. Copyright © 2010 Elsevier Inc. All rights reserved.

Enteral nutrition increases interstitial brain glucose levels in poor-grade subarachnoid hemorrhage patients.

PubMed

Kofler, Mario; Schiefecker, Alois J; Beer, Ronny; Gaasch, Maxime; Rhomberg, Paul; Stover, John; Pfausler, Bettina; Thomé, Claudius; Schmutzhard, Erich; Helbok, Raimund

2018-03-01

Low brain tissue glucose levels after acute brain injury are associated with poor outcome. Whether enteral nutrition (EN) reliably increases cerebral glucose levels remains unclear. In this retrospective analysis of prospectively collected observational data, we investigate the effect of EN on brain metabolism in 17 poor-grade subarachnoid hemorrhage (SAH) patients undergoing cerebral microdialysis (CMD) monitoring. CMD-values were obtained hourly. A nutritional intervention was defined as the clinical routine administration of EN without supplemental parenteral nutrition. Sixty-three interventions were analyzed. The mean amount of EN per intervention was 472.4 ± 10.7 kcal. CMD-glucose levels significantly increased from 1.59 ± 0.13 mmol/l at baseline to a maximum of 2.03 ± 0.2 mmol/l after 5 h (p < 0.001), independently of insulin-treatment, baseline serum glucose, baseline brain metabolic distress (CMD-lactate-to-pyruvate-ratio (LPR) > 40) and the microdialysis probe location. The increase in CMD-glucose was directly dependent on the magnitude of increase of serum glucose levels (p = 0.007). No change in CMD-lactate, CMD-pyruvate, CMD-LPR, or CMD-glutamate (p > 0.4) was observed. Routine EN also increased CMD-glucose even if baseline concentrations were critically low ( < 0.7 mmol/l, neuroglucopenia; p < 0.001). These results may have treatment implications regarding glucose management of poor-grade aneurysmal SAH patients.

Electro-acupuncture up-regulates astrocytic MCT1 expression to improve neurological deficit in middle cerebral artery occlusion rats.

PubMed

Lu, Yan; Zhao, Haijun; Wang, Yuan; Han, Bingbing; Wang, Tong; Zhao, Hong; Cui, Kemi; Wang, Shijun

2015-08-01

Cerebral ischemia is one of the common diseases treated by electro-acupuncture (EA). Although the clinical efficacy has been widely affirmed, the mechanisms of action leading to the health benefits are not understood. In this study, the role of EA in modulating the lactate energy metabolism and lactate transportation was explored on the middle cerebral artery occlusion (MCAO) ischemic rat model. Repeated EA treatments once daily for 7 days were applied to the MCAO rats and neurological function evaluation was performed. Brain tissues were harvested for lactate concentration examination, immunohistochemical staining, Western blot and qRT-PCR analyses for the expressions of lactate transporter (monocarboxylate transporter 1, MCT1) and glial fibrillary acidic protein (GFAP). The animal behavioral tests showed that the 7-day EA treatments significantly promoted the recovery of neurological deficits in the MCAO rats, which correlated with the enhanced lactate energy metabolism in the ischemic brain. In the cortical ischemic area of the MCAO rats, EA treatments led to the activation of astrocytes, and induced a further increase of lactate transporter (monocarboxylate transporter 1, MCT1) expression in astrocytes at both protein and mRNA levels. Our results suggest that the EA treatments activated lactate metabolism in the resident astrocytes around the ischemic area and up-regulated the expression of MCT1 in these astrocytes which facilitated the transfer of intracellular lactate to extracellular domain to be utilized by injured neurons to improve the neurological deficit. Copyright © 2015 Elsevier Inc. All rights reserved.

[1-13C]Glucose entry in neuronal and astrocytic intermediary metabolism of aged rats. A study of the effects of nicergoline treatment by 13C NMR spectroscopy.

PubMed

Miccheli, Alfredo; Puccetti, Caterina; Capuani, Giorgio; Di Cocco, Maria Enrica; Giardino, Luciana; Calzà, Laura; Battaglia, Angelo; Battistin, Leontino; Conti, Filippo

2003-03-14

Age-related changes in glucose utilization through the TCA cycle were studied using [1-13C]glucose and 13C, 1H NMR spectroscopy on rat brain extracts. Significant increases in lactate levels, as well as in creatine/phosphocreatine ratios (Cr/PCr), and a decrease in N-acetyl-aspartate (NAA) and aspartate levels were observed in aged rat brains as compared to adult animals following glucose administration. The total amount of 13C from [1-13C]glucose incorporated in glutamate, glutamine, aspartate and GABA was significantly decreased in control aged rat brains as compared to adult brains. The results showed a decrease in oxidative glucose utilization of control aged rat brains. The long-term nicergoline treatment increased NAA and glutamate levels, and decreased the lactate levels as well as the Cr/PCr ratios in aged rat brains as compared to adult rats. The total amount of 13C incorporated in glutamate, glutamine, aspartate, NAA and GABA was increased by nicergoline treatment, showing an improvement in oxidative glucose metabolism in aged brains. A significant increase in pyruvate carboxylase/pyruvate dehydrogenase activity (PC/PDH) in the synthesis of glutamate in nicergoline-treated aged rats is consistent with an increase in the transport of glutamine from glia to neurons for conversion into glutamate. In adult rat brains, no effect of nicergoline on glutamate PC/PDH activity was observed, although an increase in PC/PDH activity in glutamine was, suggesting that nicergoline affects the glutamate/glutamine cycle between neurons and glia in different ways depending on the age of animals. These results provide new insights into the effects of nicergoline on the CNS.

A novel mitochondrial DNA 8597T>C mutation of Leigh syndrome: report of one case.

PubMed

Tsai, Jeng-Dau; Liu, Chin-San; Tsao, Teng-Fu; Sheu, Ji-Nan

2012-02-01

Leigh syndrome is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system. The brain images of Leigh syndrome are characterized by markedly symmetrical involvement, most frequently of the putamen. We report a 2-year-old girl with Leigh syndrome manifested as acute onset of altered level of consciousness. Brain magnetic resonance images showed abnormal signal intensity over the bilateral basal ganglia and cerebellar dentate nuclei. Despite normal biochemical studies, in particular serum lactate levels, magnetic resonance spectroscopy demonstrated a downward doublet lactate peak. The diagnosis of Leigh syndrome was subsequently confirmed by genetic study which showed a novel mutation at 8597T>C of the mitochondrial ATPase6 gene. Copyright © 2012. Published by Elsevier B.V.

A patient with acute liver failure and extreme hypoglycaemia with lactic acidosis who was not in a coma: causes and consequences of lactate-protected hypoglycaemia.

PubMed

Oldenbeuving, G; McDonald, J R; Goodwin, M L; Sayilir, R; Reijngoud, D J; Gladden, L B; Nijsten, M W N

2014-07-01

Lactate can substitute for glucose as a metabolic substrate. We report a patient with acute liver failure who was awake despite a glucose level of 0.7 mmol/l with very high lactate level of 25 mmol/l. The hypoglycaemia+hyperlactataemia combination may be considered paradoxical since glucose is the main precursor of lactate and lactate is reconverted into glucose by the Cori cycle. Literature relevant to the underlying mechanism of combined deep hypoglycaemia and severe hyperlactataemia was assessed. We also assessed the literature for evidence of protection against deep hypoglycaemia by hyperlactataemia. Four syndromes demonstrating hypoglycaemia+hyperlactataemia were found: 1) paracetamol-induced acute liver failure, 2) severe malaria, 3) lymphoma and 4) glucose-6-phosphatase deficiency. An impaired Cori cycle is a key component in all of these metabolic states. Apparently the liver, after exhausting its glycogen stores, loses the gluconeogenic pathway to generate glucose and thereby its ability to remove lactate as well. Several patients with lactic acidosis and glucose levels below 1.7 mmol/l who were not in a coma have been reported. These observations and other data coherently indicate that lactate-protected hypoglycaemia is, at least transiently, a viable state under experimental and clinical conditions. Severe hypoglycaemia+hyperlactataemia reflects failure of the gluconeogenic pathway of lactate metabolism. The existence of lactate-protected hypoglycaemia implies that patients who present with this metabolic state should not automatically be considered to have sustained irreversible brain damage. Moreover, therapies that aim to achieve hypoglycaemia might be feasible with concomitant hyperlactataemia.

Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats.

PubMed

Yamada, S; Uenoyama, Y; Kinoshita, M; Iwata, K; Takase, K; Matsui, H; Adachi, S; Inoue, K; Maeda, K-I; Tsukamura, H

2007-05-01

Follicular development and ovulation are suppressed during lactation in various mammalian species, mainly due to the suppression of pulsatile GnRH/LH secretion. Metastin (kisspeptin-54), a KiSS-1 gene product, is an endogenous ligand for GPR54, a G-protein-coupled receptor, and suggested to play a critical role in regulating the gonadal axis. The present study therefore aims to determine whether metastin (kisspeptin-54)-GPR54 signaling in discrete brain areas is inhibited by the suckling stimulus that causes suppression of LH secretion in lactating rats. Quantitative RT-PCR revealed that the KiSS-1 mRNA level was significantly lower in the arcuate nucleus (ARC)-median eminence region in lactating ovariectomized (OVX) and estrogen-treated OVX rats than in nonlactating controls. KiSS-1 mRNA in the anteroventral periventricular nucleus was kept at a low level in both lactating and nonlactating rats despite estrogen treatment. GPR54 mRNA levels were significantly lower in lactating than nonlactating rats in the anteroventral periventricular nucleus, but the levels in lactating mothers of the preoptic area and ARC-median eminence were comparable with nonlactating controls. Although KiSS-1 mRNA-expressing cells or metastin (kisspeptin-54) immunoreactivities were densely located in the ARC of nonlactating controls, few were found in the ARC of lactating OVX animals. Various doses of metastin (kisspeptin-54) (0.02, 0.2, and 2 nmol) injected into the third ventricle caused a significant increase in LH secretion in both lactating and nonlactating OVX rats, suggesting that lactating rats are responsive to metastin (kisspeptin-54) stimulus. Thus, the present study demonstrated that KiSS-1 mRNA/metastin (kisspeptin-54) expression is inhibited in the ARC by the suckling stimulus, suggesting that the inhibition is most probably involved in suppressing LH secretion in lactating rats.

Contributions of glycogen to astrocytic energetics during brain activation.

PubMed

Dienel, Gerald A; Cruz, Nancy F

2015-02-01

Glycogen is the major store of glucose in brain and is mainly in astrocytes. Brain glycogen levels in unstimulated, carefully-handled rats are 10-12 μmol/g, and assuming that astrocytes account for half the brain mass, astrocytic glycogen content is twice as high. Glycogen turnover is slow under basal conditions, but it is mobilized during activation. There is no net increase in incorporation of label from glucose during activation, whereas label release from pre-labeled glycogen exceeds net glycogen consumption, which increases during stronger stimuli. Because glycogen level is restored by non-oxidative metabolism, astrocytes can influence the global ratio of oxygen to glucose utilization. Compensatory increases in utilization of blood glucose during inhibition of glycogen phosphorylase are large and approximate glycogenolysis rates during sensory stimulation. In contrast, glycogenolysis rates during hypoglycemia are low due to continued glucose delivery and oxidation of endogenous substrates; rates that preserve neuronal function in the absence of glucose are also low, probably due to metabolite oxidation. Modeling studies predict that glycogenolysis maintains a high level of glucose-6-phosphate in astrocytes to maintain feedback inhibition of hexokinase, thereby diverting glucose for use by neurons. The fate of glycogen carbon in vivo is not known, but lactate efflux from brain best accounts for the major metabolic characteristics during activation of living brain. Substantial shuttling coupled with oxidation of glycogen-derived lactate is inconsistent with available evidence. Glycogen has important roles in astrocytic energetics, including glucose sparing, control of extracellular K(+) level, oxidative stress management, and memory consolidation; it is a multi-functional compound.

Contributions of Glycogen to Astrocytic Energetics during Brain Activation

PubMed Central

Dienel, Gerald A.; Cruz, Nancy F.

2014-01-01

Glycogen is the major store of glucose in brain and is mainly in astrocytes. Brain glycogen levels in unstimulated, carefully-handled rats are 10-12 mol/g, and assuming that astrocytes account for half the brain mass, astrocytic glycogen content is twice as high. Glycogen turnover is slow under basal conditions, but it is mobilized during activation. There is no net increase in incorporation of label from glucose during activation, whereas label release from pre-labeled glycogen exceeds net glycogen consumption, which increases during stronger stimuli. Because glycogen level is restored by non-oxidative metabolism, astrocytes can influence the global ratio of oxygen to glucose utilization. Compensatory increases in utilization of blood glucose during inhibition of glycogen phosphorylase are large and approximate glycogenolysis rates during sensory stimulation. In contrast, glycogenolysis rates during hypoglycemia are low due to continued glucose delivery and oxidation of endogenous substrates; rates that preserve neuronal function in the absence of glucose are also low, probably due to metabolite oxidation. Modeling studies predict that glycogenolysis maintains a high level of glucose-6-phosphate in astrocytes to maintain feedback inhibition of hexokinase, thereby diverting glucose for use by neurons. The fate of glycogen carbon in vivo is not known, but lactate efflux from brain best accounts for the major metabolic characteristics during activation of living brain. Substantial shuttling coupled with oxidation of glycogen-derived lactate is inconsistent with available evidence. Glycogen has important roles in astrocytic energetics, including glucose sparing, control of extracellular K+ level, oxidative stress management, and memory consolidation; it is a multi-functional compound. PMID:24515302

Glycolysis-mediated control of blood-brain barrier development and function.

PubMed

Salmina, Alla B; Kuvacheva, Natalia V; Morgun, Andrey V; Komleva, Yulia K; Pozhilenkova, Elena A; Lopatina, Olga L; Gorina, Yana V; Taranushenko, Tatyana E; Petrova, Lyudmila L

2015-07-01

The blood-brain barrier (BBB) consists of differentiated cells integrating in one ensemble to control transport processes between the central nervous system (CNS) and peripheral blood. Molecular organization of BBB affects the extracellular content and cell metabolism in the CNS. Developmental aspects of BBB attract much attention in recent years, and barriergenesis is currently recognized as a very important and complex mechanism of CNS development and maturation. Metabolic control of angiogenesis/barriergenesis may be provided by glucose utilization within the neurovascular unit (NVU). The role of glycolysis in the brain has been reconsidered recently, and it is recognized now not only as a process active in hypoxic conditions, but also as a mechanism affecting signal transduction, synaptic activity, and brain development. There is growing evidence that glycolysis-derived metabolites, particularly, lactate, affect barriergenesis and functioning of BBB. In the brain, lactate produced in astrocytes or endothelial cells can be transported to the extracellular space via monocarboxylate transporters (MCTs), and may act on the adjoining cells via specific lactate receptors. Astrocytes are one of the major sources of lactate production in the brain and significantly contribute to the regulation of BBB development and functioning. Active glycolysis in astrocytes is required for effective support of neuronal activity and angiogenesis, while endothelial cells regulate bioavailability of lactate for brain cells adjusting its bidirectional transport through the BBB. In this article, we review the current knowledge with regard to energy production in endothelial and astroglial cells within the NVU. In addition, we describe lactate-driven mechanisms and action of alternative products of glucose metabolism affecting BBB structural and functional integrity in developing and mature brain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Protective role of zinc against the neurotoxicity induced by exposure to cadmium during gestation and lactation periods on hippocampal volume of pups tested in early adulthood.

PubMed

Ben Mimouna, Safa; Chemek, Marouane; Boughammoura, Sana; Haouas, Zohra; Messaoudi, Imed

2018-05-03

The present study was conducted to assess the possible effect of cadmium (Cd) throughout gestation and lactation on the volume of the subregion of the hippocampus as well as the potential protective role of zinc (Zn) against Cd neurotoxicity. For this purpose, female rats received either tap water, Cd, Zn or Cd + Zn in their drinking water during gestation and lactation. At postnatal day 35 (PND35), the male pups were sacrificed, and their brains were taken for histologic, chemical, and biochemical analysis. Hippocampal volume was measured in histologic brain slices using Cavalieri's principle. Zn depletion was observed in the brains of pups issued from mothers exposed to Cd. Biochemical analysis further revealed that Cd exposure significantly increases the superoxide dismutase (SOD) activity, as well as the metallothionein (MT) level. During histologic investigation, our results showed that gestational and lactational exposure to Cd significantly altered and decreased the volume of CA1, CA3 pyramidal cell layer and the dentate gyrus. However, there were no marked differences shown in CA2 subfield. Compared to Cd group, co-treatment with Cd and Zn provided correction of the changes induced by the Cd exposure. These results highlight the protective role of Zn against Cd-induced alteration in the hippocampus which is a crucial structure implicated in learning and memory processes.

Similar increases in extracellular lactic acid in the limbic system during epileptic and/or olfactory stimulation.

PubMed

Fornai, F; Bassi, L; Gesi, M; Giorgi, F S; Guerrini, R; Bonaccorsi, I; Alessandrì, M G

2000-01-01

Previous studies have shown that physiological stimulation of brain activity increases anaerobic glucose consumption, both in humans and in experimental animals. To investigate this phenomenon further, we measured extracellular lactate levels within different rat brain regions, using microdialysis. Experiments were performed comparing the effects of natural, physiological olfactory stimulation of the limbic system with experimental limbic seizures. Olfactory stimulation was carried out by using different odors (i.e. both conventional odors: 2-isobutyl-3-methoxypyrazine, green pepper essence; thymol; and 2-sec-butylthiazoline, a sexual pheromone). Limbic seizures were either induced by systemic injection of pilocarpine (200-400 mg/kg) or focally elicited by microinfusions of chemoconvulsants (bicuculline 118 pmol and cychlothiazide 1.2 nmol) within the anterior piriform cortex. Seizures induced by systemic pilocarpine tripled lactic acid within the hippocampus, whereas limbic seizures elicited by focal microinfusion of chemoconvulsants within the piriform cortex produced a less pronounced increase in extracellular lactic acid. Increases in extracellular lactate occurring during olfactory stimulation with the sexual pheromone (three times the baseline levels) were non-significantly different from those occurring after systemic pilocarpine. Increases in lactic acid following natural olfactory stimulation were abolished both by olfactory bulbectomy and by the focal microinfusion of tetrodotoxin, while they were significantly attenuated by the local application of the N-methyl-D-aspartate antagonist AP-5. Increases in hippocampal lactate induced by short-lasting stimuli (olfactory stimulation or microinfusion of subthreshold doses of chemoconvulsants, bicuculline 30 pmol) were reproducible after a short delay (1 h) and cumulated when applied sequentially. In contrast, limbic status epilepticus led to a long-lasting refractoriness to additional lactate-raising stimuli and there was no further increase in lactate levels when the olfactory stimulation was produced during status epilepticus. Increases in lactic acid following olfactory stimulation occurred with site specificity in the rhinencephalon (hippocampus, piriform and entorhinal cortex) but not in the dorsal striatum. Site specificity crucially relied on the quality of the stimulus. For instance, other natural stimuli (i.e. tail pinch) produced a similar increase in extracellular lactate in all brain areas under investigation. The major conclusion of this work is that the presentation of an odor known to be a rat pheromone results in lactate production as great as that induced by the systemic convulsant pylocarpine (maximum: 2.286+/-0.195 mM and 1.803+/-0.108 mM, respectively). This supports the notion that the great magnitude of lactate production known to accompany seizures can result from the intensified neural activity per se ("aerobic gycolysis"), not merely from local anoxia or other pathological changes.

Upregulation of GH, but not IGF1, in the hippocampus of the lactating dam after kainic acid injury

PubMed Central

Arellanes-Licea, Elvira C; Ávila-Mendoza, José; Ramírez-Martínez, Elizabeth C; Ramos, Eugenia; Uribe-González, Nancy; Arámburo, Carlos

2018-01-01

Lactation embodies a natural model of morphological, neurochemical, and functional brain plasticity. In this reproductive stage, the hippocampus of the female is less sensitive to excitotoxins in contrast to nulliparity. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) are known to be neuroprotective in several experimental models of brain lesion. Here, activation of the GH–IGF1 pituitary–brain axis following kainic acid (7.5 mg/kg i.p. KA) lesion was studied in lactating and nulliparous rats. Serum concentrations of GH and IGF1 were uncoupled in lactation. Compared to virgin rats, the basal concentration of GH increased up to 40% but IGF1 decreased 58% in dams, and only GH increased further after KA treatment. In the hippocampus, basal expression of GH mRNA was higher (2.8-fold) in lactating rats than in virgin rats. GH mRNA expression in lactating rats increased further after KA administration in the hippocampus and in the hypothalamus, in parallel to GH protein concentration in the hippocampus of KA-treated lactating rats (43% vs lactating control), as detected by Western blot and immunofluorescence. Except for the significantly lower mRNA concentration in the liver of lactating rats, IGF1 expression was not altered by the reproductive condition or by KA treatment in the hippocampus and hypothalamus. Present results indicate upregulation of GH expression in the hippocampus after an excitotoxic lesion, suggesting paracrine/autocrine actions of GH as a factor underlying neuroprotection in the brain of the lactating dam. Since no induction of IGF1 was detected, present data suggest a direct action of GH. PMID:29321175

Normal lactate concentration range in the neonatal brain.

PubMed

Tomiyasu, Moyoko; Aida, Noriko; Shibasaki, Jun; Tachibana, Yasuhiko; Endo, Mamiko; Nozawa, Kumiko; Shimizu, Eiji; Tsuji, Hiroshi; Obata, Takayuki

2016-11-01

Lactate peaks are occasionally observed during in vivo magnetic resonance spectroscopy (MRS) scans of the neonatal brain, even in healthy patients. The purpose of this study was to investigate the normal range of neonatal brain lactate concentration, as a definitive normal range would be clinically valuable. Using a clinical 3T scanner (echo/repetition times, 30/5000ms), single-voxel MRS data were obtained from the basal ganglia (BG) and centrum semiovale (CS) in 48 healthy neonates (postconceptional age (PCA), 30-43weeks), nine infants (age, 1-12months old), and 20 children (age, 4-15years). Lactate concentrations were calculated using an MRS signal quantification program, LCModel. Correlations between regional lactate concentration and PCA (neonates), or age (all subjects) were investigated. Absolute lactate concentrations of the BG and CS were as follows: neonates, 0.77mM (0-2.02) [median (range)] and 0.77 (0-1.42), respectively; infants, 0.38 (0-0.79) and 0.49 (0.17-1.17); and children, 0.17 (0-0.76) and 0.22 (0-0.80). Overall, subjects' lactate concentrations decreased significantly with age (Spearman: BG, n=61, ρ=-0.38, p=0.003; CS, n=68, ρ=-0.57, p<0.001). However, during the neonatal period no correlations were detected between lactate concentration in either region and PCA. We determined normal ranges of neonatal lactate concentration, which may prove useful for diagnostic purposes. Further studies regarding changes in brain lactate concentration during development would help clarify the reasons for higher concentrations observed during the neonatal period, and contribute to improvements in diagnoses. Copyright © 2016 Elsevier Inc. All rights reserved.

Determination of lactic acid with special emphasis on biosensing methods: A review.

PubMed

Pundir, Chandra S; Narwal, Vinay; Batra, Bhawna

2016-12-15

Lactic acid (2-Hydroxypropanoic acid) is generated from pyruvic acid under anaerobic condition in skeletal muscles, brain, red blood cells, and kidney. Lactate in normal human subjects get cleared very quickly at a rate of 320mmol/L/hr, mostly by liver metabolism and re-conversion of lactate back to pyruvate. Measurement of lactate level in serum is required for the differential diagnosis and medical management of hyperlactatemia, cardiac arrest and resuscitation, sepsis, reduced renal excretion, hypoxia induced cancer, decreased extra hepatic metabolism, intestinal infarction and lactic acidosis. Determination of lactate is also important in dairy products and beverages to access their quality. Among the various methods available for detection of lactate, most are complicated, nonspecific, less sensitive and require time-consuming sample pretreatment, expensive instrumental set-up and trained persons to operate, specifically for chromatographic methods. Biosensing methods overcome these drawbacks, as these are simple, fast, specific and highly sensitive. Lactate biosensors reported so far, work optimally within 3-180s, between pH, 5.5-8.5 and temperature 22°C to 37°C and lactate concentration ranging from 10 to 2000µM. These biosensors have been employed to measure lactate level in embryonic cell culture, beverages, urine, and serum samples and reused upto 200-times within a period of 7-216 days. This review presents the principles, merits and demerits of various analytical methods for lactate determination with special emphasis on lactate biosensors. The future perspective for improvement of analytic performance of lactate biosensors are discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Increased densities of monocarboxylate transporter MCT1 after chronic hyperglycemia in rat brain.

PubMed

Canis, Martin; Maurer, Martin H; Kuschinsky, Wolfgang; Duembgen, Lutz; Duelli, Roman

2009-02-27

The brain is capable of taking up monocarboxylates as energy substrates. Under physiological conditions, plasma levels of monocarboxylates are very low and glucose is the primary energy substrate in brain metabolism. However, given conditions such as hyperglycemia and ketosis, levels of circulating monocarboxylates such as lactate and pyruvate are elevated. Previous studies reported an increased expression of monocarboxylate transporter MCT1 in brain following ketotic diet. The major aim of the present study was to answer the question whether chronic hyperglycemia is likewise sufficient to change local densities of MCT1 in the brain. Moreover, chronic hyperglycemia increases local cerebral glucose utilization (LCGU) in particular brain areas. Glucose hereby enters the brain parenchyma via glucose transporters and is partially metabolised by astrocytes, which then release lactate to meet the energetic demands of surrounding neurons. Streptozotocin was given intravenously to induce chronic hyperglycemia and local densities of MCT1 were measured by immunoautoradiographic methods in cryosections of rat brains. The density of monocarboxylate transporter MCT1 was significantly increased in 10 of 24 brain structures investigated (median increase 11.7+/-3.4 %). Immunocytochemical stainings of these substructures revealed an expression of MCT1 within endothelial cells and astrocytes. A comparison of MCT1 densities with LCGU measured in a previous study under normo- and hyperglycemic conditions revealed a partial correlation between both parameters and under both conditions. Four out of 10 brain areas, which showed a significant increase in MCT1 density due to hyperglycemia, also showed a significant increase in LCGU. In summary, our data show that chronic hyperglycemia induces a moderate increase of local and global density of MCT1 in several brain structures. However, in terms of brain topologies and substructures this phenomenon did only partially match with increased LCGU. It is concluded that MCT1 transporters were up-regulated during chronic hyperglycemia at the level of brain substructures and independently of LCGU.

Detection of intracellular lactate with localized diffusion { 1H- 13C}-spectroscopy in rat glioma in vivo

NASA Astrophysics Data System (ADS)

Pfeuffer, Josef; Lin, Joseph C.; DelaBarre, Lance; Ugurbil, Kamil; Garwood, Michael

2005-11-01

The aim of this study was to compare the diffusion characteristic of lactate and alanine in a brain tumor model to that of normal brain metabolites known to be mainly intracellular such as N-acetylaspartate or creatine. The diffusion of 13C-labeled metabolites was measured in vivo with localized NMR spectroscopy at 9.4 T (400 MHz) using a previously described localization and editing pulse sequence known as ACED-STEAM ('adiabatic carbon editing and decoupling'). 13C-labeled glucose was administered and the apparent diffusion coefficients of the glycolytic products, { 1H- 13C}-lactate and { 1H- 13C}-alanine, were determined in rat intracerebral 9L glioma. To obtain insights into { 1H- 13C}-lactate compartmentation (intra- versus extracellular), the pulse sequence used very large diffusion weighting (50 ms/μm 2). Multi-exponential diffusion attenuation of the lactate metabolite signals was observed. The persistence of a lactate signal at very large diffusion weighting provided direct experimental evidence of significant intracellular lactate concentration. To investigate the spatial distribution of lactate and other metabolites, 1H spectroscopic images were also acquired. Lactate and choline-containing compounds were consistently elevated in tumor tissue, but not in necrotic regions and surrounding normal-appearing brain. Overall, these findings suggest that lactate is mainly associated with tumor tissue and that within the time-frame of these experiments at least some of the glycolytic product ([ 13C] lactate) originates from an intracellular compartment.

Histological study on hippocampus, amygdala and cerebellum following low lead exposure during prenatal and postnatal brain development in rats.

PubMed

Barkur, Rajashekar Rao; Bairy, Laxminarayana K

2016-06-01

Neuropsychological studies in children who are exposed to lead during their early brain development have shown to develop behavioural and cognitive deficit. The aim of the present study was to assess the cellular damage in hippocampus, amygdala and cerebellum of rat pups exposed to lead during different periods of early brain development. Five groups of rat pups were investigated. (a) Control group (n = 8) (mothers of these rats were given normal drinking water throughout gestation and lactation), (b) pregestation lead-exposed group (n = 8) (mothers of these rats were exposed to 0.2% lead acetate in the drinking water for one month before conception), (c) gestation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout gestation [gestation day 01 to day 21]), (d) lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout lactation [postnatal day 01 to day 21]) and (e) gestation and lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate throughout gestation and lactation). On postnatal day 30, rat pups of all the groups were killed. Numbers of surviving neurons in the hippocampus, amygdala and cerebellum regions were counted using cresyl violet staining technique. Histological data indicate that lead exposure caused significant damage to neurons of hippocampus, amygdala and cerebellum regions in all lead-exposed groups except lactation lead-exposed group. The extent of damage to neurons of hippocampus, amygdala and cerebellum regions in lactation lead-exposed group was comparable to gestation and lactation groups even though the duration of lead exposure was much less in lactation lead-exposed group. To conclude, the postnatal period of brain development seems to be more vulnerable to lead neurotoxicity compared to prenatal period of brain development. © The Author(s) 2014.

Cerebral Taurine Levels are Associated with Brain Edema and Delayed Cerebral Infarction in Patients with Aneurysmal Subarachnoid Hemorrhage.

PubMed

Kofler, Mario; Schiefecker, Alois; Ferger, Boris; Beer, Ronny; Sohm, Florian; Broessner, Gregor; Hackl, Werner; Rhomberg, Paul; Lackner, Peter; Pfausler, Bettina; Thomé, Claudius; Schmutzhard, Erich; Helbok, Raimund

2015-12-01

Cerebral edema and delayed cerebral infarction (DCI) are common complications after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome. Experimental data suggest that the amino acid taurine is released into the brain extracellular space secondary to cytotoxic edema and brain tissue hypoxia, and therefore may serve as a biomarker for secondary brain injury after aSAH. On the other hand, neuroprotective mechanisms of taurine treatment have been described in the experimental setting. We analyzed cerebral taurine levels using high-performance liquid chromatography in the brain extracellular fluid of 25 consecutive aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD). Patient characteristics and clinical course were prospectively recorded. Associations with CMD-taurine levels were analyzed using generalized estimating equations with an autoregressive process to handle repeated observations within subjects. CMD-taurine levels were highest in the first days after aSAH (11.2 ± 3.2 µM/l) and significantly decreased over time (p < 0.001). Patients with brain edema on admission or during hospitalization (N = 20; 80 %) and patients developing DCI (N = 5; 20 %) had higher brain extracellular taurine levels compared to those without (Wald = 7.3, df = 1, p < 0.01; Wald = 10.1, df = 1, p = 0.001, respectively) even after adjusting for disease severity and CMD-probe location. There was no correlation between parenteral taurine supplementation and brain extracellular taurine (p = 0.6). Moreover, a significant correlation with brain extracellular glutamate (r = 0.82, p < 0.001), lactate (r = 0.56, p < 0.02), pyruvate (r = 0.39, p < 0.01), potassium (r = 0.37, p = 0.01), and lactate-to-pyruvate ratio (r = 0.24, p = 0.02) was found. Significantly higher CMD-taurine levels were found in patients with brain edema or DCI after aneurysmal subarachnoid hemorrhage. Its value as a potential biomarker deserves further investigation.

Acidosis mediates recurrent hypoglycemia-induced increase in ischemic brain injury in treated diabetic rats.

PubMed

Rehni, Ashish K; Shukla, Vibha; Perez-Pinzon, Miguel A; Dave, Kunjan R

2018-03-15

Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats. Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury. Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats. Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Extracellular N-Acetylaspartate in Human Traumatic Brain Injury

PubMed Central

Shannon, Richard J.; Carter, Eleanor L.; Jalloh, Ibrahim; Menon, David K.; Hutchinson, Peter J.; Carpenter, Keri L.H.

2016-01-01

Abstract N-acetylaspartate (NAA) is an amino acid derivative primarily located in the neurons of the adult brain. The function of NAA is incompletely understood. Decrease in brain tissue NAA is presently considered symptomatic and a potential biomarker of acute and chronic neuropathological conditions. The aim of this study was to use microdialysis to investigate the behavior of extracellular NAA (eNAA) levels after traumatic brain injury (TBI). Sampling for this study was performed using cerebral microdialysis catheters (M Dialysis 71) perfused at 0.3 μL/min. Extracellular NAA was measured in microdialysates by high-performance liquid chromatography in 30 patients with severe TBI and for comparison, in radiographically “normal” areas of brain in six non-TBI neurosurgical patients. We established a detailed temporal eNAA profile in eight of the severe TBI patients. Microdialysate concentrations of glucose, lactate, pyruvate, glutamate, and glycerol were measured on an ISCUS clinical microdialysis analyzer. Here, we show that the temporal profile of microdialysate eNAA was characterized by highest levels in the earliest time-points post-injury, followed by a steady decline; beyond 70 h post-injury, average levels were 40% lower than those measured in non-TBI patients. There was a significant inverse correlation between concentrations of eNAA and pyruvate; eNAA showed significant positive correlations with glycerol and the lactate/pyruvate (L/P) ratio measured in microdialysates. The results of this on-going study suggest that changes in eNAA after TBI relate to the release of intracellular components, possibly due to neuronal death or injury, as well as to adverse brain energy metabolism. PMID:26159566

Zinc and glutamine improve brain development in suckling mice subjected to early postnatal malnutrition.

PubMed

Ladd, Fernando V L; Ladd, Aliny A B L; Ribeiro, Antônio Augusto C M; Costa, Samuel B C; Coutinho, Bruna P; Feitosa, George André S; de Andrade, Geanne M; de Castro-Costa, Carlos Maurício; Magalhães, Carlos Emanuel C; Castro, Ibraim C; Oliveira, Bruna B; Guerrant, Richard L; Lima, Aldo Angelo M; Oriá, Reinaldo B

2010-06-01

The effect of zinc and glutamine on brain development was investigated during the lactation period in Swiss mice. Malnutrition was induced by clustering the litter size from 6-7 pups/dam (nourished control) to 12-14 pups/dam (undernourished control) following birth. Undernourished groups received daily supplementation with glutamine by subcutaneous injections starting at day 2 and continuing until day 14. Glutamine (100 mM, 40-80 microL) was used for morphological and behavioral studies. Zinc acetate was added in the drinking water (500 mg/L) to the lactating dams. Synaptophysin and myelin basic protein brain expressions were evaluated by immunoblot. Zinc serum and brain levels and hippocampal neurotransmitters were also evaluated. Zinc with or without glutamine improved weight gain as compared to untreated, undernourished controls. In addition, zinc supplementation improved cliff avoidance and head position during swim behaviors especially on days 9 and 10. Using design-based stereological methods, we found a significant increase in the volume of CA1 neuronal cells in undernourished control mice, which was not seen in mice receiving zinc or glutamine alone or in combination. Undernourished mice given glutamine showed increased CA1 layer volume as compared with the other groups, consistent with the trend toward increased number of neurons. Brain zinc levels were increased in the nourished and undernourished-glutamine treated mice as compared to the undernourished controls on day 7. Undernourished glutamine-treated mice showed increased hippocampal gamma-aminobutyric acid and synaptophysin levels on day 14. We conclude that glutamine or zinc protects against malnutrition-induced brain developmental impairments. Copyright 2010 Elsevier Inc. All rights reserved.

Brain oxygen utilization is unchanged by hypoglycemia in normal humans: lactate, alanine, and leucine uptake are not sufficient to offset energy deficit.

PubMed

Lubow, Jeffrey M; Piñón, Ivan G; Avogaro, Angelo; Cobelli, Claudio; Treeson, David M; Mandeville, Katherine A; Toffolo, Gianna; Boyle, Patrick J

2006-01-01

During hypoglycemia, substrates other than glucose have been suggested to serve as alternate neural fuels. We evaluated brain uptake of endogenously produced lactate, alanine, and leucine at euglycemia and during insulin-induced hypoglycemia in 17 normal subjects. Cross-brain arteriovenous differences for plasma glucose, lactate, alanine, leucine, and oxygen content were quantitated. Cerebral blood flow (CBF) was measured by Fick methodology using N(2)O as the dilution indicator gas. Substrate uptake was measured as the product of CBF and the arteriovenous concentration difference. As arterial glucose concentration fell, cerebral oxygen utilization and CBF remained unchanged. Brain glucose uptake (BGU) decreased from 36.3+/-2.6 to 26.6+/-2.1 micromol.100 g of brain(-1).min(-1) (P<0.001), equivalent to a drop in ATP of 291 micromol.100 g(-1).min(-1). Arterial lactate rose (P<0.001), whereas arterial alanine and leucine fell (P<0.009 and P<0.001, respectively). Brain lactate uptake (BLU) increased from a net release of -1.8+/- 0.6 to a net uptake of 2.5+/-1.2 micromol.100 g(-1).min(-1) (P<0.001), equivalent to an increase in ATP of 74 micromol.100 g(-1).min(-1). Brain leucine uptake decreased from 7.1+/-1.2 to 2.5 +/- 0.5 micromol.100 g(-1).min(-1) (P<0.001), and brain alanine uptake trended downward (P<0.08). We conclude that the ATP generated from the physiological increase in BLU during hypoglycemia accounts for no more than 25% of the brain glucose energy deficit.

Antagonism of V1b receptors promotes maternal motivation to retrieve pups in the MPOA and impairs pup-directed behavior during maternal defense in the mpBNST of lactating rats.

PubMed

Bayerl, Doris S; Kaczmarek, Veronika; Jurek, Benjamin; van den Burg, Erwin H; Neumann, Inga D; Gaßner, Barbara M; Klampfl, Stefanie M; Bosch, Oliver J

2016-03-01

Recent studies using V1b receptor (V1bR) knockout mice or central pharmacological manipulations in lactating rats highlighted the influence of this receptor for maternal behavior. However, its role in specific brain sites known to be important for maternal behavior has not been investigated to date. In the present study, we reveal that V1bR mRNA (qPCR) and protein levels (Western blot) within either the medial preoptic area (MPOA) or the medial-posterior part of the bed nucleus of the stria terminalis (mpBNST) did not differ between virgin and lactating rats. Furthermore, we characterized the effects of V1bR blockade via bilateral injections of the receptor subtype-specific antagonist SSR149415 within the MPOA or the mpBNST on maternal behavior (maternal care under non-stress and stress conditions, maternal motivation to retrieve pups in a novel environment, maternal aggression) and anxiety-related behavior in lactating rats. Blocking V1bR within the MPOA increased pup retrieval, whereas within the mpBNST it decreased pup-directed behavior, specifically licking/grooming the pups, during the maternal defense test. In addition, immediately after termination of the maternal defense test, V1bR antagonism in both brain regions reduced nursing, particularly arched back nursing. Anxiety-related behavior was not affected by V1bR antagonism in either brain region. In conclusion our data indicate that V1bR antagonism significantly modulates different aspects of maternal behavior in a brain region-dependent manner. Copyright © 2015 Elsevier Inc. All rights reserved.

Fructose intake during gestation and lactation differentially affects the expression of hippocampal neurosteroidogenic enzymes in rat offspring.

PubMed

Mizuno, Genki; Munetsuna, Eiji; Yamada, Hiroya; Ando, Yoshitaka; Yamazaki, Mirai; Murase, Yuri; Kondo, Kanako; Ishikawa, Hiroaki; Teradaira, Ryoji; Suzuki, Koji; Ohashi, Koji

2017-02-01

Neurosteroids, steroidal hormones synthesized de novo from cholesterol within the brain, stimulate hippocampal functions such as neuron protection and synapse formation. Previously, we examined the effect of maternal fructose on the transcriptional regulation of neurosteroidogenic enzymes. We found that the mRNA expression level of the steroidogenic acute regulatory protein (StAR), peripheral benzodiazepine receptor (PBR), cytochrome P450(11β), 11β-hydroxysteroid dehydrogenase (HSD), and 17β-HSD was altered. However, we could not determine whether maternal fructose intake played a role in the gestation or lactation period because the dam rats were fed fructose solution during both periods. Thus, in this study, we analyzed the hippocampi of the offspring of dams fed fructose during the gestation or lactation period. Maternal fructose consumption during either the gestation or lactation period did not affect the mRNA levels of StAR, P450(17α), 11β-HSD-2, and 17β-HSD-1. PBR expression was down-regulated, even when rats consumed fructose during the lactation period only, while fructose consumption during gestation tended to activate the expression of P450(11β)-2. We found that maternal fructose intake during gestation and lactation differentially affected the expression of hippocampal neurosteroidogenic enzymes in the offspring.

Organochlorine insecticide residues in the free-tailed bat (Tadarida brasiliensis) at Bracken Cave, Texas

USGS Publications Warehouse

Clark, D.R.; Martin, C.O.; Swineford, D.M.

1975-01-01

Fifty-nine free-tailed bats (Tadarida brasiliensis mexicana ) were collected at Bracken Cave, Texas, and analyzed for organochlorine insecticides and polychlorinated biphenyls (PCBs). Residues of DDE in the brain were greater in 12 young collected from the floor than in 15 young taken from the ceiling, but food deprivation, not higher residues in the brain, apparently caused young to fall....Among 18 pregnant females, residues of DDE and DDT were highest in yearlings. The first lactation by yearlings caused their residue loads to drop sharply. Thereafter, increasing age was accompanied by increasing residues but amounts generally did not exceed those in yearlings.....Residue levels in embryos were a function both of levels in the female parent and degree of embryonic development. Residues accumulated rapidly in nursing young, and lactating females may excrete from 1.3 to 16.2 (mean = 4.3) micrograms of DDE in milk per day. Maximum individual residue loads may be attained toward the end of nursing, and mobilization of these residues during southward migration may subject Bracken Cave free-tails to maximum lifetime residues in the brain....Comparison of our data with residue data for the free-tail population at Eagle Creek Cave (Arizona) in 1970 produced the following conclusions: ( 1) residues of DDE appeared similar in pregnant females, embryos, lactating females, and fallen young for the two populations; (2) residues of DDT and dieldrin appeared greater in pregnant females at Bracken Cave; (3) DDE and DDT occurred at greater levels in guano samples from Bracken Cave. On this basis, the population decline observed at Eagle Creek Cave between 1963 and 1969 does not appear to be related to the residues observed in the 1970 samples taken from that cave.

Effects of organophosphorus anticholinesterase compounds on brain glucose and energy metabolism. Final summary report, 1 October 1981-29 February 1984

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medina, M.A.; Miller, A.L.

1984-09-01

The effects of Soman and paraoxon on cerebral metabolic rate (CMRg) and the levels of various metabolites in rate brain were investigated. In non-convulsing animals, 0.8 of the paraoxon LD50 and 0.5 of the Soman LD50 tended to lower CMRg. A higher dose of Soman, 0.8-0.95 of the LD50, resulted in convulsive seizures in some but not all of the animals. In convulsing rats the CMRg and lactate levels were elevated primarily in the cortex and thalamus/basal ganglia. Decreased ATP and glucose levels with an elevated CMRg and lactate concentration was observed in the cortex, suggesting that Soman may bemore » uncoupling oxidative phosphorylation. Pretreatment with atropine prevented the behavioral manifestations and the elevated CMRg but not the hyperglycemia produced by an 0.8 LD50 dose of Soman. These results suggest that Soman-induced convulsions are similar to those produced by other central nervous system (CNS) excitatory agents in that only certain brain regions are affected. The use of atropine to block the CNS disturbances produced by Soman appears to be effective also does not result in the extensive depression of CMRg observed with TAB, a mixture of trimedoxime, atropine and benactyzine.« less

Simultaneous detection of valine and lactate using MEGA-PRESS editing in pyogenic brain abscess.

PubMed

Lange, Thomas; Ko, Cheng-Wen; Lai, Ping-Hong; Dacko, Michael; Tsai, Shang-Yueh; Buechert, Martin

2016-12-01

Valine and lactate have been recognized as important metabolic markers to diagnose brain abscess by means of MRS. However, in vivo unambiguous detection and quantification is hampered by macromolecular contamination. In this work, MEGA-PRESS difference editing of valine and lactate is proposed. The method is validated in vitro and applied for quantitative in vivo experiments in one healthy subject and two brain abscess patients. It is demonstrated that with this technique the overlapping lipid signal can be reduced by more than an order of magnitude and thus the robustness of valine and lactate detection in vivo can be enhanced. Quantification of the two abscess MEGA-PRESS spectra yielded valine/lactate concentration ratios of 0.10 and 0.27. These ratios agreed with the concentration ratios determined from concomitantly acquired short-T E PRESS data and were in line with literature values. The quantification accuracy of lactate (as measured with Cramér-Rao lower bounds in LCModel processing) was better for MEGA-PRESS than for short-T E PRESS in all acquired in vivo datasets. The Cramér-Rao lower bounds of valine were only better for MEGA-PRESS in one of the two abscess cases, while in the other case coediting of isoleucine confounded the quantification in the MEGA-PRESS analysis. MEGA-PRESS and short-T E PRESS should be combined for unambiguous quantification of amino acids in abscess measurements. Simultaneous valine/lactate MEGA-PRESS editing might benefit the distinction of brain abscesses from tumors, and further categorization of bacteria with reasonable sensitivity and specificity. Copyright © 2016 John Wiley & Sons, Ltd.

Chaski, a novel Drosophila lactate/pyruvate transporter required in glia cells for survival under nutritional stress.

PubMed

Delgado, María Graciela; Oliva, Carlos; López, Estefanía; Ibacache, Andrés; Galaz, Alex; Delgado, Ricardo; Barros, L Felipe; Sierralta, Jimena

2018-01-19

The intercellular transport of lactate is crucial for the astrocyte-to-neuron lactate shuttle (ANLS), a model of brain energetics according to which neurons are fueled by astrocytic lactate. In this study we show that the Drosophila chaski gene encodes a monocarboxylate transporter protein (MCT/SLC16A) which functions as a lactate/pyruvate transporter, as demonstrated by heterologous expression in mammalian cell culture using a genetically encoded FRET nanosensor. chaski expression is prominent in the Drosophila central nervous system and it is particularly enriched in glia over neurons. chaski mutants exhibit defects in a high energy demanding process such as synaptic transmission, as well as in locomotion and survival under nutritional stress. Remarkably, locomotion and survival under nutritional stress defects are restored by chaski expression in glia cells. Our findings are consistent with a major role for intercellular lactate shuttling in the brain metabolism of Drosophila.

Lactate flux in astrocytes is enhanced by a non-catalytic action of carbonic anhydrase II

PubMed Central

Stridh, Malin H; Alt, Marco D; Wittmann, Sarah; Heidtmann, Hella; Aggarwal, Mayank; Riederer, Brigitte; Seidler, Ursula; Wennemuth, Gunther; McKenna, Robert; Deitmer, Joachim W; Becker, Holger M

2012-01-01

Rapid exchange of metabolites between different cell types is crucial for energy homeostasis of the brain. Besides glucose, lactate is a major metabolite in the brain and is primarily produced in astrocytes. In the present study, we report that carbonic anhydrase 2 (CAII) enhances both influx and efflux of lactate in mouse cerebellar astrocytes. The augmentation of lactate transport is independent of the enzyme's catalytic activity, but requires direct binding of CAII to the C-terminal of the monocarboxylate transporter MCT1, one of the major lactate/proton cotransporters in astrocytes and most tissues. By employing its intramolecular proton shuttle, CAII, bound to MCT1, can act as a ‘proton collecting antenna’ for the transporter, suppressing the formation of proton microdomains at the transporter-pore and thereby enhancing lactate flux. By this mechanism CAII could enhance transfer of lactate between astrocytes and neurons and thus provide the neurons with an increased supply of energy substrate. PMID:22451434

Comparison between cerebrospinal fluid and serum lactate concentrations in neurologic dogs with and without structural intracranial disease.

PubMed

Benedicenti, Leontine; Gianotti, Giacomo; Galban, Evelyn M

2018-04-01

The objectives of this study were to investigate the relationship between cerebrospinal fluid lactate and serum concentrations in dogs with clinical signs of central nervous system disease and to establish if cerebrospinal fluid lactate (CSF) concentrations are higher in dogs with structural intracranial disease (Group Pos-MRI) compared to dogs that have clinical signs of intracranial disease but no structural brain disease (Group Neg-MRI) based on magnetic resonance imaging (MRI) findings. Using a prospective study canine blood and cerebrospinal fluid were collected in 24 dogs with neurological signs after undergoing brain MRI. Dogs were divided in 2 groups. No significant difference between serum lactate (1.57 ± 0.9 mmol/L) and CSF lactate concentration (1.34 ± 0.3 mmol/L) was detected. There was a direct correlation between CSF and serum lactate concentration ( R = 0.731; P = 0.01). No significant difference was found in CSF lactate concentration between the 2 groups of dogs ( P = 0.13).

Hyperbaric oxygen therapy may overcome nitric oxide blockage during cyanide intoxication.

PubMed

Polzik, Peter; Hansen, Marco Bo; Olsen, Niels Vidiendal; Grøndal, Olav; Hyldegaard, Ole

2017-01-01

To determine the effects of a blockade of nitric oxide (NO) synthesis on hyperbaric oxygen (HBO₂) therapy during cyanide (CN) intoxication. 39 anesthetized female Sprague-Dawley rats were exposed to CN intoxication (5.4 mg/kg intra-arterially) with or without previous nitric oxide synthase (NOS) inhibition by L-NG-nitroarginine methyl ester (L-NAME) injection (40 mg/kg intraperitoneally). Subsequently, either HBO₂ therapy (284 kPa/90 minutes), normobaric oxygen therapy (100% oxygen/90 minutes) or nothing was administered. Intracerebral microdialysis was used to measure the interstitial brain concentration of lactate, glucose, glycerol and lactate/pyruvate ratios. L-NAME potentiated CN intoxication by higher maximum and prolonged lactate (in mM: 0. 5 ± 0.3 vs. 0.7 ± 0.4, P ⟨ 0.005) concentrations compared with solely CN-intoxicated rats. The same trend was found for mean glucose, glycerol and lactate/pyruvate ratio levels. During HBO₂ treatment a sustained reduction occurred in mean lactate levels (in mM: 0.5 ± 0.5 vs. 0.7 ± 0.4, P ⟨ 0.01) regardless of NOS blockade by L-NAME. The same trend was found for mean glucose and glycerol levels. The results suggest that blocking NOS using L-NAME can worsen acute CN intoxication. HBO₂ treatment can partially overcome this block and continue to ameliorate CN intoxication.

Sleep fragmentation alters brain energy metabolism without modifying hippocampal electrophysiological response to novelty exposure.

PubMed

Baud, Maxime O; Parafita, Julia; Nguyen, Audrey; Magistretti, Pierre J; Petit, Jean-Marie

2016-10-01

Sleep is viewed as a fundamental restorative function of the brain, but its specific role in neural energy budget remains poorly understood. Sleep deprivation dampens brain energy metabolism and impairs cognitive functions. Intriguingly, sleep fragmentation, despite normal total sleep duration, has a similar cognitive impact, and in this paper we ask the question of whether it may also impair brain energy metabolism. To this end, we used a recently developed mouse model of 2 weeks of sleep fragmentation and measured 2-deoxy-glucose uptake and glycogen, glucose and lactate concentration in different brain regions. In order to homogenize mice behaviour during metabolic measurements, we exposed them to a novel environment for 1 h. Using an intra-hippocampal electrode, we first showed that hippocampal electroencephalograph (EEG) response to exploration was unaltered by 1 or 14 days of sleep fragmentation. However, after 14 days, sleep fragmented mice exhibited a lower uptake of 2-deoxy-glucose in cortex and hippocampus and lower cortical lactate levels than control mice. Our results suggest that long-term sleep fragmentation impaired brain metabolism to a similar extent as total sleep deprivation without affecting the neuronal responsiveness of hippocampus to a novel environment. © 2016 European Sleep Research Society.

Prevention of acute/severe hypoglycemia-induced neuron death by lactate administration.

PubMed

Won, Seok Joon; Jang, Bong Geom; Yoo, Byung Hoon; Sohn, Min; Lee, Min Woo; Choi, Bo Young; Kim, Jin Hee; Song, Hong Ki; Suh, Sang Won

2012-06-01

Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD(+)), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD(+) affords neuroprotection against hypoglycemia-induced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by ∼80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD(+) due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels.

Lactate dehydrogenase activity is inhibited by methylmalonate in vitro.

PubMed

Saad, Laura O; Mirandola, Sandra R; Maciel, Evelise N; Castilho, Roger F

2006-04-01

Methylmalonic acidemia (MMAemia) is an inherited metabolic disorder of branched amino acid and odd-chain fatty acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Systemic and neurological manifestations in this disease are thought to be associated with the accumulation of methylmalonate (MMA) in tissues and biological fluids with consequent impairment of energy metabolism and oxidative stress. In the present work we studied the effect of MMA and two other inhibitors of mitochondrial respiratory chain complex II (malonate and 3-nitropropionate) on the activity of lactate dehydrogenase (LDH) in tissue homogenates from adult rats. MMA potently inhibited LDH-catalyzed conversion of lactate to pyruvate in liver and brain homogenates as well as in a purified bovine heart LDH preparation. LDH was about one order of magnitude less sensitive to inhibition by MMA when catalyzing the conversion of pyruvate to lactate. Kinetic studies on the inhibition of brain LDH indicated that MMA inhibits this enzyme competitively with lactate as a substrate (K (i)=3.02+/-0.59 mM). Malonate and 3-nitropropionate also strongly inhibited LDH-catalyzed conversion of lactate to pyruvate in brain homogenates, while no inhibition was observed by succinate or propionate, when present in concentrations of up to 25 mM. We propose that inhibition of the lactate/pyruvate conversion by MMA contributes to lactate accumulation in blood, metabolic acidemia and inhibition of gluconeogenesis observed in patients with MMAemia. Moreover, the inhibition of LDH in the central nervous system may also impair the lactate shuttle between astrocytes and neurons, compromising neuronal energy metabolism.

(13)C MR spectroscopy study of lactate as substrate for rat brain.

PubMed

Qu, H; Håberg, A; Haraldseth, O; Unsgård, G; Sonnewald, U

2000-01-01

In order to address the question whether lactate in blood can serve as a precursor for cerebral metabolites, fully awake rats were injected intravenously with [U-(13)C]lactate or [U-(13)C]glucose followed 15 min later by decapitation. Incorporation of label from [U-(13)C]glucose was seen mainly in glutamate, GABA, glutamine, aspartate, alanine and lactate. More label was found in glutamate than glutamine, underscoring the predominantly neuronal metabolism of pyruvate from [U-(13)C]glucose. It was estimated that the neuronal metabolism of acetyl CoA from glucose accounts for at least 66% and the glial for no more than 34% of the total glucose consumption. When [U-(13)C]lactate was the precursor, label incorporation was similar to that observed from [U-(13)C]glucose, but much reduced. Plasma analysis revealed the presence of approximately equal amounts of [1,2,3-(13)C]- and [1,2-(13)C]glucose, showing gluconeogenesis from [U-(13)C]lactate. It was thus possible that the labeling seen in the cerebral amino acids originated from labeled glucose, not [U-(13)C]lactate. However, the presence of significantly more label in [U-(13)C]- than in [2,3-(13)C]alanine demonstrated that [U-(13)C]lactate did indeed cross the blood-brain barrier, and was metabolized further in the brain. Furthermore, contributions from pyruvate carboxylase (glial enzyme) were detectable in glutamine, glutamate and GABA, and were comparatively more pronounced in the glucose group. This indicated that relatively more pyruvate from lactate than glucose was metabolized in neurons. Surprisingly, the same amount of lactate was synthesized via the tricarboxylic acid cycle in both groups, indicating transfer of neurotransmitters from the neuronal to the astrocytic compartment, as previous studies have shown that this lactate is synthesized primarily in astrocytes. Taking into consideration that astrocytes take up glutamate more avidly than GABA, it is conceivable that neuronal lactate metabolism was more prominent in glutamatergic neurons. Copyright 2000 S. Karger AG, Basel

Interesterified fat or palm oil as substitutes for partially hydrogenated fat during the perinatal period produces changes in the brain fatty acids profile and increases leukocyte-endothelial interactions in the cerebral microcirculation from the male offspring in adult life.

PubMed

Misan, Vanessa; Estato, Vanessa; de Velasco, Patricia Coelho; Spreafico, Flavia Brasil; Magri, Tatiana; Dos Santos, Raísa Magno de Araújo Ramos; Fragoso, Thaiza; Souza, Amanda S; Boldarine, Valter Tadeu; Bonomo, Isabela T; Sardinha, Fátima L C; Oyama, Lila M; Tibiriçá, Eduardo; Tavares do Carmo, Maria das Graças

2015-08-07

We investigated whether maternal intake of normolipidic diets with distinct fatty acid (FA) compositions alters the lipidic profile and influences the inflammatory status of the adult offsprings׳ brains. C57BL/6 female mice during pregnancy and lactation received diets containing either soybean oil (CG), partially hydrogenated vegetable fat rich in trans-fatty acids (TG), palm oil (PG), or interesterified fat (IG). After weaning, male offspring from all groups received control diet. The FA profile was measured in the offspring׳s brains at post-natal days 21 and 90. Brain functional capillary density as well as leukocyte-endothelial interactions in the cerebral post-capillary venules was assessed by intravital fluorescence microscopy at post-natal day 90. Inflammation signaling was evaluated through toll-like receptor 4 (TLR4) content in brain of the adult offspring. In the 21-day old offspring, the brains of the TG showed higher levels of trans FA and reduced levels of linoleic acid (LA) and total n-6 polyunsaturated fatty acids (PUFA). At post-natal day 90, TG and IG groups showed reduced levels of eicosapentaenoic acid (EPA) and total n-3 PUFA tended to be lower compared to CG. The offspring׳s brains exhibited an altered microcirculation with increased leukocyte rolling in groups TG, PG and IG and in TG group increased leukocyte adhesion. The TLR4 content of TG, IG and PG groups only tended to increase (23%; 20% and 35%, respectively). Maternal consumption of trans FA, palm oil or interesterified fat during pregnancy and lactation can trigger the initial steps of inflammatory pathways in the brain of offspring in adulthood. Copyright © 2015 Elsevier B.V. All rights reserved.

[Study on the relationship between iodine status and growth in infants at the key period of brain development].

PubMed

Wang, Yan-ling; Ge, Peng-fei; Ma, Qi-yi; Cao, Yong-qin; Li, Hong-bo; Zheng, Jing; Shi, Wen-quan; Sun, Wei

2012-02-01

To investigate the relationship between iodine nutrition and growth/development in infants at the key period of brain development. All women from pregnancy to the end of lactation and the weaning infants within 3 years in the Linxia Hui Autonomous Prefecture (Linxia Prefecture) were added iodized oil in 2006 - 2010. In 2006, 2010 one town was randomly selected from each of the five directions (east, south, west, north, central) of each county in Linxia Prefecture. One village was chosen from every town and 20 infants, 20 pregnant women and 20 lactating women were randomly selected in each town. Urinary iodine (UI) of the infants, pregnant and lactating women were determined. DQ value, height and weight of part of infants were measured. According to the above sampling plan, UI of pregnant women, lactating women and infants had been monitored every year after intervention. 0-3 infants were choosing to be control before intervention. UI of 1056 and 2989 0-3 infants were investigated before and after the iodine oil intervention. After the 'iodine oil' intervention, the median UI of infants increased from 107.3 µg/L to 139.6 - 190.7 µg/L, the percentage of UI level that lower than 50 µg/L, decreased from 23.9% to 6.7% - 12.9%. DQ value increased from 92.8 to 104.3, the percentage of normal height and above increased from 65.0% to 82.1% and the percentage of the normal weight and above, increased from 59.3% to 81.4%. The outcomes of DQ value, height and weight showed statistically significant differences, compared to the pre-intervention outcomes (P < 0.05). The median UI of pregnant and lactating women increased from 89.3 µg/L to 118.2 - 187.8 µg/L and from 84.9 µg/L to 135.2 - 187.5 µg/L respectively. Infant's growth and development were retarded when iodine deficiency existed at the key period of brain development. Intake of oral iodine oil at key period of brain development could provide adequate nutrition thus improve growth and development on infants.

Hyperbaric oxygen therapy ameliorates acute brain injury after porcine intracerebral hemorrhage at high altitude.

PubMed

Zhu, Hai-tao; Bian, Chen; Yuan, Ji-chao; Liao, Xiao-jun; Liu, Wei; Zhu, Gang; Feng, Hua; Lin, Jiang-kai

2015-06-15

Intracerebral hemorrhage (ICH) at high altitude is not well understood to date. This study investigates the effects of high altitude on ICH, and examines the acute neuroprotection of hyperbaric oxygen (HBO) therapy against high-altitude ICH. Minipigs were placed in a hypobaric chamber for 72 h before the operation. ICH was induced by an infusion of autologous arterial blood (3 ml) into the right basal ganglia. Animals in the high-altitude ICH group received HBO therapy (2.5 ATA for 60 min) 30 min after ICH. Blood gas, blood glucose and brain tissue oxygen partial pressure (PbtO2) were monitored continuously for animals from all groups, as were microdialysis products including glucose, lactate, pyruvate and glutamate in perihematomal tissue from 3 to 12 h post-ICH. High-altitude ICH animals showed significantly lower PbtO2, higher lactate/pyruvate ratio (LPR) and glutamate levels than low-altitude ICH animals. More severe neurological deficits, brain edema and neuronal damage were also observed in high-altitude ICH. After HBO therapy, PbtO2 was significantly increased and LPR and glutamate levels were significantly decreased. Brain edema, neurological deficits and neuronal damage were also ameliorated. The data suggested a more serious disturbance of tissue oxygenation and cerebral metabolism in the acute stage after ICH at high altitude. Early HBO treatment reduced acute brain injury, perhaps through a mechanism involving the amelioration of the derangement of cerebral oxygenation and metabolism following high-altitude ICH.

Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations.

PubMed

Steenweg, Marjan E; Ghezzi, Daniele; Haack, Tobias; Abbink, Truus E M; Martinelli, Diego; van Berkel, Carola G M; Bley, Annette; Diogo, Luisa; Grillo, Eugenio; Te Water Naudé, Johann; Strom, Tim M; Bertini, Enrico; Prokisch, Holger; van der Knaap, Marjo S; Zeviani, Massimo

2012-05-01

In the large group of genetically undetermined infantile-onset mitochondrial encephalopathies, multiple defects of mitochondrial DNA-related respiratory-chain complexes constitute a frequent biochemical signature. In order to identify responsible genes, we used exome-next-generation sequencing in a selected cohort of patients with this biochemical signature. In an isolated patient, we found two mutant alleles for EARS2, the gene encoding mitochondrial glutamyl-tRNA synthetase. The brain magnetic resonance imaging of this patient was hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim and symmetrical signal abnormalities of the thalami, midbrain, pons, medulla oblongata and cerebellar white matter. Proton magnetic resonance spectroscopy showed increased lactate. We matched this magnetic resonance imaging pattern with that of a cohort of 11 previously selected unrelated cases. We found mutations in the EARS2 gene in all. Subsequent detailed clinical and magnetic resonance imaging based phenotyping revealed two distinct groups: mild and severe. All 12 patients shared an infantile onset and rapidly progressive disease with severe magnetic resonance imaging abnormalities and increased lactate in body fluids and proton magnetic resonance spectroscopy. Patients in the 'mild' group partially recovered and regained milestones in the following years with striking magnetic resonance imaging improvement and declining lactate levels, whereas those of the 'severe' group were characterized by clinical stagnation, brain atrophy on magnetic resonance imaging and persistent lactate increases. This new neurological disease, early-onset leukoencephalopathy with thalamus and brainstem involvement and high lactate, is hallmarked by unique magnetic resonance imaging features, defined by a peculiar biphasic clinical course and caused by mutations in a single gene, EARS2, expanding the list of medically relevant defects of mitochondrial DNA translation.

Cerebral Glucose Metabolism and Sedation in Brain-injured Patients: A Microdialysis Study.

PubMed

Hertle, Daniel N; Santos, Edgar; Hagenston, Anna M; Jungk, Christine; Haux, Daniel; Unterberg, Andreas W; Sakowitz, Oliver W

2015-07-01

Disturbed brain metabolism is a signature of primary damage and/or precipitates secondary injury processes after severe brain injury. Sedatives and analgesics target electrophysiological functioning and are as such well-known modulators of brain energy metabolism. Still unclear, however, is how sedatives impact glucose metabolism and whether they differentially influence brain metabolism in normally active, healthy brain and critically impaired, injured brain. We therefore examined and compared the effects of anesthetic drugs under both critical (<1 mmol/L) and noncritical (>1 mmol/L) extracellular brain glucose levels. We performed an explorative, retrospective analysis of anesthetic drug administration and brain glucose concentrations, obtained by bedside microdialysis, in 19 brain-injured patients. Our investigations revealed an inverse linear correlation between brain glucose and both the concentration of extracellular glutamate (Pearson r=-0.58, P=0.01) and the lactate/glucose ratio (Pearson r=-0.55, P=0.01). For noncritical brain glucose levels, we observed a positive linear correlation between midazolam dose and brain glucose (P<0.05). For critical brain glucose levels, extracellular brain glucose was unaffected by any type of sedative. These findings suggest that the use of anesthetic drugs may be of limited value in attempts to influence brain glucose metabolism in injured brain tissue.

Potential of MR spectroscopy for assessment of glioma grading.

PubMed

Bulik, Martin; Jancalek, Radim; Vanicek, Jiri; Skoch, Antonin; Mechl, Marek

2013-02-01

Magnetic resonance spectroscopy (MRS) is an imaging diagnostic method based that allows non-invasive measurement of metabolites in tissues. There are a number of metabolites that can be identified by standard brain proton MRS but only a few of them has a clinical significance in diagnosis of gliomas including N-acetylaspartate, choline, creatine, myo-inositol, lactate, and lipids. In this review, we describe potential of MRS for grading of gliomas. Low-grade gliomas are generally characterized by a relatively high concentration of N-acetylaspartate, low level of choline and absence of lactate and lipids. The increase in creatine concentration indicates low-grade gliomas with earlier progression and malignant transformation. Progression in grade of a glioma is reflected in the progressive decrease in the N-acetylaspartate and myo-inositol levels on the one hand and elevation in choline level up to grade III on the other. Malignant transformation of the glial tumors is also accompanied by the presence of lactate and lipids in MR spectra of grade III but mainly grade IV gliomas. It follows that MRS is a helpful method for detection of glioma regions with aggressive growth or upgrading due to favorable correlation of the choline and N-acetylaspartate levels with histopathological proliferation index Ki-67. Thus, magnetic resonance spectroscopy is also a suitable method for the targeting of brain biopsies. Gliomas of each grade have some specific MRS features that can be used for improvement of the diagnostic value of conventional magnetic resonance imaging in non-invasive assessment of glioma grade. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Effects of experimentally-induced maternal hypothyroidism on crucial offspring rat brain enzyme activities.

PubMed

Koromilas, Christos; Liapi, Charis; Zarros, Apostolos; Stolakis, Vasileios; Tsagianni, Anastasia; Skandali, Nikolina; Al-Humadi, Hussam; Tsakiris, Stylianos

2014-06-01

Hypothyroidism is known to exert significant structural and functional changes to the developing central nervous system, and can lead to the establishment of serious mental retardation and neurological problems. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil-induced experimental hypothyroidism on crucial brain enzyme activities of Wistar rat offspring, at two time-points of their lives: at birth (day-1) and at 21 days of age (end of lactation). Under all studied experimental conditions, offspring brain acetylcholinesterase (AChE) activity was found to be significantly decreased due to maternal hypothyroidism, in contrast to the two studied adenosinetriphosphatase (Na(+),K(+)-ATPase and Mg(2+)-ATPase) activities that were only found to be significantly altered right after birth (increased and decreased, respectively, following an exposure to gestational maternal hypothyroidism) and were restored to control levels by the end of lactation. As our findings regarding the pattern of effects that maternal hypothyroidism has on the above-mentioned crucial offspring brain enzyme activities are compared to those reported in the literature, several differences are revealed that could be attributed to both the mode of the experimental simulation approach followed as well as to the time-frames examined. These findings could provide the basis for a debate on the need of a more consistent experimental approach to hypothyroidism during neurodevelopment as well as for a further evaluation of the herein presented and discussed neurochemical (and, ultimately, neurodevelopmental) effects of experimentally-induced maternal hypothyroidism, in a brain region-specific manner. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.

PubMed

Val-Laillet, David; Guérin, Sylvie; Coquery, Nicolas; Nogret, Isabelle; Formal, Michèle; Romé, Véronique; Le Normand, Laurence; Meurice, Paul; Randuineau, Gwénaëlle; Guilloteau, Paul; Malbert, Charles-Henri; Parnet, Patricia; Lallès, Jean-Paul; Segain, Jean-Pierre

2018-04-01

Butyrate can improve gut functions, whereas histone deacetylase inhibitors might alleviate neurocognitive alterations. Our aim was to assess whether oral butyrate could modulate brain metabolism and plasticity and if this would relate to gut function. Sixteen pigs were subjected to sodium butyrate (SB) supplementation via beverage water or water only [control (C)]. All pigs had blood sampled after 2 and 3 wk of treatment, and were subjected to a brain positron emission tomography after 3 wk. Animals were euthanized after 4 wk to sample pancreas, intestine, and brain for gut physiology and anatomy measurements, as well as hippocampal histology, Ki67, and doublecortin (DCX) immunohistochemistry. SB compared with C treatment triggered basal brain glucose metabolism changes in the nucleus accumbens and hippocampus ( P = 0.003), increased hippocampal granular cell layer volume ( P = 0.006), and neurogenesis (Ki67: P = 0.026; DCX: P = 0.029). After 2 wk of treatment, plasma levels of glucose, insulin, lactate, glucagon-like peptide 1, and peptide tyrosine tyrosine remained unchanged. After 3 wk, plasma levels of lactate were lower in SB compared with C animals ( P = 0.028), with no difference for glucose and insulin. Butyrate intake impacted very little gut anatomy and function. These results demonstrate that oral SB impacted brain functions with little effects on the gut.-Val-Laillet, D., Guérin, S., Coquery, N., Nogret, I., Formal, M., Romé, V., Le Normand, L., Meurice, P., Randuineau, G., Guilloteau, P., Malbert, C.-H., Parnet, P., Lallès, J.-P., Segain, J.-P. Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.

Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model.

PubMed

Park, Jae Mo; Josan, Sonal; Jang, Taichang; Merchant, Milton; Watkins, Ron; Hurd, Ralph E; Recht, Lawrence D; Mayer, Dirk; Spielman, Daniel M

2016-03-01

MRS of hyperpolarized [2-(13)C]pyruvate can be used to assess multiple metabolic pathways within mitochondria as the (13)C label is not lost with the conversion of pyruvate to acetyl-CoA. This study presents the first MR spectroscopic imaging of hyperpolarized [2-(13)C]pyruvate in glioma-bearing brain. Spiral chemical shift imaging with spectrally undersampling scheme (1042 Hz) and a hard-pulse excitation was exploited to simultaneously image [2-(13)C]pyruvate, [2-(13)C]lactate, and [5-(13)C]glutamate, the metabolites known to be produced in brain after an injection of hyperpolarized [2-(13)C]pyruvate, without chemical shift displacement artifacts. A separate undersampling scheme (890 Hz) was also used to image [1-(13)C]acetyl-carnitine. Healthy and C6 glioma-implanted rat brains were imaged at baseline and after dichloroacetate administration, a drug that modulates pyruvate dehydrogenase kinase activity. The baseline metabolite maps showed higher lactate and lower glutamate in tumor as compared to normal-appearing brain. Dichloroacetate led to an increase in glutamate in both tumor and normal-appearing brain. Dichloroacetate-induced %-decrease of lactate/glutamate was comparable to the lactate/bicarbonate decrease from hyperpolarized [1-(13)C]pyruvate studies. Acetyl-carnitine was observed in the muscle/fat tissue surrounding the brain. Robust volumetric imaging with hyperpolarized [2-(13)C]pyruvate and downstream products was performed in glioma-bearing rat brains, demonstrating changes in mitochondrial metabolism with dichloroacetate. © 2015 Wiley Periodicals, Inc.

The role of glycogen, glucose and lactate in neuronal activity during hypoxia in the hooded seal (Cystophora cristata) brain.

PubMed

Czech-Damal, N U; Geiseler, S J; Hoff, M L M; Schliep, R; Ramirez, J-M; Folkow, L P; Burmester, T

2014-09-05

The brains of diving mammals are repeatedly exposed to hypoxic conditions during diving. Brain neurons of the hooded seal (Cystophora cristata) have been shown to be more hypoxia tolerant than those of mice, but the underlying mechanisms are not clear. Here we investigated the roles of different metabolic substrates for maintenance of neuronal activity and integrity, by comparing the in vitro spontaneous neuronal activity of brain slices from layer V of the visual cortex of hooded seals with those in mice (Mus musculus). Studies were conducted by manipulating the composition of the artificial cerebrospinal fluid (aCSF), containing either 10 mM glucose, or 20 mM lactate, or no external carbohydrate supply (aglycemia). Normoxic, hypoxic and ischemic conditions were applied. The lack of glucose or the application of lactate in the aCSF containing no glucose had little effect on the neuronal activity of seal neurons in either normoxia or hypoxia, while neurons from mice survived in hypoxia only few minutes regardless of the composition of the aCSF. We propose that seal neurons have higher intrinsic energy stores. Indeed, we found about three times higher glycogen stores in the seal brain (∼4.1 ng per μg total protein in the seal cerebrum) than in the mouse brain. Notably, in aCSF containing no glucose, seal neurons can tolerate 20 mM lactate while in mouse neuronal activity vanished after few minutes even in normoxia. This can be considered as an adaptation to long dives, during which lactate accumulates in the blood. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of an overload of animal protein on the rat: brain DNA alterations and tissue morphological modifications during fetal and post-natal stage.

PubMed

Greco, A M; Sticchi, R; Boschi, G; Vetrani, A; Salvatore, G

1985-01-01

On account of many literature reports about the definite correlation between high animal protein intake and cardiovascular diseases, we have studied the effect of a hyperproteic purified diet (casein 40%, lactalbumin 20%) on fetal and post-natal (not further than 40th day) stage of the rat, when cell subdivision process is faster and therefore damage by nutritional imbalance is certainly more serious. Litters of rats were grouped according to mother's (either hyperproteic or common basic) and rat's (after lactation) diet. Brain DNA and histology of various organs were studied. Hyperproteic diet during fetal stage and lactation would inhibit brain cell subdivision since overall content of brain DNA would be decreased on autoptic finding. Structural changes were also shown in liver, heart, kidney and adrenal cortex, especially when hyperproteic diet was continued even after lactation.

Hyperpalatable Diet and Physical Exercise Modulate the Expression of the Glial Monocarboxylate Transporters MCT1 and 4.

PubMed

Portela, Luis V; Brochier, Andressa W; Haas, Clarissa B; de Carvalho, Afonso Kopczynski; Gnoato, Jussania A; Zimmer, Eduardo R; Kalinine, Eduardo; Pellerin, Luc; Muller, Alexandre P

2017-10-01

Hyperpalatable diets (HP) impair brain metabolism, and regular physical exercise has an apparent opposite effect. Here, we combined a prior long-term exposure to HP diet followed by physical exercise and evaluated the impact on some neuroenergetic components and on cognitive performance. We assessed the extracellular lactate concentration, expression of monocarboxylate transporters (MCTs), pyruvate dehydrogenase (PDH), and mitochondrial function in the hippocampus. Male C57BL/6J mice were fed 4 months with HP or a control diet. Subsequently, they were divided in the following groups: control diet sedentary (CDS), control diet exercise (CDE), HP diet sedentary (HPS), and HP diet exercise (HPE) (n = 15 per group) and were engaged for an additional 30-day period of voluntary exercise and HP diet. Relative to the control situation, exercise increased MCT1, MCT4, and PDH protein levels, while the HP diet increased MCT1 and MCT4 protein levels. The production of hydrogen peroxide (H 2 O 2 ) and the mitochondrial membrane potential (∆Ѱ m ) stimulated by succinate in hippocampal homogenates were not significantly different between groups. ADP phosphorylation and the maximal respiratory rate induced by FCCP showed similar responses between groups, implying a normal mitochondrial function. Also, extracellular brain lactate levels were increased in the HPE group compared to other groups soon after performing the Y-maze task. However, such enhanced lactate levels were not associated with improved memory performance. In summary, hippocampal protein expression levels of MCT1 and 4 were increased by physical exercise and HP diet, whereas PDH was only increased by exercise. These observations indicate that a hippocampal metabolic reprogramming takes place in response to these environmental factors.

Brain glutamine synthesis requires neuronal-born aspartate as amino donor for glial glutamate formation.

PubMed

Pardo, Beatriz; Rodrigues, Tiago B; Contreras, Laura; Garzón, Miguel; Llorente-Folch, Irene; Kobayashi, Keiko; Saheki, Takeyori; Cerdan, Sebastian; Satrústegui, Jorgina

2011-01-01

The glutamate-glutamine cycle faces a drain of glutamate by oxidation, which is balanced by the anaplerotic synthesis of glutamate and glutamine in astrocytes. De novo synthesis of glutamate by astrocytes requires an amino group whose origin is unknown. The deficiency in Aralar/AGC1, the main mitochondrial carrier for aspartate-glutamate expressed in brain, results in a drastic fall in brain glutamine production but a modest decrease in brain glutamate levels, which is not due to decreases in neuronal or synaptosomal glutamate content. In vivo (13)C nuclear magnetic resonance labeling with (13)C(2)acetate or (1-(13)C) glucose showed that the drop in brain glutamine is due to a failure in glial glutamate synthesis. Aralar deficiency induces a decrease in aspartate content, an increase in lactate production, and lactate-to-pyruvate ratio in cultured neurons but not in cultured astrocytes, indicating that Aralar is only functional in neurons. We find that aspartate, but not other amino acids, increases glutamate synthesis in both control and aralar-deficient astrocytes, mainly by serving as amino donor. These findings suggest the existence of a neuron-to-astrocyte aspartate transcellular pathway required for astrocyte glutamate synthesis and subsequent glutamine formation. This pathway may provide a mechanism to transfer neuronal-born redox equivalents to mitochondria in astrocytes.

Methylphenidate increases glucose uptake in the brain of young and adult rats.

PubMed

Réus, Gislaine Z; Scaini, Giselli; Titus, Stephanie E; Furlanetto, Camila B; Wessler, Leticia B; Ferreira, Gabriela K; Gonçalves, Cinara L; Jeremias, Gabriela C; Quevedo, João; Streck, Emilio L

2015-10-01

Methylphenidate (MPH) is the drug of choice for pharmacological treatment of attention deficit hyperactivity disorder. Studies have pointed to the role of glucose and lactate as well as in the action mechanisms of drugs used to treat these neuropsychiatric diseases. Thus, this study aims to evaluate the effects of MPH administration on lactate release and glucose uptake in the brains of young and adult rats. MPH (1.0, 2.0 and 10.0mg/kg) or saline was injected in young and adult Wistar male rats either acutely (once) or chronically (once daily for 28 days). Then, the levels of lactate release and glucose uptake were assessed in the prefrontal cortex, hippocampus, striatum, cerebellum and cerebral cortex. Chronic MPH treatment increased glucose uptake at the dose of 10.0mg/kg in the prefrontal cortex and striatum, and at the dose of 2.0mg/kg in the cerebral cortex of young rats. In adult rats, an increase in glucose uptake was observed after acute administration of MPH at the dose of 10.0mg/kg in the prefrontal cortex. After chronic treatment, there was an increase in glucose uptake with MPH doses of 2.0 and 10.0mg/kg in the prefrontal cortex, and at an MPH dose of 2.0mg/kg in the striatum of adult rats. The lactate release did not change with either acute or chronic treatments in young or adult rats. These findings indicate that MPH increases glucose consumption in the brain, and that these changes are dependent on age and posology. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats

PubMed Central

Stump, Donald G.; Beck, Melissa J.; Radovsky, Ann; Garman, Robert H.; Freshwater, Lester L.; Sheets, Larry P.; Marty, M. Sue; Waechter, John M.; Dimond, Stephen S.; Van Miller, John P.; Shiotsuka, Ronald N.; Beyer, Dieter; Chappelle, Anne H.; Hentges, Steven G.

2010-01-01

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F1 offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F1 offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F1 offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment-related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively). PMID:20164145

In vivo continuous and simultaneous monitoring of brain energy substrates with a multiplex amperometric enzyme-based biosensor device.

PubMed

Cordeiro, C A; de Vries, M G; Ngabi, W; Oomen, P E; Cremers, T I F H; Westerink, B H C

2015-05-15

Enzyme-based amperometric biosensors are widely used for monitoring key biomarkers. In experimental neuroscience there is a growing interest in in vivo continuous and simultaneous monitoring of metabolism-related biomarkers, like glucose, lactate and pyruvate. The use of multiplex biosensors will provide better understanding of brain energy metabolism and its role in neuropathologies such as diabetes, ischemia, and epilepsy. We have developed and characterized an implantable multiplex microbiosensor device (MBD) for simultaneous and continuous in vivo monitoring of glucose, lactate, and pyruvate. First, we developed and characterized amperometric microbiosensors for monitoring lactate and pyruvate. In vitro evaluation allowed us to choose the most suitable biosensors for incorporation into the MBD, along with glucose and background biosensors. Fully assembled MBDs were characterized in vitro. The calculated performance parameters (LOD, LR, LRS, IMAX and appKM) showed that the multiplex MBD was highly selective and sensitive (LRS≥100 nA/mM) for each analyte and within an adequate range for in vivo application. Finally, MBDs were implanted in the mPFC of anesthetized adult male Wistar rats for in vivo evaluation. Following an equilibration period, baseline brain levels of glucose (1.3±0.2 mM), lactate (1.5±0.4 mM) and pyruvate (0.3±0.1 mM) were established. Subsequently, the MBDs recorded the responses of the animals when submitted to hyperglycemic (40% glucose i.v.) and hypoglycemic (5 U/kg insulin i.v.) challenges. Afterwards, MBDs were recalibrated to convert electrochemical readings into accurate substrate concentrations and to assess biofouling. The presented MBD can monitor simultaneously multiple biomarkers in vivo. Copyright © 2014 Elsevier B.V. All rights reserved.

MCT Expression and Lactate Influx/Efflux in Tanycytes Involved in Glia-Neuron Metabolic Interaction

PubMed Central

Cortés-Campos, Christian; Elizondo, Roberto; Llanos, Paula; Uranga, Romina María; Nualart, Francisco; García, María Angeles

2011-01-01

Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the mechanisms involved in hypothalamic glucosensing. We have postulated that hypothalamic glial cells, also known as tanycytes, produce lactate by glycolytic metabolism of glucose. Transfer of lactate to neighboring neurons stimulates ATP synthesis and thus contributes to their activation. Because destruction of third ventricle (III-V) tanycytes is sufficient to alter blood glucose levels and food intake in rats, it is hypothesized that tanycytes are involved in the hypothalamic glucose sensing mechanism. Here, we demonstrate the presence and function of monocarboxylate transporters (MCTs) in tanycytes. Specifically, MCT1 and MCT4 expression as well as their distribution were analyzed in Sprague Dawley rat brain, and we demonstrate that both transporters are expressed in tanycytes. Using primary tanycyte cultures, kinetic analyses and sensitivity to inhibitors were undertaken to confirm that MCT1 and MCT4 were functional for lactate influx. Additionally, physiological concentrations of glucose induced lactate efflux in cultured tanycytes, which was inhibited by classical MCT inhibitors. Because the expression of both MCT1 and MCT4 has been linked to lactate efflux, we propose that tanycytes participate in glucose sensing based on a metabolic interaction with neurons of the arcuate nucleus, which are stimulated by lactate released from MCT1 and MCT4-expressing tanycytes. PMID:21297988

Biochemical changes related to hypoxia during cerebral aneurysm surgery: combined microdialysis and tissue oxygen monitoring: case report.

PubMed

Hutchinson, P J; Al-Rawi, P G; O'Connell, M T; Gupta, A K; Pickard, J D; Kirkpatrick, P J

2000-01-01

The objective of this study was to monitor brain metabolism on-line during aneurysm surgery, by combining the use of a multiparameter (brain tissue oxygen, brain carbon dioxide, pH, and temperature) sensor with microdialysis (extracellular glucose, lactate, pyruvate, and glutamate). The case illustrates the potential value of these techniques by demonstrating the effects of adverse physiological events on brain metabolism and the ability to assist in both intraoperative and postoperative decision-making. A 41-year-old woman presented with a World Federation of Neurological Surgeons Grade I subarachnoid hemorrhage. Angiography revealed a basilar artery aneurysm that was not amenable to coiling, so the aneurysm was clipped. Before the craniotomy was performed, a multiparameter sensor and a microdialysis catheter were inserted to monitor brain metabolism. During the operation, the brain oxygen level decreased, in relation to biochemical changes, including the reduction of extracellular glucose and pyruvate and the elevation of lactate and glutamate. These changes were reversible. However, when the craniotomy was closed, a second decrease in brain oxygen occurred in association with brain swelling, which immediately prompted a postoperative computed tomographic scan. The scan demonstrated acute hydrocephalus, requiring external ventricular drainage. The patient made a full recovery. The monitoring techniques influenced clinical decision-making in the treatment of this patient. On-line measurement of brain tissue gases and extracellular chemistry has the potential to assist in the perioperative and postoperative management of patients undergoing complex cerebrovascular surgery and to establish the effects of intervention on brain homeostasis.

Divergent lactate dehydrogenase isoenzyme profile in cellular compartments of primate forebrain structures.

PubMed

Duka, Tetyana; Collins, Zachary; Anderson, Sarah M; Raghanti, Mary Ann; Ely, John J; Hof, Patrick R; Wildman, Derek E; Goodman, Morris; Grossman, Lawrence I; Sherwood, Chet C

2017-07-01

The compartmentalization and association of lactate dehydrogenase (LDH) with specific cellular structures (e.g., synaptosomal, sarcoplasmic or mitochondrial) may play an important role in brain energy metabolism. Our previous research revealed that LDH in the synaptosomal fraction shifts toward the aerobic isoforms (LDH-B) among the large-brained haplorhine primates compared to strepsirrhines. Here, we further analyzed the subcellular localization of LDH in primate forebrain structures using quantitative Western blotting and ELISA. We show that, in cytosolic and mitochondrial subfractions, LDH-B expression level was relatively elevated and LDH-A declined in haplorhines compared to strepsirrhines. LDH-B expression in mitochondrial fractions of the neocortex was preferentially increased, showing a particularly significant rise in the ratio of LDH-B to LDH-A in chimpanzees and humans. We also found a significant correlation between the protein levels of LDH-B in mitochondrial fractions from haplorhine neocortex and the synaptosomal LDH-B that suggests LDH isoforms shift from a predominance of A-subunits toward B-subunits as part of a system that spatially buffers dynamic energy requirements of brain cells. Our results indicate that there is differential subcellular compartmentalization of LDH isoenzymes that evolved among different primate lineages to meet the energy requirements in neocortical and striatal cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Rise in plasma lactate concentrations with psychosocial stress: a possible sign of cerebral energy demand.

PubMed

Kubera, Britta; Hubold, Christian; Otte, Saskia; Lindenberg, Ann-Sophie; Zeiss, Irena; Krause, Regina; Steinkamp, Mirja; Klement, Johanna; Entringer, Sonja; Pellerin, Luc; Peters, Achim

2012-01-01

It is known that exogenous lactate given as an i.v. energy infusion is able to counteract a neuroglycopenic state that developed during psychosocial stress. It is unknown, however, whether the brain under stressful conditions can induce a rise in plasma lactate to satisfy its increased needs during stress. Since lactate is i) an alternative cerebral energy substrate to glucose and ii) its plasmatic concentration is influenced by the sympathetic nervous system, the present study aimed at investigating whether plasma lactate concentrations increase with psychosocial stress in humans. 30 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess plasma lactate concentrations and stress hormone profiles. Plasma lactate increased 47% during psychosocial stress (from 0.9 ± 0.05 to 1.4 ± 0.1 mmol/l; interaction time × stress intervention: F = 19.7, p < 0.001). This increase in lactate concentrations during stress was associated with an increase in epinephrine (R(2) = 0.221, p = 0.02) and ACTH concentrations (R(2) = 0.460, p < 0.001). Plasma lactate concentrations increase during acute psychosocial stress in humans. This finding suggests the existence of a demand mechanism that functions to allocate an additional source of energy from the body towards the brain, which we refer to as 'cerebral lactate demand'.

Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders.

PubMed

Poon, H Fai; Farr, Susan A; Thongboonkerd, Visith; Lynn, Bert C; Banks, William A; Morley, John E; Klein, Jon B; Butterfield, D Allan

2005-01-01

Free radical-mediated damage to neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD) and aging. The senescence accelerated prone mouse strain 8 (SAMP8) exhibits age-related deterioration in memory and learning along with increased oxidative markers. Therefore, SAMP8 is a suitable model to study brain aging and, since aging is the major risk factor for AD and SAMP8 exhibits many of the biochemical findings of AD, perhaps as a model for and the early phase of AD. Our previous studies reported higher oxidative stress markers in brains of 12-month-old SAMP8 mice when compared to that of 4-month-old SAMP8 mice. Further, we have previously shown that injecting the mice with alpha-lipoic acid (LA) reversed brain lipid peroxidation, protein oxidation, as well as the learning and memory impairments in SAMP8 mice. Recently, we reported the use of proteomics to identify proteins that are expressed differently and/or modified oxidatively in aged SAMP8 brains. In order to understand how LA reverses the learning and memory deficits of aged SAMP8 mice, in the current study, we used proteomics to compare the expression levels and specific carbonyl levels of proteins in brains from 12-month-old SAMP8 mice treated or not treated with LA. We found that the expressions of the three brain proteins (neurofilament triplet L protein, alpha-enolase, and ubiquitous mitochondrial creatine kinase) were increased significantly and that the specific carbonyl levels of the three brain proteins (lactate dehydrogenase B, dihydropyrimidinase-like protein 2, and alpha-enolase) were significantly decreased in the aged SAMP8 mice treated with LA. These findings suggest that the improved learning and memory observed in LA-injected SAMP8 mice may be related to the restoration of the normal condition of specific proteins in aged SAMP8 mouse brain. Moreover, our current study implicates neurofilament triplet L protein, alpha-enolase, ubiquitous mitochondrial creatine kinase, lactate dehydrogenase B, and dihydropyrimidinase-like protein 2 in process associated with learning and memory of SAMP8 mice.

Oxidative costs of reproduction: Oxidative stress in mice fed standard and low antioxidant diets.

PubMed

Vaanholt, L M; Milne, A; Zheng, Y; Hambly, C; Mitchell, S E; Valencak, T G; Allison, D B; Speakman, J R

2016-02-01

Lactation is one of the most energetically expensive behaviours, and trade-offs may exist between the energy devoted to it and somatic maintenance, including protection against oxidative damage. However, conflicting data exist for the effects of reproduction on oxidative stress. In the wild, a positive relationship is often observed, but in laboratory studies oxidative damage is often lower in lactating than in non-breeding animals. We hypothesised that this discrepancy may exist because during lactation food intake increases many-fold resulting in a large increase in the intake of dietary antioxidants which are typically high in laboratory rodent chow where they are added as a preservative. We supplied lactating and non-breeding control mice with either a standard or low antioxidant diet and studied how this affected the activity of endogenous antioxidants (catalase, superoxide dismutase; SOD, and glutathione peroxidise; GPx) and oxidative damage to proteins (protein carbonyls, PC) in liver and brain tissue. The low antioxidant diet did not significantly affect activities of antioxidant enzymes in brain or liver, and generally did not result in increased protein damage, except in livers of control mice on low antioxidant diet. Catalase activity, but not GPx or SOD, was decreased in both control and lactating mice on the low antioxidant diet. Lactating mice had significantly reduced oxidative damage to both liver and brain compared to control mice, independent of the diet they were given. In conclusion, antioxidant content of the diet did not affect oxidative stress in control or reproductive mice, and cannot explain the previously observed reduction in oxidative stress in lactating mammals studied in the laboratory. The reduced oxidative stress in the livers of lactating mice even under low antioxidant diet treatment was consistent with the 'shielding' hypothesis. Copyright © 2015 Elsevier Inc. All rights reserved.

Serial analysis of 3D H-1 MRSI for patients with newly diagnosed GBM treated with combination therapy that includes bevacizumab.

PubMed

Nelson, Sarah J; Li, Yan; Lupo, Janine M; Olson, Marram; Crane, Jason C; Molinaro, Annette; Roy, Ritu; Clarke, Jennifer; Butowski, Nicholas; Prados, Michael; Cha, Soonmee; Chang, Susan M

2016-10-01

Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.

Trafficking of glucose, lactate, and amyloid-β from the inferior colliculus through perivascular routes

PubMed Central

Ball, Kelly K; Cruz, Nancy F; Mrak, Robert E; Dienel, Gerald A

2010-01-01

Metabolic brain imaging is widely used to evaluate brain function and disease, and quantitative assays require local retention of compounds used to register changes in cellular activity. As labeled metabolites of [1- and 6-14C]glucose are rapidly released in large quantities during brain activation, this study evaluated release of metabolites and proteins through perivascular fluid flow, a pathway that carries solutes from brain to peripheral lymphatic drainage sites. Assays with [3,4-14C]glucose ruled out local oxidation of glucose-derived lactate as a major contributor of label loss. Brief infusion of [1-14C]glucose and -[14C]lactate into the inferior colliculus of conscious rats during acoustic stimulation labeled the meninges, consistent with perivascular clearance of [14C]metabolites from interstitial fluid. Microinfusion of Evans blue albumin and amyloid-β1−40 (Aβ) caused perivascular labeling in the inferior colliculus, labeled the surrounding meninges, and Aβ-labeled-specific blood vessels in the caudate and olfactory bulb and was deposited in cervical lymph nodes. Efflux of extracellular glucose, lactate, and Aβ into perivascular fluid pathways is a normal route for clearance of material from the inferior colliculus that contributes to underestimates of brain energetics. Convergence of ‘watershed' drainage to common pathways may facilitate perivascular amyloid plaque formation and pathway obstruction in Alzheimer's disease. PMID:19794399

Expression of hypoxia-inducible carbonic anhydrases in brain tumors

PubMed Central

Proescholdt, Martin A.; Mayer, Christina; Kubitza, Marion; Schubert, Thomas; Liao, Shu-Yuan; Stanbridge, Eric J.; Ivanov, Sergey; Oldfield, Edward H.; Brawanski, Alexander; Merrill, Marsha J.

2005-01-01

Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel–Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-1α staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target. PMID:16212811

Progressive Impairment of Lactate-based Gluconeogenesis in the Huntington's Disease Mouse Model R6/2.

PubMed

Nielsen, Signe Marie Borch; Hasholt, Lis; Nørremølle, Anne; Josefsen, Knud

2015-04-20

Huntington's disease (HD) is a neurodegenerative illness, where selective neuronal loss in the brain caused by expression of mutant huntingtin protein leads to motor dysfunction and cognitive decline in addition to peripheral metabolic changes. In this study we confirm our previous observation of impairment of lactate-based hepatic gluconeogenesis in the transgenic HD mouse model R6/2 and determine that the defect manifests very early and progresses in severity with disease development, indicating a potential to explore this defect in a biomarker context. Moreover, R6/2 animals displayed lower blood glucose levels during prolonged fasting compared to wild type animals.

Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis.

PubMed

Vespa, Paul M; Miller, Chad; McArthur, David; Eliseo, Mathew; Etchepare, Maria; Hirt, Daniel; Glenn, Thomas C; Martin, Neil; Hovda, David

2007-12-01

To determine whether nonconvulsive electrographic post-traumatic seizures result in increases in intracranial pressure and microdialysis lactate/pyruvate ratio. Prospective monitoring with retrospective data analysis. Single center academic neurologic intensive care unit. Twenty moderate to severe traumatic brain injury patients (Glasgow Coma Score 3-13). Continuous electroencephalography and cerebral microdialysis were performed for 7 days after injury. Ten patients had seizures and were compared with a matched cohort of traumatic brain injury patients without seizures. The seizures were repetitive and constituted status epilepticus in seven of ten patients. Using a within-subject design, post-traumatic seizures resulted in episodic increases in intracranial pressure (22.4 +/- 7 vs. 12.8 +/- 4.3 mm Hg; p < .001) and an episodic increase in lactate/pyruvate ratio (49.4 +/- 16 vs. 23.8 +/- 7.6; p < .001) in the seizure group. Using a between-subjects comparison, the seizure group demonstrated a higher mean intracranial pressure (17.6 +/- 6.5 vs. 12.2 +/- 4.2 mm Hg; p < .001), a higher mean lactate/pyruvate ratio (38.6 +/- 18 vs. 27 +/- 9; p < .001) compared with nonseizure patients. The intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group (p < .02). Post-traumatic seizures result in episodic as well as long-lasting increases in intracranial pressure and microdialysis lactate/pyruvate ratio. These data suggest that post-traumatic seizures represent a therapeutic target for patients with traumatic brain injury.

Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation

PubMed Central

Sobieski, Courtney; Shu, Hong-Jin

2018-01-01

Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations. PMID:29617444

Brain metastasis detection by resonant Raman optical biopsy method

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Cheng, Gangge; Zhou, Lixin; Zhang, Chunyuan; Pu, Yang; Li, Zhongwu; Liu, Yulong; Li, Qingbo; Wang, Wei; Alfano, Robert R.

2014-03-01

Resonant Raman (RR) spectroscopy provides an effective way to enhance Raman signal from particular bonds associated with key molecules due to changes on a molecular level. In this study, RR is used for detection of human brain metastases of five kinds of primary organs of lung, breast, kidney, rectal and orbital in ex-vivo. The RR spectra of brain metastases cancerous tissues were measured and compared with those of normal brain tissues and the corresponding primary cancer tissues. The differences of five types of brain metastases tissues in key bio-components of carotene, tryptophan, lactate, alanine and methyl/methylene group were investigated. The SVM-KNN classifier was used to categorize a set of RR spectra data of brain metastasis of lung cancerous tissues from normal brain tissue, yielding diagnostic sensitivity and specificity at 100% and 75%, respectively. The RR spectroscopy may provide new moleculebased optical probe tools for diagnosis and classification of brain metastatic of cancers.

Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia

PubMed Central

Lafuente, Hector; Pazos, Maria R.; Alvarez, Antonia; Mohammed, Nagat; Santos, Martín; Arizti, Maialen; Alvarez, Francisco J.; Martinez-Orgado, Jose A.

2016-01-01

Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl-aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFα (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult. PMID:27462203

Quantitative in vivo detection of brain cell death after hypoxia ischemia using the lipid peak at 1.3 ppm of proton magnetic resonance spectroscopy in neonatal rats.

PubMed

Ahn, So Yoon; Yoo, Hye Soo; Lee, Jang Hoon; Sung, Dong Kyung; Jung, Yu Jin; Sung, Se In; Lim, Keun Ho; Chang, Yun Sil; Lee, Jung Hee; Kim, Ki Soo; Park, Won Soon

2013-07-01

This study was performed to determine the accuracy of proton magnetic spectroscopy ((1)H-MRS) lipid peak as a noninvasive tool for quantitative in vivo detection of brain cell death. Seven day-old Sprague Dawley rats were subjected to 8% oxygen following a unilateral carotid artery ligation. For treatment, cycloheximide was given immediately after hypoxic ischemia (HI). Lipid peak was measured using (1)H-MRS at 24 hr after HI, and then brains were harvested for fluorocytometric analyses with annexin V/propidium iodide (PI) and fluorescent probe JC-1, and for adenosine-5'-triphosphate (ATP) and lactate. Increased lipid peak at 1.3 ppm measured with (1)H-MRS, apoptotic and necrotic cells, and loss of mitochondrial membrane potential (ΔΨ) at 24 hr after HI were significantly improved with cycloheximide treatment. Significantly reduced brain ATP and increased lactate levels observed at 24 hr after HI showed a tendency to improve without statistical significance with cycloheximide treatment. Lipid peak at 1.3 ppm showed significant positive correlation with both apoptotic and necrotic cells and loss of ΔΨ, and negative correlation with normal live cells. Lipid peak at 1.3 ppm measured by (1)H-MRS might be a sensitive and reliable diagnostic tool for quantitative in vivo detection of brain cell death after HI.

Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model

PubMed Central

Harada, Kuniaki; Honmou, Osamu; Liu, He; Bando, Michio; Houkin, Kiyohiro; Kocsis, Jeffery D.

2008-01-01

Proton magnetic resonance spectroscopy (1-H MRS) has revealed changes of metabolites in acute cerebral infarction. Although the drastic changes of lactate and N-acetyl-aspartate have been reported to be useful indicators of the ischemic damage in both humans and experimental animals, lipid signals are also detected by the short echo time sequence 1–5 days after ischemia. The objective of this study was to find a novel technique to isolate lactate signals from lipid signals in the ischemic brain. First, MRS was used to study the lipid and lactate components of a spherical phantom in vitro, and parameters were established to separate these components in vitro. Then, MR measurements were obtained from the brains of middle cerebral artery occlusion rats. All MR measurements were performed using a 7-T (300 MHz), 18.3-cm-bore superconducting magnet (Oxford Magnet Technologies) interfaced to a Unity INOVA Imaging System (Varian Technologies). T2-weighted images were obtained from a 1.0-mm-thick coronal section using a 3-cm field of view. It is well known that lipid has a shorter and lactate a longer T2 relaxation time. These distinct magnetic characteristics allowed us to separate the lactate signal from the lipid signal. Thus, adjustment of the echo time is essential to analyze the metabolites in acute cerebral infarction, which may be useful in both the clinic and laboratory. PMID:17196558

Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo.

PubMed

Itoh, Yoshiaki; Esaki, Takanori; Shimoji, Kazuaki; Cook, Michelle; Law, Mona J; Kaufman, Elaine; Sokoloff, Louis

2003-04-15

Neuronal cultures in vitro readily oxidized both D-[(14)C]glucose and l-[(14)C]lactate to (14)CO(2), whereas astroglial cultures oxidized both substrates sparingly and metabolized glucose predominantly to lactate and released it into the medium. [(14)C]Glucose oxidation to (14)CO(2) varied inversely with unlabeled lactate concentration in the medium, particularly in neurons, and increased progressively with decreasing lactate concentration. Adding unlabeled glucose to the medium inhibited [(14)C]lactate oxidation to (14)CO(2) only in astroglia but not in neurons, indicating a kinetic preference in neurons for oxidation of extracellular lactate over intracellular pyruvatelactate produced by glycolysis. Protein kinase-catalyzed phosphorylation inactivates pyruvate dehydrogenase (PDH), which regulates pyruvate entry into the tricarboxylic acid cycle. Dichloroacetate inhibits this kinase, thus enhancing PDH activity. In vitro dichloroacetate stimulated glucose and lactate oxidation to CO(2) and reduced lactate release mainly in astroglia, indicating that limitations in glucose and lactate oxidation by astroglia may be due to a greater balance of PDH toward the inactive form. To assess the significance of astroglial export of lactate to neurons in vivo, we attempted to diminish this traffic in rats by administering dichloroacetate (50 mgkg) intravenously to stimulate astroglial lactate oxidation and then examined the effects on baseline and functionally activated local cerebral glucose utilization (lCMR(glc)). Dichloroacetate raised baseline lCMR(glc) throughout the brain and decreased the percent increases in lCMR(glc) evoked by functional activation. These studies provide evidence in support of the compartmentalization of glucose metabolism between astroglia and neurons but indicate that the compartmentalization may be neither complete nor entirely obligatory.

Brain histological changes in young mice submitted to diets with different ratios of n-6/n-3 polyunsaturated fatty acids during maternal pregnancy and lactation.

PubMed

Tian, Chunyu; Fan, Chaonan; Liu, Xinli; Xu, Feng; Qi, Kemin

2011-10-01

N-3 polyunsaturated fatty acids (n-3 PUFAs) are essential for brain development and function, but the appropriate quantity of dietary n-3 PUFAs and ratio of n-6/n-3 PUFAs have not been clearly determined. In this study, we investigated the effects of different dietary ratios of n-6/n-3 PUFAs on the brain structural development in mice and the expression of associated transcription factors. C57 BL/6J mice were fed with one of two categories of n-3 PUFA-containing diets (a flaxseed oil diet and a flaxseed/fish oil mixed diet) or an n-3 PUFA-deficient diet. For each of the n-3 PUFA diets, flaxseed oil or flaxseed/fish oil was combined with other oils to yield three different n-6/n-3 ratios, which ranged from 15.7:1 to 1.6:1. The feeding regimens began two months before mouse conception and continued throughout lactation for new pups. As compared with the n-3 PUFA-deficient diet, both the flaxseed oil n-3 PUFA diets and the flaxseed/fish oil n-3 PUFA diets significantly increased the expression levels of brain neuron-specific enolase, glial fibrillary acidic protein and myelin basic protein, somewhat dose-dependently, in new pup mice at 21 d and 42 d of age. The expression of PPAR-γ in the brains of pup mice was increased only at 7 d of age with the n-3 PUFA diet, and no changes in the expression of PPAR-α and PPAR-β were found among all the diet groups. These results suggest that the higher intake amount of n-3 PUFAs with a low ratio of n-6/n-3 PUFAs at about 1-2:1, supplied during both maternal pregnancy and lactation, may be more beneficial for early brain development, and PPAR-γ may act in one of the pathways by which n-3 PUFAs promote early brain development. Copyright © 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

[Levels of unified metabolites and thyroid hormones in blood and oral fluid of children with minimal brain dysfunction].

PubMed

Gil'miiarova, F N; Pervova, Iu V; Radomskaia, V M; Gergel', N I; Tarasova, S V

2004-01-01

Minimal brain dysfunctions in children with various perinatal complications are accompanied by metabolic imbalance manifested by decreased total protein content, the tendency to reduced triglycerides, increased cholesterol concentrations in the oral fluid, the trend to hypoproteinaemia, hypoglycaemia, hypotriglyceridaemia. The most significant changes in the redox systems alpha-ketoglutarate-glutamate, oxaloacetate-malate, pyruvate-lactate, dioxyacetone phosphate-alpha-glycerophosphate in biological fluids were revealed in cases of antenatal alcoholisation. A certain correlation was found between anemia in pregnant women and hypothyroidal background in children. In addition, a high level of free and total thyroxine, that of total triiodthyronine were found in the oral fluid. Hypophysis--thyroid dysregulation in children with minimal brain dysfunction associated with gestosis in their mothers during pregnancy, was manifested by decreased content of total and free T4 and T3 in blood serum and increased level of the thyroid-stimulating hormone.

Hypoglycemia Prevents Increase in Lactic Acidosis During Reperfusion After Temporary Cerebral Ischemia in Rats

PubMed Central

Sappey-Marinier, Dominique; Chileuitt, Laureano; Weiner, Michael W.; Faden, Alan I.; Weinstein, Philip R.

2009-01-01

Sequential 31P and 1H MRS was used to measure cerebral phosphate metabolites, intracellular pH, and lactate in normoglycemic and hypoglycemic rats during 30 min of complete cerebral ischemia and 5.5 h of reperfusion. These results were correlated with brain levels of free fatty acids (FFAs), excitatory amino acids, cations, and water content at death. The lactate/N-acetyl aspartate ratio was not significantly different between groups before or during occlusion. During reperfusion, the ratio was higher in normoglycemic rats from 3 to 85 min (p≤ 0.05), and recovery time was faster in hypoglycemic rats (29 vs 45 min; p = 0.04), suggesting reduced lactate production and faster recovery of aerobic metabolism. During occlusion, significant but comparable decrease of intracellular pH occurred in each group. Intracellular pH was higher in hypoglycemic rats at 140 min and 260 min of reperfusion. Water content, Na and K+ concentrations, and FFA and excitatory amino acid levels were not significantly different between groups, but hypoglycemic rats had less depletion of levels of Mg2+ (p=0.011). These results show that hypoglycemia has a limited but potentially beneficial effect on postischemic lactic acidosis. PMID:8771092

Cerebral lactic acidosis correlates with neurological impairment in MELAS.

PubMed

Kaufmann, P; Shungu, D C; Sano, M C; Jhung, S; Engelstad, K; Mitsis, E; Mao, X; Shanske, S; Hirano, M; DiMauro, S; De Vivo, D C

2004-04-27

To evaluate the role of chronic cerebral lactic acidosis in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). The authors studied 91 individuals from 34 families with MELAS and the A3243G point mutation and 15 individuals from two families with myoclonus epilepsy and ragged red fibers (MERRF) and the A8344G mutation. Subjects were divided into four groups. Paternal relatives were studied as controls (Group 1). The maternally related subjects were divided clinically into three groups: asymptomatic (no clinical evidence of neurologic disease) (Group 2), oligosymptomatic (neurologic symptoms but without the full clinical picture of MELAS or MERRF) (Group 3), and symptomatic (fulfilling MELAS or MERRF criteria) (Group 4). The authors performed a standardized neurologic examination, neuropsychological testing, MRS, and leukocyte DNA analysis in all subjects. The symptomatic and oligosymptomatic MELAS subjects had significantly higher ventricular lactate than the other groups. There was a significant correlation between degree of neuropsychological and neurologic impairment and cerebral lactic acidosis as estimated by ventricular MRS lactate levels. High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.

Misconceptions regarding basic thermodynamics and enzyme kinetics have led to erroneous conclusions regarding the metabolic importance of lactate dehydrogenase isoenzyme expression.

PubMed

Bak, Lasse K; Schousboe, Arne

2017-11-01

Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate involving the coenzyme NAD + . Part of the foundation for the proposed shuttling of lactate from astrocytes to neurons during brain activation is the differential distribution of LDH isoenzymes between the two cell types. In this short review, we outline the basic kinetic properties of the LDH isoenzymes expressed in neurons and astrocytes, and argue that the distribution of LDH isoenzymes does not in any way govern directional flow of lactate between the two cellular compartments. The two main points are as follows. First, in line with the general concept of chemical catalysis, enzymes do not influence the thermodynamic equilibrium of a chemical reaction but merely the speed at which equilibrium is obtained. Thus, differential distribution of LDH isoenzymes with different kinetic parameters does not predict which cells are producing and which are consuming lactate. Second, the thermodynamic equilibrium of the reaction is toward the reduced substrate (i.e., lactate), which is reflected in the concentrations measured in brain tissue, suggesting that the reaction is at near-equilibrium at steady state. To conclude, the cellular distribution of LDH isoenzymes is of little if any consequence in determining any directional flow of lactate between neurons and astrocytes. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Transplacental passage of 26Al from pregnant rats to fetuses and 26Al transfer through maternal milk to suckling rats

NASA Astrophysics Data System (ADS)

Yumoto, S.; Nagai, H.; Matsuzaki, H.; Kobayashi, T.; Tada, W.; Ohki, Y.; Kakimi, S.; Kobayashi, K.

2000-10-01

Aluminium (Al) is toxic to the growth of fetuses and sucklings. However, the incorporation of Al into fetuses and sucklings in the periods of gestation and lactation has not been well clarified because Al lacks a suitable isotope for a tracer experiment. In this study, we used 26Al (a radioisotope of Al with half-life of 716,000 yr) as a tracer, and measured 26Al incorporation into fetuses and sucklings by accelerator mass spectrometry (AMS). To investigate Al incorporation into fetuses through transplacental passage, 26Al ( 26AlCl 3) was subcutaneously injected into pregnant rats on day 15 of gestation. 26Al was also subcutaneoulsy injected into lactating rats from day 1 to day 20 postpartum. By day 20 of gestation, 0.2% of the 26Al injected into a pregnant rat had been transferred to the fetuses, and 26Al was detected in the brain and liver of the fetuses. On day 9 postpartum, high levels of 26Al were demonstrated in the brain, liver, kidneys and blood of suckling rats. It is concluded that 26Al subcutaneously injected into pregnant rats and/or lactating rats is incorporated into their offspring through transplacental passage and/or maternal milk.

Protective effects of ascorbic acid and garlic extract against lead-induced apoptosis in developing rat hippocampus.

PubMed

Ebrahimzadeh-Bideskan, Ali-Reza; Hami, Javad; Alipour, Fatemeh; Haghir, Hossein; Fazel, Ali-Reza; Sadeghi, Akram

2016-10-01

Lead exposure has negative effects on developing nervous system and induces apoptosis in newly generated neurons. Natural antioxidants (i.e. Ascorbic acid and Garlic) might protect against lead-induced neuronal cell damage. The aim of the present study was to investigate the protective effects of Ascorbic acid and Garlic administration during pregnancy and lactation on lead-induced apoptosis in rat developing hippocampus. Timed pregnant Wistar rats were administrated with Lead (1500 ppm) via drinking water (Pb group) or lead plus Ascorbic acid (Pb + AA Group, 500 mg/kg, IP), or lead plus Garlic Extract (Pb + G Group, 1 ml garlic juice/100 g BW, via Gavage) from early gestation (GD 0) until postnatal day 50 (PN 50). At the end of experiments, the pups' brains were carefully dissected. To identify neuronal death, the brain sections were stained with TUNEL assay. Mean of blood and brain lead levels increased significantly in Pb group comparing to other studied groups (P < 0.01). There was significant reduction in blood and brain lead level in Pb + AA and Pb + G groups when compared to those of Pb group (P < 0.01). The mean number of TUNEL positive cells in the CA1, CA3, and DG was significantly lower in the groups treated by either Ascorbic acid or Garlic (P < 0.05). Administration of Ascorbic acid and Garlic during pregnancy and lactation protect against lead-induced neuronal cell apoptosis in the hippocampus of rat pups partially via the reduction of Pb concentration in the blood and in the brain.

Improvement of Neuroenergetics by Hypertonic Lactate Therapy in Patients with Traumatic Brain Injury Is Dependent on Baseline Cerebral Lactate/Pyruvate Ratio

PubMed Central

Quintard, Hervé; Patet, Camille; Zerlauth, Jean-Baptiste; Suys, Tamarah; Bouzat, Pierre; Pellerin, Luc; Meuli, Reto; Magistretti, Pierre J.

2016-01-01

Abstract Energy dysfunction is associated with worse prognosis after traumatic brain injury (TBI). Recent data suggest that hypertonic sodium lactate infusion (HL) improves energy metabolism after TBI. Here, we specifically examined whether the efficacy of HL (3h infusion, 30–40 μmol/kg/min) in improving brain energetics (using cerebral microdialysis [CMD] glucose as a main therapeutic end-point) was dependent on baseline cerebral metabolic state (assessed by CMD lactate/pyruvate ratio [LPR]) and cerebral blood flow (CBF, measured with perfusion computed tomography [PCT]). Using a prospective cohort of 24 severe TBI patients, we found CMD glucose increase during HL was significant only in the subgroup of patients with elevated CMD LPR >25 (n = 13; +0.13 [95% confidence interval (CI) 0.08–0.19] mmol/L, p < 0.001; vs. +0.04 [–0.05–0.13] in those with normal LPR, p = 0.33, mixed-effects model). In contrast, CMD glucose increase was independent from baseline CBF (coefficient +0.13 [0.04–0.21] mmol/L when global CBF was <32.5 mL/100 g/min vs. +0.09 [0.04–0.14] mmol/L at normal CBF, both p < 0.005) and systemic glucose. Our data suggest that improvement of brain energetics upon HL seems predominantly dependent on baseline cerebral metabolic state and support the concept that CMD LPR – rather than CBF – could be used as a diagnostic indication for systemic lactate supplementation following TBI. PMID:26421521

Tuning the brain for motherhood: prolactin-like central signalling in virgin, pregnant, and lactating female mice.

PubMed

Salais-López, Hugo; Lanuza, Enrique; Agustín-Pavón, Carmen; Martínez-García, Fernando

2017-03-01

Prolactin is fundamental for the expression of maternal behaviour. In virgin female rats, prolactin administered upon steroid hormone priming accelerates the onset of maternal care. By contrast, the role of prolactin in mice maternal behaviour remains unclear. This study aims at characterizing central prolactin activity patterns in female mice and their variation through pregnancy and lactation. This was revealed by immunoreactivity of phosphorylated (active) signal transducer and activator of transcription 5 (pSTAT5-ir), a key molecule in the signalling cascade of prolactin receptors. We also evaluated non-hypophyseal lactogenic activity during pregnancy by administering bromocriptine, which suppresses hypophyseal prolactin release. Late-pregnant and lactating females showed significantly increased pSTAT5-ir resulting in a widespread pattern of immunostaining with minor variations between pregnant and lactating animals, which comprises nuclei of the sociosexual and maternal brain, including telencephalic (septum, nucleus of the stria terminalis, and amygdala), hypothalamic (preoptic, paraventricular, supraoptic, and ventromedial), and midbrain (periaqueductal grey) regions. During late pregnancy, this pattern was not affected by the administration of bromocriptine, suggesting it to be elicited mostly by non-hypophyseal lactogenic agents, likely placental lactogens. Virgin females displayed, instead, a variable pattern of pSTAT5-ir restricted to a subset of the brain nuclei labelled in pregnant and lactating mice. A hormonal substitution experiment confirmed that estradiol and progesterone contribute to the variability found in virgin females. Our results reflect how the shaping of the maternal brain takes place prior to parturition and suggest that lactogenic agents are important candidates in the development of maternal behaviours already during pregnancy.

Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

PubMed

Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

2014-06-01

Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

Lactate as a Metabolite and a Regulator in the Central Nervous System

PubMed Central

Proia, Patrizia; Di Liegro, Carlo Maria; Schiera, Gabriella; Fricano, Anna; Di Liegro, Italia

2016-01-01

More than two hundred years after its discovery, lactate still remains an intriguing molecule. Considered for a long time as a waste product of metabolism and the culprit behind muscular fatigue, it was then recognized as an important fuel for many cells. In particular, in the nervous system, it has been proposed that lactate, released by astrocytes in response to neuronal activation, is taken up by neurons, oxidized to pyruvate and used for synthesizing acetyl-CoA to be used for the tricarboxylic acid cycle. More recently, in addition to this metabolic role, the discovery of a specific receptor prompted a reconsideration of its role, and lactate is now seen as a sort of hormone, even involved in processes as complex as memory formation and neuroprotection. As a matter of fact, exercise offers many benefits for our organisms, and seems to delay brain aging and neurodegeneration. Now, exercise induces the production and release of lactate into the blood which can reach the liver, the heart, and also the brain. Can lactate be a beneficial molecule produced during exercise, and offer neuroprotection? In this review, we summarize what we have known on lactate, discussing the roles that have been attributed to this molecule over time. PMID:27598136

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu Qingfeng; Shao Xiayan; Chen Jie

Biodegradable polymer-based nanoparticles have been widely studied to deliver therapeutic agents to the brain after intranasal administration. However, knowledge as to the side effects of nanoparticle delivery system to the brain is limited. The aim of this study was to investigate the in vivo toxicity and immunogenicity of wheat germ agglutinin (WGA) conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (WGA-NP) after intranasal instillation. Sprague-Dawley rats were intranasally given WGA-NP for 7 continuous days. Amino acid neurotransmitters, lactate dehydrogenase (LDH) activity, reduced glutathione (GSH), acetylcholine, acetylcholinesterase activity, tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin-8 (IL-8) in rat olfactory bulb (OB) and brain weremore » measured to estimate the in vivo toxicity of WGA-NP. Balb/C mice were intranasally immunized by WGA-NP and then WGA-specific antibodies in serum and nasal wash were detected by indirect ELISA. WGA-NP showed slight toxicity to brain tissue, as evidenced by increased glutamate level in rat brain and enhanced LDH activity in rat OB. No significant changes in acetylcholine level, acetylcholinesterase activity, GSH level, TNF-{alpha} level and IL-8 level were observed in rat OB and brain for the WGA-NP group. WGA-specific antibodies in mice serum and nasal wash were not increased after two intranasal immunizations of WGA-NP. These results demonstrate that WGA-NP is a safe carrier system for intranasal delivery of therapeutic agents to the brain.« less

Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution.

PubMed

Ayuste, Eduardo C; Chen, Huazhen; Koustova, Elena; Rhee, Peter; Ahuja, Naresh; Chen, Zhang; Valeri, C Robert; Spaniolas, Konstantinos; Mehrani, Tina; Alam, Hasan B

2006-01-01

Cytotoxic properties of racemic (D-,L-isomers) lactated Ringer's solution detected in vitro and in small animal experiments, have not been confirmed in large animal models. Our hypothesis was that in a clinically relevant large animal model of hemorrhage, resuscitation with racemic lactated Ringer's solution would induce cellular apoptosis, which can be attenuated by elimination of d-lactate. Yorkshire swine (n = 49, weight 40-58 kg) were subjected to uncontrolled (iliac arterial and venous injuries) and controlled hemorrhage, totaling 40% of estimated blood volume. They were randomized (n = 7/group) to control groups, which consisted of (1) no hemorrhage (NH), (2) no resuscitation (NR), or resuscitation groups, which consisted of (3) 0.9% saline (NS), (4) racemic lactated Ringer's (DL-LR), (5) L-isomer lactated Ringer's (L-LR), (6) Ketone Ringer's (KR), (7) 6% hetastarch in 0.9% saline (Hespan). KR was identical to LR except for equimolar substitution of lactate with beta-hydroxybutyrate. Resuscitation was performed in three phases, simulating (1) prehospital, (2) operative, (3) postoperative/recovery periods. Arterial blood gasses, circulating cytokines (TNF-alpha, IL-1, -6, -10), and markers of organ injury were serially measured. Metabolic activity of brain, and liver, was measured with microdialysis. Four hours postinjury, organs were harvested for Western blotting, ELISA, TUNEL assay, and immunohistochemistry. All resuscitation strategies restored blood pressure, but clearance of lactic acidosis was impeded following DL-LR resuscitation. Metabolic activity decreased during shock and improved with resuscitation, without any significant inter-group differences. Levels of cytokines in circulation were similar, but tissue levels of TNF in liver and lung increased six- and threefolds (p < 0.05) in NR group. In liver, all resuscitation strategies significantly decreased TNF levels compared with the NR group, but in the lung resuscitation with lactated Ringer (DL and L isomers) failed to decrease tissue TNF levels. DL-LR resuscitation also increased apoptosis (p < 0.05) in liver and lung, which was not seen after resuscitation with other solutions. In this large animal model of hemorrhagic shock, resuscitation with conventional (racemic) LR solution increased apoptotic cell death in liver and lung. This effect can be prevented by simple elimination of D-lactate from the Ringer's solution.

Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency.

PubMed

Pliss, Lioudmila; Jatania, Urvi; Patel, Mulchand S

2016-06-01

Pyruvate dehydrogenase complex (PDC) deficiency is a major inborn error of oxidative metabolism of pyruvate in the mitochondria causing congenital lactic acidosis and primarily structural and functional abnormalities of the central nervous system. To provide an alternate source of acetyl-CoA derived from ketone bodies to the developing brain, a formula high in fat content is widely employed as a treatment. In the present study we investigated efficacy of a high-fat diet given to mothers during pregnancy and lactation on lessening of the impact of PDC deficiency on brain development in PDC-deficient female progeny. A murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene was employed in this study. Maternal consumption of a high-fat diet during pregnancy and lactation had no effect on number of live-birth, body growth, tissue PDC activity levels, as well as the in vitro rates of glucose oxidation and fatty acid biosynthesis by the developing brain of PDC-deficient female offspring during the postnatal age 35 days, as compared to the PDC-deficient progeny born to dams on a chow diet. Interestingly, brain weight was normalized in PDC-deficient progeny of high fat-fed mothers with improvement in impairment in brain structure deficit whereas brain weight was significantly decreased and was associated with greater cerebral structural defects in progeny of chow-fed mothers as compared to control progeny of mothers fed either a chow or high fat diet. The findings provide for the first time experimental support for beneficial effects of a ketogenic diet during the prenatal and early postnatal periods on the brain development of PDC-deficient mammalian progeny.

Exposure to sublethal concentrations of copper changes biochemistry parameters in silver catfish, Rhamdia quelen, Quoy & Gaimard.

PubMed

Pretto, Alexandra; Loro, Vania Lucia; Silva, Vera M Machado; Salbego, Joseânia; de Menezes, Charlene Cavalheiro; Souza, Carine de Freitas; Gioda, Carolina Rosa; Baldisserotto, Bernardo

2014-04-01

The effects of Cu exposure on catalase (CAT) and acetylcholinesterase (AChE) activity, formation of thiobarbituric acid-reactive species (TBARS) and metabolic parameters were evaluated in silver catfish (Rhamdia quelen). The fish were exposed for 45 days to 0, 16 and 29 μg/L Cu. The fish that were exposed to Cu exhibited lower TBARS levels in the muscle and higher TBARS levels in the liver. They also showed lower CAT activity in the liver and lower AChE activity in the brain and muscle. Higher glucose and lactate and lower protein plasma levels were observed in the fish exposed to Cu. The changes in the hepatic metabolic parameters were Cu concentration dependent. In the muscle, lower glycogen and higher lactate levels were observed in the fish exposed to Cu. Alterations in the metabolic parameters showed a preference for the anaerobic pathway of energy production and liver protein catabolism to supply the energy demand.

Retrograde Cerebral Perfusion Results in Better Perfusion to the Striatum Than the Cerebral Cortex During Deep Hypothermic Circulatory Arrest: A Microdialysis Study.

PubMed

Liang, Meng-Ya; Chen, Guang-Xian; Tang, Zhi-Xian; Rong, Jian; Yao, Jian-ping; Wu, Zhong-Kai

2016-03-01

It remains controversial whether contemporary cerebral perfusion techniques, utilized during deep hypothermic circulatory arrest (DHCA), establish adequate perfusion to deep structures in the brain. This study aimed to investigate whether selective antegrade cerebral perfusion (SACP) or retrograde cerebral perfusion (RCP) can provide perfusion equally to various anatomical positions in the brain using metabolic evidence obtained from microdialysis. Eighteen piglets were randomly assigned to 40 min of circulatory arrest (CA) at 18°C without cerebral perfusion (DHCA group, n = 6) or with SACP (SACP group, n = 6) or RCP (RCP group, n = 6). Microdialysis parameters (glucose, lactate, pyruvate, and glutamate) were measured every 30 min in cortex and striatum. After 3 h of reperfusion, brain tissue was harvested for Western blot measurement of α-spectrin. After 40 min of CA, the DHCA group showed marked elevations of lactate and glycerol and a reduction in glucose in the microdialysis perfusate (all P < 0.05). The changes in glucose, lactate, and glycerol in the perfusate and α-spectrin expression in brain tissue were similar between cortex and striatum in the SACP group (all P > 0.05). In the RCP group, the cortex exhibited lower glucose, higher lactate, and higher glycerol in the perfusate and higher α-spectrin expression in brain tissue compared with the striatum (all P < 0.05). Glutamate showed no difference between cortex and striatum in all groups (all P > 0.05). In summary, SACP provided uniform and continuous cerebral perfusion to most anatomical sites in the brain, whereas RCP resulted in less sufficient perfusion to the cortex but better perfusion to the striatum. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors.

PubMed

Schulz, Kalynn M; Pearson, Jennifer N; Gasparrini, Mary E; Brooks, Kayla F; Drake-Frazier, Chakeer; Zajkowski, Megan E; Kreisler, Alison D; Adams, Catherine E; Leonard, Sherry; Stevens, Karen E

2014-07-15

Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress. Published by Elsevier B.V.

Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors

PubMed Central

Schulz, Kalynn M.; Pearson, Jennifer N.; Gasparrini, Mary E.; Brooks, Kayla F.; Drake-Frazier, Chakeer; Zajkowski, Megan E.; Kreisler, Alison D.; Adams, Catherine E.; Leonard, Sherry; Stevens, Karen E.

2014-01-01

Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress. PMID:24675162

Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

PubMed

Thevenet, Jonathan; De Marchi, Umberto; Domingo, Jaime Santo; Christinat, Nicolas; Bultot, Laurent; Lefebvre, Gregory; Sakamoto, Kei; Descombes, Patrick; Masoodi, Mojgan; Wiederkehr, Andreas

2016-05-01

Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. © FASEB.

Brain interstitial fluid TNF-α after subarachnoid hemorrhage

PubMed Central

Hanafy, Khalid A.; Grobelny, Bartosz; Fernandez, Luis; Kurtz, Pedro; Connolly, ES; Mayer, Stephan A.; Schindler, Christian; Badjatia, Neeraj

2010-01-01

Objective: TNF-α is an inflammatory cytokine that plays a central role in promoting the cascade of events leading to an inflammatory response. Recent studies have suggested that TNF-α may play a key role in the formation and rupture of cerebral aneurysms, and that the underlying cerebral inflammatory response is a major determinate of outcome following subrarachnoid hemorrhage (SAH). Methods: We studied 14 comatose SAH patients who underwent multimodality neuromonitoring with intracranial pressure (ICP) and cerebral microdialysis as part of their clinical care. Continuous physiological variables were time-locked every 8 hours and recorded at the same point that brain interstitial fluid TNF-α was measured in brain microdialysis samples. Significant associations were determined using generalized estimation equations. Results: Each patient had a mean of 9 brain tissue TNF-α measurements obtained over an average of 72 hours of monitoring. TNF-α levels rose progressively over time. Predictors of elevated brain interstitial TNF-α included higher brain interstitial fluid glucose levels (β=0.066, P<0.02), intraventricular hemorrhage (β=0.085, P<0.021), and aneurysm size >6 mm (β=0.14, p<0.001). There was no relationship between TNF-α levels and the burden of cisternal SAH; concurrent measurements of serum glucose, or lactate-pyruvate ratio. Interpretation: Brain interstitial TNF-α levels are elevated after SAH, and are associated with large aneurysm size, the burden of intraventricular blood, and elevation brain interstitial glucose levels. PMID:20110094

A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra.

PubMed

Rae, Caroline D

2014-01-01

The current knowledge of the normal biochemistry of compounds that give rise to resonances in human brain proton magnetic resonance spectra measureable at readily available field strengths (i.e. ≤3 T) is reviewed. Molecules covered include myo- and scyllo-inositol, glycerophospho- and phospho-choline and choline, creatine and phosphocreatine, N-acetylaspartate, N-acetylaspartylglutamate, glutamate, glutamine, γ-aminobutyrate, glucose, glutathione and lactate. The factors which influence changes in the levels of these compounds are discussed. As most proton resonances in the brain at low field are derived from a combination of moieties whose biochemistry is complex and interrelated, an understanding of the mechanisms underlying why these species change is crucial to meaningful interpretation of human brain spectra.

Cerebral perfusion during cardiopulmonary bypass in children: correlations between near-infrared spectroscopy, temperature, lactate, pump flow, and blood pressure.

PubMed

Haydin, Sertac; Onan, Burak; Onan, Ismihan Selen; Ozturk, Erkut; Iyigun, Muzeyyen; Yeniterzi, Mehmet; Bakir, Ihsan

2013-01-01

Near-infrared spectroscopy (NIRS) is a noninvasive modality to monitor regional brain oxygenation (rSO(2) ). In this study, we aimed to investigate the correlation between cerebral rSO(2) and lactate, pump flow, hematocrit, pCO(2) , and mean blood pressure (MBP) during cardiopulmonary bypass (CPB). Between March and September 2011, 50 pediatric patients who underwent congenital heart surgery were enrolled into the study. Ages ranged from 6 days to 168 months (median 14 months). A NIRS sensor (Somanetics 5100B, Troy, MI, USA) was placed on the right forehead of patients. CPB period was divided into five stages: 1-at the beginning of CBP, 2-cooling at 32°C, 3-at final hypothermic temperature, 4-rewarming at 32°C, 5-before weaning from CPB. Data collection included measurements of each parameter at five stages of CPB. Data were analyzed using multivariate analysis within groups and Spearman's correlation to test association between parameters. Lactate levels increased significantly from stage 1 to stage 5 during CPB (P < 0.05). There was no significant correlation between cerebral rSO(2) and MBPs, pump flows, hematocrit, or pCO(2) during CPB. Cerebral rSO(2) levels showed changes between the stages; there was a significant increase during cooling period, compared to stage 1 (P < 0.05). Significant changes during cooling stage did not happen for other parameters. At stage 3, there was a negative correlation between lactate level and MBP. At stage 4, there was no significant change in cerebral rSO(2) levels despite decreased MBP. At the warming stage, low MBPs, but normal rSO(2) values, are observed despite increased pump flows. Increased rSO(2) levels despite insignificant changes at other parameters during the cooling stage of CPB may show that optimal pump flow with adequate intravascular volume may provide effective cerebral perfusion even without changes in MBP. Considering normal rSO(2) values during CPB in this study, it may be speculated that brain protection can be assessed by using NIRS and applying a standard bypass protocol. © 2012, Copyright the Authors. Artificial Organs © 2012, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Effects of hypothermia and cerebral ischemia on cold-inducible RNA-binding protein mRNA expression in rat brain.

PubMed

Liu, Aijun; Zhang, Zhiwen; Li, Anmin; Xue, Jinghui

2010-08-06

CIRP (cold-inducible RNA-binding protein) mRNA is highly expressed in hypothermic conditions in mammalian cells, and the relationship between CIRP and neuroprotection for cerebral ischemia under hypothermia has been focused upon. At present, however, the expression characteristics of CIRP under hypothermia and cerebral ischemia in vivo are not clearly elucidated. In this study, CIRP mRNA expression in various regions of rat brain was examined by reverse transcriptase polymerase chain reaction (RT-PCR). CIRP expression levels were found to be similar in the hippocampus and cortex. Real-time quantitative PCR analysis revealed increasing CIRP mRNA expression in the cortex during the 24-h observation period following treatment with hypothermia or cerebral ischemia, with a greater increase in the hypothermia group. When cerebral ischemia was induced following hypothermia, CIRP mRNA expression in the cortex again showed a significant increasing tendency, but ischemia delayed the appearance of this increase. To reveal the relationship between CIRP and energy metabolism in the rat brain, lactate and pyruvate concentrations in the cortex of the rats treated with hypothermia, ischemia and ischemia after hypothermia were determined by spectrophotometric assay, and levels of phosphofructokinas-1 (PFK-1), the major regulatory enzyme of the glycolytic pathway, in the rat cortex in the three groups was also analyzed by Western blot. Using linear correlation, lactate and pyruvate concentrations, and PFK-1 levels, were each analyzed in the three groups in association with CIRP mRNA expression levels. The analysis did not reveal any correlation between the three metabolic parameters and CIRP mRNA expression induced by hypothermia, suggesting that while playing a role in neuroprotection under hypothermia, CIRP does not affect cerebral energy metabolism. Copyright 2010. Published by Elsevier B.V.

Exercise-induced expression of monocarboxylate transporter 2 in the cerebellum and its contribution to motor performance.

PubMed

Hoshino, Daisuke; Setogawa, Susumu; Kitaoka, Yu; Masuda, Hiroyuki; Tamura, Yuki; Hatta, Hideo; Yanagihara, Dai

2016-10-28

Monocarboxylate transporter 2 (MCT2) is an important component of the lactate transport system in neurons of the adult brain. Purkinje cells in the cerebellum have been shown to have high levels of MCT2, suggesting that this protein has a key function in energy metabolism and neuronal activities in these cells. However, it is not known whether inhibition of lactate transport via MCT2 in the cerebellum affects motor performance. To address this question, we examined motor performance in mice following the inhibition of lactate transport via MCT2 in the cerebellum using α-cyano-4-hydroxycinnamate (4-CIN). 4-CIN or saline was injected into the subarachnoidal space of the cerebellum of mice and motor performance was analyzed by a rotarod test both before and after injection. 4-CIN injection reduced retention time in the rotarod test by approximately 80% at 1h post-injection compared with pre-injection. No effect was observed at 2h post-injection or in mice treated with the vehicle control. Because we observed that MCT2 plays an important role in motor performance, we next investigated the effects of acute exercise on MCT2 transcription and protein levels in mice sampled pre-exercise and at 0 and 5h after 2h of treadmill running. We found a significant increase in MCT2 mRNA levels, but not of protein levels, in the cerebellum at 5h after exercise. Our results indicate that lactate transport via MCT2 in the cerebellum may play an important role in motor performance and that exercise can increase MCT2 expression at the transcriptional level. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Monochloroacetic acid lethality in the rat in relation to lactic acid accumulation in the cerebrospinal fluid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitroka, J.G.

1989-01-01

Potential antidotes for human exposure to monochloroacetic acid (MCA) were evaluated using a rodent model. Dichloroacetic acid (DCA) and phenobarbital (PB) but not ethanol or phenytoin, were found to be effective antidotes to monochloroacetic acid (MCA) in rats. DCA (110 mg/kg, ip), administered to rats 15 minutes after a LD-80 of MCA (80 mg/kg, iv), consistently reduced mortality to 0%, while PB reduced mortality to less than 20%. Both DCA and PB were found to be similarly effective in mice. The hypothesis that PB reduces mortality in MCA treated rats by altering the metabolic disposition of MCA was evaluated andmore » rejected. Administration of PB to rats treated with a lethal dose of ({sup 14}C)MCA did not alter the concentrations of MCA or its metabolites in plasma or cerebrospinal fluid (CSF), or the extent of covalent binding between radioactivity equivalent to ({sup 14}C)MCA and brain proteins. The relationship between altered blood-brain barrier permeability and death in MCA treated rats was investigated. Treatment with MCA (80 mg/kg, iv) was associated with a significant (50%) increase in the permeability of the rat blood-brain barrier to ({sup 125}I)BSA. The effect was not altered by treatment with PB, however, suggesting that altered blood-brain barrier permeability does not have an important role in the lethal effect of MCA in rats. The effect of MCA on brain carbohydrate metabolism in vivo was investigated. CSF and blood lactic acid concentrations increased in MCA treated rats, and the increase in CSF levels was dose related. In individual MCA treated rats, CSF lactate concentrations paralleled the time course of ataxia and a discrete threshold for death (18 mmol/L) was observed. The relationship between excess brain lactate levels and death in MCA treated rats was investigated further.« less

A metabolic switch in brain: glucose and lactate metabolism modulation by ascorbic acid.

PubMed

Castro, Maite A; Beltrán, Felipe A; Brauchi, Sebastián; Concha, Ilona I

2009-07-01

In this review, we discuss a novel function of ascorbic acid in brain energetics. It has been proposed that during glutamatergic synaptic activity neurons preferably consume lactate released from glia. The key to this energetic coupling is the metabolic activation that occurs in astrocytes by glutamate and an increase in extracellular [K(+)]. Neurons are cells well equipped to consume glucose because they express glucose transporters and glycolytic and tricarboxylic acid cycle enzymes. Moreover, neuronal cells express monocarboxylate transporters and lactate dehydrogenase isoenzyme 1, which is inhibited by pyruvate. As glycolysis produces an increase in pyruvate concentration and a decrease in NAD(+)/NADH, lactate and glucose consumption are not viable at the same time. In this context, we discuss ascorbic acid participation as a metabolic switch modulating neuronal metabolism between rest and activation periods. Ascorbic acid is highly concentrated in CNS. Glutamate stimulates ascorbic acid release from astrocytes. Ascorbic acid entry into neurons and within the cell can inhibit glucose consumption and stimulate lactate transport. For this switch to occur, an ascorbic acid flow is necessary between astrocytes and neurons, which is driven by neural activity and is part of vitamin C recycling. Here, we review the role of glucose and lactate as metabolic substrates and the modulation of neuronal metabolism by ascorbic acid.

Monocarboxylate transporters in the brain and in cancer.

PubMed

Pérez-Escuredo, Jhudit; Van Hée, Vincent F; Sboarina, Martina; Falces, Jorge; Payen, Valéry L; Pellerin, Luc; Sonveaux, Pierre

2016-10-01

Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1-4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Single-cell imaging tools for brain energy metabolism: a review

PubMed Central

San Martín, Alejandro; Sotelo-Hitschfeld, Tamara; Lerchundi, Rodrigo; Fernández-Moncada, Ignacio; Ceballo, Sebastian; Valdebenito, Rocío; Baeza-Lehnert, Felipe; Alegría, Karin; Contreras-Baeza, Yasna; Garrido-Gerter, Pamela; Romero-Gómez, Ignacio; Barros, L. Felipe

2014-01-01

Abstract. Neurophotonics comes to light at a time in which advances in microscopy and improved calcium reporters are paving the way toward high-resolution functional mapping of the brain. This review relates to a parallel revolution in metabolism. We argue that metabolism needs to be approached both in vitro and in vivo, and that it does not just exist as a low-level platform but is also a relevant player in information processing. In recent years, genetically encoded fluorescent nanosensors have been introduced to measure glucose, glutamate, ATP, NADH, lactate, and pyruvate in mammalian cells. Reporting relative metabolite levels, absolute concentrations, and metabolic fluxes, these sensors are instrumental for the discovery of new molecular mechanisms. Sensors continue to be developed, which together with a continued improvement in protein expression strategies and new imaging technologies, herald an exciting era of high-resolution characterization of metabolism in the brain and other organs. PMID:26157964

Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats

PubMed Central

Ruderman, Neil B.; Ross, Peter S.; Berger, Michael; Goodman, Michael N.

1974-01-01

1. The effects of starvation and diabetes on brain fuel metabolism were examined by measuring arteriovenous differences for glucose, lactate, acetoacetate and 3-hydroxybutyrate across the brains of anaesthetized fed, starved and diabetic rats. 2. In fed animals glucose represented the sole oxidative fuel of the brain. 3. After 48h of starvation, ketone-body concentrations were about 2mm and ketone-body uptake accounted for 25% of the calculated O2 consumption: the arteriovenous difference for glucose was not diminished, but lactate release was increased, suggesting inhibition of pyruvate oxidation. 4. In severe diabetic ketosis, induced by either streptozotocin or phlorrhizin (total blood ketone bodies >7mm), the uptake of ketone bodies was further increased and accounted for 45% of the brain's oxidative metabolism, and the arteriovenous difference for glucose was decreased by one-third. The arteriovenous difference for lactate was increased significantly in the phlorrhizin-treated rats. 5. Infusion of 3-hydroxybutyrate into starved rats caused marked increases in the arteriovenous differences for lactate and both ketone bodies. 6. To study the mechanisms of these changes, steady-state concentrations of intermediates and co-factors of the glycolytic pathway were determined in freeze-blown brain. 7. Starved rats had increased concentrations of acetyl-CoA. 8. Rats with diabetic ketosis had increased concentrations of fructose 6-phosphate and decreased concentrations of fructose 1,6-diphosphate, indicating an inhibition of phosphofructokinase. 9. The concentrations of acetyl-CoA, glycogen and citrate, a potent inhibitor of phosphofructokinase, were increased in the streptozotocin-treated rats. 10. The data suggest that cerebral glucose uptake is decreased in diabetic ketoacidosis owing to inhibition of phosphofructokinase as a result of the increase in brain citrate. 11. The inhibition of brain pyruvate oxidation in starvation and diabetes can be related to the accelerated rate of ketone-body metabolism; however, we found no correlation between the decrease in glucose uptake in the diabetic state and the arteriovenous difference for ketone bodies. 12. The data also suggest that the rates of acetoacetate and 3-hydroxybutyrate utilization by brain are governed by their concentrations in plasma. 13. The finding of very low concentrations of acetoacetate and 3-hydroxybutyrate in brain compared with plasma suggests that diffusion across the blood–brain barrier may be the rate-limiting step in their metabolism. PMID:4275704

26Al incorporation into the tissues of suckling rats through maternal milk

NASA Astrophysics Data System (ADS)

Yumoto, S.; Nagai, H.; Kobayashi, K.; Tada, W.; Horikawa, T.; Matsuzaki, H.

2004-08-01

Aluminium (Al) is highly neurotoxic and inhibits prenatal and postnatal development of the brain in humans and experimental animals. However, Al incorporation into the brain of sucklings through maternal milk has not yet been well clarified because Al lacks a suitable isotope for radioactive tracer experiments. Using 26Al as a tracer, we measured 26Al incorporation into the brain of suckling rats by accelerator mass spectrometry. Lactating rats were subcutaneously injected with 26AlCl3 from day 1 to day 20 postpartum. Suckling rats were weaned from day 21 postpartum. From day 5 to day 20 postpartum, the 26Al levels measured in the brain, liver, kidneys and bone of suckling rats increased significantly. After weaning, the amounts of 26Al in the liver and kidneys decreased remarkably. However, the 26Al amount in the brain had diminished only slightly up to 140 days after weaning.

Reproductive Experience Alters Prolactin Receptor Expression in Mammary and Hepatic Tissues in Female Rats1

PubMed Central

Bridges, Robert S.; Scanlan, Victoria F.; Lee, Jong-O; Byrnes, Elizabeth M.

2011-01-01

Recent studies have reported that reproductive experience in female rats alters prolactin (PRL) receptor gene expression in the brain as well as neural sensitivity to PRL. Given PRL's actions in nonneural tissues, that is, mammary tissue and liver, it was asked whether reproductive experience may also alter prolactin receptor (Prlr) gene expression in these tissues. Groups of age-matched female rats were generated with varying reproductive histories. Separate groups of primiparous (first lactation) and multiparous (second lactation) had mammary tissue and liver samples collected on Day 3 or 10 of lactation. A fifth group raised one litter to weaning and then resumed estrous cyclicity. This group and a final group of age-matched, virgin controls were killed on diestrus. Tissue was processed by quantitative PCR for expression rates of the long and short forms of Prlr mRNA as well as casein beta mRNA (mammary tissue only). Western blots were performed to quantify receptor protein content. Multiple lactations as well as lactation itself resulted in alterations in Prlr expression. Prlr gene expression in mammary tissue was increased in primiparous mothers compared with that in multiparous dams, whereas in the liver, Prlr expression was reduced during an initial lactation. In contrast, PRLR protein levels declined during lactation in mammary, but not hepatic, tissues. Overall, the results demonstrate that the prolactin receptor system is altered in nonneural tissues as a result of the female's reproductive history. The findings are discussed in the context of milk and bile production and PRL's possible role in breast cancer. PMID:21508351

Reproductive experience alters prolactin receptor expression in mammary and hepatic tissues in female rats.

PubMed

Bridges, Robert S; Scanlan, Victoria F; Lee, Jong-O; Byrnes, Elizabeth M

2011-08-01

Recent studies have reported that reproductive experience in female rats alters prolactin (PRL) receptor gene expression in the brain as well as neural sensitivity to PRL. Given PRL's actions in nonneural tissues, that is, mammary tissue and liver, it was asked whether reproductive experience may also alter prolactin receptor (Prlr) gene expression in these tissues. Groups of age-matched female rats were generated with varying reproductive histories. Separate groups of primiparous (first lactation) and multiparous (second lactation) had mammary tissue and liver samples collected on Day 3 or 10 of lactation. A fifth group raised one litter to weaning and then resumed estrous cyclicity. This group and a final group of age-matched, virgin controls were killed on diestrus. Tissue was processed by quantitative PCR for expression rates of the long and short forms of Prlr mRNA as well as casein beta mRNA (mammary tissue only). Western blots were performed to quantify receptor protein content. Multiple lactations as well as lactation itself resulted in alterations in Prlr expression. Prlr gene expression in mammary tissue was increased in primiparous mothers compared with that in multiparous dams, whereas in the liver, Prlr expression was reduced during an initial lactation. In contrast, PRLR protein levels declined during lactation in mammary, but not hepatic, tissues. Overall, the results demonstrate that the prolactin receptor system is altered in nonneural tissues as a result of the female's reproductive history. The findings are discussed in the context of milk and bile production and PRL's possible role in breast cancer.

Benefits of Docosahexaenoic Acid, Folic Acid, Vitamin D and Iodine on Foetal and Infant Brain Development and Function Following Maternal Supplementation during Pregnancy and Lactation

PubMed Central

Morse, Nancy L.

2012-01-01

Scientific literature is increasingly reporting on dietary deficiencies in many populations of some nutrients critical for foetal and infant brain development and function. Purpose: To highlight the potential benefits of maternal supplementation with docosahexaenoic acid (DHA) and other important complimentary nutrients, including vitamin D, folic acid and iodine during pregnancy and/or breast feeding for foetal and/or infant brain development and/or function. Methods: English language systematic reviews, meta-analyses, randomised controlled trials, cohort studies, cross-sectional and case-control studies were obtained through searches on MEDLINE and the Cochrane Register of Controlled Trials from January 2000 through to February 2012 and reference lists of retrieved articles. Reports were selected if they included benefits and harms of maternal supplementation of DHA, vitamin D, folic acid or iodine supplementation during pregnancy and/or lactation. Results: Maternal DHA intake during pregnancy and/or lactation can prolong high risk pregnancies, increase birth weight, head circumference and birth length, and can enhance visual acuity, hand and eye co-ordination, attention, problem solving and information processing. Vitamin D helps maintain pregnancy and promotes normal skeletal and brain development. Folic acid is necessary for normal foetal spine, brain and skull development. Iodine is essential for thyroid hormone production necessary for normal brain and nervous system development during gestation that impacts childhood function. Conclusion: Maternal supplementation within recommended safe intakes in populations with dietary deficiencies may prevent many brain and central nervous system malfunctions and even enhance brain development and function in their offspring. PMID:22852064

Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet

PubMed Central

Lee, Linda L.; Puchowicz, Michelle; Golub, Mari S.; Befroy, Douglas E.; Wilson, Dennis W.; Anderson, Steven; Cline, Gary; Bini, Jason; Borkowski, Kamil; Knotts, Trina A.; Rutledge, John C.

2018-01-01

Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways. PMID:29444171

Lactate: link between glycolytic and oxidative metabolism.

PubMed

Brooks, George A

2007-01-01

Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilised continuously under fully aerobic conditions. 'Cell-cell' and 'intracellular lactate shuttle' concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signalling. Examples of cell-cell shuttles include lactate exchanges (i) between white-glycolytic and red-oxidative fibres within a working muscle bed; (ii) between working skeletal muscle and heart; and (iii) between tissues of net lactate release and gluconeogenesis. Lactate shuttles exist in diverse tissues including in the brain, where a shuttle between astrocytes and neurons is linked to glutamatergic signalling. Because lactate, the product of glycogenolysis and glycolysis, is disposed of by oxidative metabolism, lactate shuttling unites the two major processes of cellular energy transduction. Lactate disposal is mainly through oxidation, especially during exercise when oxidation accounts for 70-75% of removal and gluconeogenesis the remainder. Lactate flux occurs down proton and concentration gradients that are established by the mitochondrial lactate oxidation complex. Marathon running is a power activity requiring high glycolytic and oxidative fluxes; such activities require lactate shuttling. Knowledge of the lactate shuttle is yet to be imparted to the sport.

Cobalt supplementation promotes hypoxic tolerance and facilitates acclimatization to hypobaric hypoxia in rat brain.

PubMed

Shrivastava, Kalpana; Ram, M Sai; Bansal, Anju; Singh, S S; Ilavazhagan, G

2008-01-01

In the present study, we report the molecular mechanisms of action by cobalt in facilitating acclimatization to hypobaric hypoxia using male Sprague-Dawley rats as the model system. We determined hypoxic gasping time and survival time as a measure to assess the degree of tolerance of animals to hypobaric hypoxia by exposing the animals to an altitude of 10,668 m. Oral administration of cobalt chloride (12.5 mg Co/kg body weight, BW, for 7 days) increased gasping time and hypoxic survival time by 3 to 4 times compared to the control animals. This could be attributed to an increased expression and the DNA binding activity of hypoxia inducible transcriptional factor (HIF-1alpha) and its regulated genes, that is, erythropoietin (EPO), vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1), and nitric oxide synthase (NOS) levels. This in turn leads to better oxygenation, oxygen delivery, glucose transport, and maintenance of vascular tone, respectively, under oxygen-limited conditions. This was further confirmed by lower levels of lactate dehydrogenase (LDH) activity and lactate in the brain of cobalt + hypoxia group compared with animals exposed to hypoxia. Glucose levels also increased after cobalt supplementation. The findings of the study provide a basis for the possible use of cobalt for facilitating acclimatization to hypoxia and other conditions involving oxygen deprivation.

Glucose is necessary to maintain neurotransmitter homeostasis during synaptic activity in cultured glutamatergic neurons.

PubMed

Bak, Lasse K; Schousboe, Arne; Sonnewald, Ursula; Waagepetersen, Helle S

2006-10-01

Glucose is the primary energy substrate for the adult mammalian brain. However, lactate produced within the brain might be able to serve this purpose in neurons. In the present study, the relative significance of glucose and lactate as substrates to maintain neurotransmitter homeostasis was investigated. Cultured cerebellar (primarily glutamatergic) neurons were superfused in medium containing [U-13C]glucose (2.5 mmol/L) and lactate (1 or 5 mmol/L) or glucose (2.5 mmol/L) and [U-13C]lactate (1 mmol/L), and exposed to pulses of N-methyl-D-aspartate (300 micromol/L), leading to synaptic activity including vesicular release. The incorporation of 13C label into intracellular lactate, alanine, succinate, glutamate, and aspartate was determined by mass spectrometry. The metabolism of [U-13C]lactate under non-depolarizing conditions was high compared with that of [U-13C]glucose; however, it decreased significantly during induced depolarization. In contrast, at both concentrations of extracellular lactate, the metabolism of [U-13C]glucose was increased during neuronal depolarization. The role of glucose and lactate as energy substrates during vesicular release as well as transporter-mediated influx and efflux of glutamate was examined using preloaded D-[3H]aspartate as a glutamate tracer and DL-threo-beta-benzyloxyaspartate to inhibit glutamate transporters. The results suggest that glucose is essential to prevent depolarization-induced reversal of the transporter (efflux), whereas vesicular release was unaffected by the choice of substrate. In conclusion, the present study shows that glucose is a necessary substrate to maintain neurotransmitter homeostasis during synaptic activity and that synaptic activity does not induce an upregulation of lactate metabolism in glutamatergic neurons.

Hindbrain medulla catecholamine cell group involvement in lactate-sensitive hypoglycemia-associated patterns of hypothalamic norepinephrine and epinephrine activity.

PubMed

Shrestha, P K; Tamrakar, P; Ibrahim, B A; Briski, K P

2014-10-10

Cell-type compartmentation of glucose metabolism in the brain involves trafficking of the oxidizable glycolytic end product, l-lactate, by astrocytes to fuel neuronal mitochondrial aerobic respiration. Lactate availability within the hindbrain medulla is a monitored function that regulates systemic glucostasis as insulin-induced hypoglycemia (IIH) is exacerbated by lactate repletion of that brain region. A2 noradrenergic neurons are a plausible source of lactoprivic input to the neural gluco-regulatory circuit as caudal fourth ventricular (CV4) lactate infusion normalizes IIH-associated activation, e.g. phosphorylation of the high-sensitivity energy sensor, adenosine 5'-monophosphate-activated protein kinase (AMPK), in these cells. Here, we investigated the hypothesis that A2 neurons are unique among medullary catecholamine cells in directly screening lactate-derived energy. Adult male rats were injected with insulin or vehicle following initiation of continuous l-lactate infusion into the CV4. Two hours after injections, A1, C1, A2, and C2 neurons were collected by laser-microdissection for Western blot analysis of AMPKα1/2 and phosphoAMPKα1/2 proteins. Results show that AMPK is expressed in each cell group, but only a subset, e.g. A1, C1, and A2 neurons, exhibit increased sensor activity in response to IIH. Moreover, hindbrain lactate repletion reversed hypoglycemic augmentation of pAMPKα1/2 content in A2 and C1 but not A1 cells, and normalized hypothalamic norepinephrine and epinephrine content in a site-specific manner. The present evidence for discriminative reactivity of AMPK-expressing medullary catecholamine neurons to the screened energy substrate lactate implies that that lactoprivation is selectively signaled to the hypothalamus by A2 noradrenergic and C1 adrenergic cells. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Maternal protein-free diet during lactation programs male Wistar rat offspring for increased novelty-seeking, locomotor activity, and visuospatial performance.

PubMed

Lotufo, Bruna M; Tenório, Frank; Barradas, Penha C; Guedes, Paulo L; Lima, Sebastião S; Rocha, Michael L M; Duarte-Pinheiro, Vitor Hugo; Rodrigues, Vanessa S T; Lisboa, Patrícia C; Filgueiras, Cláudio C; Abreu-Villaça, Yael; Manhães, Alex C

2018-04-01

It is well established that chronic undernutrition has detrimental impacts on brain development and maturation. However, protein malnutrition during the period specifically encompassing the brain growth spurt has not been widely studied, particularly regarding its effects on adolescent and adult offspring behavior. Here, we assessed the effects of a protein-free diet during the 1st 10 postnatal days on the macronutrient content of the milk produced by lactating Wistar rats, on their maternal behavior, and on the offspring's behavior. Lactating dams were fed either a protein-free or a normoprotein diet from litter parturition to Postnatal Day 10 (P10). All dams received the normoprotein diet after P10. Offspring were tested in the elevated plus-maze (anxiety-like behavior), hole board arena (novelty-seeking and locomotor activity), and radial arm water maze (memory-learning) at either P40 (adolescents) or P90 (adults). The protein-free diet reduced milk protein content at P10 but not at P20. Carbohydrate and lipid contents were unaffected. Serum corticosterone levels in the offspring (at P10, P40, or P90) and dams (at P21) were not affected by the protein-free diet. Maternal behavior was also unchanged. In the offspring, no differences were observed between groups regarding anxiety-like behaviors at both ages. The protein-free diet increased adolescent locomotor activity as well as adult novelty-seeking behavior and memory performance. Our results indicate that the brain growth spurt period is particularly sensitive to protein malnutrition, showing that even a brief nutritional insult during this period can cause specific age-dependent behavioral effects on the offspring. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse.

PubMed

Lucas, Sarah J; Michel, Christophe B; Marra, Vincenzo; Smalley, Joshua L; Hennig, Matthias H; Graham, Bruce P; Forsythe, Ian D

2018-05-01

Synapses have high energy demands which increase during intense activity. We show that presynaptic terminals can utilise extracellular glucose or lactate to generate energy to maintain synaptic transmission. Reducing energy substrates induces a metabolic stress: presynaptic ATP depletion impaired synaptic transmission through a reduction in the number of functional synaptic vesicle release sites and a slowing of vesicle pool replenishment, without a consistent change in release probability. Metabolic function is compromised in many pathological conditions (e.g. stroke, traumatic brain injury and neurodegeneration). Knowledge of how synaptic transmission is constrained by metabolic stress, especially during intense brain activity, will provide insights to improve cognition following pathological insults. The synapse has high energy demands, which increase during intense activity. Presynaptic ATP production depends on substrate availability and usage will increase during activity, which in turn could influence transmitter release and information transmission. We investigated transmitter release at the mouse calyx of Held synapse using glucose or lactate (10, 1 or 0 mm) as the extracellular substrates while inducing metabolic stress. High-frequency stimulation (HFS) and recovery paradigms evoked trains of EPSCs monitored under voltage-clamp. Whilst postsynaptic intracellular ATP was stabilised by diffusion from the patch pipette, depletion of glucose increased EPSC depression during HFS and impaired subsequent recovery. Computational modelling of these data demonstrated a reduction in the number of functional release sites and slowed vesicle pool replenishment during metabolic stress, with little change in release probability. Directly depleting presynaptic terminal ATP impaired transmitter release in an analogous manner to glucose depletion. In the absence of glucose, presynaptic terminal metabolism could utilise lactate from the aCSF and this was blocked by inhibition of monocarboxylate transporters (MCTs). MCT inhibitors significantly suppressed transmission in low glucose, implying that lactate is a presynaptic substrate. Additionally, block of glycogenolysis accelerated synaptic transmission failure in the absence of extracellular glucose, consistent with supplemental supply of lactate by local astrocytes. We conclude that both glucose and lactate support presynaptic metabolism and that limited availability, exacerbated by high-intensity firing, constrains presynaptic ATP, impeding transmission through a reduction in functional presynaptic release sites as vesicle recycling slows when ATP levels are low. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Changes in lactate dehydrogenase are associated with central gray matter lesions in newborns with hypoxic-ischemic encephalopathy.

PubMed

Yum, Sook Kyung; Moon, Cheong-Jun; Youn, Young-Ah; Sung, In Kyung

2017-05-01

Biomarkers may predict neurological prognosis in infants with hypoxic-ischemic encephalopathy (HIE). We evaluated the relationship between serum lactate dehydrogenase (LDH) and brain magnetic resonance imaging (MRI), which predicts neurodevelopmental outcomes, in order to assess whether LDH levels are similarly predictive. Medical records were reviewed for infants with HIE and LDH levels were assessed on the first (LDH 1 ) and third (LDH 3 ) days following birth. Receiver operating characteristic curves were obtained in relation to central gray matter hypoxic-ischemic lesions. Of 92 patients, 52 (56.5%) had hypoxic-ischemic lesions on brain MRI, and 21 of these infants (40.4%) had central gray matter lesions. LDH 1 and LDH 3 did not differ; however, the percentage change (ΔLDH%) was significantly higher in infants with central gray matter lesions (36.9% versus 6.6%, p = 0.006). With cutoffs of 187 (IU/L, ΔLDH) and 19.4 (%, ΔLDH%), the sensitivity, specificity, positive predictive value and negative predictive value were 71.4, 69.0, 40.5 and 89.1%, respectively. The relative risk was 5.57 (p = 0.001). Changes in serum LDH may be a useful biomarker for predicting future neurodevelopmental prognosis in infants with HIE.

Brain glucose metabolism in an animal model of depression.

PubMed

Detka, J; Kurek, A; Kucharczyk, M; Głombik, K; Basta-Kaim, A; Kubera, M; Lasoń, W; Budziszewska, B

2015-06-04

An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on α-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to all experimental conditions, i.e., prenatal stress, acute stress, and glucose administration. Our data indicate that glycolysis is increased and the Krebs cycle is decreased in the brain of a prenatal stress animal model of depression. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of organophosphorus anticholinesterase compounds on brain glucose and energy metabolism. Annual summary report, 1 October 1982-29 February 1984

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medina, M.A.; Miller, A.L.

1984-09-01

The effects of paraoxon and Soman on glucose utilization and of Soman on the levels of intermediary metabolites were investigated in rat brain. The rate of glucose utilization and the levels of intermediary metabolites were determined in six brain areas at varying time periods after administration of 0.5 or 0.8 of the paraoxon or Soman LD50. Behavioral changes were observed only with the 0.8 LD50 dose of both compounds and some of the animals exhibited convulsive activity with this dose of Soman. Brain glucose utilization tended to be decreased by 0.8 LD50 paraoxon and 0.5 LD50 Soman. Some alterations inmore » metabolite levels were observed but these were not consistent and could not be correlated with the rate of glucose utilization. In animals with Soman-induced convulsions, glucose utilization and lactate levels were elevated only in the cortex and thalamus/basal ganglia. ATP, creatine phosphate and glucose levels were decreased in the cortex but not in other brain areas, suggesting the possibility of uncoupling of oxidative phosphorylation. Pretreatment with atropine prevented the behavioral responses and the changes in glucose utilization previously observed with 0.8 Soman LD50. Our results in convulsing animals are similar to those which have been observed with the excitatorytoxins kainic acid and bicuculline.« less

Maternal Oxytocin Administration Before Birth Influences the Effects of Birth Anoxia on the Neonatal Rat Brain.

PubMed

Boksa, Patricia; Zhang, Ying; Nouel, Dominique

2015-08-01

Ineffective contractions and prolonged labor are common birth complications in primiparous women, and oxytocin is the most common agent given for induction or augmentation of labor. Clinical studies in humans suggest oxytocin might adversely affect the CNS response to hypoxia at birth. In this study, we used a rat model of global anoxia during Cesarean section birth to test if administering oxytocin to pregnant dams prior to birth affects the acute neonatal CNS response to birth anoxia. Anoxic pups born from dams pre-treated with intravenous injections or infusions of oxytocin before birth showed significantly increased brain lactate, a metabolic indicator of CNS hypoxia, compared to anoxic pups from dams pre-treated with saline. Anoxic pups born from dams given oxytocin before birth also showed decreased brain ATP compared to anoxic pups from saline dams. Direct injection of oxytocin to postnatal day 2 rat pups followed by exposure to anoxia also resulted in increased brain lactate and decreased brain ATP, compared to anoxia exposure alone. Oxytocin pre-treatment of the dam decreased brain malondialdehyde, a marker of lipid peroxidation, as well as protein kinase C activity, both in anoxic pups and controls, suggesting oxytocin may reduce aspects of oxidative stress. Finally, when dams were pretreated with indomethacin, a cyclooxygenase (COX) inhibitor, maternal oxytocin no longer potentiated effects of anoxia on neonatal brain lactate, suggesting this effect of oxytocin may be mediated via prostaglandin production or other COX-derived products. The results indicate that maternal oxytocin administration may have multiple acute effects on CNS metabolic responses to anoxia at birth.

Glucose metabolism in the developing brain.

PubMed

Vannucci, R C; Vannucci, S J

2000-04-01

As in adults, glucose is the predominant cerebral energy fuel for the fetus and newborn. Studies in experimental animals and humans indicate that cerebral glucose utilization initially is low and increases with maturation with increasing regional heterogeneity. The increases in cerebral glucose utilization with advancing age occurs as a consequence of increasing functional activity and cerebral energy demands. The levels of expression of the 2 primary facilitative glucose transporter proteins in brain, GLUT1 (blood-brain barrier and glia) and GLUT3 (neuronal), display a similar maturational pattern. Alternate cerebral energy fuels, specifically the ketone bodies and lactate, can substitute for glucose, especially during hypoglycemia, thereby protecting the immature brain from potential untoward effects of hypoglycemia. Unlike adults, glucose supplementation during hypoxia-ischemia is protective in the immature brain, whereas hypoglycemia is deleterious. Accordingly, glucose plays a critical role in the developing brain, not only as the primary substrate for energy production but also to allow for normal biosynthetic processes to proceed.

Energy Metabolism of the Brain, Including the Cooperation between Astrocytes and Neurons, Especially in the Context of Glycogen Metabolism.

PubMed

Falkowska, Anna; Gutowska, Izabela; Goschorska, Marta; Nowacki, Przemysław; Chlubek, Dariusz; Baranowska-Bosiacka, Irena

2015-10-29

Glycogen metabolism has important implications for the functioning of the brain, especially the cooperation between astrocytes and neurons. According to various research data, in a glycogen deficiency (for example during hypoglycemia) glycogen supplies are used to generate lactate, which is then transported to neighboring neurons. Likewise, during periods of intense activity of the nervous system, when the energy demand exceeds supply, astrocyte glycogen is immediately converted to lactate, some of which is transported to the neurons. Thus, glycogen from astrocytes functions as a kind of protection against hypoglycemia, ensuring preservation of neuronal function. The neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported in literature. This review goes on to emphasize that while neurons and astrocytes differ in metabolic profile, they interact to form a common metabolic cooperation.

Glucose, Lactate, and Shuttling of Metabolites in Vertebrate Retinas

PubMed Central

Hurley, James B.; Lindsay, Kenneth J.; Du, Jianhai

2016-01-01

The vertebrate retina has specific functions and structures that give it a unique set of constraints on the way in which it can produce and use metabolic energy. The retina’s response to illumination influences its energy requirements, and the retina’s laminated structure influences the extent to which neurons and glia can access metabolic fuels. There are fundamental differences between energy metabolism in retina and that in brain. The retina relies on aerobic glycolysis much more than the brain does, and morphological differences between retina and brain limit the types of metabolic relationships that are possible between neurons and glia. This Mini-Review summarizes the unique metabolic features of the retina with a focus on the role of lactate shuttling. PMID:25801286

TLR4 response mediates ethanol-induced neurodevelopment alterations in a model of fetal alcohol spectrum disorders.

PubMed

Pascual, María; Montesinos, Jorge; Montagud-Romero, Sandra; Forteza, Jerónimo; Rodríguez-Arias, Marta; Miñarro, José; Guerri, Consuelo

2017-07-24

Inflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Prenatal ethanol exposure affects the developing brain and causes neural impairment, cognitive and behavioral effects, collectively known as fetal alcohol spectrum disorders (FASD). Our previous studies demonstrate that ethanol activates the innate immune response and TLR4 receptor and causes neuroinflammation, brain damage, and cognitive defects in the developmental brain stage of adolescents. We hypothesize that by activating the TLR4 response, maternal alcohol consumption during pregnancy triggers the release of cytokines and chemokines in both the maternal sera and brains of fetuses/offspring, which impairs brain ontogeny and causes cognitive dysfunction. WT and TLR4-KO female mice treated with or without 10% ethanol in the drinking water during gestation and lactation were used. Cytokine/chemokine levels were determined by ELISA in the amniotic fluid, maternal serum, and cerebral cortex, as well as in the offspring cerebral cortex. Microglial and neuronal markers (evaluated by western blotting), myelin proteins (immunohistochemical and western blotting) and synaptic parameters (western blotting and electron microscopy) were assessed in the cortices of the WT and TLR4-KO pups on PND 0, 20, and 66. Behavioral tests (elevated plus maze and passive avoidance) were performed in the WT and TLR4-KO mice on PND 66 exposed or not to ethanol. We show that alcohol intake during gestation and lactation increases the levels of several cytokines/chemokines (IL-1β, IL-17, MIP-1α, and fractalkine) in the maternal sera, amniotic fluid, and brains of fetuses and offspring. The upregulation of cytokines/chemokines is associated with an increase in activated microglia markers (CD11b and MHC-II), and with a reduction in some synaptic (synaptotagmin, synapsin IIa) and myelin (MBP, PLP) proteins in the brains of offspring on days 0, 20, and 66 (long-term effects). These changes are associated with long-term behavioral impairments, in the 66-day-old alcohol-exposed pups. TLR4-deficient mice are protected against ethanol-induced cytokine/chemokine production in alcohol-treated dams and offspring, along with synaptic and myelin alterations, and the log-term behavioral dysfunction induced by ethanol in offspring. These results suggest that the immune system activation, through the TLR4 response, might play an important role in the neurodevelopmental defects in FASD.

Extracellular levels of lactate, but not oxygen, reflect sleep homeostasis in the rat cerebral cortex.

PubMed

Dash, Michael B; Tononi, Giulio; Cirelli, Chiara

2012-07-01

It is well established that brain metabolism is higher during wake and rapid eye movement (REM) sleep than in nonrapid eye movement (NREM) sleep. Most of the brain's energy is used to maintain neuronal firing and glutamatergic transmission. Recent evidence shows that cortical firing rates, extracellular glutamate levels, and markers of excitatory synaptic strength increase with time spent awake and decline throughout NREM sleep. These data imply that the metabolic cost of each behavioral state is not fixed but may reflect sleep-wake history, a possibility that is investigated in the current report. Chronic (4d) electroencephalographic (EEG) recordings in the rat cerebral cortex were coupled with fixed-potential amperometry to monitor the extracellular concentration of oxygen ([oxy]) and lactate ([lac]) on a second-by-second basis across the spontaneous sleep-wake cycle and in response to sleep deprivation. Basic sleep research laboratory. Wistar Kyoto (WKY) adult male rats. N/A. Within 30-60 sec [lac] and [oxy] progressively increased during wake and REM sleep and declined during NREM sleep (n = 10 rats/metabolite), but with several differences. [Oxy], but not [lac], increased more during wake with high motor activity and/or elevated EEG high-frequency power. Meanwhile, only the NREM decline of [lac] reflected sleep pressure as measured by slow-wave activity, mirroring previous results for cortical glutamate. The observed state-dependent changes in cortical [lac] and [oxy] are consistent with higher brain metabolism during waking and REM sleep in comparison with NREM sleep. Moreover, these data suggest that glycolytic activity, most likely through its link with glutamatergic transmission, reflects sleep homeostasis.

Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Toward the therapeutics of cognitive impairment of schizophrenia.

PubMed

Uehara, Takashi; Matsuoka, Tadasu; Sumiyoshi, Tomiki

2014-01-01

Augmentation therapy with serotonin-1A (5-HT1A) receptor partial agonists has been suggested to improve cognitive impairment in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production. The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days) of tandospirone (0.05 or 5 mg/kg) on brain energy metabolism, as represented by extracellular lactate concentration (eLAC) in the medial prefrontal cortex (mPFC) of a rat model of schizophrenia. Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot-shock stress (FS). Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment. These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism, based on brain energy metabolism, by which 5-HT1A agonism improve cognitive impairment of schizophrenia and related disorders.

Importance of measuring lactate levels in children with sepsis.

PubMed

Anil, Nisha

2017-10-10

Sepsis is a major public health problem as well as one of the leading causes of preventable death in children because of failure to recognise the early signs and symptoms and to resuscitate rapidly. Blood lactate levels are used to assess the severity of sepsis and the effectiveness of resuscitation. Lactate levels are easily obtainable and should be checked in all patients admitted with suspected sepsis within six hours of presentation. The test should be repeated four and eight-hours post-diagnosis of sepsis. For the diagnosis of sepsis, patients' clinical symptoms, along with the combined analysis of partial pressure of oxygen, carbon dioxide and lactate levels, should be used. A multitude of factors can cause elevated lactate levels and so clinicians should use elevated levels cautiously by considering all other aetiologies. This article, which focuses on practice in Australia but makes reference to the UK, discusses the importance of measuring lactate levels in sepsis, the pathophysiology of lactate production, causes of elevated lactate levels, lactate measurement, nursing management of patients with elevated lactate levels, limitations of using lactate as a biomarker for diagnosing sepsis and implications for practice. ©2012 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

MATERNAL EXPOSURE TO ATRAZINE DURING LACTATION SUPPRESSES SUCKLING-INDUCED PROLACTIN RELEASE AND RESULTS IN PROSTATITIS IN THE ADULT OFFSPRING

EPA Science Inventory

The availability of prolactin (PRL) to the neonatal brain is known to affect the development of the tuberoinfundibular (TIDA) neurons and, as a consequence, lead to alterations in subsequent PRL regulation. Without early lactational exposure to PRL (derived from the dam's milk), ...

Rapamycin ameliorates brain metabolites alterations after transient focal ischemia in rats.

PubMed

Chauhan, Anjali; Sharma, Uma; Jagannathan, Naranamangalam R; Gupta, Yogendra Kumar

2015-06-15

Rapamycin has been shown to protect against middle cerebral artery occlusion (MCAo) induced ischemic injury. In this study, the neuroprotective effect of rapamycin on the metabolic changes induced by MCAo was evaluated using nuclear magnetic resonance (NMR) spectroscopy of brain tissues. MCAo in rats was induced by insertion of nylon filament. One hour after ischemia, rapamycin (250 µg/kg, i.p.) in dimethyl sulfoxide was administered. Reperfusion was done 2h after ischemia. Twenty-four hours after ischemia phospholipase A2 (PLA2) levels and metabolic changes were assessed. Perchloric acid extraction was performed on the brain of all animals (n=7; sham, vehicle; DMSO and rapamycin 250 µg/kg) and the various brain metabolites were assessed by NMR spectroscopy. In all 44 metabolites were assigned in the proton NMR spectrum of rat brain tissues. In the vehicle group, we observed increased lactate levels and decreased levels of glutamate/glutamine, choline containing compounds, creatine/phosphocreatine (Cr/PCr), taurine, myo-inositol, γ-amino butryic acid (GABA), N-aspartyl aspartate (NAA), purine and pyrimidine metabolites. In rapamycin treated rats, there was increase in the levels of choline containing compounds, NAA, myo-inositol, glutamate/glutamine, GABA, Cr/PCr and taurine as compared to those of vehicle control (P<0.05). Rapamycin treatment reduced PLA2 levels as compared to vehicle group (P<0.05). Our findings indicated that rapamycin reduced the increased PLA2 levels and altered brain metabolites after MCAo. These protective effects might be attributed to its effect on cell membrane metabolism; glutamate induced toxicity and calcium homeostasis in stroke. Copyright © 2015 Elsevier B.V. All rights reserved.

Brain activity-induced neuronal glucose uptake/glycolysis: Is the lactate shuttle not required?

PubMed

Tang, Bor Luen

2018-03-01

The astrocyte-neuron lactate shuttle (ANLS) hypothesis posits that during neuronal activation, astrocytic glycolysis consumes glucose and generates lactate, with the latter then imported by neurons as a preferred fuel. The hypothesis has been controversial, with multiple theoretical postulates for and against, and with empirical evidence that were either supportive or otherwise. Recent findings using direct in vivo imaging of lactate and glucose uptake as well as associated metabolic changes in neurons have now placed important constraints on the hypothesis. Here, I review these recent findings and discuss their implications on neuronal energetics. Copyright © 2017 Elsevier Inc. All rights reserved.

Stimulus-dependent changes of extracellular glucose in the rat hippocampus determined by in vivo microdialysis.

PubMed

Rex, A; Bert, B; Fink, H; Voigt, J-P

2009-10-19

Neuronal activity is tightly coupled with brain energy metabolism; and glucose is an important energy substrate for neurons. The present in vivo microdialysis study was aimed at investigating changes in extracellular glucose concentrations in the rat ventral hippocampus due to exposure to the elevated plus maze. Determination of basal hippocampal glucose and lactate/pyruvate ratio in male Wistar rats was conducted in the home cage using in vivo microdialysis. Rats were exposed to the elevated plus maze, a rodent model of anxiety-related behaviour, or to unspecific stress induced by white noise (95dB) as a control condition. Basal hippocampal levels of glucose, as determined by zero-net-flux, and the basal lactate/pyruvate ratio were 1.49+/-0.05mmol/l and 13.8+/-1.1, respectively. In rats without manipulation, glucose levels remained constant throughout the experiment (120min). By contrast, exposure to the elevated plus maze led to a temporary decline in hippocampal glucose (-33.2+/-4.4%) which returned to baseline level in the home cage. White noise caused only a non-significant decrease in extracellular glucose level (-9.3+/-3.5%). In all groups, the lactate/pyruvate ratio remained unchanged by the experimental procedures. Our microdialysis study demonstrates that exposure to the elevated plus maze induces a transient decrease in extracellular hippocampal glucose concentration. In contrast, an unspecific stimulus did not change hippocampal glucose. The latter suggests that only specific behavioural stimuli increase hippocampal glucose utilization in the ventral hippocampus.

Perfluorocarbon Enhanced Glasgow Oxygen Level Dependent (GOLD) Magnetic Resonance Metabolic Imaging Identifies the Penumbra Following Acute Ischemic Stroke

PubMed Central

Deuchar, Graeme A; Brennan, David; Holmes, William M; Shaw, Martin; Macrae, I Mhairi; Santosh, Celestine

2018-01-01

The ability to identify metabolically active and potentially salvageable ischaemic penumbra is crucial for improving treatment decisions in acute stroke patients. Our solution involves two complementary novel MRI techniques (Glasgow Oxygen Level Dependant (GOLD) Metabolic Imaging), which when combined with a perfluorocarbon (PFC) based oxygen carrier and hyperoxia can identify penumbra due to dynamic changes related to continued metabolism within this tissue compartment. Our aims were (i) to investigate whether PFC offers similar enhancement of the second technique (Lactate Change) as previously demonstrated for the T2*OC technique (ii) to demonstrate both GOLD metabolic imaging techniques working concurrently to identify penumbra, following administration of Oxycyte® (O-PFC) with hyperoxia. Methods: An established rat stroke model was utilised. Part-1: Following either saline or PFC, magnetic resonance spectroscopy was applied to investigate the effect of hyperoxia on lactate change in presumed penumbra. Part-2; rats received O-PFC prior to T2*OC (technique 1) and MR spectroscopic imaging, which was used to identify regions of tissue lactate change (technique 2) in response to hyperoxia. In order to validate the techniques, imaging was followed by [14C]2-deoxyglucose autoradiography to correlate tissue metabolic status to areas identified as penumbra. Results: Part-1: PFC+hyperoxia resulted in an enhanced reduction of lactate in the penumbra when compared to saline+hyperoxia. Part-2: Regions of brain tissue identified as potential penumbra by both GOLD metabolic imaging techniques utilising O-PFC, demonstrated maintained glucose metabolism as compared to adjacent core tissue. Conclusion: For the first time in vivo, enhancement of both GOLD metabolic imaging techniques has been demonstrated following intravenous O-PFC+hyperoxia to identify ischaemic penumbra. We have also presented preliminary evidence of the potential therapeutic benefit offered by O-PFC. These unique theranostic applications would enable treatment based on metabolic status of the brain tissue, independent of time from stroke onset, leading to increased uptake and safer use of currently available treatment options. PMID:29556351

Temporal dynamics of lactate concentration in the human brain during acute inspiratory hypoxia

PubMed Central

Harris, Ashley D; Roberton, Victoria H; Huckle, Danielle L; Saxena, Neeraj; Evans, C John; Murphy, Kevin; Hall, Judith E; Bailey, Damian M; Mitsis, Georgios; Edden, Richard A E; Wise, Richard G

2012-01-01

Purpose To demonstrate the feasibility of measuring the temporal dynamics of cerebral lactate concentration and examine these dynamics in human subjects using MRS during hypoxia. Methods A respiratory protocol consisting of 10 min baseline normoxia, 20 min inspiratory hypoxia and ending with 10 min normoxic recovery was used, throughout which lactate-edited MRS was performed. This was repeated four times in three subjects. A separate session was performed to measure blood lactate. Impulse response functions using end-tidal oxygen and blood lactate as system inputs and cerebral lactate as the system output were examined to describe the dynamics of the cerebral lactate response to a hypoxic challenge. Results The average lactate increase was 20%±15% during the last half of the hypoxic challenge. Significant changes in cerebral lactate concentration were observed after 400s. The average relative increase in blood lactate was 188%±95%. The temporal dynamics of cerebral lactate concentration was reproducibly demonstrated with 200s time bins of MRS data (coefficient of variation 0.063±0.035 between time bins in normoxia). The across subject coefficient of variation was 0.333. Conclusions The methods for measuring the dynamics of the cerebral lactate response developed here would be useful to further investigate the brain’s response to hypoxia. PMID:23197421

Regional differences in brain glucose metabolism determined by imaging mass spectrometry.

PubMed

Kleinridders, André; Ferris, Heather A; Reyzer, Michelle L; Rath, Michaela; Soto, Marion; Manier, M Lisa; Spraggins, Jeffrey; Yang, Zhihong; Stanton, Robert C; Caprioli, Richard M; Kahn, C Ronald

2018-06-01

Glucose is the major energy substrate of the brain and crucial for normal brain function. In diabetes, the brain is subject to episodes of hypo- and hyperglycemia resulting in acute outcomes ranging from confusion to seizures, while chronic metabolic dysregulation puts patients at increased risk for depression and Alzheimer's disease. In the present study, we aimed to determine how glucose is metabolized in different regions of the brain using imaging mass spectrometry (IMS). To examine the relative abundance of glucose and other metabolites in the brain, mouse brain sections were subjected to imaging mass spectrometry at a resolution of 100 μm. This was correlated with immunohistochemistry, qPCR, western blotting and enzyme assays of dissected brain regions to determine the relative contributions of the glycolytic and pentose phosphate pathways to regional glucose metabolism. In brain, there are significant regional differences in glucose metabolism, with low levels of hexose bisphosphate (a glycolytic intermediate) and high levels of the pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolite hexose phosphate in thalamus compared to cortex. The ratio of ATP to ADP is significantly higher in white matter tracts, such as corpus callosum, compared to less myelinated areas. While the brain is able to maintain normal ratios of hexose phosphate, hexose bisphosphate, ATP, and ADP during fasting, fasting causes a large increase in cortical and hippocampal lactate. These data demonstrate the importance of direct measurement of metabolic intermediates to determine regional differences in brain glucose metabolism and illustrate the strength of imaging mass spectrometry for investigating the impact of changing metabolic states on brain function at a regional level with high resolution. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Energy Metabolism of the Brain, Including the Cooperation between Astrocytes and Neurons, Especially in the Context of Glycogen Metabolism

PubMed Central

Falkowska, Anna; Gutowska, Izabela; Goschorska, Marta; Nowacki, Przemysław; Chlubek, Dariusz; Baranowska-Bosiacka, Irena

2015-01-01

Glycogen metabolism has important implications for the functioning of the brain, especially the cooperation between astrocytes and neurons. According to various research data, in a glycogen deficiency (for example during hypoglycemia) glycogen supplies are used to generate lactate, which is then transported to neighboring neurons. Likewise, during periods of intense activity of the nervous system, when the energy demand exceeds supply, astrocyte glycogen is immediately converted to lactate, some of which is transported to the neurons. Thus, glycogen from astrocytes functions as a kind of protection against hypoglycemia, ensuring preservation of neuronal function. The neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported in literature. This review goes on to emphasize that while neurons and astrocytes differ in metabolic profile, they interact to form a common metabolic cooperation. PMID:26528968

Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble.

PubMed

Jolivet, Renaud; Coggan, Jay S; Allaman, Igor; Magistretti, Pierre J

2015-02-01

Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

Long-Term Alterations in Neural and Endocrine Processes Induced by Motherhood

PubMed Central

Bridges, Robert S.

2015-01-01

The reproductive experience of pregnancy, lactation and motherhood can significantly remodel the female’s biological state, affecting endocrine, neuroendocrine, neural, and immunological processes. The brain, pituitary gland, liver, thymus, and mammary tissue are among the structures that are modified by reproductive experience. The present review that focuses on rodent research, but also includes pertinent studies in sheep and other species, identifies specific changes in these processes brought about by the biological states of pregnancy, parturition, and lactation and how the components of reproductive experience contribute to the remodeling of the maternal brain and organ systems. Findings indicate that prior parity alters key circulating hormone levels and neural receptor gene expression. Moreover, reproductive experience results in modifications in neural processes and glial support. The possible role of pregnancy-induced neurogenesis is considered in the context of neuroplasticity and behavior, and the effects of reproductive experience on maternal memory, i.e. the retention of maternal behavior, together with anxiety and learning are presented. Together, these sets of findings support the concept that the neural and biological state of the adult female is significantly and dramatically altered on a long-term basis by the experiences of parity and motherhood. Remodeling of the maternal brain and other biological systems is posited to help facilitate adaptations to environmental/ecological challenges as the female raises young and ages. PMID:26388065

Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms

PubMed Central

Bolton, Jessica L.; Bilbo, Staci D.

2014-01-01

Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment. PMID:25364282

Localized 1H NMR measurement of glucose consumption in the human brain during visual stimulation.

PubMed Central

Chen, W; Novotny, E J; Zhu, X H; Rothman, D L; Shulman, R G

1993-01-01

Spatially localized 1H NMR spectroscopy has been applied to measure changes in brain glucose concentration during 8-Hz photic stimulation. NMR spectroscopic measurements were made in a 12-cm3 volume centered on the calcarine fissure and encompassing the primary visual cortex. The average maximum change in glucose levels was 0.34 mumol.g-1 (n = 5) at 15 min; glucose level had turned toward resting level at 25 min. The glucose change was used to calculate the increase of glucose cerebral metabolic rate in the visual cortex region for individual subjects by using the Michaelis-Menten model of glucose transport on the assumption of constant transport kinetics. The glucose cerebral metabolic rate was calculated to increase over the nonstimulated rate by 22% during the first 15 min of photic stimulation. A model in which the glucose metabolic rate gradually decreases during stimulation was proposed as a possible explanation for the recovery of brain glucose and previously measured lactate concentrations to prestimulus values after 15 min. Images Fig. 1 PMID:8234332

Infantile cobalamin deficiency with cerebral lactate accumulation and sustained choline depletion.

PubMed

Horstmann, M; Neumaier-Probst, E; Lukacs, Z; Steinfeld, R; Ullrich, K; Kohlschütter, A

2003-06-01

A remarkable, intermittent sudden-onset vigilance and movement disorder in an exclusively breast-fed infant is reported, which was caused by cobalamin depletion due to maternal vitamin B12 malabsorption. The lack of cobalamin caused a severe encephalopathy in the infant, whose brain displayed a striking loss of volume and a delay of myelination. Proton magnetic resonance spectroscopy revealed an accumulation of lactate in the gray and white matter of the brain and a sustained depletion of choline-containing compounds in the white matter, reflecting a reversible disturbance of oxidative energy metabolism in brain cells and a long-lasting hypomyelination disorder. The clinical picture in conjunction with MRI and spectroscopic data of this case study yields more insight into the functions of cobalamin in the cerebral metabolism.

Prognostic factors for acute encephalopathy with bright tree appearance.

PubMed

Azuma, Junji; Nabatame, Shin; Nakano, Sayaka; Iwatani, Yoshiko; Kitai, Yukihiro; Tominaga, Koji; Kagitani-Shimono, Kuriko; Okinaga, Takeshi; Yamamoto, Takehisa; Nagai, Toshisaburo; Ozono, Keiichi

2015-02-01

To determine the prognostic factors for encephalopathy with bright tree appearance (BTA) in the acute phase through retrospective case evaluation. We recruited 10 children with encephalopathy who presented with BTA and classified them into 2 groups. Six patients with evident regression and severe psychomotor developmental delay after encephalopathy were included in the severe group, while the remaining 4 patients with mild mental retardation were included in the mild group. We retrospectively analyzed their clinical symptoms, laboratory data, and magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings. Patients in the severe group developed subsequent complications such as epilepsy and severe motor impairment. Univariate analysis revealed that higher maximum lactate dehydrogenase (LDH) levels (p=0.055) were a weak predictor of poor outcome. Maximum creatinine levels were significantly higher (p<0.05) and minimal platelet counts were significantly lower (p<0.05) in the severe group than in the mild group. Acute renal failure was not observed in any patient throughout the study. MRS of the BTA lesion during the BTA period showed elevated lactate levels in 5 children in the severe group and 1 child in the mild group. MRI performed during the chronic phase revealed severe brain atrophy in all patients in the severe group. Higher creatinine and LDH levels and lower platelet counts in the acute phase correlated with poor prognosis. Increased lactate levels in the BTA lesion during the BTA period on MRS may predict severe physical and mental disability. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Metabolism of [U-13C]glucose in Human Brain Tumors In Vivo

PubMed Central

Maher, Elizabeth A.; Marin-Valencia, Isaac; Bachoo, Robert M.; Mashimo, Tomoyuki; Raisanen, Jack; Hatanpaa, Kimmo J.; Jindal, Ashish; Jeffrey, F. Mark; Choi, Changho; Madden, Christopher; Mathews, Dana; Pascual, Juan M.; Mickey, Bruce E.; Malloy, Craig R.; DeBerardinis, Ralph J.

2012-01-01

Glioblastomas (GBMs) and brain metastases demonstrate avid uptake of 18fluoro-2-deoxyglucose (FDG) by positron emission tomography (PET) and display perturbations of intracellular metabolite pools by 1H magnetic resonance spectroscopy (MRS). These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. FDG-positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation compared to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain malignancies to oxidize glucose in the tricarboxylic acid cycle is unknown. Here we studied the metabolism of human brain tumors in situ. [U-13C]glucose was infused during surgical resection, and tumor samples were subsequently subjected to 13C NMR spectroscopy. Analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the TCA cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl-CoA pool was derived from blood-borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of 13C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse malignancies growing in their native microenvironment. PMID:22419606

Improving 1H MRSI measurement of cerebral lactate for clinical applications

PubMed Central

Corrigan, Neva M.; Richards, Todd L.; Friedman, Seth D.; Petropoulos, Helen; Dager, Stephen R.

2010-01-01

Accurate measurement of cerebral lactate is critical to the understanding of brain function for psychiatric disorders such as panic disorder and bipolar disorder as well as mitochondrial dysfunction. Proton magnetic spectroscopic imaging (MRSI) techniques can be used to study lactate in vivo; however, accurate measurement of cerebral lactate, which is normally at low basal abundance, can be challenging. In this study, regional lactate measurements obtained with two different MRSI analytic approaches were evaluated using proton echo-planar spectroscopic imaging (PEPSI) data from 18 healthy adults participating in an in vivo sodium lactate infusion study. The results demonstrate that averaging data within a region of interest (ROI) before spectral fitting with LCModel results in significantly improved lactate measurement as compared to averaging chemical concentrations derived from the fitting of individual voxels in the ROI. Simulation results that confirm this finding are also presented. This study additionally outlines an atlas-based approach for the systematic computation of regional distributions of chemical concentrations in large MRSI data sets. PMID:20236806

Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study.

PubMed

Zhou, Qi; Zheng, Hong; Chen, Jiuxia; Li, Chen; Du, Yao; Xia, Huanhuan; Gao, Hongchang

2018-06-26

Alzheimer's disease (AD) has been associated with the disturbance of brain glucose metabolism. The present study investigates brain glucose metabolism using 13 C NMR metabolomics in combination with intravenous [1- 13 C]-glucose infusion in APP/PS1 transgenic mouse model of amyloid pathology at 10 months of age. We found that brain glucose was significantly accumulated in APP/PS1 mice relative to wild-type (WT) mice. Reductions in 13 C fluxes into the specific carbon sites of tricarboxylic acid (TCA) intermediate (succinate) as well as neurotransmitters (glutamate, glutamine, γ-aminobutyric acid and aspartate) from [1- 13 C]-glucose were also detected in the brain of APP/PS1 mice. In addition, our results reveal that the 13 C-enrichments of the C3 of alanine were significantly lower and the C3 of lactate have a tendency to be lower in the brain of APP/PS1 mice than WT mice. Taken together, the development of amyloid pathology could cause a reduction in glucose utilization and further result in decreases in energy and neurotransmitter metabolism as well as the lactate-alanine shuttle in the brain.

Cerebral effects of resuscitation with hypertonic saline and a new low-sodium hypertonic fluid in hemorrhagic shock and head injury.

PubMed

Sheikh, A A; Matsuoka, T; Wisner, D H

1996-07-01

A 2400-mOsm/L hypertonic solution (isosal) with a lower sodium content, compared with conventional 7.5% hypertonic saline, was formulated using a mixture of sodium chloride, glucose, and mixed amino acids. This solution was developed to minimize hypernatremia during resuscitation. We assessed the effects of isosal on hemodynamics, brain edema, and plasma sodium concentration after head injury associated with hemorrhagic shock. DESIGN. Prospective, randomized laboratory study. University research laboratory. Twenty-one adult female Suffolk sheep, weighing 39 to 49 kg. Animals were subjected to a 2-hr period of hemorrhagic shock to a mean arterial pressure (MAP) of 40 to 45 mm Hg in the presence of a freeze injury to the cerebral cortex. The hemorrhagic shock/head injury phase was followed by 2 hrs of resuscitation with isosal, a new 2400-mosm/L low-sodium hypertonic fluid, 2400 mosm/L of 7.5% hypertonic saline, or lactated Ringer's solution. Initial resuscitation was with a bolus injection of 8 mL/kg of the study solution; subsequent resuscitation in all three groups was with lactated Ringer's solution as needed to maintain baseline cardiac output. Serial hemodynamics, intracranial pressure, electrolytes, and osmolarity were measured. AT the end of resuscitation, the animals were killed and brain water content (mL H2O/g dry weight) of the injured and uninjured areas was determined. Resuscitation volumes were significantly lower in the isosal (19 +/- 5 mL/kg) and 7.5% hypertonic saline (14 +/- 2 mL/mg) groups compared with the lactated Ringer's solution (35 +/- 5 mL/kg) group. Intracranial pressure after 2 hrs of resuscitation was significantly lower in the isosal (7 +/- 1 mm Hg) and hypertonic saline groups (4 +/- 1 mm Hg). Water content in all areas of the brain was significantly lower in the hypertonic saline group compared with the lactated Ringer's solution group. Brain water content in the isosal group was lower than in the lactated Ringer's solution group only in the cerebellum. Plasma sodium content was lower in the isosal group than in the hypertonic saline group. After combined head injury and shock, isosal and 7.5% hypertonic saline have similar effects on hemodynamics and intracranial pressure. Hypertonic saline induces a greater degree of brain dehydration; isosal resuscitation results in smaller increases in plasma sodium.

Effects of experimentally induced maternal hypothyroidism and hyperthyroidism on the development of rat offspring: I. The development of the thyroid hormones-neurotransmitters and adenosinergic system interactions.

PubMed

Ahmed, O M; Abd El-Tawab, S M; Ahmed, R G

2010-10-01

The adequate functioning of the maternal thyroid gland plays an important role to ensure that the offspring develop normally. Thus, maternal hypo- and hyperthyroidism are used from the gestation day 1 to lactation day 21, in general, to recognize the alleged association of offspring abnormalities associated with the different thyroid status. In maternal rats during pregnancy and lactation, hypothyroidism in one group was performed by antithyroid drug, methimazole (MMI) that was added in drinking water at concentration 0.02% and hyperthyroidism in the other group was induced by exogenous thyroxine (T4) (from 50 microg to 200 microg/kg body weight) intragastric administration beside adding 0.002% T4 to the drinking water. The hypothyroid and hyperthyroid states in mothers during pregnancy and lactation periods were confirmed by measuring total thyroxine (TT4) and triiodothyronine (TT3) at gestational day 10 and 10 days post-partum, respectively; the effect was more pronounced at the later period than the first. In offspring of control maternal rats, the free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH) and growth hormone (GH) concentrations were pronouncedly increased as the age progressed from 1 to 3 weeks. In hypothyroid group, a marked decrease in serum FT3, FT4 and GH levels was observed while there was a significant increase in TSH level with age progress as compared with the corresponding control. The reverse pattern to latter state was recorded in hyperthyroid group. The thyroid gland of offspring of hypothyroid group, exhibited some histopathological changes as luminal obliteration of follicles, hyperplasia, fibroblastic proliferation and some degenerative changes throughout the experimental period. The offspring of hyperthyroid rats showed larger and less thyroid follicles with flattened cell lining epithelium, decreased thyroid gland size and some degenerative changes along the experimental period. On the other hand, the biochemical data revealed that in control offspring, the levels of iodothyronine 5'-monodeiodinase (5'-DI), monoamines, gamma-aminobutyric acid (GABA), acetylcholinesterase (AchE), ATPase-enzymes (Na(+),K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase) follow a synchronized course of development in all investigated brain regions (cerebrum, cerebellum and medulla oblongata). In addition, the depression in 5'-DI activity, monoamines levels with age progress in all investigated regions, was more pronounced in hypothyroid offspring, while they were increased significantly in hyperthyroid ones in comparison with their respective controls. Conversely, the reverse pattern was recorded in level of the inhibitory transmitter, GABA while there was a disturbance in AchE and ATPases activities in both treated groups along the experimental period in all studied regions. In conclusion, the hypothyroid status during pregnancy and lactation produced inhibitory effects on monoamines, AchE and ATPases and excitatory actions on GABA in different brain regions of the offspring while the hyperthyroid state induced a reverse effect. Thus, the maternal hypothyroidism and hyperthyroidism may cause a number of biochemical disturbances in different brain regions of their offspring and may lead to a pathophysiological state. These alterations were age dependent. Copyright 2010 ISDN. Published by Elsevier Ltd. All rights reserved.

BrainPhys® increases neurofilament levels in CNS cultures, and facilitates investigation of axonal damage after a mechanical stretch-injury in vitro.

PubMed

Jackson, Travis C; Kotermanski, Shawn E; Jackson, Edwin K; Kochanek, Patrick M

2018-02-01

Neurobasal®/B27 is a gold standard culture media used to study primary neurons in vitro. An alternative media (BrainPhys®/SM1) was recently developed which robustly enhances neuronal activity vs. Neurobasal® or DMEM. To the best of our knowledge BrainPhys® has not been explored in the setting of neuronal injury. Here we characterized the utility of BrainPhys® in a model of in vitro mechanical-stretch injury. Primary rat cortical neurons were maintained in classic Neurobasal®, or sequentially maintained in Neurocult® followed by BrainPhys® (hereafter simply referred to as "BrainPhys® maintained neurons"). The levels of axonal markers and proteins involved in neurotransmission were compared on day in vitro 10 (DIV10). BrainPhys® maintained neurons had higher levels of GluN2B, GluR1, Neurofilament light/heavy chain (NF-L & NF-H), and protein phosphatase 2 A (PP2A) vs. neurons in Neurobasal®. Mechanical stretch-injury (50ms/54% biaxial stretch) to BrainPhys® maintained neurons modestly (albeit significantly) increased 24h lactate dehydrogenase (LDH) levels but markedly decreased axonal NF-L levels post-injury vs. uninjured controls or neurons given a milder 38% stretch-injury. Furthermore, two 54% stretch-injuries (in tandem) exacerbated 24h LDH release, increased α-spectrin breakdown products (SBDPs), and decreased Tau levels. Also, BrainPhys® maintained cultures had decreased markers of cell damage 24h after a single 54% stretch-injury vs. neurons in Neurobasal®. Finally, we tested the hypothesis that lentivirus mediated overexpression of the pro-death protein RBM5 exacerbates neuronal and/or axonal injury in primary CNS cultures. RBM5 overexpression vs. empty-vector controls increased 24h LDH release, and SBDP levels, after a single 54% stretch-injury but did not affect NF-L levels or Tau. BrainPhys® is a promising new reagent which facilities the investigation of molecular targets involved in axonal and/or neuronal injury in vitro. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Change in Lactate Levels After Hemodialysis in Patients With End-Stage Renal Disease.

PubMed

Hourmozdi, Justin J; Gill, Jasreen; Miller, Joseph B; Markin, Abraham; Adams, Beth; Soi, Vivek; Jaehne, Anja K; Taylor, Andrew R; Langberg, Sam; Rodriguez, Lauren; Fox, Carynne; Uduman, Junior; Yessayan, Lenar T; Rivers, Emanuel P

2018-06-01

Patients with end-stage renal disease commonly visit the emergency department (ED). The purpose of this investigation is to examine the prevalence of baseline abnormal lactate levels and to evaluate the effects of hemodialysis on serum lactate levels. This was a prospective observational cohort study performed at an outpatient dialysis facility at an urban tertiary care hospital. The study consisted of 226 patients with end-stage renal disease who were receiving long-term hemodialysis and were enrolled during a 2-day period at the beginning of December 2015. Blood drawn for lactate levels was immediately analyzed before and after hemodialysis sessions. All patients completed their hemodialysis sessions. The prevalence of an abnormal lactate level (greater than 1.8 mmol/L) before hemodialysis was 17.7% (n=40). Overall, lactate levels decreased by 27% (SD 35%) after hemodialysis, with a decrease of 37% (SD 31%) for subgroups with a lactate level of 1.9 to 2.4 mmol/L, and 62% (SD 14%) with a lactate of 2.5 to 3.9 mmol/L. The data presented help providers understand the prevalence of abnormal lactate values in an outpatient end-stage renal disease population. After hemodialysis, lactate levels decreased significantly. This information may help medical providers interpret lactate values when patients with end-stage renal disease present to the ED. Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Sweet sixteen for ANLS

PubMed Central

Pellerin, Luc; Magistretti, Pierre J

2012-01-01

Since its introduction 16 years ago, the astrocyte–neuron lactate shuttle (ANLS) model has profoundly modified our understanding of neuroenergetics by bringing a cellular and molecular resolution. Praised or disputed, the concept has never ceased to attract attention, leading to critical advances and unexpected insights. Here, we summarize recent experimental evidence further supporting the main tenets of the model. Thus, evidence for distinct metabolic phenotypes between neurons (mainly oxidative) and astrocytes (mainly glycolytic) have been provided by genomics and classical metabolic approaches. Moreover, it has become clear that astrocytes act as a syncytium to distribute energy substrates such as lactate to active neurones. Glycogen, the main energy reserve located in astrocytes, is used as a lactate source to sustain glutamatergic neurotransmission and synaptic plasticity. Lactate is also emerging as a neuroprotective agent as well as a key signal to regulate blood flow. Characterization of monocarboxylate transporter regulation indicates a possible involvement in synaptic plasticity and memory. Finally, several modeling studies captured the implications of such findings for many brain functions. The ANLS model now represents a useful, experimentally based framework to better understand the coupling between neuronal activity and energetics as it relates to neuronal plasticity, neurodegeneration, and functional brain imaging. PMID:22027938

Change in plasma lactate concentration during arctigenin administration in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer

PubMed Central

Fujioka, Rumi; Mochizuki, Nobuo; Ikeda, Masafumi; Sato, Akihiro; Nomura, Shogo; Owada, Satoshi; Yomoda, Satoshi; Tsuchihara, Katsuya; Kishino, Satoshi

2018-01-01

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle. PMID:29856804

Change in plasma lactate concentration during arctigenin administration in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer.

PubMed

Fujioka, Rumi; Mochizuki, Nobuo; Ikeda, Masafumi; Sato, Akihiro; Nomura, Shogo; Owada, Satoshi; Yomoda, Satoshi; Tsuchihara, Katsuya; Kishino, Satoshi; Esumi, Hiroyasu

2018-01-01

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.

Prolonged continuous intravenous infusion of the dipeptide L-alanine- L-glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe traumatic brain injury

PubMed Central

2014-01-01

Introduction Low plasma glutamine levels are associated with worse clinical outcome. Intravenous glutamine infusion dose- dependently increases plasma glutamine levels, thereby correcting hypoglutaminemia. Glutamine may be transformed to glutamate which might limit its application at a higher dose in patients with severe traumatic brain injury (TBI). To date, the optimal glutamine dose required to normalize plasma glutamine levels without increasing plasma and cerebral glutamate has not yet been defined. Methods Changes in plasma and cerebral glutamine, alanine, and glutamate as well as indirect signs of metabolic impairment reflected by increased intracranial pressure (ICP), lactate, lactate-to-pyruvate ratio, electroencephalogram (EEG) activity were determined before, during, and after continuous intravenous infusion of 0.75 g L-alanine-L-glutamine which was given either for 24 hours (group 1, n = 6) or 5 days (group 2, n = 6) in addition to regular enteral nutrition. Lab values including nitrogen balance, urea and ammonia were determined daily. Results Continuous L-alanine-L-glutamine infusion significantly increased plasma and cerebral glutamine as well as alanine levels, being mostly sustained during the 5 day infusion phase (plasma glutamine: from 295 ± 62 to 500 ± 145 μmol/ l; brain glutamine: from 183 ± 188 to 549 ± 120 μmol/ l; plasma alanine: from 327 ± 91 to 622 ± 182 μmol/ l; brain alanine: from 48 ± 55 to 89 ± 129 μmol/ l; p < 0.05, ANOVA, post hoc Dunn’s test). Plasma glutamate remained unchanged and cerebral glutamate was decreased without any signs of cerebral impairment. Urea and ammonia were significantly increased within normal limits without signs of organ dysfunction (urea: from 2.7 ± 1.6 to 5.5 ± 1.5 mmol/ l; ammonia: from 12 ± 6.3 to 26 ± 8.3 μmol/ l; p < 0.05, ANOVA, post hoc Dunn’s test). Conclusions High dose L-alanine-L-glutamine infusion (0.75 g/ kg/ d up to 5 days) increased plasma and brain glutamine and alanine levels. This was not associated with elevated glutamate or signs of potential glutamate-mediated cerebral injury. The increased nitrogen load should be considered in patients with renal and hepatic dysfunction. Trial registration Clinicaltrials.gov NCT02130674. Registered 5 April 2014 PMID:24992948

Improving 1H MRSI measurement of cerebral lactate for clinical applications.

PubMed

Corrigan, Neva M; Richards, Todd L; Friedman, Seth D; Petropoulos, Helen; Dager, Stephen R

2010-04-30

Accurate measurement of cerebral lactate is critical to the understanding of brain function for psychiatric disorders such as panic disorder and bipolar disorder as well as mitochondrial dysfunction. Proton magnetic spectroscopic imaging (MRSI) techniques can be used to study lactate in vivo; however, accurate measurement of cerebral lactate, which is normally at low basal abundance, can be challenging. In this study, regional lactate measurements obtained with two different MRSI analytic approaches were evaluated using proton echo-planar spectroscopic imaging (PEPSI) data from 18 healthy adults participating in an in vivo sodium lactate infusion study. The results demonstrate that averaging data within a region of interest (ROI) before spectral fitting with LCModel results in significantly improved lactate measurement as compared to averaging chemical concentrations derived from the fitting of individual voxels in the ROI. Simulation results that confirm this finding are also presented. This study additionally outlines an atlas-based approach for the systematic computation of regional distributions of chemical concentrations in large MRSI data sets. Copyright @ 2009 Elsevier Ireland Ltd. All rights reserved.

Energy metabolism and glutamate-glutamine cycle in the brain: a stoichiometric modeling perspective.

PubMed

Massucci, Francesco A; DiNuzzo, Mauro; Giove, Federico; Maraviglia, Bruno; Castillo, Isaac Perez; Marinari, Enzo; De Martino, Andrea

2013-10-10

The energetics of cerebral activity critically relies on the functional and metabolic interactions between neurons and astrocytes. Important open questions include the relation between neuronal versus astrocytic energy demand, glucose uptake and intercellular lactate transfer, as well as their dependence on the level of activity. We have developed a large-scale, constraint-based network model of the metabolic partnership between astrocytes and glutamatergic neurons that allows for a quantitative appraisal of the extent to which stoichiometry alone drives the energetics of the system. We find that the velocity of the glutamate-glutamine cycle (Vcyc) explains part of the uncoupling between glucose and oxygen utilization at increasing Vcyc levels. Thus, we are able to characterize different activation states in terms of the tissue oxygen-glucose index (OGI). Calculations show that glucose is taken up and metabolized according to cellular energy requirements, and that partitioning of the sugar between different cell types is not significantly affected by Vcyc. Furthermore, both the direction and magnitude of the lactate shuttle between neurons and astrocytes turn out to depend on the relative cell glucose uptake while being roughly independent of Vcyc. These findings suggest that, in absence of ad hoc activity-related constraints on neuronal and astrocytic metabolism, the glutamate-glutamine cycle does not control the relative energy demand of neurons and astrocytes, and hence their glucose uptake and lactate exchange.

Energy metabolism and glutamate-glutamine cycle in the brain: a stoichiometric modeling perspective

PubMed Central

2013-01-01

Background The energetics of cerebral activity critically relies on the functional and metabolic interactions between neurons and astrocytes. Important open questions include the relation between neuronal versus astrocytic energy demand, glucose uptake and intercellular lactate transfer, as well as their dependence on the level of activity. Results We have developed a large-scale, constraint-based network model of the metabolic partnership between astrocytes and glutamatergic neurons that allows for a quantitative appraisal of the extent to which stoichiometry alone drives the energetics of the system. We find that the velocity of the glutamate-glutamine cycle (Vcyc) explains part of the uncoupling between glucose and oxygen utilization at increasing Vcyc levels. Thus, we are able to characterize different activation states in terms of the tissue oxygen-glucose index (OGI). Calculations show that glucose is taken up and metabolized according to cellular energy requirements, and that partitioning of the sugar between different cell types is not significantly affected by Vcyc. Furthermore, both the direction and magnitude of the lactate shuttle between neurons and astrocytes turn out to depend on the relative cell glucose uptake while being roughly independent of Vcyc. Conclusions These findings suggest that, in absence of ad hoc activity-related constraints on neuronal and astrocytic metabolism, the glutamate-glutamine cycle does not control the relative energy demand of neurons and astrocytes, and hence their glucose uptake and lactate exchange. PMID:24112710

Cerebrospinal fluid acid-base status and lactate and pyruvate concentrations after convulsions of varied duration and aetiology in children.

PubMed Central

Simpson, H; Habel, A H; George, E L

1977-01-01

Twenty-two infants and children were studied after convulsions of varied cause and duration. Arterial and CSF acid-base variables, lactate and pyruvate concentrations, and lactate/pyruvate ratios were measured between 3 and 18 hours after convulsive episodes. Biochemical signs of cerebral hypoxia were found in 7 patients with prolonged (greater than 30 minutes) or recurrent short convulsions. These signs were absent in patients with single short convulsions. These findings indicate that cerebral hypoxia and possible brain damage is a hazard of prolonged or rapidly recurring short convulsions. PMID:23078

Long-term alterations in neural and endocrine processes induced by motherhood in mammals.

PubMed

Bridges, Robert S

2016-01-01

This article is part of a Special Issue "Parental Care". The reproductive experience of pregnancy, lactation and motherhood can significantly remodel the female's biological state, affecting endocrine, neuroendocrine, neural, and immunological processes. The brain, pituitary gland, liver, thymus, and mammary tissue are among the structures that are modified by reproductive experience. The present review that focuses on rodent research, but also includes pertinent studies in sheep and other species, identifies specific changes in these processes brought about by the biological states of pregnancy, parturition, and lactation and how the components of reproductive experience contribute to the remodeling of the maternal brain and organ systems. Findings indicate that prior parity alters key circulating hormone levels and neural receptor gene expression. Moreover, reproductive experience results in modifications in neural processes and glial support. The possible role of pregnancy-induced neurogenesis is considered in the context of neuroplasticity and behavior, and the effects of reproductive experience on maternal memory, i.e. the retention of maternal behavior, together with anxiety and learning are presented. Together, these sets of findings support the concept that the neural and biological state of the adult female is significantly and dramatically altered on a long-term basis by the experiences of parity and motherhood. Remodeling of the maternal brain and other biological systems is posited to help facilitate adaptations to environmental/ecological challenges as the female raises young and ages. Copyright © 2015 Elsevier Inc. All rights reserved.

Grade classification of neuroepithelial tumors using high-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy and pattern recognition.

PubMed

Chen, WenXue; Lou, HaiYan; Zhang, HongPing; Nie, Xiu; Lan, WenXian; Yang, YongXia; Xiang, Yun; Qi, JianPin; Lei, Hao; Tang, HuiRu; Chen, FenEr; Deng, Feng

2011-07-01

Clinical data have shown that survival rates vary considerably among brain tumor patients, according to the type and grade of the tumor. Metabolite profiles of intact tumor tissues measured with high-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy (HRMAS (1)H NMRS) can provide important information on tumor biology and metabolism. These metabolic fingerprints can then be used for tumor classification and grading, with great potential value for tumor diagnosis. We studied the metabolic characteristics of 30 neuroepithelial tumor biopsies, including two astrocytomas (grade I), 12 astrocytomas (grade II), eight anaplastic astrocytomas (grade III), three glioblastomas (grade IV) and five medulloblastomas (grade IV) from 30 patients using HRMAS (1)H NMRS. The results were correlated with pathological features using multivariate data analysis, including principal component analysis (PCA). There were significant differences in the levels of N-acetyl-aspartate (NAA), creatine, myo-inositol, glycine and lactate between tumors of different grades (P<0.05). There were also significant differences in the ratios of NAA/creatine, lactate/creatine, myo-inositol/creatine, glycine/creatine, scyllo-inositol/creatine and alanine/creatine (P<0.05). A soft independent modeling of class analogy model produced a predictive accuracy of 87% for high-grade (grade III-IV) brain tumors with a sensitivity of 87% and a specificity of 93%. HRMAS (1)H NMR spectroscopy in conjunction with pattern recognition thus provides a potentially useful tool for the rapid and accurate classification of human brain tumor grades.

Incorporation of radioactivity from [14C]lactate into the glycogen of cultured mouse astroglial cells. Evidence for gluconeogenesis in brain cells.

PubMed

Dringen, R; Schmoll, D; Cesar, M; Hamprecht, B

1993-05-01

A pure population of astroglial cells was selected from heterogeneous astroglia-rich primary cultures in a medium containing sorbitol instead of glucose. It was shown that astroglial cells synthesize glycogen when they are returned to a glucose-containing medium, and that when [14C]lactate is also present the synthesized glycogen is radioactively labelled. Compared with the degree of incorporation of radioactivity in the presence of tritiated glucose, the incorporation of radioactivity from lactate was small but significant. After incubation of astroglial cells with radioactively labelled lactate, the glycogen was isolated and enzymatically hydrolysed to glucose, which was found to be radioactively labelled. Astrocytes are therefore able to convert lactate to glucosyl residues, a metabolic pathway known as gluconeogenesis. It is proposed that astrocytic gluconeogenesis may consume lactic acid formed in neighboring cells such as neurons, during anaerobic glycolysis at times of high energy demand.

Proton Resonance Spectroscopy Study of the Effects of L-Ornithine-L-Aspartate on the Development of Encephalopathy, Using Localization Pulses with Reduced Specific Absorption Rate

NASA Astrophysics Data System (ADS)

Slotboom, J.; Vogels, B. A. P. M.; Dehaan, J. G.; Creyghton, J. H. N.; Quack, G.; Chamuleau, R. A. F. M.; Bovee, W. M. M. J.

Using the SADLOVE ( single-shot adiabatic localized volume excitation) localization technique with reduced specific absorption rate phase-compensated 2π pulses for localization, in vivo rat brain spectra were obtained in order to study the possible beneficial effects of L-ornithine-L-aspartate (OA) on the development of encephalopathy induced by hyperammonemia in portacaval shunted rats, an experimental model for subacute hepatic encephalopathy. The in vivo1H spectra were quantified using a conjugate-gradient-based frequency-domain fitting procedure. OA treatment resulted in an about threefold lower increase in train lactate ( P < 0.0001) and a slower increase of brain glutamine ( P = 0.022) concentration. However, these changes in brain metabolism, including a significantly lower ammonia concentration during OA treatment, were not associated with a sig significant improvement in clinical symptoms of encephalopathy, suggesting either insufficient decrease in brain ammonia concentration or another effect of OA treatment counteracting the lowering effect on blood and brain ammonia and on brain glutamine and lactate. It is concluded that localized in vivo1H MRS of the brain in combination with other analytical techniques, such as in vivo microdialysis, is helpful in explaining pathophysiological changes during hyperammonemia-induced encephalopathy.

Early metabolic responses to lithium/pilocarpine-induced status epilepticus in rat brain.

PubMed

Imran, Imran; Hillert, Markus H; Klein, Jochen

2015-12-01

The lithium-pilocarpine model of status epilepticus is a well-known animal model of temporal lobe epilepsy. We combined this model with in vivo microdialysis to investigate energy metabolites and acute cellular membrane damage during seizure development. Rats were implanted with dialysis probes and pretreated with lithium chloride (127 mg/kg i.p.). Twenty-four hours later, they received pilocarpine (30 mg/kg s.c.) which initiated seizures within 30 min. In the dialysate from rat hippocampus, we observed a transient increase in glucose and a prominent, five-fold increase in lactate during seizures. Lactate release was because of neuronal activation as it was strongly reduced by infusion of tetrodotoxin, administration of atropine or when seizures were terminated by diazepam or ketamine. In ex vivo assays, mitochondrial function as measured by respirometry was not affected by 90 min of seizures. Extracellular levels of choline, however, increased two-fold and glycerol levels 10-fold, which indicate cellular phospholipid breakdown during seizures. Within 60 min of pilocarpine administration, hydroxylation of salicylate increased two-fold and formation of isoprostanes 20-fold, revealing significant oxidative stress in hippocampal tissue. Increases in lactate, glycerol and isoprostanes were abrogated, and increases in choline were completely prevented, when hippocampal probes were perfused with calcium-free solution. Similarly, administration of pregabalin (100 mg/kg i.p.), a calcium channel ligand, 15 min prior to pilocarpine strongly attenuated parameters of membrane damage and oxidative stress. We conclude that seizure development in a rat model of status epilepticus is accompanied by increases in extracellular lactate, choline and glycerol, and by oxidative stress, while mitochondrial function remains intact for at least 90 min. Membrane damage depends on calcium influx and can be prevented by treatment with pregabalin. Status epilepticus (SE) was induced in rats by lithium-pilocarpine ('Pilo') administration, and extracellular metabolites were measured by microdialysis. Seizures caused several-fold increases in lactate levels which were attenuated by diazepam ('Diaz'), ketamine, atropine and tetrodotoxin (TTX). Indicators of oxidative stress and membrane damage were also increased during seizures. Omission of calcium and pregabalin, a calcium channel blocker, reduced cellular damage induced by SE. © 2015 International Society for Neurochemistry.

An In Vitro Model of the Horse Gut Microbiome Enables Identification of Lactate-Utilizing Bacteria That Differentially Respond to Starch Induction

PubMed Central

Biddle, Amy S.; Black, Samuel J.; Blanchard, Jeffrey L.

2013-01-01

Laminitis is a chronic, crippling disease triggered by the sudden influx of dietary starch. Starch reaches the hindgut resulting in enrichment of lactic acid bacteria, lactate accumulation, and acidification of the gut contents. Bacterial products enter the bloodstream and precipitate systemic inflammation. Hindgut lactate levels are normally low because specific bacterial groups convert lactate to short chain fatty acids. Why this mechanism fails when lactate levels rapidly rise, and why some hindgut communities can recover is unknown. Fecal samples from three adult horses eating identical diets provided bacterial communities for this in vitro study. Triplicate microcosms of fecal slurries were enriched with lactate and/or starch. Metabolic products (short chain fatty acids, headspace gases, and hydrogen sulfide) were measured and microbial community compositions determined using Illumina 16S rRNA sequencing over 12-hour intervals. We report that patterns of change in short chain fatty acid levels and pH in our in vitro system are similar to those seen in in vivo laminitis induction models. Community differences between microcosms with disparate abilities to clear excess lactate suggest profiles conferring resistance of starch-induction conditions. Where lactate levels recover following starch induction conditions, propionate and acetate levels rise correspondingly and taxa related to Megasphaera elsdenii reach levels exceeding 70% relative abundance. In lactate and control cultures, taxa related to Veillonella montpellierensis are enriched as lactate levels fall. Understanding these community differences and factors promoting the growth of specific lactate utilizing taxa may be useful to prevent acidosis under starch-induction conditions. PMID:24098591

An in vitro model of the horse gut microbiome enables identification of lactate-utilizing bacteria that differentially respond to starch induction.

PubMed

Biddle, Amy S; Black, Samuel J; Blanchard, Jeffrey L

2013-01-01

Laminitis is a chronic, crippling disease triggered by the sudden influx of dietary starch. Starch reaches the hindgut resulting in enrichment of lactic acid bacteria, lactate accumulation, and acidification of the gut contents. Bacterial products enter the bloodstream and precipitate systemic inflammation. Hindgut lactate levels are normally low because specific bacterial groups convert lactate to short chain fatty acids. Why this mechanism fails when lactate levels rapidly rise, and why some hindgut communities can recover is unknown. Fecal samples from three adult horses eating identical diets provided bacterial communities for this in vitro study. Triplicate microcosms of fecal slurries were enriched with lactate and/or starch. Metabolic products (short chain fatty acids, headspace gases, and hydrogen sulfide) were measured and microbial community compositions determined using Illumina 16S rRNA sequencing over 12-hour intervals. We report that patterns of change in short chain fatty acid levels and pH in our in vitro system are similar to those seen in in vivo laminitis induction models. Community differences between microcosms with disparate abilities to clear excess lactate suggest profiles conferring resistance of starch-induction conditions. Where lactate levels recover following starch induction conditions, propionate and acetate levels rise correspondingly and taxa related to Megasphaeraelsdenii reach levels exceeding 70% relative abundance. In lactate and control cultures, taxa related to Veillonellamontpellierensis are enriched as lactate levels fall. Understanding these community differences and factors promoting the growth of specific lactate utilizing taxa may be useful to prevent acidosis under starch-induction conditions.

Lactate shuttles in nature.

PubMed

Brooks, G A

2002-04-01

Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilized continuously under fully aerobic conditions. "Cell-cell" and "intracellular lactate shuttle" concepts describe the roles of lactate in the delivery of oxidative and gluconeogenic substrates, as well as in cell signalling. Examples of cell-cell shuttles include lactate exchanges between white-glycolytic and red-oxidative fibres within a working muscle bed, between working skeletal muscle and heart, and between tissues of net lactate release and gluconeogenesis. Lactate exchange between astrocytes and neurons that is linked to glutamatergic signalling in the brain is an example of a lactate shuttle supporting cell-cell signalling. Lactate uptake by mitochondria and pyruvate-lactate exchange in peroxisomes are examples of intracellular lactate shuttles. Lactate exchange between sites of production and removal is facilitated by monocarboxylate transport proteins, of which there are several isoforms, and, probably, also by scaffolding proteins. The mitochondrial lactate-pyruvate transporter appears to work in conjunction with mitochondrial lactate dehydrogenase, which permits lactate to be oxidized within actively respiring cells. Hence mitochondria function to establish the concentration and proton gradients necessary for cells with high mitochondrial densities (e.g. cardiocytes) to take up and oxidize lactate. Arteriovenous difference measurements on working cardiac and skeletal muscle beds as well as NMR spectral analyses of these tissues show that lactate is formed and oxidized within the cells of formation in vivo. Glycolysis and lactate oxidation within cells permits high flux rates and the maintenance of redox balance in the cytosol and mitochondria. Other examples of intracellular lactate shuttles include lactate uptake and oxidation in sperm mitochondria and the facilitation of beta-oxidation in peroxisomes by pyruvate-lactate exchange. An ancient origin to the utility of lactate shuttling is implied by the observation that mitochondria of Saccharomyces cerevisiae contain flavocytochrome b(2), a lactate-cytochrome c oxidoreductase that couples lactate dehydrogenation to the reduction of cytochrome c. The presence of cell-cell and intracellular lactate shuttles gives rise to the notion that glycolytic and oxidative pathways can be viewed as linked, as opposed to alternative, processes, because lactate, the product of one pathway, is the substrate for the other.

Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study.

PubMed

Colen, Chaim B; Shen, Yimin; Ghoddoussi, Farhad; Yu, Pingyang; Francis, Todd B; Koch, Brandon J; Monterey, Michael D; Galloway, Matthew P; Sloan, Andrew E; Mathupala, Saroj P

2011-07-01

Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity.

Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism

PubMed Central

Lundgaard, Iben; Li, Baoman; Xie, Lulu; Kang, Hongyi; Sanggaard, Simon; Haswell, John Douglas R; Sun, Wei; Goldman, Siri; Blekot, Solomiya; Nielsen, Michael; Takano, Takahiro; Deane, Rashid; Nedergaard, Maiken

2015-01-01

Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using 2-photon imaging of a near-infrared 2-deoxyglucose analogue (2DG-IR), that glucose is taken up preferentially by neurons in awake behaving mice. Anesthesia suppressed neuronal 2DG-IR uptake and sensory stimulation was associated with a sharp increase in neuronal, but not astrocytic, 2DG-IR uptake. Moreover, hexokinase, which catalyze the first enzymatic steps in glycolysis, was highly enriched in neurons compared with astrocytes, in mouse as well as in human cortex. These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identifies the neuron as the principal locus of glucose uptake as visualized by functional brain imaging. PMID:25904018

Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism.

PubMed

Lundgaard, Iben; Li, Baoman; Xie, Lulu; Kang, Hongyi; Sanggaard, Simon; Haswell, John D R; Sun, Wei; Goldman, Siri; Blekot, Solomiya; Nielsen, Michael; Takano, Takahiro; Deane, Rashid; Nedergaard, Maiken

2015-04-23

Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using two-photon imaging of a near-infrared 2-deoxyglucose analogue (2DG-IR), that glucose is taken up preferentially by neurons in awake behaving mice. Anaesthesia suppressed neuronal 2DG-IR uptake and sensory stimulation was associated with a sharp increase in neuronal, but not astrocytic, 2DG-IR uptake. Moreover, hexokinase, which catalyses the first enzymatic steps in glycolysis, was highly enriched in neurons compared with astrocytes, in mouse as well as in human cortex. These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identify the neuron as the principal locus of glucose uptake as visualized by functional brain imaging.

¹H MRS characterization of neurochemical profiles in orthotopic mouse models of human brain tumors.

PubMed

Hulsey, Keith M; Mashimo, Tomoyuki; Banerjee, Abhishek; Soesbe, Todd C; Spence, Jeffrey S; Vemireddy, Vamsidhara; Maher, Elizabeth A; Bachoo, Robert M; Choi, Changho

2015-01-01

Glioblastoma (GBM), the most common primary brain tumor, is resistant to currently available treatments. The development of mouse models of human GBM has provided a tool for studying mechanisms involved in tumor initiation and growth as well as a platform for preclinical investigation of new drugs. In this study we used (1) H MR spectroscopy to study the neurochemical profile of a human orthotopic tumor (HOT) mouse model of human GBM. The goal of this study was to evaluate differences in metabolite concentrations in the GBM HOT mice when compared with normal mouse brain in order to determine if MRS could reliably differentiate tumor from normal brain. A TE =19 ms PRESS sequence at 9.4 T was used for measuring metabolite levels in 12 GBM mice and 8 healthy mice. Levels for 12 metabolites and for lipids/macromolecules at 0.9 ppm and at 1.3 ppm were reliably detected in all mouse spectra. The tumors had significantly lower concentrations of total creatine, GABA, glutamate, total N-acetylaspartate, aspartate, lipids/macromolecules at 0.9 ppm, and lipids/macromolecules at 1.3 ppm than did the brains of normal mice. The concentrations of glycine and lactate, however, were significantly higher in tumors than in normal brain. Copyright © 2014 John Wiley & Sons, Ltd.

Isoenzymes of protein kinase C in rat mammary tissue: changes in properties and relative amounts during pregnancy and lactation.

PubMed

Connor, K; Clegg, R A

1993-05-01

Protein kinase isoenzymes belonging to the protein kinase C (PK-C) family present in rat mammary tissue have been resolved from one another by chromatography on hydroxyapatite, and characterized. PK-C alpha is the predominant isoenzyme and is present at a constant level of activity throughout mammary-gland development and differentiation. In contrast, marked changes in the relative abundance of other mammary PK-C isoenzymes accompany the transition from pregnancy to lactation. The sensitivity of mammary PK-C alpha to Ca2+ is greater in tissue from pregnant than from lactating rats. This isoenzyme has other atypical properties consistent with its being more highly phosphorylated than PK-C alpha in rat brain and spleen. One of the protein kinase isoenzymes resolved from mammary tissue recognizes the peptide substrate used to assay AMP-activated kinase and may thus interfere in the determination of this activity. Another is fully active in the absence of Ca2+ and is more than 80% active in the absence of added lipid effectors. A 'housekeeping' role is proposed for PK-C alpha in mammary tissue, whereas the less abundant PK-C isoenzymes may be involved in mammary cell proliferation and differentiation.

Prognostic significance of blood lactate and lactate clearance in trauma patients.

PubMed

Régnier, Marie-Alix; Raux, Mathieu; Le Manach, Yannick; Asencio, Yves; Gaillard, Johann; Devilliers, Catherine; Langeron, Olivier; Riou, Bruno

2012-12-01

Lactate has been shown to be a prognostic biomarker in trauma. Although lactate clearance has already been proposed as an intermediate endpoint in randomized trials, its precise role in trauma patients remains to be determined. Blood lactate levels and lactate clearance (LC) were calculated at admission and 2 and 4 h later in trauma patients. The association of initial blood lactate level and lactate clearance with mortality was tested using receiver-operating characteristics curve, logistic regression using triage scores, Trauma Related Injury Severity Score as a reference standard, and reclassification method. The authors evaluated 586 trauma patients (mean age 38±16 yr, 84% blunt and 16% penetrating, mortality 13%). Blood lactate levels at admission were elevated in 327 (56%) patients. The lactate clearance should be calculated within the first 2 h after admission as LC0-2 h was correlated with LC0-4 h (R=0.55, P<0.001) but not with LC2-4 h (R=0.04, not significant). The lactate clearance provides additional predictive information to initial blood lactate levels and triage scores and the reference score. This additional information may be summarized using a categorical approach (i.e., less than or equal to -20 %/h) in contrast to initial blood lactate. The results were comparable in patients with high (5 mM/l or more) initial blood lactate. Early (0-2 h) lactate clearance is an important and independent prognostic variable that should probably be incorporated in future decision schemes for the resuscitation of trauma patients.

Magnetic resonance imaging spectroscopy in pediatric atypical teratoid rhabdoid tumors of the brain.

PubMed

Bruggers, Carol S; Moore, Kevin

2014-08-01

Pediatric central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRT) are highly malignant tumors characterized by SMARCB1 gene abnormalities. Despite chemoradiation responsiveness, most children die of disease. No imaging findings distinguish ATRT from other malignant brain tumors. This study sought to describe magnetic resonance spectroscopy (MRS) of childhood CNS ATRT and identify metabolite patterns for diagnosis and disease status monitoring. Data from 7 children diagnosed with CNS ATRT from 2007 to 2010, whose imaging included MRS, were retrospectively reviewed. Age at diagnosis ranged from 2.5 to 54 months. Tumors were large with calcium and cysts and avid gadolinium enhancement. All were isointense on T1-weighted imaging and mildly hyperintense on T2-weighted imaging. Short-TE MRS showed prominent lactate+lipid and choline, minimal N-acetyl acetate (NAA), and rarely minimal myoinositol and low creatine peaks. Long TE showed prominent choline, minimal NAA, and rarely low lactate peaks. The combination of prominent choline and lactate+lipids peaks, and generally absent NAA and myoinositol peaks by MRS in this panel of ATRT expands existing information and provides a potentially distinct metabolite profile from other malignant pediatric brain tumors, including medulloblastoma. Prospective, comparative quantitative MRS of ATRT with other pediatric CNS tumors is warranted.

Tissue Proteome Analysis of Different Grades of Human Gliomas Provides Major Cues for Glioma Pathogenesis.

PubMed

Gollapalli, Kishore; Ghantasala, Saicharan; Atak, Apurva; Rapole, Srikanth; Moiyadi, Aliasgar; Epari, Sridhar; Srivastava, Sanjeeva

2017-05-01

Gliomas are heterogeneous and most commonly occurring brain tumors. Blood-brain barrier restricts the entry of brain tumor proteins into blood stream thus limiting the usage of serum or plasma for proteomic analysis. Our study aimed at understanding the molecular basis of aggressiveness of various grades of brain tumors using isobaric tagging for relative and absolute quantification (iTRAQ) based mass spectrometry. Tissue proteomic analysis of various grades of gliomas was performed using four-plex iTRAQ. We labeled five sets (each set consists of control, grade-II, III, and IV tumor samples) of individual glioma patients using iTRAQ reagents. Significantly altered proteins were subjected to bioinformatics analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID). Various metabolic pathways like glycolysis, TCA-cycle, electron transport chain, lactate metabolism, and blood coagulation pathways were majorly observed to be perturbed in gliomas. Most of the identified proteins involved in redox reactions, protein folding, pre-messenger RNA (mRNA) processing, antiapoptosis, and blood coagulation were found to be upregulated in gliomas. Transcriptomics data of glioblastoma multiforme (GBM), low-grade gliomas (LGGs), and controls were downloaded from The Cancer Genome Atlas (TCGA) data portal and further analyzed using BRB-Array tools. Expression levels of a few significantly altered proteins like lactate dehydrogenase, alpha-1 antitrypsin, fibrinogen alpha chain, nucleophosmin, annexin A5, thioredoxin, ferritin light chain, thymosin beta-4-like protein 3, superoxide dismutase-2, and peroxiredoxin-1 and 6 showed a positive correlation with increasing grade of gliomas thereby offering an insight into molecular basis behind their aggressive nature. Several proteins identified in different grades of gliomas are potential grade-specific markers, and perturbed pathways provide comprehensive overview of molecular cues involved in glioma pathogenesis.

Monitoring of glycolytic activity secondary to ischaemia in knee replacement surgery.

PubMed

León-Muñoz, V J; Lisón-Almagro, A J; Hernández-García, C H; López-López, M

2018-04-17

To non-invasively assess tissue lesion secondary to ischaemia applied during knee replacement surgery. Secondary objectives: to assess whether this lesion correlates with the duration of ischaemia and whether instrumental and gender variables influence it. Prospective cohort study. Pre and postoperative serum lactate levels have been determined as an indicator of glycolytic activity secondary to ischaemia in 88 patients. Serum lactate determination was performed by reactive strips of enzymatic-amperometric detection on capillary blood. Preoperative serum lactate levels (mean and SD): 2.467±1.036 mmol/L. Postoperative serum lactate levels: 3.938±2.018 mmol/L. Ischaemia time 102.98±18.25minutes. Postoperative serum lactate levels were significantly higher than preoperative lactate levels. There are no statistical differences according to the time that the ischaemia was prolonged, gender or type of instrumentation used. In our study, postoperative serum lactate values were significantly higher than preoperative lactate values, with no correlation to the duration of ischaemia during knee replacement surgery. Copyright © 2018 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.

Functional significance of brain glycogen in sustaining glutamatergic neurotransmission.

PubMed

Sickmann, Helle M; Walls, Anne B; Schousboe, Arne; Bouman, Stephan D; Waagepetersen, Helle S

2009-05-01

The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present unclear. The significance of glycogen in fueling glutamate uptake into astrocytes was specifically addressed in cultured astrocytes. Moreover, the objective was to elucidate whether glycogen derived energy is important for maintaining glutamatergic neurotransmission, induced by repetitive exposure to NMDA in co-cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue D-[3H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important for the astrocytic compartment. By inhibiting glycogen degradation in co-cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d-lactate, a competitive substrate for the monocarboxylate transporters. Neurotransmitter release was affected by the presence of d-lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment.

Local cerebral hypothermia induced by selective infusion of cold lactated ringer's: a feasibility study in rhesus monkeys.

PubMed

Wang, Bincheng; Wu, Di; Dornbos Iii, David; Shi, Jingfei; Ma, Yanhui; Zhang, Mo; Liu, Yumei; Chen, Jian; Ding, Yuchuan; Luo, Yinghao; Ji, Xunming

2016-06-01

Hypothermia has shown promise as a neuroprotective strategy for stroke. The use of whole body hypothermia has limited clinical utility due to many severe side effects. Selective brain cooling, or local brain hypothermia, has been previously proposed as an alternative treatment strategy. This study investigated the safety, feasibility, and efficacy of selective brain hypothermia induced by local infusion of ice-cold lactated Ringer's solution in rhesus monkeys. Eight male rhesus monkeys were used in this study. Brain temperature in the territory supplied by middle cerebral artery (MCA) was reduced by infusing 100 mL of ice-cold (0 °C) lactated Ringer's solution over 20 min via a micro-catheter placed in the proximal MCA (n = 4). Vital signs and the temperature of the brain and rectum were monitored before and after infusion. Transcranial Doppler, Magnetic resonance imaging (MRI), and digital subtraction angiography (DSA) were used to evaluate cerebral blood flow, cerebrovascular reactivity (CVR), cerebral edema, and vasospasm. Another cohort of rhesus monkeys (n = 4) were used as systemic cooling controls. Oxygen saturation, blood pressure, heart rate, and hematologic analysis of the two groups remained within the normal range after infusion. Mild cerebral hypothermia (<35 °C) was achieved in 10 min (0.3 °C/min) and was maintained for 20 min in local cortex and striatum following local infusion. The average lowest cerebral temperature in the locally cooled animals was 33.9 ± 0.3 °C in the striatum following 20-min infusion. This was not observed in animals cooled by systemic infusion. The decreases in the rectal temperature for local and systemic infusion were 0.5 ± 0.2 °C and 0.5 ± 0.3 °C, respectively. Selective brain cooling did not cause any cerebral edema as determined by MRI or vasospasm in the perfused vessel based on DSA. Selective cerebral hypothermia did not significantly alter CVR. Local infusion of ice-cold lactated Ringer's solution via micro-catheter is a safe and effective method for selective cerebral hypothermia. This cooling method could potentially be developed as a new treatment in acute ischemic stroke.

Consumption of Alcopops During Brain Maturation Period: Higher Impact of Fructose Than Ethanol on Brain Metabolism.

PubMed

El Hamrani, Dounia; Gin, Henri; Gallis, Jean-Louis; Bouzier-Sore, Anne-Karine; Beauvieux, Marie-Christine

2018-01-01

Alcopops are flavored alcoholic beverages sweetened by sodas, known to contain fructose. These drinks have the goal of democratizing alcohol among young consumers (12-17 years old) and in the past few years have been considered as fashionable amongst teenagers. Adolescence, however, is a key period for brain maturation, occurring in the prefrontal cortex and limbic system until 21 years old. Therefore, this drinking behavior has become a public health concern. Despite the extensive literature concerning the respective impacts of either fructose or ethanol on brain, the effects following joint consumption of these substrates remains unknown. Our objective was to study the early brain modifications induced by a combined diet of high fructose (20%) and moderate amount of alcohol in young rats by 13 C Nuclear Magnetic Resonance (NMR) spectroscopy. Wistar rats had isocaloric pair-fed diets containing fructose (HF, 20%), ethanol (Et, 0.5 g/day/kg) or both substrates at the same time (HFEt). After 6 weeks of diet, the rats were infused with 13 C-glucose and brain perchloric acid extracts were analyzed by NMR spectroscopy ( 1 H and 13 C). Surprisingly, the most important modifications of brain metabolism were observed under fructose diet. Alterations, observed after only 6 weeks of diet, show that the brain is vulnerable at the metabolic level to fructose consumption during late-adolescence throughout adulthood in rats. The main result was an increase in oxidative metabolism compared to glycolysis, which may impact lactate levels in the brain and may, at least partially, explain memory impairment in teenagers consuming alcopops.

Economic weights for genetic improvement of lactation persistency and milk yield.

PubMed

Togashi, K; Lin, C Y

2009-06-01

This study aimed to establish a criterion for measuring the relative weight of lactation persistency (the ratio of yield at 280 d in milk to peak yield) in restricted selection index for the improvement of net merit comprising 3-parity total yield and total lactation persistency. The restricted selection index was compared with selection based on first-lactation total milk yield (I(1)), the first-two-lactation total yield (I(2)), and first-three-lactation total yield (I(3)). Results show that genetic response in net merit due to selection on restricted selection index could be greater than, equal to, or less than that due to the unrestricted index depending upon the relative weight of lactation persistency and the restriction level imposed. When the relative weight of total lactation persistency is equal to the criterion, the restricted selection index is equal to the selection method compared (I(1), I(2), or I(3)). The restricted selection index yielded a greater response when the relative weight of total lactation persistency was above the criterion, but a lower response when it was below the criterion. The criterion varied depending upon the restriction level (c) imposed and the selection criteria compared. A curvilinear relationship (concave curve) exists between the criterion and the restricted level. The criterion increases as the restriction level deviates in either direction from 1.5. Without prior information of the economic weight of lactation persistency, the imposition of the restriction level of 1.5 on lactation persistency would maximize change in net merit. The procedure presented allows for simultaneous modification of multi-parity lactation curves.

Low level light in combination with metabolic modulators for effective therapy

NASA Astrophysics Data System (ADS)

Dong, Tingting; Zhang, Qi; Hamblin, Michael R.; Wu, Mei X.

2015-03-01

Vascular damage occurs frequently at the injured brain causing hypoxia and is associated with poor outcomes in the clinics. We found high levels of glycolysis, reduced ATP generation, and increased formation of reactive oxygen species (ROS) and apoptosis in neurons under hypoxia. Strikingly, these adverse events were reversed significantly by noninvasive exposure of injured brain to low-level light (LLL). LLL illumination sustained the mitochondrial membrane potential, constrained cytochrome C leakage in hypoxic cells, and protected them from apoptosis, underscoring a unique property of LLL. The effect of LLL was further bolstered by combination with metabolic substrates such as pyruvate or lactate both in vivo and in vitro. The combinational treatment retained memory and learning activities of injured mice to a normal level, whereas those treated with LLL or pyruvate alone, or sham light displayed partial or severe deficiency in these cognitive functions. In accordance with well-protected learning and memory function, the hippocampal region primarily responsible for learning and memory was completely protected by a combination of LLL and pyruvate, in marked contrast to the severe loss of hippocampal tissue due to secondary damage in control mice. These data clearly suggest that energy metabolic modulators can additively or synergistically enhance the therapeutic effect of LLL in energy-producing insufficient tissues like injured brain. Keywords:

Can we predict pneumococcal bacteremia in patients with severe community-acquired pneumonia?

PubMed

Pereira, José Manuel; Teixeira-Pinto, Armando; Basílio, Carla; Sousa-Dias, Conceição; Mergulhão, Paulo; Paiva, José Artur

2013-12-01

This study aimed to evaluate the role of biomarkers as markers of pneumococcal bacteremia in severe community-acquired pneumonia (SCAP). A prospective, single-center, observational cohort study of 108 patients with SCAP admitted to the intensive care department of a university hospital in Portugal was conducted. Leucocytes, C-reactive protein (CRP), lactate, procalcitonin (PCT), d-dimer, brain natriuretic peptide (BNP), and cortisol were measured within 12 hours after the first antibiotic dose. Fifteen patients (14%) had bacteremic pneumococcal pneumonia (BPP). They had significantly higher levels of median CRP (301 [interquartile range, or IQR], 230-350] mg/L vs 201 [IQR, 103-299] mg/L; P = .023), PCT (40 [IQR, 25-102] ng/mL vs 8 [IQR, 2-26] ng/mL; P < .001), BNP (568 [IQR, 478-2841] pg/mL vs 407 [IQR, 175-989] pg/mL; P = .027), and lactate (5.5 [IQR, 4.5-9.8] mmol/L vs 3.1 [IQR, 1.9-6.2] mmol/L; P = .009) than did patients without BPP. The discriminatory power evaluated by the area under the receiver operating characteristic curve (aROC) for PCT (aROC, 0.79) was superior to lactate (aROC, 0.71), BNP (aROC, 0.67), and CRP (aROC, 0.70). At a cutoff point of 17 ng/mL, PCT showed a sensitivity of 87%, a specificity of 67%, a positive predictive value of 30% and a negative predictive value of 97%, as a marker of pneumococcal bacteremia. In this cohort, significantly higher PCT, BNP, lactate, and CRP levels were found in BPP, and PCT presented the best ability to identify pneumococcal bacteremia. A PCT serum level lower than 17 ng/mL could identify patients with SCAP unlikely to have pneumococcal bacteremia. Copyright © 2013 Elsevier Inc. All rights reserved.

Independent Prognostic Factors for Acute Organophosphorus Pesticide Poisoning.

PubMed

Tang, Weidong; Ruan, Feng; Chen, Qi; Chen, Suping; Shao, Xuebo; Gao, Jianbo; Zhang, Mao

2016-07-01

Acute organophosphorus pesticide poisoning (AOPP) is becoming a significant problem and a potential cause of human mortality because of the abuse of organophosphate compounds. This study aims to determine the independent prognostic factors of AOPP by using multivariate logistic regression analysis. The clinical data for 71 subjects with AOPP admitted to our hospital were retrospectively analyzed. This information included the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, admission blood cholinesterase levels, 6-h post-admission blood cholinesterase levels, cholinesterase activity, blood pH, and other factors. Univariate analysis and multivariate logistic regression analyses were conducted to identify all prognostic factors and independent prognostic factors, respectively. A receiver operating characteristic curve was plotted to analyze the testing power of independent prognostic factors. Twelve of 71 subjects died. Admission blood lactate levels, 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, blood pH, and APACHE II scores were identified as prognostic factors for AOPP according to the univariate analysis, whereas only 6-h post-admission blood lactate levels, post-admission 6-h lactate clearance rates, and blood pH were independent prognostic factors identified by multivariate logistic regression analysis. The receiver operating characteristic analysis suggested that post-admission 6-h lactate clearance rates were of moderate diagnostic value. High 6-h post-admission blood lactate levels, low blood pH, and low post-admission 6-h lactate clearance rates were independent prognostic factors identified by multivariate logistic regression analysis. Copyright © 2016 by Daedalus Enterprises.

NMR-based metabolomics approach to study the toxicity of lambda-cyhalothrin to goldfish (Carassius auratus).

PubMed

Li, Minghui; Wang, Junsong; Lu, Zhaoguang; Wei, Dandan; Yang, Minghua; Kong, Lingyi

2014-01-01

In this study, a (1)H nuclear magnetic resonance (NMR) based metabolomics approach was applied to investigate the toxicity of lambda-cyhalothrin (LCT) in goldfish (Carassius auratus). LCT showed tissue-specific damage to gill, heart, liver and kidney tissues of goldfish. NMR profiling combined with statistical methods such as orthogonal partial least squares discriminant analysis (OPLS-DA) and two-dimensional statistical total correlation spectroscopy (2D-STOCSY) was developed to discern metabolite changes occurring after one week LCT exposure in brain, heart and kidney tissues of goldfish. LCT exposure influenced levels of many metabolites (e.g., leucine, isoleucine and valine in brain and kidney; lactate in brain, heart and kidney; alanine in brain and kidney; choline in brain, heart and kidney; taurine in brain, heart and kidney; N-acetylaspartate in brain; myo-inositol in brain; phosphocreatine in brain and heart; 2-oxoglutarate in brain; cis-aconitate in brain, and etc.), and broke the balance of neurotransmitters and osmoregulators, evoked oxidative stress, disturbed metabolisms of energy and amino acids. The implication of glutamate-glutamine-gamma-aminobutyric axis in LCT induced toxicity was demonstrated for the first time. Our findings demonstrated the applicability and potential of metabolomics approach for the elucidation of toxicological effects of pesticides and the underlying mechanisms, and the discovery of biomarkers for pesticide pollution in aquatic environment. Copyright © 2013 Elsevier B.V. All rights reserved.

Blood lactate changes in professional Indian divers under hyperbaric conditions

PubMed Central

Sikri, Gaurav; Singh, S.P.; Srinivasa, A.B.; Chaudhry, H.B.S.

2016-01-01

Background Hyperoxia due to hyperbaric conditions influences lactate metabolism. Previous studies on lactate levels in hyperbaric conditions have reported varied results depending on the depth of evaluation and breathing gas mixture used. Methods This study compared post-exercise blood lactate levels of Indian professional male divers (breathing ambient air under normobaric conditions) with their post-exercise blood lactate levels measured under simulated hyperbaric conditions. Result In the present study, blood lactate levels in divers were found to have decreased significantly during recovery phase of exercise in hyperbaric conditions of dry diving at 2.8 Atmospheres Absolute (ATA) as compared to normobaric conditions. A significant improvement was observed in physical performance in terms of HR max and duration of exercise. Conclusion This study revealed that hyperoxia due to moderate hyperbaric condition leads to improvement in lactate metabolism in muscles and organs (liver and heart) for its removal. PMID:26900221

The potential for oxytocin (OT) to prevent breast cancer: a hypothesis.

PubMed

Murrell, T G

1995-08-01

This hypothesis proposes that carcinogens in the breast are generated by the action of superoxide free radicals released when acinal gland distension, under the influence of unopposed prolactin, causes microvessel ischaemia. Inadequate nipple care in the at-risk years leads to ductal obstruction preventing the elimination of carcinogens from the breast. The regular production of oxytocin (OT) from nipple stimulation would cause contraction of the myoepithelial cells, relieving acinal gland distension and aiding the active elimination of carcinogenic fluid from the breast. Mechanical breast pump stimulation causes an increase in plasma OT levels in the luteal but not in the follicular phase of the menstrual cycle. OT production upon nipple stimulation in the luteal phase of premenopausal, non-lactating women may be protective against the high rates of mitotic breast cell division noted at this time via the potential to block the effect of oestrogen. The epidemiology of breast cancer suggests that lengthy lactation time is beneficial. Sexual activity in nulliparous women also protects and OT levels have been shown to rise with orgasm in women and in men. OT systems in the brain are intricately linked to oestrogen and progesterone levels, and it is possible that these hormones may modify the OT secretory response both centrally and through an effect on the sensitivity of the breast. OT production with nipple care and in sex and lactation, and the reduction in cycling ovarian hormones that occurs with pregnancy, may all be important preventative factors in the development of breast cancer both pre- and post-menopausally.

Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis.

PubMed

Li, H; Sun, J; Du, J; Wang, F; Fang, R; Yu, C; Xiong, J; Chen, W; Lu, Z; Liu, J

2018-05-01

Traumatic brain injury (TBI) is a common occurrence following gastrointestinal dysfunction. Recently, more and more attentions are being focused on gut microbiota in brain and behavior. Glucagon-like peptide-1 (GLP-1) is considered as a mediator that links the gut-brain axis. The aim of this study was to explore the neuroprotective effects of Clostridium butyricum (Cb) on brain damage in a mouse model of TBI. Male C57BL/6 mice were subjected to a model of TBI-induced by weight-drop impact head injury and were treated intragastrically with Cb. The cognitive deficits, brain water content, neuronal death, and blood-brain barrier (BBB) permeability were evaluated. The expression of tight junction (TJ) proteins, Bcl-2, Bax, GLP-1 receptor (GLP-1R), and phosphorylation of Akt (p-Akt) in the brain were also measured. Moreover, the intestinal barrier permeability, the expression of TJ protein and GLP-1, and IL-6 level in the intestine were detected. Cb treatment significantly improved neurological dysfunction, brain edema, neurodegeneration, and BBB impairment. Meanwhile, Cb treatment also significantly increased the expression of TJ proteins (occludin and zonula occluden-1), p-Akt and Bcl-2, but decreased expression of Bax. Moreover, Cb treatment exhibited more prominent effects on decreasing the levels of plasma d-lactate and colonic IL-6, upregulating expression of Occludin, and protecting intestinal barrier integrity. Furthermore, Cb-treated mice showed increased the secretion of intestinal GLP-1 and upregulated expression of cerebral GLP-1R. Our findings demonstrated the neuroprotective effect of Cb in TBI mice and the involved mechanisms were partially attributed to the elevating GLP-1 secretion through the gut-brain axis. © 2017 John Wiley & Sons Ltd.

In utero and Lactational Exposure to Acetamiprid Induces Abnormalities in Socio-Sexual and Anxiety-Related Behaviors of Male Mice

PubMed Central

Sano, Kazuhiro; Isobe, Tomohiko; Yang, Jiaxin; Win-Shwe, Tin-Tin; Yoshikane, Mitsuha; Nakayama, Shoji F.; Kawashima, Takaharu; Suzuki, Go; Hashimoto, Shunji; Nohara, Keiko; Tohyama, Chiharu; Maekawa, Fumihiko

2016-01-01

Neonicotinoids, a widely used group of pesticides designed to selectively bind to insect nicotinic acetylcholine receptors, were considered relatively safe for mammalian species. However, they have been found to activate vertebrate nicotinic acetylcholine receptors and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most widely used neonicotinoids, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control group), 1.0 mg/kg (low-dose group), or 10.0 mg/kg (high-dose group) from gestational day 6 to lactation day 21. The results of a battery of behavior tests for socio-sexual and anxiety-related behaviors, the numbers of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and testosterone levels were used as endpoints. In addition, behavioral flexibility in mice was assessed in a group-housed environment using the IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, a significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety levels nor the sexual behaviors of females were altered. No reductions in the testosterone level, the number of vasopressin-immunoreactive cells, or behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically. PMID:27375407

Increase of extracellular glutamate concentration increases its oxidation and diminishes glucose oxidation in isolated mouse hippocampus: reversible by TFB-TBOA.

PubMed

Torres, Felipe Vasconcelos; Hansen, Fernanda; Locks-Coelho, Lucas Doridio

2013-08-01

Glutamate concentration at the synaptic level must be kept low in order to prevent excitotoxicity. Astrocytes play a key role in brain energetics, and also astrocytic glutamate transporters are responsible for the vast majority of glutamate uptake in CNS. Experiments with primary astrocytic cultures suggest that increased influx of glutamate cotransported with sodium at astrocytes favors its flux to the tricarboxylic acid cycle instead of the glutamate-glutamine cycle. Although metabolic coupling can be considered an emergent field of research with important recent discoveries, some basic aspects of glutamate metabolism still have not been characterized in brain tissue. Therefore, the aim of this study was to investigate whether the presence of extracellular glutamate is able to modulate the use of glutamate and glucose as energetic substrates. For this purpose, isolated hippocampi of mice were incubated with radiolabeled substrates, and CO2 radioactivity and extracellular lactate were measured. Our results point to a diminished oxidation of glucose with increasing extracellular glutamate concentration, glutamate presumably being the fuel, and might suggest that oxidation of glutamate could buffer excitotoxic conditions by high glutamate concentrations. In addition, these findings were reversed when glutamate uptake by astrocytes was impaired by the presence of (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]-L-aspartic acid (TFB-TBOA). Taken together, our findings argue against the lactate shuttle theory, because glutamate did not cause any detectable increase in extracellular lactate content (or, presumably, in glycolysis), because the glutamate is being used as fuel instead of going to glutamine and back to neurons. Copyright © 2013 Wiley Periodicals, Inc.

Altered brain functional connectivity and behaviour in a mouse model of maternal alcohol binge-drinking.

PubMed

Cantacorps, Lídia; González-Pardo, Héctor; Arias, Jorge L; Valverde, Olga; Conejo, Nélida M

2018-06-08

Prenatal and perinatal alcohol exposure caused by maternal alcohol intake during gestation and lactation periods can have long-lasting detrimental effects on the brain development and behaviour of offspring. Children diagnosed with Foetal Alcohol Spectrum Disorders (FASD) display a wide range of cognitive, emotional and motor deficits, together with characteristic morphological abnormalities. Maternal alcohol binge drinking is particularly harmful for foetal and early postnatal brain development, as it involves exposure to high levels of alcohol over short periods of time. However, little is known about the long-term effects of maternal alcohol binge drinking on brain function and behaviour. To address this issue, we used pregnant C57BL/6 female mice with time-limited access to a 20% v/v alcohol solution as a procedure to model alcohol binge drinking during gestation and lactational periods. Male offspring were behaviourally tested during adolescence (30 days) and adulthood (60 days), and baseline neural metabolic capacity of brain regions sensitive to alcohol effects were also evaluated in adult animals from both groups. Our results show that prenatal and postnatal alcohol exposure caused age-dependent changes in spontaneous locomotor activity, increased anxiety-like behaviour and attenuated alcohol-induced conditioned place preference in adults. Also, significant changes in neural metabolic capacity using cytochrome c oxidase (CCO) quantitative histochemistry were found in the hippocampal dentate gyrus, the mammillary bodies, the ventral tegmental area, the lateral habenula and the central lobules of the cerebellum in adult mice with prenatal and postnatal alcohol exposure. In addition, the analysis of interregional CCO activity correlations in alcohol-exposed adult mice showed disrupted functional brain connectivity involving the limbic, brainstem, and cerebellar regions. Finally, increased neurogenesis was found in the dentate gyrus of the hippocampus of alcohol-exposed offspring, suggesting neuroadaptive effects due to early alcohol exposure. Our results demonstrate that maternal binge-like alcohol drinking causes long-lasting effects on motor and emotional-related behaviours associated with impaired neuronal metabolic capacity and altered functional brain connectivity. Copyright © 2018 Elsevier Inc. All rights reserved.

Ethylene glycol ethers induce apoptosis and disturb glucose metabolism in the rat brain.

PubMed

Pomierny, Bartosz; Krzyżanowska, Weronika; Niedzielska, Ewa; Broniowska, Żaneta; Budziszewska, Bogusława

2016-02-01

Ethylene glycol ethers (EGEs) are compounds widely used in industry and household products, but their potential, adverse effect on brain is poorly understood, so far. The aim of the present study was to determine whether 4-week administration of 2-buthoxyethanol (BE), 2-phenoxyethanol (PHE), and 2-ethoxyethanol (EE) induces apoptotic process in the rat hippocampus and frontal cortex, and whether their adverse effect on the brain cells can result from disturbances in the glucose metabolism. Experiments were conducted on 40 rats, exposed to BE, PHE, EE, saline or sunflower oil for 4 weeks. Markers of apoptosis and glucose metabolism were determined in frontal cortex and hippocampus by western blot, ELISA, and fluorescent-based assays. BE and PHE, but not EE, increased expression of the active form of caspase-3 in the examined brain regions. BE and PHE increased caspase-9 level in the cortex and PHE also in the hippocampus. BE and PHE increased the level of pro-apoptotic proteins (Bax, Bak) and/or reduced the concentration of anti-apoptotic proteins (Bcl-2, Bcl-xL); whereas, the effect of BE was observed mainly in the cortex and that of PHE in the hippocampus. It has also been found that PHE increased brain glucose level, and both BE and PHE elevated pyruvate and lactate concentration. It can be concluded that chronic treatment with BE and PHE induced mitochondrial pathway of apoptosis, and disturbed glucose metabolism in the rat brain. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease.

PubMed

Kolko, Miriam; Vosborg, Fia; Henriksen, Ulrik L; Hasan-Olive, Md Mahdi; Diget, Elisabeth Holm; Vohra, Rupali; Gurubaran, Iswariya Raja Sridevi; Gjedde, Albert; Mariga, Shelton Tendai; Skytt, Dorte M; Utheim, Tor Paaske; Storm-Mathisen, Jon; Bergersen, Linda H

2016-06-01

In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.

Maternal Western diet during gestation and lactation modifies adult offspring's cognitive and hedonic brain processes, behavior, and metabolism in Yucatan minipigs.

PubMed

Gautier, Yentl; Luneau, Isabelle; Coquery, Nicolas; Meurice, Paul; Malbert, Charles-Henri; Guerin, Sylvie; Kemp, Bas; Bolhuis, J Elizabeth; Clouard, Caroline; Le Huërou-Luron, Isabelle; Blat, Sophie; Val-Laillet, David

2018-06-13

This study explores the long-term effects of exposure to a maternal Western diet (WD) vs. standard diet (SD) in the Yucatan minipig, on the adult progeny at lean status ( n = 32), and then overweight status. We investigated eating behavior, cognitive abilities, brain basal glucose metabolism, dopamine transporter availability, microbiota activity, blood lipids, and glucose tolerance. Although both groups demonstrated similar cognitive abilities in a holeboard test, WD pigs expressed a higher stress level than did SD pigs (immobility, P < 0.05) and lower performance in an alley maze ( P = 0.06). WD pigs demonstrated lower dopamine transporter binding potential in the hippocampus and parahippocampal cortex ( P < 0.05 for both), as well as a trend in putamen ( P = 0.07), associated with lower basal brain activity in the prefrontal cortex and nucleus accumbens ( P < 0.05) compared with lean SD pigs. Lean WD pigs demonstrated a lower glucose tolerance than did SD animals (higher glucose peak, P < 0.05) and a tendency to a higher incremental area under the curve of insulin from 0 to 30 minutes after intravenous glucose injection ( P < 0.1). Both groups developed glucose intolerance with overweight, but WD animals were less impacted than SD animals. These results demonstrate that maternal diet shaped the offspring's brain functions and cognitive responses long term, even after being fed a balanced diet from weaning, but behavioral effects were only revealed in WD pigs under anxiogenic situation; however, WD animals seemed to cope better with the obesogenic diet from a metabolic standpoint.-Gautier, Y., Luneau, I., Coquery, N., Meurice, P., Malbert, C.-H., Guerin, S., Kemp, B., Bolhuis, J. E., Clouard, C., Le Huërou-Luron, I., Blat, S., Val-Laillet, D. Maternal Western diet during gestation and lactation modifies adult offspring's cognitive and hedonic brain processes, behavior, and metabolism in Yucatan minipigs.

Elevated lactate during psychogenic hyperventilation.

PubMed

ter Avest, E; Patist, F M; Ter Maaten, J C; Nijsten, M W N

2011-04-01

Elevated arterial lactate levels are closely related to morbidity and mortality in various patient categories. In the present retrospective study, the relation between arterial lactate, partial pressure of carbon dioxide (Pco(2)) and pH was systematically investigated in patients who visited the emergency department (ED) with psychogenic hyperventilation. Over a 5-month period, all the patients who visited the ED of a university hospital with presumed psychogenic hyperventilation were evaluated. Psychogenic hyperventilation was presumed to be present when an increased respiratory rate (>20 min) was documented at or before the ED visit and when somatic causes explaining the hyperventilation were absent. Arterial blood gas and lactate levels (reference values 0.5-1.5 mmol/l) were immediately measured by a point-of-care analyser that was managed and calibrated by the central laboratory. During the study period, 46 patients were diagnosed as having psychogenic hyperventilation. The median (range) Pco(2) for this group was 4.3 (2.0-5.5) kPa, the pH was 7.47 (7.40-7.68) and the lactate level was 1.2 (0.5-4.4) mmol/l. 14 participants (30%) had a lactate level above the reference value of 1.5 mmol/l. Pco(2) was the most important predictor of lactate in multivariate analysis. None of the participants underwent any medical treatment other than observation at the ED or had been hospitalised after their ED visit. In patients with psychogenic hyperventilation, lactate levels are frequently elevated. Whereas high lactates are usually associated with acidosis and an increased risk of poor outcome, in patients with psychogenic hyperventilation, high lactates are associated with hypocapnia and alkalosis. In this context, elevated arterial lactate levels should not be regarded as an adverse sign.

In VivoLactate Editing with Simultaneous Detection of Choline, Creatine, NAA, and Lipid Singlets at 1.5 T Using PRESS Excitation with Applications to the Study of Brain and Head and Neck Tumors

NASA Astrophysics Data System (ADS)

Star-Lack, Josh; Spielman, Daniel; Adalsteinsson, Elfar; Kurhanewicz, John; Terris, David J.; Vigneron, Daniel B.

1998-08-01

Two T2-independentJ-difference lactate editing schemes for the PRESS magnetic resonance spectroscopy localization sequence are introduced. The techniques, which allow for simultaneous acquisition of the lactate doublet (1.3 ppm) and edited singlets upfield of and including choline (3.2 ppm), exploit the dependence of the in-phase intensity of the methyl doublet upon the time interval separating two inversion (BASING) pulses applied to its coupling partner after initial excitation. Editing method 1, which allows for echo times TE =n/J(n= 1, 2, 3, …), alters the BASING carrier frequency for each of two cycles so that, for one cycle, the quartet is inverted, whereas, for the other cycle, the quartet is unaffected. Method 2, which also provides water suppression, allows for editing for TE > 1/Jby alternating, between cycles, the time interval separating the inversion pulses. Experimental results were obtained at 1.5 T using a Shinnar Le-Roux-designed maximum phase inversion pulse with a filter transition bandwidth of 55 Hz. Spectra were acquired from phantoms andin vivofrom the human brain and neck. In a neck muscle study, the lipid suppression factor, achieved partly through the use of a novel phase regularization algorithm, was measured to be over 103. Spectra acquired from a primary brain and a metastatic neck tumor demonstrated the presence of lactate and choline signals consistent with abnormal spectral patterns. The advantages and limitations of the methods are analyzed theoretically and experimentally, and significance of the results is discussed.

Metabolic Targeting of Lactate Efflux by Malignant Glioma Inhibits Invasiveness and Induces Necrosis: An In Vivo Study1

PubMed Central

Colen, Chaim B; Shen, Yimin; Ghoddoussi, Farhad; Yu, Pingyang; Francis, Todd B; Koch, Brandon J; Monterey, Michael D; Galloway, Matthew P; Sloan, Andrew E; Mathupala, Saroj P

2011-01-01

Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity. PMID:21750656

Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain.

PubMed

Martin, Pamela M; Gopal, Elangovan; Ananth, Sudha; Zhuang, Lina; Itagaki, Shiro; Prasad, Balakrishna M; Smith, Sylvia B; Prasad, Puttur D; Ganapathy, Vadivel

2006-07-01

SMCT1 is a sodium-coupled (Na(+)-coupled) transporter for l-lactate and short-chain fatty acids. Here, we show that the ketone bodies, beta-d-hydroxybutyrate and acetoacetate, and the branched-chain ketoacid, alpha-ketoisocaproate, are also substrates for the transporter. The transport of these compounds via human SMCT1 is Na(+)-coupled and electrogenic. The Michaelis constant is 1.4 +/- 0.1 mm for beta-d-hydroxybutyrate, 0.21 +/- 0.04 mm for acetoacetate and 0.21 +/- 0.03 mm for alpha-ketoisocaproate. The Na(+) : substrate stoichiometry is 2 : 1. As l-lactate and ketone bodies constitute primary energy substrates for neurons, we investigated the expression pattern of this transporter in the brain. In situ hybridization studies demonstrate widespread expression of SMCT1 mRNA in mouse brain. Immunofluorescence analysis shows that SMCT1 protein is expressed exclusively in neurons. SMCT1 protein co-localizes with MCT2, a neuron-specific Na(+)-independent monocarboxylate transporter. In contrast, there was no overlap of signals for SMCT1 and MCT1, the latter being expressed only in non-neuronal cells. We also demonstrate the neuron-specific expression of SMCT1 in mixed cultures of rat cortical neurons and astrocytes. This represents the first report of an Na(+)-coupled transport system for a major group of energy substrates in neurons. These findings suggest that SMCT1 may play a critical role in the entry of l-lactate and ketone bodies into neurons by a process driven by an electrochemical Na(+) gradient and hence, contribute to the maintenance of the energy status and function of neurons.

[Bone loss in lactating women and post-pregnancy osteoporosis].

PubMed

Hirata, Go; Chaki, Osamu

2011-09-01

Measurement of the bone mineral density have shown that lactating women had 1 to 3% decrease in bone mineral density. Post pregnancy osteoporosis is rare condition that causes fragile fracture mostly in vertebrae. The bone loss in lactating women is caused by calcium loss, decrease in estrogen level, and increase in PTHrP (parathyroid hormone related protein) level. Some data have shown that extended lactation and amenorrhea had an association with the degree of bone loss. Mostly, the bone loss of the lactating women recovers to the baseline level, soon after the weaning, and there is no long term effect. Post pregnancy osteoporosis should be concerned, when we see a lactating woman with fragile fracture of the vertebrae.

Brain MRI and MR Spectroscopy Findings in Children with Nutritional Vitamin B12 Deficiency.

PubMed

Ekici, F; Tekbas, G; Hattapoğlu, S; Yaramış, A; Önder, H; Bilici, A

2016-06-01

Our aim in this study was to analyze the findings of brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) of children with vitamin B12 deficiency. This study included 14 cases. The findings of brain MRI and MRS in all cases were investigated. Four patients had been followed up and mean follow-up time 71.8 (59-85) day. Eight patients of the cases (57 %) had at least one abnormal MRI finding. The most commonly found MRI findings were thinning of the corpus callosum and brain atrophy, respectively. The mean ratio of NAA/Cr and Cho/Cr were measured in MRS, with values of 1.31 ± 0.17 and 1.04 ± 0.27, respectively. In two of three patients with abnormal MRI studies at presentation, subsequent MRI showed improvement while one patient remained unchanged. An increase in the ratios of metabolites were found in one case with control MRS. There was no lactate peak. Brain MRI was abnormal in more than half of the cases of children with vitamin B12 deficiency. Our radiologic findings similar with literature. There was no identifiable lactate peak. B12 deficiency could be the cause of the thinning of the corpus callosum and brain atrophy in the children that were given a brain MRI.

The prognostic value of blood lactate levels relative to that of vital signs in the pre-hospital setting: a pilot study

PubMed Central

Jansen, Tim C; van Bommel, Jasper; Mulder, Paul G; Rommes, Johannes H; Schieveld, Selma JM; Bakker, Jan

2008-01-01

Introduction A limitation of pre-hospital monitoring is that vital signs often do not change until a patient is in a critical stage. Blood lactate levels are suggested as a more sensitive parameter to evaluate a patient's condition. The aim of this pilot study was to find presumptive evidence for a relation between pre-hospital lactate levels and in-hospital mortality, corrected for vital sign abnormalities. Methods In this prospective observational study (n = 124), patients who required urgent ambulance dispatching and had a systolic blood pressure below 100 mmHg, a respiratory rate less than 10 or more than 29 breaths/minute, or a Glasgow Coma Scale (GCS) below 14 were enrolled. Nurses from Emergency Medical Services measured capillary or venous lactate levels using a hand-held device on arrival at the scene (T1) and just before or on arrival at the emergency department (T2). The primary outcome measured was in-hospital mortality. Results The average (standard deviation) time from T1 to T2 was 27 (10) minutes. Non-survivors (n = 32, 26%) had significantly higher lactate levels than survivors at T1 (5.3 vs 3.7 mmol/L) and at T2 (5.4 vs 3.2 mmol/L). Mortality was significantly higher in patients with lactate levels of 3.5 mmol/L or higher compared with those with lactate levels below 3.5 mmol/L (T1: 41 vs 12% and T2: 47 vs 15%). Also in the absence of hypotension, mortality was higher in those with higher lactate levels. In a multivariable Cox proportional hazard analysis including systolic blood pressure, heart rate, GCS (all at T1) and delta lactate level (from T1 to T2), only delta lactate level (hazard ratio (HR) = 0.20, 95% confidence interval (CI) = 0.05 to 0.76, p = 0.018) and GCS (HR = 0.93, 95% CI = 0.88 to 0.99, p = 0.022) were significant independent predictors of in-hospital mortality. Conclusions In a cohort of patients that required urgent ambulance dispatching, pre-hospital blood lactate levels were associated with in-hospital mortality and provided prognostic information superior to that provided by the patient's vital signs. There is potential for early detection of occult shock and pre-hospital resuscitation guided by lactate measurement. However, external validation is required before widespread implementation of lactate measurement in the out-of-hospital setting. PMID:19091118

Correlation of Lactate Concentration in Peripheral Plasma and Cerebrospinal Fluid with Glasgow Outcome Scale for Patients with Tuberculous Meningitis Complicated by Acute Hydrocephalus Treated with Fluid Diversions.

PubMed

Faried, Ahmad; Arief, Gusman; Arifin, Muhammad Z; Nataprawira, Heda M

2018-03-01

Tuberculous meningitis (TBM) is an endemic infectious disease in developing countries, and it can become a serious illness in children. Treatment of TBM is more difficult and prone to failure than treatment of pulmonary tuberculosis. TBM causes hydrocephalus, cerebral edema, increased intracranial pressure, global ischemia, and neurologic deficits, which disturb cellular metabolism and increase lactate levels. A reliable, widely available clinical indicator of TBM severity is needed. Successful treatment of TBM is assessed using the Glasgow Outcome Scale (GOS). This prospective cohort study included 34 patients with TBM and acute hydrocephalus who had undergone fluid diversions and were admitted to Dr. Hasan Sadikin Hospital in Bandung from 2014 to 2015. A portable machine for blood glucose measurement was used to measure lactate concentrations. Statistical significance was defined as P ≤ 0.05. Average levels of plasma and cerebrospinal fluid (CSF) lactate were 1.99 ± 0.70 mmol/L and 3.04 ± 1.05 mmol/L, respectively. A significantly higher level of lactate was observed in CSF compared with plasma. Preoperative plasma lactate was negatively correlated to GOS (r = -0.539; P = 0.013), and CSF lactate was negatively correlated to GOS (r = -0.412; P = 0.027). Average lactate levels in CSF (central) were higher than plasma (peripheral) levels. GOS scale of patients decreased with increased plasma and CSF lactate levels. Examination of plasma and CSF lactate levels should be included in routine examinations to determine extent of cellular damage and GOS score in patients with TBM and acute hydrocephalus who have undergone fluid diversions. Copyright © 2017 Elsevier Inc. All rights reserved.

The Transcriptional Response of Listeria monocytogenes during Adaptation to Growth on Lactate and Diacetate Includes Synergistic Changes That Increase Fermentative Acetoin Production▿†

PubMed Central

Stasiewicz, Matthew J.; Wiedmann, Martin; Bergholz, Teresa M.

2011-01-01

The organic acids lactate and diacetate are commonly used in combination in ready-to-eat foods because they show synergistic ability to inhibit the growth of Listeria monocytogenes. Full-genome microarrays were used to investigate the synergistic transcriptomic responses of two L. monocytogenes strains, H7858 (serotype 4b) and F6854 (serotype 1/2a), to these two organic acids under conditions representing osmotic and cold stress encountered in foods. Strains were exposed to brain heart infusion (BHI) broth at 7°C with 4.65% water-phase (w.p.) NaCl at pH 6.1 with (i) 2% w.p. potassium lactate, (ii) 0.14% w.p. sodium diacetate, (iii) the combination of both at the same levels, or (iv) no organic acids as a control. RNA was extracted 8 h after exposure, during lag phase, to capture gene transcription changes during adaptation to the organic acid stress. Significant differential transcription of 1,041 genes in H7858 and 640 genes in F6854 was observed in at least one pair of the 4 different treatments. The effects of combined treatment with lactate and diacetate included (i) synergistic transcription differences for 474 and 209 genes in H7858 and F6854, respectively, (ii) differential transcription of genes encoding cation transporters and ABC transporters of metals, and (iii) altered metabolism, including induction of a nutrient-limiting stress response, reduction of menaquinone biosynthesis, and a shift from fermentative production of acetate and lactate to energetically less favorable, neutral acetoin. These data suggest that additional treatments that interfere with cellular energy generation processes could more efficiently inhibit the growth of L. monocytogenes. PMID:21666015

Aging-associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte-to-neuron lactate shuttle.

PubMed

Drulis-Fajdasz, Dominika; Gizak, Agnieszka; Wójtowicz, Tomasz; Wiśniewski, Jacek R; Rakus, Dariusz

2018-03-01

Lactate derived from astrocytic glycogen has been shown to support memory formation in hippocampi of young animals, inhibiting it in old animals. Here we show, using quantitative mass spectrometry-based proteomics, immunofluorescence, and qPCR that aging is associated with an increase of glycogen metabolism enzymes concentration and shift in their localization from astrocytes to neurons. These changes are accompanied with reorganization of hippocampal energy metabolism which is manifested by elevated capacity of aging neurons to oxidize glucose in glycolysis and mitochondria, and decreased ability for fatty acids utilization. Our observations suggest that astrocyte-to-neuron lactate shuttle may operate in young hippocampi, however, during aging neurons become independent on astrocytic lactate and the metabolic crosstalk between the brain's cells is disrupted. © 2018 The Authors GLIA Published by Wiley Periodicals, Inc.

[ARTCEREB irrigation and perfusion solution for cerebrospinal surgery: pharmacological assessment using human astrocytes exposed to test solutions].

PubMed

Nishimura, Masuhiro; Doi, Kazuhisa; Enomoto, Riyo; Lee, Eibai; Naito, Shinsaku; Yamauchi, Aiko

2009-09-01

ARTCEREB irrigation and perfusion solution (Artcereb) is a preparation intended for the irrigation and perfusion of the cerebral ventricles, and it is therefore important to evaluate the effects of Artcereb on brain cells. In vitro assessment of the effects of Artcereb in cell cultures of human fetal astrocytes was conducted in comparison with normal saline and lactated Ringer's solution. The effects of exposure to Artcereb were evaluated based on microscopic images of the mitochondria stained with rhodamine 123. The effects of exposure to Artcereb on cell function were also evaluated by quantitative analysis of mitochondrial activity based on rhodamine 123 and (3)H-thymidine incorporation. Morphological changes in nuclear structure were also evaluated. The results of the present study showed that cell function in cell cultures of human astrocytes was relatively unaffected by exposure to Artcereb as compared with normal saline or lactated Ringer's solution, suggesting that Artcereb has less effect on brain cells than normal saline or lactated Ringer's solution when used for the irrigation or perfusion of the cerebral ventricles.

The effect of level of feeding, genetic merit, body condition score and age on biological parameters of a mammary gland model.

PubMed

Bryant, J R; Lopez-Villalobos, N; Holmes, C W; Pryce, J E; Pitman, G D; Davis, S R

2007-03-01

An evolutionary algorithm was applied to a mechanistic model of the mammary gland to find the parameter values that minimised the difference between predicted and actual lactation curves of milk yields in New Zealand Jersey cattle managed at different feeding levels. The effect of feeding level, genetic merit, body condition score at parturition and age on total lactation yields of milk, fat and protein, days in milk, live weight and evolutionary algorithm derived mammary gland parameters was then determined using a multiple regression model. The mechanistic model of the mammary gland was able to fit lactation curves that corresponded to actual lactation curves with a high degree of accuracy. The senescence rate of quiescent (inactive) alveoli was highest at the very low feeding level. The active alveoli population at peak lactation was highest at very low feeding levels, but lower nutritional status at this feeding level prevented high milk yields from being achieved. Genetic merit had a significant linear effect on the active alveoli population at peak and mid to late lactation, with higher values in animals, which had higher breeding values for milk yields. A type of genetic merit × feeding level scaling effect was observed for total yields of milk and fat, and total number of alveoli produced from conception until the end of lactation with the benefits of increases in genetic merit being greater at high feeding levels. A genetic merit × age scaling effect was observed for total lactation protein yields. Initial rates of differentiation of progenitor cells declined with age. Production levels of alveoli from conception to the end of lactation were lowest in 5- to 8-year-old animals; however, in these older animals, quiescent alveoli were reactivated more frequently. The active alveoli population at peak lactation and rates of active alveoli proceeding to quiescence were highest in animals of intermediate body condition scores of 4.0 to 5.0. The results illustrate the potential uses of a mechanistic model of the mammary gland to fit a lactation curve and to quantify the effects of feeding level, genetic merit, body condition score, and age on mammary gland dynamics throughout lactation.

Bisphenol S (BPS) Alters Maternal Behavior and Brain in Mice Exposed During Pregnancy/Lactation and Their Daughters

PubMed Central

Catanese, Mary C.

2017-01-01

Estrogenic endocrine disrupting chemicals have been shown to disrupt maternal behavior in rodents. We investigated the effects of an emerging xenoestrogen, bisphenol S (BPS), on maternal behavior and brain in CD-1 mice exposed during pregnancy and lactation (F0 generation) and in female offspring exposed during gestation and perinatal development (F1 generation). We observed different effects in F0 and F1 dams for a number of components of maternal behavior, including time on the nest, time spent on nest building, latency to retrieve pups, and latency to retrieve the entire litter. We also characterized expression of estrogen receptor α in the medial preoptic area (MPOA) and quantified tyrosine hydroxylase immunoreactive cells in the ventral tegmental area, 2 brain regions critical for maternal care. BPS-treated females in the F0 generation had a statistically significant increase in estrogen receptor α expression in the caudal subregion of the central MPOA in a dose-dependent manner. In contrast, there were no statistically significant effects of BPS on the MPOA in F1 dams or the ventral tegmental area in either generation. This work demonstrates that BPS affects maternal behavior and brain with outcomes depending on generation, dose, and postpartum period. Many studies examining effects of endocrine disrupting chemicals view the mother as a means by which offspring can be exposed during critical periods of development. Here, we demonstrate that pregnancy and lactation are vulnerable periods for the mother. We also show that developmental BPS exposure alters maternal behavior later in adulthood. Both findings have potential public health implications. PMID:28005399

Lactate clearance as a marker of mortality in pediatric intensive care unit.

PubMed

Munde, A; Kumar, N; Beri, R S; Puliyel, J M

2014-07-01

To correlate lactate clearance with Pediatric Intensive Care Unit (PICU) mortality. 45 (mean age 40.15 mo, 60% males) consecutive admissions in the PICU were enrolled between May 2012 to June 2013. Lactate clearance (Lactate level at admission - level 6 hr later x 100 / lactate level at admission) in first 6 hours of hospitalization was correlated to in-hospital mortality and PRISM score. Twelve out of 45 patients died. 90% died among those with delayed/poor clearance (clearance <30%) compared to 8.5% in those with good clearance (clearance >30%) (P<0.001). Lactate clearance <30% predicted mortality with sensitivity of 75%, specificity of 97%, positive predictive value of 90%, and negative predictive value of 91.42%. Predictability was comparable to PRISM score >30. Lactate clearance at six hours correlates with mortality in the PICU.

Maternal intake of cashew nuts accelerates reflex maturation and facilitates memory in the offspring.

PubMed

de Melo, Marília Ferreira Frazão Tavares; Pereira, Diego Elias; Sousa, Morgana Moura; Medeiros, Dilian Maise Ferreira; Lemos, Leanderson Tulio Marques; Madruga, Marta Suely; Santos, Nayane Medeiros; de Oliveira, Maria Elieidy Gomes; de Menezes, Camila Carolina; Soares, Juliana Késsia Barbosa

2017-10-01

Essential fatty acids, being indispensable during the stages of pregnancy, lactation and infancy influence the transmission of nerve impulses and brain function, and cashew nuts are a good source of these fatty acids. The objective of this study was to evaluate the effects of cashew nut consumption on reflex development, memory and profile of fatty acids of rat offspring treated during pregnancy and lactation. The animals were divided into three groups: Control (CONT), treated with 7% lipid derived from soybean oil; Normolipidic (NL) treated with 7% lipids derived from cashew nuts; and Hyperlipidic (HL) treated with 20% lipids derived from cashew nuts. Reflex ontogeny, Open-field habituation test and the Object Recognition Test (ORT) were assessed. The profile of fatty acids in the brain was carried out when the animals were zero, 21 and 60days old. Accelerated reflex maturation was observed in animals treated with cashew nuts (p<0.05). NL presented better memory in the Open-field habituation test; the NL and HL showed improvement of short-term memory in the ORT, but long term damage in HL (p<0.05). The results of the lipid profile of the brain at the end of the experiment showed an increase in levels of saturated fatty acids and less Docosahexaenoic acid (DHA) in animals of the HL. The data showed that maternal consumption of cashew nuts can accelerate reflex maturation and facilitate memory in offspring when offered in adequate quantities. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Neuroprotective Effects of Sevoflurane against Electromagnetic Pulse-Induced Brain Injury through Inhibition of Neuronal Oxidative Stress and Apoptosis

PubMed Central

Wang, Jin; Han, Li-Chun; Li, Li-Ya; Wu, Guang-Li; Hou, Yan-Ning; Guo, Guo-Zhen; Wang, Qiang; Sang, Han-Fei; Xu, Li-Xian

2014-01-01

Electromagnetic pulse (EMP) causes central nervous system damage and neurobehavioral disorders, and sevoflurane protects the brain from ischemic injury. We investigated the effects of sevoflurane on EMP-induced brain injury. Rats were exposed to EMP and immediately treated with sevoflurane. The protective effects of sevoflurane were assessed by Nissl staining, Fluoro-Jade C staining and electron microscopy. The neurobehavioral effects were assessed using the open-field test and the Morris water maze. Finally, primary cerebral cortical neurons were exposed to EMP and incubated with different concentration of sevoflurane. The cellular viability, lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were assayed. TUNEL staining was performed, and the expression of apoptotic markers was determined. The cerebral cortexes of EMP-exposed rats presented neuronal abnormalities. Sevoflurane alleviated these effects, as well as the learning and memory deficits caused by EMP exposure. In vitro, cell viability was reduced and LDH release was increased after EMP exposure; treatment with sevoflurane ameliorated these effects. Additionally, sevoflurane increased SOD activity, decreased MDA levels and alleviated neuronal apoptosis by regulating the expression of cleaved caspase-3, Bax and Bcl-2. These findings demonstrate that Sevoflurane conferred neuroprotective effects against EMP radiation-induced brain damage by inhibiting neuronal oxidative stress and apoptosis. PMID:24614080

Neuroprotective effects of sevoflurane against electromagnetic pulse-induced brain injury through inhibition of neuronal oxidative stress and apoptosis.

PubMed

Deng, Bin; Xu, Hao; Zhang, Jin; Wang, Jin; Han, Li-Chun; Li, Li-Ya; Wu, Guang-Li; Hou, Yan-Ning; Guo, Guo-Zhen; Wang, Qiang; Sang, Han-Fei; Xu, Li-Xian

2014-01-01

Electromagnetic pulse (EMP) causes central nervous system damage and neurobehavioral disorders, and sevoflurane protects the brain from ischemic injury. We investigated the effects of sevoflurane on EMP-induced brain injury. Rats were exposed to EMP and immediately treated with sevoflurane. The protective effects of sevoflurane were assessed by Nissl staining, Fluoro-Jade C staining and electron microscopy. The neurobehavioral effects were assessed using the open-field test and the Morris water maze. Finally, primary cerebral cortical neurons were exposed to EMP and incubated with different concentration of sevoflurane. The cellular viability, lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were assayed. TUNEL staining was performed, and the expression of apoptotic markers was determined. The cerebral cortexes of EMP-exposed rats presented neuronal abnormalities. Sevoflurane alleviated these effects, as well as the learning and memory deficits caused by EMP exposure. In vitro, cell viability was reduced and LDH release was increased after EMP exposure; treatment with sevoflurane ameliorated these effects. Additionally, sevoflurane increased SOD activity, decreased MDA levels and alleviated neuronal apoptosis by regulating the expression of cleaved caspase-3, Bax and Bcl-2. These findings demonstrate that Sevoflurane conferred neuroprotective effects against EMP radiation-induced brain damage by inhibiting neuronal oxidative stress and apoptosis.

[Laboratory diagnostics in transient loss of consciousness : Serum lactate compared to serum creatine kinase as diagnostic indicator for generalized tonic-clonic seizures].

PubMed

Dafotakis, M; Heckelmann, J; Zechbauer, S; Litmathe, J; Brokmann, J; Willmes, K; Surges, R; Matz, O

2018-03-21

Laboratory parameters can help in the differential diagnostics of acute episodes of transient loss of consciousness. Especially serum lactate and serum creatine kinase (CK) levels may provide valuable hints to distinguish generalized tonic-clonic seizures (GTCS) from syncope. Serum lactate levels at admission and CK levels 10-48 h after the episodes that led to admission were compared between patients with GTCS (n = 30) and those with syncope (n = 15). In addition, sensitivity and specificity of lactate and CK as diagnostic markers for syncope and GTCS were determined. The serum lactate and serum CK levels were significantly increased in patients with GTCS as compared to syncope patients (serum lactate: p < 0.001; CK: p < 0.005). The area under the curve (AUC) for serum lactate as an indicator for GTCS was 0.94 (95% confidence interval [CI] 0.88-1.0). For CK the receiver operating characteristics (ROC) analysis produced an AUC of only 0.77 (95% CI: 0.63-0.9). The determination of the lactate value as point-of-care diagnostics appears to be highly relevant in the rapid clarification of unclear episodes with transient loss of consciousness. The CK level at follow-up is also suitable for distinguishing GTCS from syncope but is inferior to the serum lactate value.

A maternal Western diet during gestation and lactation modifies offspring's microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs.

PubMed

Val-Laillet, David; Besson, Marie; Guérin, Sylvie; Coquery, Nicolas; Randuineau, Gwénaëlle; Kanzari, Ameni; Quesnel, Hélène; Bonhomme, Nathalie; Bolhuis, J Elizabeth; Kemp, Bas; Blat, Sophie; Le Huërou-Luron, Isabelle; Clouard, Caroline

2017-05-01

A suboptimal early nutritional environment ( i.e., excess of energy, sugar, and fat intake) can increase susceptibility to diseases and neurocognitive disorders. The purpose of this study was to investigate in nonobese Yucatan minipigs ( Sus scrofa ) the impact of maternal diet [standard diet (SD) vs. Western diet (WD)] during gestation and 25 d of lactation on milk composition, blood metabolism, and microbiota activity of sows ( n = 17) and their piglets ( n = 65), and on spatial cognition ( n = 51), hippocampal plasticity ( n = 17), and food preferences/motivation ( n = 51) in the progeny. Milk dry matter and lipid content, as well as plasma total cholesterol and free fatty acid (FFA) concentrations ( P < 0.05) were higher in WD than in SD sows. Microbiota activity decreased in both WD sows and 100-d-old piglets ( P < 0.05 or P < 0.10, depending on short-chain FAs [SCFAs]). At weaning [postnatal day (PND) 25], WD piglets had increased blood triglyceride and FFA levels ( P < 0.01). Both SD and WD piglets consumed more of a known SD than an unknown high-fat and -sucrose (HFS) diet ( P < 0.0001), but were quicker to obtain HFS rewards compared with SD rewards ( P < 0.01). WD piglets had higher working memory ( P = 0.015) and reference memory ( P < 0.001) scores, which may reflect better cognitive abilities in the task context and a higher motivation for the food rewards. WD piglets had a smaller hippocampal granular cell layer ( P = 0.03) and decreased neurogenesis ( P < 0.005), but increased cell proliferation ( P < 0.001). A maternal WD during gestation and lactation, even in the absence of obesity, has significant consequences for piglets' blood lipid levels, microbiota activity, gut-brain axis, and neurocognitive abilities after weaning.-Val-Laillet, D., Besson, M., Guérin, S., Coquery, N., Randuineau, G., Kanzari, A., Quesnel, H., Bonhomme, N., Bolhuis, J. E., Kemp, B., Blat, S., Le Huërou-Luron, I., Clouard, C. A maternal Western diet during gestation and lactation modifies offspring's microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs. © FASEB.

The presence of vaginal Lactobacillus species does not contribute to a measureable difference in amniotic fluid lactate levels collected from the vaginal tract of laboring women.

PubMed

Hall, Beverley; Wong, Diana; Healy, Clare; Tracy, Mark B; Tracy, Sally K; Rawlinson, William D

2017-04-01

Amniotic fluid lactate research is based on the hypothesis that a relationship exists between fatigued uterine muscles and raised concentrations of the metabolite lactate, which is excreted into the amniotic fluid during labor. To assess potentially confounding effects of lactate-producing organisms on amniotic fluid lactate measurements, we aimed to determine if the presence of vaginal Lactobacillus species was associated with elevated levels of amniotic fluid lactate, measured from the vaginal tract of women in labor. Results from this study contribute to a large prospective longitudinal study of amniotic fluid lactate at a teaching hospital in Sydney, Australia. Amniotic fluid lactate measurement was assessed at the time of routine vaginal examination, after membranes had ruptured, using a hand-held lactate meter StatStripXPress (Nova Biomedical). Vaginal swab samples were collected at the time of the first amniotic fluid lactate measurement and stored for later detection and quantification of Lactobacillus species using a TaqMan real-time PCR assay. Swab sample and amniotic fluid lactate results were paired and analyzed. The PCR assay detected Lactobacillus species in 48 of 388 (12%) vaginal swab specimens (8% positive, 4% low positive) collected from women in labor after membranes had ruptured. There was no significant difference in median and mean (respectively) amniotic fluid lactate levels with (8.35 mmol/L; 8.95 mmol/L) or without (8.5 mmol/L; 9.08 mmol/L) Lactobacillus species detected. There was no association between the presence or level of vaginal Lactobacillus species and the measurement of amniotic fluid lactate collected from the vaginal tract of women during labor. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

Is there an association between body temperature and serum lactate levels in hip fracture patients?

PubMed

Murtuza, F; Farrier, A J; Venkatesan, M; Smith, R; Khan, A; Uzoigwe, C E; Chami, G

2015-10-01

Introduction Hyperlactataemia is associated with adverse outcomes in trauma cases. It is thought to be the result of anaerobic respiration during hypoperfusion. This produces much less energy than complete aerobic glycolysis. Low body temperature in the injured patient carries an equally poor prognosis. Significant amounts of energy are expended in maintaining euthermia. Consequently, there may be a link between lactate levels and dysthermia. Hyperlactataemia may be indicative of inefficient energy production and therefore insufficient energy to maintain euthermia. Alternatively, significant amounts of available oxygen may be sequestered in thermoregulation, resulting in anaerobic respiration and lactate production. Our study investigated whether there is an association between lactate levels and admission body temperature in hip fracture patients. Furthermore, it looked at whether there is a difference in the mean lactate levels between hip fracture patients with low (<36.5°C), normal (36.5-37.5°C) and high (>37.5°C) body temperature on admission, and for patients who have low body temperature, whether there is a progressive rise in serum lactate levels as body temperature falls. Methods The admission temperature and serum lactate of 1,162 patients presenting with hip fracture were recorded. Patients were divided into the euthermic (body temperature 36.5-37.5°C), the pyrexial (>37.5°C) and those with low body temperature (<36.5°C). Admission lactate and body temperature were compared. Results There was a significant difference in age between the three body temperature groups (p=0.007). The pyrexial cohort was younger than the low body temperature group (mean: 78 vs 82 years). Those with low body temperature had a higher mean lactate level than the euthermic (2.2mmol/l vs 2.0mmol/l, p=0.03). However, there was no progressive rise in serum lactate level as admission temperature fell. Conclusions The findings suggest that in hip fracture patients, the body attempts initially to maintain euthermia, incurring an oxygen debt. This would explain the difference in lactate level between the low body temperature and euthermic cohorts. The fact that there is no correlation with the degree of temperature depression and lactate levels indicates that the body does not fuel thermohomeostasis indefinitely with oxygen. Instead, in part, it abandons thermoregulatory mechanisms. Consequently, in this population, active rewarming may be indicated rather than depending on patients' own thermogenic ability.

The effects of copper-histidine therapy on brain metabolism in a patient with Menkes disease: a proton magnetic resonance spectroscopic study.

PubMed

Munakata, Mitsutoshi; Sakamoto, Osamu; Kitamura, Taro; Ishitobi, Mamiko; Yokoyama, Hiroyuki; Haginoya, Kazuhiro; Togashi, Noriko; Tamura, Hajime; Higano, Shuichi; Takahashi, Shoki; Ohura, Toshihiro; Kobayashi, Yasuko; Onuma, Akira; Iinuma, Kazuie

2005-06-01

We report on metabolic changes in the brain of a boy with Menkes disease. He was treated with parenteral copper (Cu)-histidine supplementation, from 5 months of age, and assessed with proton magnetic resonance spectroscopy ((1)H-MRS). The single-voxel (1)H-MRS before treatment revealed an accumulation of lactate and a reduced N-acetyl aspartate (NAA)/total creatine (tCr) ratio with a z-score of -3.0. During treatment, the lactate signal faded away, whereas the NAA signal gradually increased to a z-score of -1.5 at 120 days of treatment. The choline/tCr ratio did not deviate much initially (z-score +0.5), but the ratio increased markedly during treatment (z-score +4.8). Consequently, the Cu-histidine therapy initiated after the critical period still improved the neuronal metabolism, suggesting that some Cu was delivered to neurons. Nevertheless, the brain atrophy, impaired myelination, and severe neurological symptoms were not ameliorated.

Astrocyte glycogen and brain energy metabolism.

PubMed

Brown, Angus M; Ransom, Bruce R

2007-09-01

The brain contains glycogen but at low concentration compared with liver and muscle. In the adult brain, glycogen is found predominantly in astrocytes. Astrocyte glycogen content is modulated by a number of factors including some neurotransmitters and ambient glucose concentration. Compelling evidence indicates that astrocyte glycogen breaks down during hypoglycemia to lactate that is transferred to adjacent neurons or axons where it is used aerobically as fuel. In the case of CNS white matter, this source of energy can extend axon function for 20 min or longer. Likewise, during periods of intense neural activity when energy demand exceeds glucose supply, astrocyte glycogen is degraded to lactate, a portion of which is transferred to axons for fuel. Astrocyte glycogen, therefore, offers some protection against hypoglycemic neural injury and ensures that neurons and axons can maintain their function during very intense periods of activation. These emerging principles about the roles of astrocyte glycogen contradict the long held belief that this metabolic pool has little or no functional significance.

Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats.

PubMed

Pudell, Claudia; Vicente, Bianca A; Delattre, Ana M; Carabelli, Bruno; Mori, Marco A; Suchecki, Deborah; Machado, Ricardo B; Zanata, Sílvio M; Visentainer, Jesuí V; de Oliveira Santos Junior, Oscar; Lima, Marcelo M S; Ferraz, Anete C

2014-01-01

Depression is increasingly present in the population, and its pathophysiology and treatment have been investigated with several animal models, including olfactory bulbectomy (Obx). Fish oil (FO) supplementation during the prenatal and postnatal periods decreases depression-like and anxiety-like behaviors. The present study evaluated the effect of FO supplementation on Obx-induced depressive-like behavior and cognitive impairment. Female rats received supplementation with FO during habituation, mating, gestation, and lactation, and their pups were subjected to Obx in adulthood; after the recovery period, the adult offspring were subjected to behavioral tests, and the hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin (5-HT) and the metabolite 5-hydroxyindoleacetic (5-HIAA) were determined. Obx led to increased anxiety-like and depressive-like behaviors, and impairment in the object location task. All behavioral changes were reversed by FO supplementation. Obx caused reductions in the levels of hippocampal BDNF and 5-HT, whereas FO supplementation restored these levels to normal values. In control rats, FO increased the hippocampal level of 5-HT and reduced that of 5-HIAA, indicating low 5-HT metabolism in this brain region. The present results indicate that FO supplementation during critical periods of brain development attenuated anxiety-like and depressive-like behaviors and cognitive dysfunction induced by Obx. These results may be explained by increased levels of hippocampal BDNF and 5-HT, two major regulators of neuronal survival and long-term plasticity in this brain structure. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Hypothalamic neuropeptides, not leptin sensitivity, contributes to the hyperphagia in lactating Brandt's voles, Lasiopodomys brandtii.

PubMed

Cui, Jian-Guo; Tang, Gang-Bing; Wang, De-Hua

2011-07-01

Both pregnancy and lactation are associated with hyperphagia, and circulating leptin levels are elevated during pregnancy but decreased during lactation in Brandt's voles, Lasiopodomys brandtii. Previous findings suggest that impaired leptin sensitivity contributes to hyperphagia during pregnancy. The present study aimed to examine whether the decreased circulating leptin level and/or hypothalamic leptin sensitivity contributed to the hyperphagia during lactation in Brandt's voles. The serum leptin level and mRNA expression of the long form of the leptin receptor (Ob-Rb), suppressor-of-cytokine-signalling-3 (SOCS-3), neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus were examined on dioestrous, day 5, day 17 of lactation and day 27 (1 week after weaning) in Brandt's voles. Compared with controls, hypothalamic Ob-Rb and SOCS-3 mRNA expression was not significantly changed during lactation. The serum leptin level was significantly lower in lactating females than in the non-reproductive group. Hypothalamic NPY and AgRP mRNA expression significantly increased whereas POMC mRNA expression was significantly decreased during lactation compared with controls. However, there were no significant changes in hypothalamic CART mRNA expression. Food intake was positively correlated with NPY and AgRP mRNA expression but negatively correlated with POMC mRNA expression during lactation. These data suggest that hyperphagia during lactation was associated with low leptin levels, but not impaired leptin sensitivity, and that the hypothalamic neuropeptides NPY, AgRP and POMC are involved in mediating the role of leptin in food intake regulation in lactating Brandt's voles.

The composition of polyunsaturated fatty acids in erythrocytes of lactating mothers and their infants.

PubMed

Jørgensen, Marianne Hørby; Nielsen, Pernille Kjaer; Michaelsen, Kim Fleischer; Lund, Pia; Lauritzen, Lotte

2006-01-01

Long-chain polyunsaturated fatty acids (LCPUFA) in breastmilk, specifically docosahexaenoic acid (DHA), are important for infant brain development. Accretion of DHA in the infant brain is dependent on DHA-status, intake and metabolism. The aim of this study was to describe changes in maternal and infant erythrocyte (RBC) DHA-status during the first four months of lactation. We examined 17 mothers and their term infants at 1, 2 and 4 months of age. Milk samples and RBC from the mothers and infants were obtained and analysed for fatty acid composition. Comparative analysis of the results showed that the content of DHA in maternal RBC-phosphatidylcholine (PE) decreased over the four month period and this was not accompanied by a decrease in DHA in infant RBC-PE (P = 0.005). The ratio of n-6 PUFA to n-3 PUFA increased over time in maternal RBC-PE, but not in infant RBC-PE (P < 0.001). The level of 22:5n-6 and the ratio of LCPUFA to precursor PUFAs in infant RBC was higher than in maternal RBC phospholipids. (P = and P < 0.001 respectively). We found a decrease in the level of LCPUFA in milk, specifically AA. However, we did not observe a significant decrease in milk DHA, which may have been due to two outliers. These results indicate better DHA-status and a higher n-3/n-6 PUFA in RBC of infants than in mothers. Whether these differences reflect preferential n-3 PUFA transfer via breastmilk or differences in PUFA-metabolism and utilization remains to be shown.

REGULATION OF MEMORY – FROM THE ADRENAL MEDULLA TO LIVER TO ASTROCYTES TO NEURONS1

PubMed Central

Gold, Paul E.

2014-01-01

Epinephrine, released into blood from the adrenal medulla in response to arousing experiences, is a potent enhancer of learning and memory processing. This review examines mechanisms by which epinephrine exerts its effects on these cognitive functions. Because epinephrine is largely blocked from moving from blood to brain, it is likely that the hormone's effects on memory are mediated by peripheral actions. A classic effect of epinephrine is to act at the liver to break down glycogen stores, resulting in increased blood glucose levels. The increase in blood glucose provides additional energy substrates to the brain to buttress the processes needed for an experience to be learned and remembered. In part, it appears that the increased glucose may act in the brain in a manner akin to that evident in the liver, engaging glycogenolysis in astrocytes to provide an energy substrate, in this case lactate, to augment neuronal functions. Together, the findings reveal a mechanism underlying modulation of memory that integrates the physiological functions of multiple organ systems to support brain processes. PMID:24406469

Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain.

PubMed

Lin, Ai-Ling; Zhang, Wei; Gao, Xiaoli; Watts, Lora

2015-07-01

Caloric restriction (CR) has been shown to increase the life span and health span of a broad range of species. However, CR effects on in vivo brain functions are far from explored. In this study, we used multimetric neuroimaging methods to characterize the CR-induced changes of brain metabolic and vascular functions in aging rats. We found that old rats (24 months of age) with CR diet had reduced glucose uptake and lactate concentration, but increased ketone bodies level, compared with the age-matched and young (5 months of age) controls. The shifted metabolism was associated with preserved vascular function: old CR rats also had maintained cerebral blood flow relative to the age-matched controls. When investigating the metabolites in mitochondrial tricarboxylic acid cycle, we found that citrate and α-ketoglutarate were preserved in the old CR rats. We suggest that CR is neuroprotective; ketone bodies, cerebral blood flow, and α-ketoglutarate may play important roles in preserving brain physiology in aging. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The Role of Lactate-Mediated Metabolic Coupling between Astrocytes and Neurons in Long-Term Memory Formation

PubMed Central

Steinman, Michael Q.; Gao, Virginia; Alberini, Cristina M.

2016-01-01

Long-term memory formation, the ability to retain information over time about an experience, is a complex function that affects multiple behaviors, and is an integral part of an individual’s identity. In the last 50 years many scientists have focused their work on understanding the biological mechanisms underlying memory formation and processing. Molecular studies over the last three decades have mostly investigated, or given attention to, neuronal mechanisms. However, the brain is composed of different cell types that, by concerted actions, cooperate to mediate brain functions. Here, we consider some new insights that emerged from recent studies implicating astrocytic glycogen and glucose metabolisms, and particularly their coupling to neuronal functions via lactate, as an essential mechanism for long-term memory formation. PMID:26973477

Lactate Clearance and Normalization and Prolonged Organ Dysfunction in Pediatric Sepsis.

PubMed

Scott, Halden F; Brou, Lina; Deakyne, Sara J; Fairclough, Diane L; Kempe, Allison; Bajaj, Lalit

2016-03-01

To evaluate whether lactate clearance and normalization during emergency care of pediatric sepsis is associated with lower rates of persistent organ dysfunction. This was a prospective cohort study of 77 children <18 years of age in the emergency department with infection and acute organ dysfunction per consensus definitions. In consented patients, lactate was measured 2 and/or 4 hours after an initial lactate; persistent organ dysfunction was assessed through laboratory and physician evaluation at 48 hours. A decrease of ≥ 10% from initial to final level was considered lactate clearance; a final level < 2 mmol/L was considered lactate normalization. Relative risk (RR) with 95% CIs, adjusted in a log-binomial model, was used to evaluate associations between lactate clearance/normalization and organ dysfunction. Lactate normalized in 62 (81%) patients and cleared in 70 (91%). The primary outcome, persistent 48-hour organ dysfunction, was present in 32 (42%). Lactate normalization was associated with decreased risk of persistent organ dysfunction (RR 0.46, 0.29-0.73; adjusted RR 0.47, 0.29-0.78); lactate clearance was not (RR 0.70, 0.35-1.41; adjusted RR 0.75, 0.38-1.50). The association between lactate normalization and decreased risk of persistent organ dysfunction was retained in the subgroups with initial lactate ≥ 2 mmol/L and hypotension. In children with sepsis and organ dysfunction, lactate normalization within 4 hours was associated with decreased persistent organ dysfunction. Serial lactate level measurement may provide a useful prognostic tool during the first hours of resuscitation in pediatric sepsis. Copyright © 2016 Elsevier Inc. All rights reserved.

Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

PubMed

Boury-Jamot, B; Carrard, A; Martin, J L; Halfon, O; Magistretti, P J; Boutrel, B

2016-08-01

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine.

Pre- and postnatal health: evidence of increased choline needs.

PubMed

Caudill, Marie A

2010-08-01

Choline, a micronutrient found in food, serves as the starting material for several important metabolites that play key roles in fetal development, particularly the brain. Although human beings' requirement for choline is unknown, an Adequate Intake level of 425 mg/day was established for women with upward adjustments to 450 and 550 mg/day during pregnancy and lactation, respectively. The importance of choline in human development is supported by observations that a human fetus receives a large supply of choline during gestation; pregnancy causes depletion of hepatic choline pools in rats consuming a normal diet; human neonates are born with blood levels that are three times higher than maternal blood concentrations; and large amounts of choline are present in human milk. The development of the central nervous system is particularly sensitive to choline availability with evidence of effects on neural tube closure and cognition. Existing data show that the majority of pregnant (and presumably lactating) women are not achieving the target intake levels and that certain common genetic variants may increase requirements for choline beyond current recommendations. Because choline is not found in most varieties of prenatal vitamins (or regular multivitamins), increased consumption of choline-rich foods may be needed to meet the high pre- and postnatal demands for choline. 2010 American Dietetic Association. Published by Elsevier Inc. All rights reserved.

Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase.

PubMed

Choi, Hyun B; Gordon, Grant R J; Zhou, Ning; Tai, Chao; Rungta, Ravi L; Martinez, Jennifer; Milner, Teresa A; Ryu, Jae K; McLarnon, James G; Tresguerres, Martin; Levin, Lonny R; Buck, Jochen; MacVicar, Brian A

2012-09-20

Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO₃⁻) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO₃⁻ entry via the electrogenic NaHCO₃ cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space, which is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of [K⁺](ext) and also during aglycemic episodes, helping to maintain synaptic function. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons. Copyright © 2012 Elsevier Inc. All rights reserved.

Metabolic Communication between Astrocytes and Neurons via Bicarbonate-Responsive Soluble Adenylyl Cyclase

PubMed Central

Choi, Hyun B.; Gordon, Grant R.J.; Zhou, Ning; Tai, Chao; Rungta, Ravi L.; Martinez, Jennifer; Milner, Teresa A.; Ryu, Jae K.; McLarnon, James G.; Tresguerres, Martin; Levin, Lonny R.; Buck, Jochen; MacVicar, Brian A.

2013-01-01

SUMMARY Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO3−) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO3− entry via the electrogenic NaHCO3 cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space, which is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of [K+]ext and also during aglycemic episodes, helping to maintain synaptic function. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons. PMID:22998876

l-Arginine Pathway Metabolites Predict Need for Intra-operative Shunt During Carotid Endarterectomy.

PubMed

Szabo, P; Lantos, J; Nagy, L; Keki, S; Volgyi, E; Menyhei, G; Illes, Z; Molnar, T

2016-12-01

Asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthesis and is a marker of atherosclerosis. This study examined the correlation between pre-operative l-arginine and ADMA concentration during carotid endarterectomy (CEA), and jugular lactate indicating anaerobic cerebral metabolism, jugular S100B reflecting blood-brain barrier integrity, and with factors of surgical intervention. The concentration of l-arginine, ADMA, and symmetric dimethylarginine was measured in blood taken under regional anaesthesia from the radial artery of 55 patients prior to CEA. Blood gas parameters, concentration of lactate, and S100B were also serially measured in blood taken from both the radial artery and the jugular bulb before and after carotid clamping, and after release of the clamp. To estimate anaerobic metabolism, the jugulo-arterial ratio of CO 2 gap/oxygen extraction was calculated. Positive correlation was found between pre-operative ADMA levels and the ratio of jugulo-arterial CO 2 gap/oxygen extraction during clamp and reperfusion (p = .005 and p = .01, respectively). An inverse correlation was found between the pre-operative l-arginine concentration and jugular lactate at each time point (both p = .002). The critical pre-operative level of l-arginine was determined by receiver operator curve analysis. If l-arginine was below the cutoff value of 35 μmol/L, jugular S100B concentration was higher 24 h post-operatively (p = .03), and jugular lactate levels were increased during reperfusion (p = .02). The median pre-operative concentration of l-arginine was lower in patients requiring an intra-operative shunt than in patients without need of shunt (median: 30.3 μmol/L [interquartile range 24.4-34.4 μmol/L] vs. 57.6 μmol/L [interquartile range 42.3-74.5 μmol/L]; p = .002). High pre-operative ADMA concentration predicts poor cerebral perfusion indicated by elevated jugulo-arterial CO 2 gap/oxygen extraction. Low pre-operative l-arginine concentration predicts the need for a shunt. The inverse correlation between pre-operative l-arginine concentration and both jugular lactate and S100B during carotid clamping suggests a protective role of the NO donor l-arginine. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Effect of mastitis treatment and somatic cell counts on milk yield in Danish organic dairy cows.

PubMed

Bennedsgaard, T W; Enevoldsen, C; Thamsborg, S M; Vaarst, M

2003-10-01

Production and disease data from 17,488 lactations in 48 Danish organic dairy herds from 1997 to 2001 were analyzed to obtain estimates on the effect of somatic cell counts (SCC) and mastitis treatment on milk production. A multilevel three-parameter piecewise random coefficients linear model with energy-corrected milk (ECM) as dependent variable and herd, lactation, and test days as levels, was used to model the lactation curve. Covariates related to production, SCC, veterinary treatments, and reproductive performance in the previous lactation as well as information on other diseases in the current lactation were included to describe the production capacity of the individual cow. The average daily milk production at herd level was 20.8, 24.2, and 25.8 kg of ECM/d in first, second, and third or later lactation. The estimates for production losses were on average 0.2, 0.3, and 0.4 kg of ECM/d in first, second, and third or later lactation with each twofold increase in SCC between 100,000 and 1,500,000 cells/ml. The effect varied with the stage of lactation and was nonsignificant around 60 d postpartum and highest at the end of the lactation. The production losses in cows treated for mastitis varied with parity and stage of lactation and were modified by the SCC after treatment. For a cow in third lactation with a SCC below 100,000 cells/ ml before treatment at days in milk = 15, the predicted loss was 435 kg of ECM, including a loss of 135 kg of ECM because of higher SCC compared with the level before treatment. Most of the variation in production related to SCC and mastitis was at the lactation level, and no significant differences were found between herds grouped according to milk production level, SCC, or prevalence of mastitis treatment.

Lactate clearance as the predictor of outcome in pediatric septic shock.

PubMed

Choudhary, Richa; Sitaraman, Sadasivan; Choudhary, Anita

2017-01-01

Septic shock can rapidly evolve into multiple system organ failure and death. In the recent years, hyperlactatemia has been found to be a risk factor for mortality in critically ill adults. To evaluate the predictive value of lactate clearance and to determine the optimal cut-off value for predicting outcome in children with septic shock. A prospective observational study was performed on children with septic shock admitted to pediatric Intensive Care Unit (PICU). Serial lactate levels were measured at PICU admission, 24 and 48 h later. Lactate clearance, percent decrease in lactate level in 24 h, was calculated. The primary outcome measure was survival or nonsurvival at the end of hospital stay. We performed receiver operating characteristic analyses to calculate optimal cut-off values. The mean lactate levels at admission were significantly higher in the nonsurvivors than survivors, 5.12 ± 3.51 versus 3.13 ± 1.71 mmol/L ( P = 0.0001). The cut-off for lactate level at admission for the best prediction of mortality was determined as ≥4 mmol/L (odds ratio 5.4; 95% confidence interval [CI] =2.45-12.09). Mean lactate clearance was significantly higher in survivors than nonsurvivors (17.9 ± 39.9 vs. -23.2 ± 62.7; P < 0.0001). A lactate clearance rate of <10% at 24 h had a sensitivity and specificity of 78.7% and 72.2%, respectively and a positive predictive value of 83.1% for death. Failure to achieve a lactate clearance of more than 10% was associated with greater risk of mortality (likelihood ratio + 2.83; 95% CI = 1.82-4.41). Serial lactate levels can be used to predict outcome in pediatric septic shock. A 24 h lactate clearance cut-off of <10% is a predictor of in-hospital mortality in such patients.

[Syndrome Leigh caused by mutations in the SURF1 gene: clinical and molecular-genetic characteristics].

PubMed

Tsygankova, P G; Mikhaĭlova, S V; Zakharova, E Iu; Pichkur, N A; Il'ina, E S; Nikolaeva, E A; Rudenskaia, G E; Dadali, E L; Kolpakchi, L M; Fedoniuk, I D; Matiushchenko, G N

2010-01-01

Syndrome Leigh (SL) or subacute necrotizing encephalomyelopathy - is a rare hereditary genetically heterogeneous disease from the group of mitochondrial encephalomyopathies. Twenty-seven children with SL were examined using clinical, laboratory (measuring lactate levels), MRI and molecular-genetic (polymerase chain reaction genotyping of 9 exons of the SURF1 gene) studies. The mean age of manifestation was 11,6 months. The main manifestations of SL were: delay of psychomotor development, diffuse muscle hypertonic, cerebellar syndrome, ophthalmoparesis, hypertrichosis. The disease had a progressive course with the loss of acquired skills. The blood lactate concentration was increased on average up to 3,1 mM/ml (from 1,9 to 5,1 mM/ml) compared to normal values (1,8 mM/ml). Brain MRI revealed the subcortical and cortical atrophy (80% of cases), symmetrical distinctly delineated hyperintense lesions on T2-weighted images (demyelization) in the basal ganglia and the brain stem (50%), as well as in the cerebellum (25%). Genotyping identified 7 different mutations. The most frequent (64,8%) was the deletion of 2 nucleotides (845delCT) in exon 8 that was in line with early data of Polish researchers thus indicating the Slavic origin of this mutation. Other mutations (574-575insCTGT, 311-321del10insAT and IVS8-1G>) were also frequent in the Russian population.

Comparison of fMRI and PEPSI during language processing in children.

PubMed

Serafini, S; Steury, K; Richards, T; Corina, D; Abbott, R; Dager, S R; Berninger, V

2001-02-01

The present study explored the correlation between lactate as detected by MR spectroscopy (MRS) and blood oxygenation level dependent (BOLD) responses in male children during auditory-based language tasks. All subjects (N = 8) participated in one proton echo planar spectroscopic imaging (PEPSI) and one functional magnetic resonance imaging (fMRI) session that required phonological and lexical judgments to aurally presented stimuli. Valid PEPSI data was limited in the frontal areas of the brain due to the magnetic susceptibility of the eye orbits and frontal sinuses. Findings from the remainder of the brain indicate that subjects show a significant consistency across imaging techniques in the left temporal area during the lexical task, but not in any other measurable area or during the phonological task. Magn Reson Med 45:217-225, 2001. Copyright 2001 Wiley-Liss, Inc.

A paradigm of undernourishing and neonatal rehabilitation in the newborn rat.

PubMed

Perez-Torrero, Esther; Torrerob, Carmen; Collado, Paloma; Salas, Manuel

2003-04-01

Perinatal undernutrition as a deficiency of nutrient availability, affects body and brain developmental processes and promotes recurrent health problems. Thus, altered mother-litter bonds and deficient environmental interactions may interfere with the brain pluripotential capabilities of the newborn. To gather information concerning the mechanisms underlying perinatal undernutrition we designed a paradigm of undernutrition and neonatal rehabilitation in the rat. An underfed group came from pregnant Wistar rats fed with 50% of the diet from G6 to G12 and with 60% from G13 until G21. After birth, pups were daily undernourished during 12 h daily by rotating a pair of lactating well-nourished dams which had one of their nipples subcutaneously ligated. The rehabilitated animals were undernourished pups neonatally fed by a pair of normally lactating dams. Controls received plenty of food during the pre- and neonatal periods. Pups were sacrificed at 12, 20 and 30 days of age. Perinatal underfeeding significantly reduced body and brain weights and neuronal morphometric parameters. Normal neonatal feeding in the newborn ameliorated the damages associated to food deprivation. The current undernourishing paradigm may be helpful to assess brain development alterations, as well as to study the compensatory mechanisms associated to salutary epigenetic influences.

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

PubMed Central

Jolivet, Renaud; Coggan, Jay S.; Allaman, Igor; Magistretti, Pierre J.

2015-01-01

Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging. PMID:25719367

Cerebral Gluconeogenesis and Diseases.

PubMed

Yip, James; Geng, Xiaokun; Shen, Jiamei; Ding, Yuchuan

2016-01-01

The gluconeogenesis pathway, which has been known to normally present in the liver, kidney, intestine, or muscle, has four irreversible steps catalyzed by the enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Studies have also demonstrated evidence that gluconeogenesis exists in brain astrocytes but no convincing data have yet been found in neurons. Astrocytes exhibit significant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 activity, a key mechanism for regulating glycolysis and gluconeogenesis. Astrocytes are unique in that they use glycolysis to produce lactate, which is then shuttled into neurons and used as gluconeogenic precursors for reduction. This gluconeogenesis pathway found in astrocytes is becoming more recognized as an important alternative glucose source for neurons, specifically in ischemic stroke and brain tumor. Further studies are needed to discover how the gluconeogenesis pathway is controlled in the brain, which may lead to the development of therapeutic targets to control energy levels and cellular survival in ischemic stroke patients, or inhibit gluconeogenesis in brain tumors to promote malignant cell death and tumor regression. While there are extensive studies on the mechanisms of cerebral glycolysis in ischemic stroke and brain tumors, studies on cerebral gluconeogenesis are limited. Here, we review studies done to date regarding gluconeogenesis to evaluate whether this metabolic pathway is beneficial or detrimental to the brain under these pathological conditions.

Astrocyte glycogen and lactate: New insights into learning and memory mechanisms.

PubMed

Alberini, Cristina M; Cruz, Emmanuel; Descalzi, Giannina; Bessières, Benjamin; Gao, Virginia

2018-06-01

Memory, the ability to retain learned information, is necessary for survival. Thus far, molecular and cellular investigations of memory formation and storage have mainly focused on neuronal mechanisms. In addition to neurons, however, the brain comprises other types of cells and systems, including glia and vasculature. Accordingly, recent experimental work has begun to ask questions about the roles of non-neuronal cells in memory formation. These studies provide evidence that all types of glial cells (astrocytes, oligodendrocytes, and microglia) make important contributions to the processing of encoded information and storing memories. In this review, we summarize and discuss recent findings on the critical role of astrocytes as providers of energy for the long-lasting neuronal changes that are necessary for long-term memory formation. We focus on three main findings: first, the role of glucose metabolism and the learning- and activity-dependent metabolic coupling between astrocytes and neurons in the service of long-term memory formation; second, the role of astrocytic glucose metabolism in arousal, a state that contributes to the formation of very long-lasting and detailed memories; and finally, in light of the high energy demands of the brain during early development, we will discuss the possible role of astrocytic and neuronal glucose metabolisms in the formation of early-life memories. We conclude by proposing future directions and discussing the implications of these findings for brain health and disease. Astrocyte glycogenolysis and lactate play a critical role in memory formation. Emotionally salient experiences form strong memories by recruiting astrocytic β2 adrenergic receptors and astrocyte-generated lactate. Glycogenolysis and astrocyte-neuron metabolic coupling may also play critical roles in memory formation during development, when the energy requirements of brain metabolism are at their peak. © 2017 Wiley Periodicals, Inc.

Bisphenol S (BPS) Alters Maternal Behavior and Brain in Mice Exposed During Pregnancy/Lactation and Their Daughters.

PubMed

Catanese, Mary C; Vandenberg, Laura N

2017-03-01

Estrogenic endocrine disrupting chemicals have been shown to disrupt maternal behavior in rodents. We investigated the effects of an emerging xenoestrogen, bisphenol S (BPS), on maternal behavior and brain in CD-1 mice exposed during pregnancy and lactation (F0 generation) and in female offspring exposed during gestation and perinatal development (F1 generation). We observed different effects in F0 and F1 dams for a number of components of maternal behavior, including time on the nest, time spent on nest building, latency to retrieve pups, and latency to retrieve the entire litter. We also characterized expression of estrogen receptor α in the medial preoptic area (MPOA) and quantified tyrosine hydroxylase immunoreactive cells in the ventral tegmental area, 2 brain regions critical for maternal care. BPS-treated females in the F0 generation had a statistically significant increase in estrogen receptor α expression in the caudal subregion of the central MPOA in a dose-dependent manner. In contrast, there were no statistically significant effects of BPS on the MPOA in F1 dams or the ventral tegmental area in either generation. This work demonstrates that BPS affects maternal behavior and brain with outcomes depending on generation, dose, and postpartum period. Many studies examining effects of endocrine disrupting chemicals view the mother as a means by which offspring can be exposed during critical periods of development. Here, we demonstrate that pregnancy and lactation are vulnerable periods for the mother. We also show that developmental BPS exposure alters maternal behavior later in adulthood. Both findings have potential public health implications. Copyright © 2017 by the Endocrine Society.

Kinetics of lactate metabolism during acellular normothermic ex vivo lung perfusion.

PubMed

Koike, Terumoto; Yeung, Jonathan C; Cypel, Marcelo; Rubacha, Matthew; Matsuda, Yasushi; Sato, Masaaki; Waddell, Thomas K; Liu, Mingyao; Keshavjee, Shaf

2011-12-01

Plasma lactate has been used as a marker of poor prognosis in clinical conditions. However, the relationship between lactate production and lung function during acellular normothermic ex vivo lung perfusion (EVLP) is unclear. We investigated the kinetics of lactate metabolism during EVLP and the correlation of this marker with outcomes after transplant. Human donor lungs in our clinical EVLP trial (CLs; n = 28) and rejected donor lungs for experimental use (Els; n = 8) were perfused ex vivo using the Toronto technique. Lactate level, lactate/pyruvate (L/P) ratio, and glucose level in the perfusate were measured. In CLs, we examined the relationship between lactate metabolism during EVLP and early post-transplant outcomes. The hypoxia-inducible factor 1 sub-unit 1α (HIF-1α) level in lung tissue was examined in ELs. We performed double-lung EVLP in CLs and single-lung EVLP in ELs. In CLs, the lactate and L/P ratios at the end of EVLP had no correlation with early post-transplant outcomes despite lactate elevation during EVLP. Although lactate elevation was also present in all ELs, we were able to identify 2 groups based on L/P ratio at the end of EVLP. The group with the high L/P ratio had higher airway pressure during EVLP and higher HIF-1α in lung tissue at the end of EVLP. Lactate increases seen in the EVLP perfusate most often represent physiologic lactate production by the lung in a setting with reduced lactate clearance. Thus, patients who underwent transplantation after EVLP had good outcomes despite lactate elevation during EVLP. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation.

PubMed

Jury, Nicholas J; McCormick, Betsy A; Horseman, Nelson D; Benoit, Stephen C; Gregerson, Karen A

2015-01-01

The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD.

Enhanced Responsiveness to Selective Serotonin Reuptake Inhibitors during Lactation

PubMed Central

Jury, Nicholas J.; McCormick, Betsy A.; Horseman, Nelson D.; Benoit, Stephen C.; Gregerson, Karen A.

2015-01-01

The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD. PMID:25689282

Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism

NASA Astrophysics Data System (ADS)

Lam, Tony K. T.; Gutierrez-Juarez, Roger; Pocai, Alessandro; Rossetti, Luciano

2005-08-01

The brain keenly depends on glucose for energy, and mammalians have redundant systems to control glucose production. An increase in circulating glucose inhibits glucose production in the liver, but this negative feedback is impaired in type 2 diabetes. Here we report that a primary increase in hypothalamic glucose levels lowers blood glucose through inhibition of glucose production in rats. The effect of glucose requires its conversion to lactate followed by stimulation of pyruvate metabolism, which leads to activation of adenosine triphosphate (ATP)-sensitive potassium channels. Thus, interventions designed to enhance the hypothalamic sensing of glucose may improve glucose homeostasis in diabetes.

Is there an association between body temperature and serum lactate levels in hip fracture patients?

PubMed Central

Murtuza, F; Farrier, AJ; Venkatesan, M; Smith, R; Khan, A; Uzoigwe, CE; Chami, G

2015-01-01

Introduction Hyperlactataemia is associated with adverse outcomes in trauma cases. It is thought to be the result of anaerobic respiration during hypoperfusion. This produces much less energy than complete aerobic glycolysis. Low body temperature in the injured patient carries an equally poor prognosis. Significant amounts of energy are expended in maintaining euthermia. Consequently, there may be a link between lactate levels and dysthermia. Hyperlactataemia may be indicative of inefficient energy production and therefore insufficient energy to maintain euthermia. Alternatively, significant amounts of available oxygen may be sequestered in thermoregulation, resulting in anaerobic respiration and lactate production. Our study investigated whether there is an association between lactate levels and admission body temperature in hip fracture patients. Furthermore, it looked at whether there is a difference in the mean lactate levels between hip fracture patients with low (<36.5°C), normal (36.5–37.5°C) and high (>37.5°C) body temperature on admission, and for patients who have low body temperature, whether there is a progressive rise in serum lactate levels as body temperature falls. Methods The admission temperature and serum lactate of 1,162 patients presenting with hip fracture were recorded. Patients were divided into the euthermic (body temperature 36.5–37.5°C), the pyrexial (>37.5°C) and those with low body temperature (<36.5°C). Admission lactate and body temperature were compared. Results There was a significant difference in age between the three body temperature groups (p=0.007). The pyrexial cohort was younger than the low body temperature group (mean: 78 vs 82 years). Those with low body temperature had a higher mean lactate level than the euthermic (2.2mmol/l vs 2.0mmol/l, p=0.03). However, there was no progressive rise in serum lactate level as admission temperature fell. Conclusions The findings suggest that in hip fracture patients, the body attempts initially to maintain euthermia, incurring an oxygen debt. This would explain the difference in lactate level between the low body temperature and euthermic cohorts. The fact that there is no correlation with the degree of temperature depression and lactate levels indicates that the body does not fuel thermohomeostasis indefinitely with oxygen. Instead, in part, it abandons thermoregulatory mechanisms. Consequently, in this population, active rewarming may be indicated rather than depending on patients’ own thermogenic ability. PMID:26274739

The clinical diagnostic significance of cerebrospinal fluid D-lactate for bacterial meningitis.

PubMed

Chen, Zengqiang; Wang, Yumin; Zeng, Aibing; Chen, Lijiang; Wu, Ruihao; Chen, Bicheng; Chen, Mengquan; Bo, Jinshuang; Zhang, Hu; Peng, Qian; Lu, Jianxin; Meng, Qing H

2012-10-09

To study the clinical and laboratory significance of D‐lactate in the diagnosis of bacterial meningitis (BM). The levels of D‐lactate, L‐lactate, IL-6, IL-8, and other biochemical markers were determined in 83 CSF samples from different types of meningitis and the controls. The CSF values of D‐lactate, L‐lactate, IL-6, IL-8, erythrocytes, leukocytes, and protein were higher in patients with BM than those in the controls and patients with viral meningitis. The levels of D‐lactate, L‐lactate, IL-6, and erythrocytes in the BM group were higher than those in the tuberculous meningitis group. At the cutoff 12.8 μmol/l, D‐lactate showed the diagnostic sensitivity of 94.7%. D‐lactate gave the area under the curve (AUC) 0.905, which was higher than those of other markers. Using multiple marker detection, the AUC reached 0.956, which was the highest among all the parameters. Pearson correlation analysis revealed that D‐lactate was positively correlated to IL-6 and L‐lactate (r=0.727, 0.789 and P=0.000, 0.000, respectively). THE CSF concentrations of D‐lactate are significantly increased in the presence of BM. Measurement of D‐lactate provides a rapid diagnosis and differential diagnosis for BM. Combination of D‐lactate with other biochemical markers improves the specificity. Copyright © 2012 Elsevier B.V. All rights reserved.

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL): assessment of the involved white matter tracts by MRI.

PubMed

Kassem, Hassan; Wafaie, Ahmed; Abdelfattah, Sherif; Farid, Tarek

2014-01-01

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a recently identified autosomal recessive disorder with early onset of symptoms and slowly progressive pyramidal, cerebellar and dorsal column dysfunction. LBSL is characterized by distinct white matter abnormalities and selective involvement of brainstem and spinal cord tracts. The purpose of this study is to assess the imaging features of the involved white matter tracts in cases of LBSL by MRI. We retrospectively reviewed the imaging features of the selectively involved white matter tracts in sixteen genetically proven cases of leukoencephalopathy with brainstem and spinal cord involvement and elevated brain lactate (LBSL). All patients presented with slowly progressive cerebellar sensory ataxia with spasticity and dorsal column dysfunction. MRI of the brain and spine using 1.5 T machine and proton magnetic resonance spectroscopy (1H MRS) on the abnormal white matter were done to all patients. The MRI and MRS data sets were analyzed according to lesion location, extent, distribution and signal pattern as well as metabolite values and ratios in MRS. Laboratory examinations ruled out classic leukodystrophies. In all cases, MRI showed high signal intensity in T2-weighted and FLAIR images within the cerebral subcortical, periventricular and deep white matter, posterior limbs of internal capsules, centrum semiovale, medulla oblongata, intraparenchymal trajectory of trigeminal nerves and deep cerebellar white matter. In the spine, the signal intensity of the dorsal column and lateral cortico-spinal tracts were altered in all patients. The subcortical U fibers, globi pallidi, thalami, midbrain and transverse pontine fibers were spared in all cases. In 11 cases (68.8%), the signal changes were inhomogeneous and confluent whereas in 5 patients (31.2%), the signal abnormalities were spotty. MRI also showed variable signal abnormalities in the sensory and pyramidal tracts in addition to the brainstem and cerebellar connections. Proton MRS showed consistent elevation of the lactate within the abnormal white matter. Distinct MRI findings in the form of selective affection of subcortical and deep white matter tracts of the brain (involving the posterior limb of internal capsules and sparing the subcortical U fibers), dorsal column and lateral cortico-spinal tracts of the spinal cord should lead to the diagnosis of LBSL supported by the presence of lactate peak in 1H MRS. The disease can be confirmed by the analysis of the disease gene DARS2.

Diagnostic accuracy of routine blood examinations and CSF lactate level for post-neurosurgical bacterial meningitis.

PubMed

Zhang, Yang; Xiao, Xiong; Zhang, Junting; Gao, Zhixian; Ji, Nan; Zhang, Liwei

2017-06-01

To evaluate the diagnostic accuracy of routine blood examinations and Cerebrospinal Fluid (CSF) lactate level for Post-neurosurgical Bacterial Meningitis (PBM) at a large sample-size of post-neurosurgical patients. The diagnostic accuracies of routine blood examinations and CSF lactate level to distinguish between PAM and PBM were evaluated with the values of the Area Under the Curve of the Receiver Operating Characteristic (AUC -ROC ) by retrospectively analyzing the datasets of post-neurosurgical patients in the clinical information databases. The diagnostic accuracy of routine blood examinations was relatively low (AUC -ROC <0.7). The CSF lactate level achieved rather high diagnostic accuracy (AUC -ROC =0.891; CI 95%, 0.852-0.922). The variables of patient age, operation duration, surgical diagnosis and postoperative days (the interval days between the neurosurgery and examinations) were shown to affect the diagnostic accuracy of these examinations. The variables were integrated with routine blood examinations and CSF lactate level by Fisher discriminant analysis to improve their diagnostic accuracy. As a result, the diagnostic accuracy of blood examinations and CSF lactate level was significantly improved with an AUC -ROC value=0.760 (CI 95%, 0.737-0.782) and 0.921 (CI 95%, 0.887-0.948) respectively. The PBM diagnostic accuracy of routine blood examinations was relatively low, whereas the accuracy of CSF lactate level was high. Some variables that are involved in the incidence of PBM can also affect the diagnostic accuracy for PBM. Taking into account the effects of these variables significantly improves the diagnostic accuracies of routine blood examinations and CSF lactate level. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Elevated levels of liver methylglyoxal and d-lactate in early-stage hepatitis in rats.

PubMed

Wang, Wen-Chuang; Chou, Chu-Kuang; Chuang, Ming-Cheng; Li, Yi-Chieh; Lee, Jen-Ai

2018-02-01

Methylglyoxal (MGO) is highly cytotoxic and its levels are elevated in diabetes, nephropathy and atherosclerosis. However, it has never been studied in liver disease. For this reason, we aimed to assess the levels of MGO and its metabolite d-lactate in an early hepatitis model. Wistar rats were administered CCl 4 (0.75 mL/kg, i.p.) to induce hepatitis. In either CCl 4 -treated or untreated rats, alanine transaminase and aspartate transaminase levels did not change over the course of the study, indicating that significant liver damage did not occur following CCl 4 treatment. However, the levels of MGO and d-lactate were higher in the livers of CCl 4 -treated animals than in untreated animals (MGO: 128.2 ± 18.8 and 248.1 ± 64.9 μg/g protein, p < 0.01; d-lactate: 0.860 ± 0.040 and 1.293 ± 0.078 μmol/g protein, respectively p < 0.01). Furthermore, in untreated and treated animals, serum d-lactate levels were 57.65 ± 2.59 and 92.16 ± 16.69 μm and urine d-lactate levels were 1.060 ± 0.007 and 1.555 ± 0.366 μmol/mg UCr, respectively (p < 0.01). These data show that in this model of early-stage liver damage, the levels of MGO and its metabolite d-lactate are elevated and that d-lactate could be useful as a reference marker for the early stage of hepatitis. Copyright © 2017 John Wiley & Sons, Ltd.

Vitamin D levels among pregnant and lactating women.

PubMed

Sharif, Saima; Farasat, Tasnim; Shoaib, Hamna; Saqib, Muhammad; Fazal, Sabiha

2013-12-01

To assess the serum level of vitamin D in pregnant and lactating women. Case-control study. Gynaecological Unit 1 of Jinnah Hospital, Lahore, from December 2010 to May 2011. A total of 100 women comprised of three groups: pregnant (n = 40), lactating (n = 40) and control (n = 20) groups. The information regarding age, educational level, socioeconomic status, exposure to sunlight and dietary vitamin D intake were collected through self-structured questionnaire. Serum concentration of vitamin D was measured by ELISA and serum calcium and phosphate levels were measured by chemistry analyzer. Statistical analysis was done using SPSS (version 13). The values were considered significant at 0.05 level of significance. The mean serum vitamin D level in the pregnant and lactating mothers was 26.5 ± 17.1 nmol/L and 21.4 ± 16.3 nmol/L respectively and in control group was 33.8 ± 21.1 nmol/L. The mean calcium level in the pregnant, lactating and control group was 10.3 ± 1.2 mg/dL, 9.7 ± 1.3 mg/dL and 9.7 ± 1.3 mg/dL respectively. The mean phosphate in pregnant was 3.2 ± 0.76 mg/dl, in lactating was 3.3 ± 0.76 mg/dl and in control was 3.5 ± 0.92 mg/dl. Significant difference (p = 0.041 and p = 0.037 respectively) in the serum levels of vitamin D and calcium was observed among the pregnant and lactating women as compared to control group. Low serum vitamin D concentration was observed in lactating women and pregnant women as compared to control group.

Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors.

PubMed

Marin-Valencia, Isaac; Cho, Steve K; Rakheja, Dinesh; Hatanpaa, Kimmo J; Kapur, Payal; Mashimo, Tomoyuki; Jindal, Ashish; Vemireddy, Vamsidhara; Good, Levi B; Raisanen, Jack; Sun, Xiankai; Mickey, Bruce; Choi, Changho; Takahashi, Masaya; Togao, Osamu; Pascual, Juan M; Deberardinis, Ralph J; Maher, Elizabeth A; Malloy, Craig R; Bachoo, Robert M

2012-10-01

It has been hypothesized that increased flux through the pentose phosphate pathway (PPP) is required to support the metabolic demands of rapid malignant cell growth. Using orthotopic mouse models of human glioblastoma (GBM) and renal cell carcinoma metastatic to brain, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-(13) C(2) ]glucose. The [3-(13) C]lactate/[2,3-(13) C(2) ]lactate ratio was similar for both the GBM and brain metastasis and their respective surrounding brains (GBM, 0.197 ± 0.011 and 0.195 ± 0.033, respectively (p = 1); metastasis: 0.126 and 0.119 ± 0.033, respectively). This suggests that the rate of glycolysis is significantly greater than the PPP flux in these tumors, and that the PPP flux into the lactate pool is similar in both tumors. Remarkably, (13) C-(13) C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrast with GBM, (13) C multiplets of γ-aminobutyric acid (GABA) differed from its precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. In addition, the orthotopic renal tumor, the patient's primary renal mass and brain metastasis were all strongly immunopositive for the 67-kDa isoform of glutamate decarboxylase, as were 84% of tumors on a renal cell carcinoma tissue microarray of the same histology, suggesting that GABA synthesis is cell autonomous in at least a subset of renal cell carcinomas. Taken together, these data demonstrate that (13) C-labeled glucose can be used in orthotopic mouse models to study tumor metabolism in vivo and to ascertain new metabolic targets for cancer diagnosis and therapy. Copyright © 2012 John Wiley & Sons, Ltd.

Reference values of blood parameters in beef cattle of different ages and stages of lactation.

PubMed Central

Doornenbal, H; Tong, A K; Murray, N L

1988-01-01

Reference (normal) values for 12 blood serum components were determined for 48 Shorthorn cows (2-10 years old) and their 48 calves, 357 crossbred cows (12-14 years old), 36 feedlot bulls and 36 feedlot steers. In addition, hemoglobin, hematocrit, triiodothyronine, thyroxine and cortisol levels were determined for the crossbred cows, and feedlot bulls and steers. Reference values were tabulated according to sex, age and stage of lactation. Serum concentrations of urea, total protein and bilirubin, and serum activity of aspartate aminotransferase and lactate dehydrogenase increased with age (P less than 0.05), while calcium, phosphorus and alkaline phosphatase decreased with age (P less than 0.05) from birth to the age of ten years. The Shorthorn cows had the highest levels of glucose at parturition (P less than 0.05) with decreasing levels during lactation. Creatinine concentration decreased during lactation and increased during postweaning. Both lactate dehydrogenase and aspartate aminotransferase levels increased (P less than 0.05) during lactation. Urea and uric acid were present at higher concentrations in lactating than nonlactating cows (P less than 0.05). The values reported, based on a wide age range and large number of cattle, could serve as clinical guides and a basis for further research. PMID:3349406

Blood lactate accumulation in top level swimmers following competition.

PubMed

Bonifazi, M; Martelli, G; Marugo, L; Sardella, F; Carli, G

1993-03-01

The purposes of this study were to evaluate the significance of blood lactate values after competitions and the blood lactate-swimming speed relationship to swimming performances. Auricular blood samples (N = 421) were collected in 203 top level Italian swimmers (116 males and 87 females) at the end of competitions performed in a 25 m swimming pool. The distribution of all lactate values differed between males and females. The lowest lactate values occurred in swimmers performing the longest distances both in males (1500 m) and females (800 m). In swimmers performing freestyle events a relationship between V-4 mM (swimming speed at 4 mmol/l blood lactate value) and competition velocities was observed, in males, at 200, 400 and 1500 m and, in females, at 400 and 800 m. The predicted velocity corresponding to the competition lactate value assessed by the individual blood lactate-swimming speed relationship was found to be highly related to the actual competition velocity. Results suggest that blood lactate values in swimmers are a useful indication of individual aptitudes.

Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats – a test of the astrocyte-neuron lactate-shuttle hypothesis

PubMed Central

Erlichman, J.S.; Hewitt, Amy; Damon, Tracey L.; Hart, Michael; Kurascz, Jennifer; Li, A.; Leiter, J.C.

2009-01-01

The astrocyte-neuronal lactate shuttle hypothesis (ANLSH) posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 microM α-cyano-4-hydroxy-cinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT2), but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly, but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 microM 4-CIN significantly reduced the magnitude of the acidosis in neurons, but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-d-glucose analogue in neurons, but did not alter the uptake rate of this 2-deoxy-d-glucose analogue in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Thus, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates. PMID:18463242

Alcohol consumption decreases lactate clearance in acutely injured patients☆

PubMed Central

Dezman, Zachary D.W.; Comer, Angela C.; Narayan, Mayur; Scalea, Thomas M.; Hirshon, Jon Mark; Smith, Gordon S.

2017-01-01

Introduction Alcohol, a common risk factor for injury, has direct toxic effects on the liver. The use of lactate clearance has been well described as an indicator of the adequacy of resuscitation in injured patients. We investigated whether acutely injured patients with positive blood alcohol content (+BAC) had less lactate clearance than sober patients. Methods We conducted a retrospective cohort study of acutely injured patients treated at an urban Level 1 trauma centre between January 2010 and December 2012. Blood alcohol and venous lactate levels were measured on all patients at the time of arrival. Study subjects were patients transported directly from the scene of injury, who had an elevated lactate concentration on arrival (≥3.0 mmol/L) and at least one subsequent lactate measurement within 24 h after admission. Lactate clearance ([Lactate1 − Lactate2]/Lactate1) was calculated for all patients. Chi-squared tests were used to compare values from sober and intoxicated subjects. Lactate clearance was plotted against alcohol levels and stratified by age and Injury Severity Score (ISS). Results Serial lactate concentration measurements were obtained in 3910 patients; 1674 of them had +BAC. Patients with +BAC were younger (mean age: 36.6 [SD 14.7] vs 41.0 [SD 19.9] years [p = 0.0001]), were more often male (83.4% vs 75.9% [p = 0.0001]), had more minor injuries (ISS < 9) (33.8% vs 27.1% [p = 0.0001]), had a lower in-hospital mortality rate (1.4% vs 3.9% [p = 0.0001]), but also had lower average lactate clearance (37.8% vs 47.6% [p = 0.0001]). The lactate clearance of the sober patients (47.6 [SD 33.5]) was twice that of those with +BAC >400 (23.5 [SD 6.5]). Lactate clearance decreased with increasing BAC irrespective of age and ISS. Conclusions In a large group of acutely injured patients, a dose-dependent decrease in lactate clearance was seen in those with elevated BAC. This relationship will cause a falsely elevated lactate reading or prolong lactate clearance and should be taken into account when evaluating patients with +BAC. PMID:27025567

Two Levels of Caffeine Ingestion on Blood Lactate and Free Fatty Acid Responses during Incremental Exercise.

ERIC Educational Resources Information Center

McNaughton, Lars

1987-01-01

Research was conducted to determine the effects of two doses of caffeine on the lactate threshold and also to examine the effects on substrate utilization during incremental cycle ergometry. Results found that caffeine increased heart rates and free fatty acid levels for all workloads and decreased blood lactate levels at some of the workloads.…

Analysis of neuron–astrocyte metabolic cooperation in the brain of db/db mice with cognitive decline using 13C NMR spectroscopy

PubMed Central

Zheng, Hong; Zheng, Yongquan; Wang, Dan; Cai, Aimin; Lin, Qiuting; Zhao, Liangcai; Chen, Minjiang; Deng, Mingjie; Ye, Xinjian

2016-01-01

Type 2 diabetes has been linked to cognitive impairment, but its potential metabolic mechanism is still unclear. The present study aimed to explore neuron–astrocyte metabolic cooperation in the brain of diabetic (db/db, BKS.Cg-m+/+ Leprdb/J) mice with cognitive decline using 13C NMR technique in combination with intravenous [2-13C]-acetate and [3-13C]-lactate infusions. We found that the 13C-enrichment from [2-13C]-acetate into tricarboxylic acid cycle intermediate, succinate, was significantly decreased in db/db mice with cognitive decline compared with wild-type (WT, C57BLKS/J) mice, while an opposite result was obtained after [3-13C]-lactate infusion. Relative to WT mice, db/db mice with cognitive decline had significantly lower 13C labeling percentages in neurotransmitters including glutamine, glutamate, and γ-aminobutyric acid after [2-13C]-acetate infusion. However, [3-13C]-lactate resulted in increased 13C-enrichments in neurotransmitters in db/db mice with cognitive decline. This may indicate that the disturbance of neurotransmitter metabolism occurred during the development of cognitive decline. In addition, a reduction in 13C-labeling of lactate and an increase in gluconeogenesis were found from both labeled infusions in db/db mice with cognitive decline. Therefore, our results suggest that the development of cognitive decline in type 2 diabetes may be implicated to an unbalanced metabolism in neuron–astrocyte cooperation and an enhancement of gluconeogenesis. PMID:26762505

Karnofsky Performance Status and Lactate Dehydrogenase Predict the Benefit of Palliative Whole-Brain Irradiation in Patients With Advanced Intra- and Extracranial Metastases From Malignant Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Partl, Richard, E-mail: richard.partl@medunigraz.at; Richtig, Erika; Avian, Alexander

2013-03-01

Purpose: To determine prognostic factors that allow the selection of melanoma patients with advanced intra- and extracerebral metastatic disease for palliative whole-brain radiation therapy (WBRT) or best supportive care. Methods and Materials: This was a retrospective study of 87 patients who underwent palliative WBRT between 1988 and 2009 for progressive or multiple cerebral metastases at presentation. Uni- and multivariate analysis took into account the following patient- and tumor-associated factors: gender and age, Karnofsky performance status (KPS), neurologic symptoms, serum lactate dehydrogenase (LDH) level, number of intracranial metastases, previous resection or stereotactic radiosurgery of brain metastases, number of extracranial metastasis sites,more » and local recurrences as well as regional lymph node metastases at the time of WBRT. Results: In univariate analysis, KPS, LDH, number of intracranial metastases, and neurologic symptoms had a significant influence on overall survival. In multivariate survival analysis, KPS and LDH remained as significant prognostic factors, with hazard ratios of 3.3 (95% confidence interval [CI] 1.6-6.5) and 2.8 (95% CI 1.6-4.9), respectively. Patients with KPS ≥70 and LDH ≤240 U/L had a median survival of 191 days; patients with KPS ≥70 and LDH >240 U/L, 96 days; patients with KPS <70 and LDH ≤240 U/L, 47 days; and patients with KPS <70 and LDH >240 U/L, only 34 days. Conclusions: Karnofsky performance status and serum LDH values indicate whether patients with advanced intra- and extracranial tumor manifestations are candidates for palliative WBRT or best supportive care.« less

Prognosis of patients excluded by the definition of septic shock based on their lactate levels after initial fluid resuscitation: a prospective multi-center observational study.

PubMed

Ko, Byuk Sung; Kim, Kyuseok; Choi, Sung-Hyuk; Kang, Gu Hyun; Shin, Tae Gun; Jo, You Hwan; Ryoo, Seung Mok; Beom, Jin Ho; Kwon, Woon Yong; Han, Kap Su; Choi, Han Sung; Chung, Sung Phil; Suh, Gil Joon; Lim, Tae Ho; Kim, Won Young

2018-02-24

Septic shock can be defined both by the presence of hyperlactatemia and need of vasopressors. Lactate levels should be measured after volume resuscitation (as per the Sepsis-3 definition). However, currently, no studies have evaluated patients who have been excluded by the new criteria for septic shock. The aim of this study was to determine the clinical characteristics and prognosis of these patients, based on their lactate levels after initial fluid resuscitation. This observational study was performed using a prospective, multi-center registry of septic shock, with the participation of 10 hospitals in the Korean Shock Society, between October 2015 and February 2017. We compared the 28-day mortality between patients who were excluded from the new definition (defined as lactate level <2 mmol/L after volume resuscitation) and those who were not (≥2 mmol/L after volume resuscitation), from among a cohort of patients with refractory hypotension, and requiring the use of vasopressors. Other outcome variables such as in-hospital mortality, intensive care unit (ICU) stay (days), Sequential Organ Failure Assessment (SOFA) scores and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were also analyzed. Of 567 patients with refractory hypotension, requiring the use of vasopressors, 435 had elevated lactate levels, while 83 did not have elevated lactate levels (either initially or after volume resuscitation), and 49 (8.2%) had elevated lactate levels initially, which normalized after fluid resuscitation. Thus, these 49 patients were excluded by the new definition of septic shock. These patients, in whom perfusion was restored, demonstrated significantly lower age, platelet count, and initial and subsequent lactate levels (all p < 0.01). Similarly, significantly lower 28-day mortality was observed in these patients than in those who had not been excluded (8.2% vs 25.5%, p = 0.02). In-hospital mortality and the maximum SOFA score were also significantly lower in the excluded patients group (p = 0.03, both). It seems reasonable for septic shock to be defined by the lactate levels after volume resuscitation. However, owing to the small number of patients in whom lactate levels were improved, further study is warranted.

Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury.

PubMed

Fukushima, Masamichi; Lee, Stefan M; Moro, Nobuhiro; Hovda, David A; Sutton, Richard L

2009-07-01

This study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MD(glc)), lactate (MD(lac)), and pyruvate (MD(pyr)), and the effects of SP treatment on neuropathology after left cortical contusion injury (CCI) in rats. SP injection (1000 mg/kg) 5 min after sham injury (Sham-SP) or CCI (CCI-SP) significantly increased arterial pyruvate (p < 0.005) and lactate (p < 0.001) compared to that of saline-treated rats with CCI (CCI-Sal). Serum glucose also increased significantly in CCI-SP compared to that in CCI-Sal rats (p < 0.05), but not in Sham-SP rats. MD(pyr) was not altered after CCI-Sal, whereas MD(lac) levels within the cerebral cortex significantly increased bilaterally (p < 0.05) and those for MD(glc) decreased bilaterally (p < 0.05). MD(pyr) levels increased significantly in both Sham-SP and CCI-SP rats (p < 0.05 vs. CCI-Sal) and were higher in left/injured cortex of the CCI-SP group (p < 0.05 vs. sham-SP). In CCI-SP rats the contralateral MD(lac) decreased below CCI-Sal levels (p < 0.05) and the ipsilateral MD(glc) levels exceeded those of CCI-Sal rats (p < 0.05). Rats with a single low (500 mg/kg) or high dose (1000 mg/kg) SP treatment had fewer damaged cortical cells 6 h post-CCI than did saline-treated rats (p < 0.05), but three hourly injections of SP (1000 mg/kg) were needed to significantly reduce contusion volume 2 weeks after CCI. Thus, a single intraperitoneal SP treatment increases circulating levels of three potential brain fuels, attenuates a CCI-induced reduction in extracellular glucose while increasing extracellular levels of pyruvate, but not lactate, and can attenuate cortical cell damage occurring within 6 h of injury. Enduring (2 week) neuronal protection was achieved only with multiple SP treatments within the first 2 h post-CCI, perhaps reflecting the need for additional fuel throughout the acute period of increased metabolic demands induced by CCI.

Metabolic and Histologic Effects of Sodium Pyruvate Treatment in the Rat after Cortical Contusion Injury

PubMed Central

Fukushima, Masamichi; Lee, Stefan M.; Moro, Nobuhiro; Hovda, David A.

2009-01-01

Abstract This study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MDglc), lactate (MDlac), and pyruvate (MDpyr), and the effects of SP treatment on neuropathology after left cortical contusion injury (CCI) in rats. SP injection (1000 mg/kg) 5 min after sham injury (Sham-SP) or CCI (CCI-SP) significantly increased arterial pyruvate (p < 0.005) and lactate (p < 0.001) compared to that of saline-treated rats with CCI (CCI-Sal). Serum glucose also increased significantly in CCI-SP compared to that in CCI-Sal rats (p < 0.05), but not in Sham-SP rats. MDpyr was not altered after CCI-Sal, whereas MDlac levels within the cerebral cortex significantly increased bilaterally (p < 0.05) and those for MDglc decreased bilaterally (p < 0.05). MDpyr levels increased significantly in both Sham-SP and CCI-SP rats (p < 0.05 vs. CCI-Sal) and were higher in left/injured cortex of the CCI-SP group (p < 0.05 vs. sham-SP). In CCI-SP rats the contralateral MDlac decreased below CCI-Sal levels (p < 0.05) and the ipsilateral MDglc levels exceeded those of CCI-Sal rats (p < 0.05). Rats with a single low (500 mg/kg) or high dose (1000 mg/kg) SP treatment had fewer damaged cortical cells 6 h post-CCI than did saline-treated rats (p < 0.05), but three hourly injections of SP (1000 mg/kg) were needed to significantly reduce contusion volume 2 weeks after CCI. Thus, a single intraperitoneal SP treatment increases circulating levels of three potential brain fuels, attenuates a CCI-induced reduction in extracellular glucose while increasing extracellular levels of pyruvate, but not lactate, and can attenuate cortical cell damage occurring within 6 h of injury. Enduring (2 week) neuronal protection was achieved only with multiple SP treatments within the first 2 h post-CCI, perhaps reflecting the need for additional fuel throughout the acute period of increased metabolic demands induced by CCI. PMID:19594384

[Variations of peripheral blood autoantibody, immunoglobuliln, and complement levels in patients with non-lactational mastitis and their clinical significances].

PubMed

Xu, Rui; Guo, Qian-Qian; Yang, Le-Ping; Lai, Mi-Lin; Tong, Lin

2016-08-20

To detect the variations in peripheral blood levels of autoantibodies, immunoglobulilns and complements in patients with non-lactational mastitis and investigate whether non-lactational mastitis is an autoimmune disease with immune dysfunction. Seven-eight patients with non-lactational mastitis treated in our hospital between September 2013 and May 2015 and 88 healthy women (control) were examined for peripheral blood levels of antinuclear antibody (ANA), anti-histone antibody (AHA), immunoglobulins (IgA, IgM, and IgG) and complements (C3, C4, and total complements). s Of the 78 patients with non-lactational mastitis, 50 (64.10%) were positive of ANA showing mainly the granular and cytoplasmic granular fluorescence patterns, and the positivity rate was significantly higher than that in the control group (P<0.000). Twenty-eight (36.00%) of the patients were positive of AHA, a rate significantly higher than that in the control group (P<0.000). The levels of IgA, IgM, C4, and total complements levels were all significantly elevated in the patients compared with those in the control group (P<0.05). Patients with non-lactational mastitis have abnormal changes in peripheral blood levels of immunoglobulins and complements with high positivity rates for ANA and AHA, indicating that non-lactational mastitis is an autoimmune disease with immune dysfunction.

Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature.

PubMed

Dell'Aglio, Damon M; Perino, Louis J; Kazzi, Ziad; Abramson, Jerome; Schwartz, Michael D; Morgan, Brent W

2009-12-01

Metformin is known to cause potentially fatal metabolic acidosis with an increased lactate level in both overdose and therapeutic use. No association between mortality and serum pH, lactate level, or metformin concentrations, though intuitive, has yet been described. This systematic literature review is designed to evaluate the association between mortality and serum pH, lactate level, and metformin concentrations in acute metformin overdose. We reviewed the literature by using the MEDLINE, EMBASE, CINAHL, and TOXNET databases for cases of metformin overdose with documented mortality data and values of serum pH, lactate level, and metformin concentrations. When available, patient age, patient sex, and whether patients received intravenous sodium bicarbonate therapy or hemodialysis were also analyzed. Cases meeting inclusion criteria were analyzed to determine whether a difference in distribution of nadir serum pH, peak serum lactate level, or peak serum metformin concentrations existed between overdose survivors and nonsurvivors. We identified 10 articles that had 1 or more cases meeting our inclusion criteria. In total, there were 22 cases of metformin overdose (5/22 died) that met inclusion criteria. No intentional overdose patients died whose serum pH nadir was greater than 6.9, maximum lactate concentration less than 25 mol/L, or maximum metformin concentration less than 50 microg/mL (therapeutic range 1 to 2 microg/mL). Intentional overdose patients with a nadir serum pH less than 6.9 had 83% mortality (5/6), those with lactate concentration greater than 25 mmol/L had 83% mortality (5/6), and those with metformin concentration greater than 50 microg/mL had 38% mortality (5/12). Nadir serum pH and peak serum lactate and metformin concentration distributions in survivors and nonsurvivors revealed that survivors had a median nadir pH of 7.30, interquartile range (IQR) 7.22, 7.36; nonsurvivors, a median nadir pH of 6.71, IQR 6.71, 6.73; survivors, a median peak lactate level of 10.8 mmol/L, IQR 4.2, 12.9; nonsurvivors, a median peak lactate level of 35.0 mmol/L, IQR 33.3, 39.0; survivors, a median peak metformin level of 42 microg/mL, IQR 6.6, 67.6; and nonsurvivors, a median peak metformin level of 110 microg/mL, IQR 110, 110. No cases of acute metformin overdose meeting the study's inclusion criteria were found in which patients with a nadir serum pH greater than 6.9, peak serum lactate concentrations less than 25 mmol/L, or peak serum metformin concentrations less than 50 microg/mL died. Patients with acute metformin overdose who died had much lower serum pH nadirs and much higher peak serum lactate and metformin concentrations than those who survived.

Cumulative lactate and hospital mortality in ICU patients

PubMed Central

2013-01-01

Background Both hyperlactatemia and persistence of hyperlactatemia have been associated with bad outcome. We compared lactate and lactate-derived variables in outcome prediction. Methods Retrospective observational study. Case records from 2,251 consecutive intensive care unit (ICU) patients admitted between 2001 and 2007 were analyzed. Baseline characteristics, all lactate measurements, and in-hospital mortality were recorded. The time integral of arterial blood lactate levels above the upper normal threshold of 2.2 mmol/L (lactate-time-integral), maximum lactate (max-lactate), and time-to-first-normalization were calculated. Survivors and nonsurvivors were compared and receiver operating characteristic (ROC) analysis were applied. Results A total of 20,755 lactate measurements were analyzed. Data are srpehown as median [interquartile range]. In nonsurvivors (n = 405) lactate-time-integral (192 [0–1881] min·mmol/L) and time-to-first normalization (44.0 [0–427] min) were higher than in hospital survivors (n = 1846; 0 [0–134] min·mmol/L and 0 [0–75] min, respectively; all p < 0.001). Normalization of lactate <6 hours after ICU admission revealed better survival compared with normalization of lactate >6 hours (mortality 16.6% vs. 24.4%; p < 0.001). AUC of ROC curves to predict in-hospital mortality was the largest for max-lactate, whereas it was not different among all other lactate derived variables (all p > 0.05). The area under the ROC curves for admission lactate and lactate-time-integral was not different (p = 0.36). Conclusions Hyperlactatemia is associated with in-hospital mortality in a heterogeneous ICU population. In our patients, lactate peak values predicted in-hospital mortality equally well as lactate-time-integral of arterial blood lactate levels above the upper normal threshold. PMID:23446002

Lactate Parameters Predict Clinical Outcomes in Patients with Nonvariceal Upper Gastrointestinal Bleeding.

PubMed

Lee, Seung Hoon; Min, Yang Won; Bae, Joohwan; Lee, Hyuk; Min, Byung Hoon; Lee, Jun Haeng; Rhee, Poong Lyul; Kim, Jae J

2017-11-01

The predictive role of lactate in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) has been suggested. This study evaluated several lactate parameters in terms of predicting outcomes of bleeding patients and sought to establish a new scoring model by combining lactate parameters and the AIMS65 score. A total of 114 patients with NVUGIB who underwent serum lactate level testing at least twice and endoscopic hemostasis within 24 hours after admission were retrospectively analyzed. The associations between five lactate parameters and clinical outcomes were evaluated and the predictive power of lactate parameter combined AIMS65s (L-AIMS65s) and AIMS56 scoring was compared. The most common cause of bleeding was gastric ulcer (48.2%). Lactate clearance rate (LCR) was associated with 30-day rebleeding (odds ratio [OR], 0.931; 95% confidence interval [CI], 0.872-0.994; P = 0.033). Initial lactate (OR, 1.313; 95% CI, 1.050-1.643; P = 0.017), maximal lactate (OR, 1.277; 95% CI, 1.037-1.573; P = 0.021), and average lactate (OR, 1.535; 95% CI, 1.137-2.072; P = 0.005) levels were associated with 30-day mortality. Initial lactate (OR, 1.213; 95% CI, 1.027-1.432; P = 0.023), maximal lactate (OR, 1.271; 95% CI, 1.074-1.504; P = 0.005), and average lactate (OR, 1.501; 95% CI, 1.150-1.959; P = 0.003) levels were associated with admission over 7 days. Although L-AIMS65s showed the highest area under the curve for prediction of each outcome, differences between L-AIMS65s and AIMS65 did not reach statistical significance. In conclusion, lactate parameters have a prognostic role in patients with NVUGIB. However, they do not increase the predictive power of AIMS65 when combined. © 2017 The Korean Academy of Medical Sciences.

Relationship among blood indicators of lipomobilization and hepatic function during early lactation in high-yielding dairy cows.

PubMed

González, Felix Diaz; Muiño, Rodrigo; Pereira, Víctor; Campos, Rómulo; Benedito, José Luis

2011-09-01

Blood indicators are used as a tool to diagnose metabolic disorders. The present work was conducted to study the relationships among blood indicators of lipomobilization and hepatic function in high-yielding dairy cows. Two groups of Holstein cows were studied: 27 early lactation cows and 14 mid lactation cows from four different herds with similar husbandry characteristics in Galicia, Spain. Blood samples were obtained to measure beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA), triglycerides (TG), and the activity of aspartate transaminase (AST) and gamma-glutamyl transferase. Cows in early lactation had higher levels of BHB and NEFA than mid lactation cows. High lipomobilization (NEFA > 400 µmol/L) was detected in 67% and 7% of early lactation and mid lactation cows, respectively, while subclinical ketosis (BHB > 1.2 mmol/L) was detected in 41% and 28% of the early lactation and lactation cows, respectively. TG concentrations were low in all cows suffering subclinical ketosis and in 61% of the cows with high lipomobilization. During early lactation, 30% of cows suffered hepatic lipidosis as detected by levels of AST. Compromised hepatic function was observed in early lactation cows as shown by lower concentrations of glucose, total protein, and urea.

Urinary excretion levels of water-soluble vitamins in pregnant and lactating women in Japan.

PubMed

Shibata, Katsumi; Fukuwatari, Tsutomu; Sasaki, Satoshi; Sano, Mitsue; Suzuki, Kahoru; Hiratsuka, Chiaki; Aoki, Asami; Nagai, Chiharu

2013-01-01

Recent studies have shown that the urinary excretion levels of water-soluble vitamins can be used as biomarkers for the nutritional status of these vitamins. To determine changes in the urinary excretion levels of water-soluble vitamins during pregnant and lactating stages, we surveyed and compared levels of nine water-soluble vitamins in control (non-pregnant and non-lactating women), pregnant and lactating women. Control women (n=37), women in the 2nd (16-27 wk, n=24) and 3rd trimester of pregnancy (over 28 wk, n=32), and early- (0-5 mo, n=54) and late-stage lactating (6-11 mo, n=49) women took part in the survey. The mean age of subjects was ~30 y, and mean height was ~160 cm. A single 24-h urine sample was collected 1 d after the completion of a validated, self-administered comprehensive diet history questionnaire to measure water-soluble vitamins or metabolites. The average intake of each water-soluble vitamin was ≍ the estimated average requirement value and adequate intake for the Japanese Dietary Reference Intakes in all life stages, except for vitamin B6 and folate intakes during pregnancy. No change was observed in the urinary excretion levels of vitamin B2, vitamin B6, vitamin B12, biotin or vitamin C among stages. Urine nicotinamide and folate levels were higher in pregnant women than in control women. Urine excretion level of vitamin B1 decreased during lactation and that of pantothenic acid decreased during pregnancy and lactation. These results provide valuable information for setting the Dietary Reference Intakes of water-soluble vitamins for pregnant and lactating women.

Effect of level of chronic immune system activation on the lactational performance of sows.

PubMed

Sauber, T E; Stahly, T S; Nonnecke, B J

1999-08-01

The effect of the level of chronic immune system (IS) activation on sow lactational performance was determined in 11 pairs of littermate, primiparous sows. Sows with a low level of IS activation were created by rearing the animals via early weaning, isolated rearing schemes. During lactation, two levels of IS activation were achieved in each littermate sow pair by subcutaneous administration of either 0 (saline) or 5 microg/kg of sow BW of Escherichia coli lipopolysaccharide (LPS) in a mineral oil adjuvant emulsion on d 2 and 10 of lactation. Litters were standardized to 13 pigs by 8 h postpartum. Sows were offered daily 6.0 kg of a corn-soy diet formulated to contain a minimum of 250% of the dietary nutrient concentrations estimated to be needed by lactating sows. Based on antibody titers to LPS and serum concentrations of alpha-1 acid glycoprotein (AGP), high IS sows mounted an immune response to the LPS during lactation, and low IS sows maintained a low level of IS activation. Over an 18-d lactation, a high level of chronic activation of the sows' immune systems depressed daily sow feed intakes by .56 kg, litter weight gains by .32 kg, and daily milk by 1.4 kg, milk energy by 1.7 Mcal, and milk protein yields by 71 g, but did not alter sow body weight loss. The reductions in yields of milk and milk nutrients likely were because of proinflammatory cytokine-induced inhibition of the lactogenic hormones resulting from high chronic IS activation. Based on these data, the level of chronic IS activation alters the lactational performance of sows.

Taurine reverses sodium fluoride-mediated increase in inflammation, caspase-3 activity, and oxidative damage along the brain-pituitary-gonadal axis in male rats.

PubMed

Adedara, Isaac A; Olabiyi, Bolanle F; Ojuade, TeminiJesu D; Idris, Umar F; Onibiyo, Esther M; Farombi, Ebenezer O

2017-09-01

Excessive exposure to fluoride is associated with male reproductive dysfunction in humans and animals. Taurine (2-aminoethane sulfonic acid) is a free intracellular β-amino acid with antioxidant, anti-inflammatory, and neuroprotective properties. However, the effect of taurine on fluoride-induced reproductive toxicity has not been reported. The present study investigated the influence of taurine on sodium fluoride (NaF)-induced functional changes along the brain-pituitary-gonadal axis in male rats. NaF was administered singly in drinking water at 15 mg·L -1 alone or orally co-administered by gavage with taurine at 100 and 200 mg·(kg body mass) -1 for 45 consecutive days. Results showed that taurine significantly prevented NaF-induced increase in oxidative stress indices as well as augmented antioxidant enzymes activities and glutathione level in the brain, testes, and epididymis of the treated rats. Moreover, taurine reversed NaF-induced elevation in inflammatory biomarkers and caspase-3 activity as well as histological damage in the brain, testes, and epididymis of the treated rats. The significant reversal of NaF-induced decreases in testosterone level and testicular activities of acid phosphatase, alkaline phosphatase, and lactate dehydrogenase by taurine was accompanied by enhancement of sperm functional characteristics in the treated rats. Taurine may be a possible chemopreventive candidate against reproductive dysfunction resulting from fluoride exposure.

Association between Brain and Kidney Near-Infrared Spectroscopy and Early Postresuscitation Mortality in Asphyxiated Newborn Piglets.

PubMed

Solevåg, Anne Lee; Schmölzer, Georg M; Nakstad, Britt; Saugstad, Ola Didrik; Cheung, Po-Yin

2017-01-01

Early outcome predictors after delivery room cardiopulmonary resuscitation (CPR) of asphyxiated newborns are needed. To investigate if cerebral (rScO2) and renal (rSrO2) tissue oxygen saturation 30 min after return of spontaneous circulation (ROSC) are different between surviving versus nonsurviving piglets with asphyxia-induced cardiac arrest and CPR. Further, to investigate the relationship of rScO2 and rSrO2 to cardiac output (CO), blood pressure (BP), and biochemical variables 30 min and 4 h after ROSC. Anesthetized, mechanically ventilated piglets (1-3 days, 1.7-2.4 kg) were used. rScO2, rSrO2, SpO2, right common carotid artery flow, and arterial BP were measured continuously. CO was measured with echocardiography. The piglets were asphyxiated until cardiac arrest and resuscitated. Piglets that survived 4 h after ROSC (n = 12) were compared with piglets that died before planned euthanasia at 4 h (n = 13). Left ventricular, and kidney and brain tissue lactate were analyzed. Correlations between variables were assessed. Thirty minutes after ROSC, median rSrO2 (43% [n = 10] vs. 25% [n = 2], p = 0.003) but not rScO2 (46% [41-55] [n = 10] vs. 40% [22-45] [n = 5], p = 0.08) was higher in survivors than in nonsurvivors. Arterial lactate was negatively correlated and pH positively correlated with rScO2 and rSrO2. Left ventricular, but not kidney or brain lactate was negatively correlated with rScO2 and rSrO2. There was no correlation between CO or BP and rScO2 or rSrO2. Despite satisfactory CO and BP vital organ oxygenation can be poor. Tissue oxygen saturation, pH, and lactate, as measures of anaerobic metabolism, may reflect vital organ oxygenation and outcome. © 2017 S. Karger AG, Basel.

Effects of perinatal exposure to PCBs on neuropsychological functions in the Rotterdam cohort at 9 years of age.

PubMed

Vreugdenhil, Hestien J I; Mulder, Paul G H; Emmen, Harry H; Weisglas-Kuperus, Nynke

2004-01-01

PCBs are known for their neurotoxic properties, especially on the developing brain. To increase insight into the neurotoxic effects of PCB exposure, the authors studied the effects of perinatal exposure to environmental levels of these compounds on different neuropsychological domains. In 9-year-old children of the Rotterdam PCB--dioxin cohort, higher prenatal PCB levels were associated with longer response times (RTs), more variation in RTs, and lower scores on the Tower of London (TOL; Shallice, 1982). A longer breast-feeding duration was associated with lower TOL scores and with better spatial organizational skills. There was some evidence of negative effects of lactational exposure to PCBs on scores on the TOL. ((c) 2004 APA, all rights reserved)

Developmental treatment with bisphenol A or ethinyl estradiol causes few alterations on early preweaning measures.

PubMed

Ferguson, Sherry A; Law, Charles D; Abshire, Jordan S

2011-11-01

Because bisphenol A (BPA) exposure is nearly ubiquitous, increased knowledge of its potential effects on development will enable better risk assessment and regulatory guidance. Here, Sprague-Dawley rats were reared in low exogenous estrogen environments. After breeding at adulthood, dams were gavaged on gestational days (GDs) 6-21 with vehicle (VEH), 2.5 or 25.0 μg/kg/day BPA, or 5.0 or 10.0 μg/kg/day ethinyl estradiol (EE₂). Offspring were orally treated on postnatal days (PNDs) 1-21 with the same dose the dam received. Relative to the VEH group, dams of both EE₂-treated groups weighed less throughout gestation and lactation. PND 1 absolute anogenital distance and anogenital index were unaltered by any treatment. Ages at fur development and eye and ear opening were unaffected by any treatment. Despite a significant treatment effect, no group was significantly different from VEH in PNDs 3-6 righting latencies; although males had shorter latencies and all latencies decreased with age. PNDs 8-11 slant board behavior was unaffected by any treatment; however, males had shorter turning latencies and latencies decreased with age. Preweaning body weights of BPA- and EE₂-treated groups as well as naive controls were less than VEH. No treatment affected PND 21 whole or regional brain weights or levels of estradiol, testosterone, corticosterone, T3, T4, luteinizing hormone, ghrelin, or leptin. These results add to the literature indicating that developmental BPA treatment at these doses has no effects on gestational or lactational body weight, offspring anogenital distance, preweaning behaviors or hormone levels, and whole and regional brain weights measured at weaning.

Trpc2-deficient lactating mice exhibit altered brain and behavioral responses to bedding stimuli

PubMed Central

Hasen, Nina S.; Gammie, Stephen C.

2010-01-01

The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2-/- knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female. PMID:21070815

Inhibition, by 2-oxo acids that accumulate in maple-syrup-urine disease, of lactate, pyruvate, and 3-hydroxybutyrate transport across the blood-brain barrier.

PubMed

Cremer, J E; Teal, H M; Cunningham, V J

1982-09-01

Data are presented in support of the transport of (-)-D-3-hydroxybutyrate across the blood-brain barrier (BBB) being a carrier-mediated process. The kinetic parameters in 21-day-old pentobarbital-anaesthetized rats were Vmax 2.0 mumol.g-1.min-1, Km 29 mM, and KD 0.024 ml.g-1.min-1. The value for Vmax was the same as that for L-lactate and pyruvate transport in animals of the same age. The transport of all three substrates was sensitive to inhibition by low concentrations of either 2-oxo-3-methylbutanoate or 2-oxo-4-methylpentanoate, the 2-oxo acids that can accumulate in patients with maple-syrup-urine disease. The Ki values for the 2-oxo acids were severalfold lower than the respective Km values. 2-Oxo-3-phenylpropionate was a poor inhibitor. The relative affinities of the various monocarboxylic acids for the transport system of the BBB distinguished it from similar systems described in brain, heart, and liver mitochondria; human erythrocytes; and Ehrlich ascites-tumour cells.

In vivo measurement of regional brain metabolic response to hyperventilation using magnetic resonance: proton echo planar spectroscopic imaging (PEPSI).

PubMed

Posse, S; Dager, S R; Richards, T L; Yuan, C; Ogg, R; Artru, A A; Müller-Gärtner, H W; Hayes, C

1997-06-01

A new rapid spectroscopic imaging technique with improved sensitivity and lipid suppression, referred to as Proton Echo Planar Spectroscopic Imaging (PEPSI), has been developed to measure the 2-dimensional distribution of brain lactate increases during hyperventilation on a conventional clinical scanner equipped with a head surface coil phased array. PEPSI images (nominal voxel size: 1.125 cm3) in five healthy subjects from an axial section approximately 20 mm inferior to the intercommissural line were obtained during an 8.5-min baseline period of normocapnia and during the final 8.5 min of a 10-min period of capnometry-controlled hyperventilation (end-tidal PCO2 of 20 mmHg). The lactate/N-acetyl aspartate signal increased significantly from baseline during hyperventilation for the insular cortex, temporal cortex, and occipital regions of both the right and left hemisphere, but not in the basal ganglia. Regional or hemispheric right-to-left differences were not found. The study extends previous work using single-voxel MR spectroscopy to dynamically study hyperventilation effects on brain metabolism.

Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis.

PubMed

Vellinga, Namkje A R; Boerma, E Christiaan; Koopmans, Matty; Donati, Abele; Dubin, Arnaldo; Shapiro, Nathan I; Pearse, Rupert M; van der Voort, Peter H J; Dondorp, Arjen M; Bafi, Tony; Fries, Michael; Akarsu-Ayazoglu, Tulin; Pranskunas, Andrius; Hollenberg, Steven; Balestra, Gianmarco; van Iterson, Mat; Sadaka, Farid; Minto, Gary; Aypar, Ulku; Hurtado, F Javier; Martinelli, Giampaolo; Payen, Didier; van Haren, Frank; Holley, Anthony; Gomez, Hernando; Mehta, Ravindra L; Rodriguez, Alejandro H; Ruiz, Carolina; Canales, Héctor S; Duranteau, Jacques; Spronk, Peter E; Jhanji, Shaman; Hubble, Sheena; Chierego, Marialuisa; Jung, Christian; Martin, Daniel; Sorbara, Carlo; Bakker, Jan; Ince, Can

2017-10-18

Mildly elevated lactate levels (i.e., 1-2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80-1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1-5.7, P = 0.027). In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. ClinicalTrials.gov, NCT01179243 . Registered on August 3, 2010.

Changes in behavioural parameters, oxidative stress and neurotrophins in the brain of adult offspring induced to an animal model of schizophrenia: The effects of FA deficient or FA supplemented diet during the neurodevelopmental phase.

PubMed

Canever, L; Freire, T G; Mastella, G A; Damázio, L; Gomes, S; Fachim, I; Michels, C; Carvalho, G; Godói, A K; Peterle, B R; Gava, F F; Valvassori, S S; Budni, J; Quevedo, J; Zugno, A I

2018-05-18

A deficiency of maternal folic acid (FA) can compromise the function and development of the brain, and may produce a susceptibility to diseases such as schizophrenia (SZ) in the later life of offspring. The aim of this study was to evaluate the effects of both FA deficient and FA supplemented diets during gestation and lactation on behavioural parameters, the markers of oxidative stress and neurotrophic factors in adult offspring which had been subjected to an animal model of SZ. Female mother rats (Dam's) were separated into experimental maternal groups, which began receiving a special diet (food) consisting of the AIN-93 diet, a control diet, or an FA deficient diet during the periods of pregnancy and lactation. Dam's receiving the control diet were further subdivided into four groups: one group received only control diet, while three groups to receive supplementation with FA at different doses (5, 10 and 50 mg/kg). Adult offspring bred from the Dam's were divided into ten groups for induction of the animal model of SZ through the administration of ketamine (Ket) (25 mg/kg). After the last administration of the drug, the animals were subjected to the behavioural tests and were then euthanized. The frontal cortex (FC) and hippocampus (Hip) were then dissected for later biochemical analysis. Our data demonstrates that Ket induced the model of SZ by altering the behavioural parameters (e.g. hyperlocomotion, social impairment, deficits in the sensory-motor profile and memory damage in the adult animals); and also caused changes in the parameters of oxidative stress (lipid hydroperoxide - LPO; 8-isoprostane - 8-ISO; 4-hydroxynonenal - 4-HNE; protein carbonyl content; superoxide dismutase - SOD and catalase - CAT) as well as in the levels of neurotrophic factors (brain-derived neurotrophic factor - BDNF and nerve growth factor - NGF) particularly within the FC of adult offspring. A deficiency in maternal FA, alone or in combination with ket, was able to induce hyperlocomotion and social impairment in the offspring with increased levels of lipid and protein damage (LPO, 8-ISO, 4-HNE, carbonylation of protein) within the FC, increased activity of antioxidant enzymes (SOD and CAT) in both of the brain structures studied, and also reduced the levels of neurotrophins (BDNF and NGF), particularly within the Hip of the adult offspring. Supplementation of FA (5, 10 and 50 mg/kg) to the Dam's was mostly able to prevent the cognitive damage which was induced by Ket in the adult animals. FA (10 and 50 mg/kg) attenuated the action of Ket in the animals in relation to the biochemical parameters, proving the possible neuroprotective effect of FA in the adulthood of offspring that were subjected to the animal model of SZ. Our study indicates that the intake of maternal FA during pregnancy and lactation plays an important role, particularly in the regulation of markers of oxidative stress and neurotrophins. Copyright © 2018 Elsevier Inc. All rights reserved.

[Pharmacological study of nicergoline. (II). Protective effect on ischemic brain damages in animals].

PubMed

Shintomi, K; Itakura, T; Yoshimoto, K; Ogawa, Y; Fukushima, T; Matsuoka, Y

1986-04-01

Effects of nicergoline on ischemic brain damages induced by bilateral carotid arterial ligation (BCAL) in ICR-strain mice and mongolian gerbils and lipid peroxide formation (LPOF) in normal brain homogenate of rats were compared with those of dihydroergotoxine (DHE). In mice, nicergoline (16 mg/kg, i.p.) significantly reduced the cumulative mortality rate after BCAL (from 80-83% in the control to 50-55%). In gerbils, nicergoline (32 mg/kg, i.p.) significantly prolonged the mean onset time of ischemic seizure following recirculation after the 30-min BCAL (from 45.8 min in the control to 94.9 min). DHE also showed protective effects in these animals. In the ischemic brain of mice, marked decreases of creatine-P, ATP, glucose and glycogen; a remarkable increase of lactate; and elevation of L/P ratio were observed 1 to 10 min after BCAL. Nicergoline (16 mg/kg, i.p.) slightly prevented these decreases and significantly suppressed the increase of lactate and the elevation of L/P ratio 2 min after BCAL. The inhibitory action of nicergoline (20-100 microM) on LPOF is more potent than those of alpha-tocopherol and DHE. These results suggest that nicergoline may have protective effects against ischemic brain damages due to its ameliorating action on cerebral energy metabolism and partially due to its inhibitory action of LPOF.

Response to ‘comment on recent modeling studies of astrocyte–neuron metabolic interactions': much ado about nothing

PubMed Central

Mangia, Silvia; DiNuzzo, Mauro; Giove, Federico; Carruthers, Anthony; Simpson, Ian A; Vannucci, Susan J

2011-01-01

For many years, a tenet of cerebral metabolism held that glucose was the obligate energy substrate of the mammalian brain and that neuronal oxidative metabolism represented the majority of this glucose utilization. In 1994, Pellerin and Magistretti formulated the astrocyte–neuron lactate shuttle (ANLS) hypothesis, in which astrocytes, not neurons, metabolized glucose, with subsequent transport of the glycolytically derived lactate to fuel the energy needs of the neuron during neurotransmission. By considering the concentrations and kinetic characteristics of the nutrient transporter proteins, Simpson et al later supported the opposite view, in which lactate flows from neurons to astrocytes, thus leading to the neuron–astrocyte lactate shuttle (NALS). Most recently, a commentary was published in this journal attempting to discredit the NALS. This challenge has stimulated the present response in which we detail the inaccuracies of the commentary and further model several different possibilities. Although our simulations continue to support the predominance of neuronal glucose utilization during activation and neuronal to astrocytic lactate flow, the most important result is that, regardless of the direction of the flow, the overall contribution of lactate to cerebral glucose metabolism is found to be so small as to make this ongoing debate ‘much ado about nothing'. PMID:21427731

Differential microRNA expression in the prefrontal cortex of mouse offspring induced by glyphosate exposure during pregnancy and lactation.

PubMed

Ji, Hua; Xu, Linhao; Wang, Zheng; Fan, Xinli; Wu, Lihui

2018-03-01

Glyphosate is the active ingredient in numerous herbicide formulations. The role of glyphosate in neurotoxicity has been reported in human and animal models. However, the detailed mechanism of the role of glyphosate in neuronal development remains unknown. Recently, several studies have reported evidence linking neurodevelopmental disorders (NDDs) with gestational glyphosate exposure. The current group previously identified microRNAs (miRNAs) that are associated with the etiology of NDDs, but their expression levels in the developing brain following glyphosate exposure have not been characterized. In the present study, miRNA expression patterns were evaluated in the prefrontal cortex (PFC) of 28 postnatal day mouse offspring following glyphosate exposure during pregnancy and lactation. An miRNA microarray detected 55 upregulated and 19 downregulated miRNAs in the PFC of mouse offspring, and 20 selected deregulated miRNAs were further evaluated by quantitative polymerase chain reaction (PCR). A total of 11 targets of these selected deregulated miRNAs were analyzed using bioinformatics. Gene Ontology (GO) terms associated with the relevant miRNAs included neurogenesis (GO:0050769), neuron differentiation (GO:0030182) and brain development (GO:0007420). The genes Cdkn1a, Numbl, Notch1, Fosl1 and Lef1 are involved in the Wnt and Notch signaling pathways, which are closely associated with neural development. PCR arrays for the mouse Wnt and Notch signaling pathways were used to validate the effects of glyphosate on the expression pattern of genes involved in the Wnt and Notch pathways. Nr4a2 and Wnt7b were downregulated, while Dkk1, Dixdc1, Runx1, Shh, Lef-1 and Axin2 were upregulated in the PFC of mice offspring following glyphosate exposure during pregnancy and lactation. These results indicated abnormalities of the Wnt/β-catenin and Notch pathways. These findings may be of particular interest for understanding the mechanism of glyphosate-induced neurotoxicity, as well as helping to clarify the association between glyphosate and NDDs.

Differential microRNA expression in the prefrontal cortex of mouse offspring induced by glyphosate exposure during pregnancy and lactation

PubMed Central

Ji, Hua; Xu, Linhao; Wang, Zheng; Fan, Xinli; Wu, Lihui

2018-01-01

Glyphosate is the active ingredient in numerous herbicide formulations. The role of glyphosate in neurotoxicity has been reported in human and animal models. However, the detailed mechanism of the role of glyphosate in neuronal development remains unknown. Recently, several studies have reported evidence linking neurodevelopmental disorders (NDDs) with gestational glyphosate exposure. The current group previously identified microRNAs (miRNAs) that are associated with the etiology of NDDs, but their expression levels in the developing brain following glyphosate exposure have not been characterized. In the present study, miRNA expression patterns were evaluated in the prefrontal cortex (PFC) of 28 postnatal day mouse offspring following glyphosate exposure during pregnancy and lactation. An miRNA microarray detected 55 upregulated and 19 downregulated miRNAs in the PFC of mouse offspring, and 20 selected deregulated miRNAs were further evaluated by quantitative polymerase chain reaction (PCR). A total of 11 targets of these selected deregulated miRNAs were analyzed using bioinformatics. Gene Ontology (GO) terms associated with the relevant miRNAs included neurogenesis (GO:0050769), neuron differentiation (GO:0030182) and brain development (GO:0007420). The genes Cdkn1a, Numbl, Notch1, Fosl1 and Lef1 are involved in the Wnt and Notch signaling pathways, which are closely associated with neural development. PCR arrays for the mouse Wnt and Notch signaling pathways were used to validate the effects of glyphosate on the expression pattern of genes involved in the Wnt and Notch pathways. Nr4a2 and Wnt7b were downregulated, while Dkk1, Dixdc1, Runx1, Shh, Lef-1 and Axin2 were upregulated in the PFC of mice offspring following glyphosate exposure during pregnancy and lactation. These results indicated abnormalities of the Wnt/β-catenin and Notch pathways. These findings may be of particular interest for understanding the mechanism of glyphosate-induced neurotoxicity, as well as helping to clarify the association between glyphosate and NDDs. PMID:29467848

Regulation of bone mineral loss during lactation

NASA Technical Reports Server (NTRS)

Brommage, R.; Deluca, H. F.

1985-01-01

The effects of varyng dietary calcium and phosphorous levels, vitamin D deficiency, oophorectomy, adrenalectomy, and simultaneous pregnancy on bone mineral loss during lactation in rats are studied. The experimental procedures and evaluations are described. The femur ash weight of lactating and nonlactating rats are calculated. The data reveals that a decrease in dietary calcium of 0.02 percent results in an increased loss of bone mineral, an increase in calcium to 1.4 percent does not lessen bone mineral loss, and bone mineral loss in vitamin D deficient rats is independent of calcium levels. It is observed that changes in dietary phosphorous level, oophorectomy, adrenalectomy, and simultaneous pragnancy do not reduce bone mineral loss during lactation. The analysis of various hormones to determine the mechanism that triggers bone mineral loss during lactation is presented.

Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells.

PubMed

Moreira, Tiago J T P; Pierre, Karin; Maekawa, Fumihiko; Repond, Cendrine; Cebere, Aleta; Liljequist, Sture; Pellerin, Luc

2009-07-01

Monocarboxylate transporters (MCTs) are essential for the use of lactate, an energy substrate known to be overproduced in brain during an ischemic episode. The expression of MCT1 and MCT2 was investigated at 48 h of reperfusion from focal ischemia induced by unilateral extradural compression in Wistar rats. Increased MCT1 mRNA expression was detected in the injured cortex and hippocampus of compressed animals compared to sham controls. In the contralateral, uncompressed hemisphere, increases in MCT1 mRNA level in the cortex and MCT2 mRNA level in the hippocampus were noted. Interestingly, strong MCT1 and MCT2 protein expression was found in peri-lesional macrophages/microglia and in an isolectin B4+/S100beta+ cell population in the corpus callosum. In vitro, MCT1 and MCT2 protein expression was observed in the N11 microglial cell line, whereas an enhancement of MCT1 expression by tumor necrosis factor-alpha (TNF-alpha) was shown in these cells. Modulation of MCT expression in microglia suggests that these transporters may help sustain microglial functions during recovery from focal brain ischemia. Overall, our study indicates that changes in MCT expression around and also away from the ischemic area, both at the mRNA and protein levels, are a part of the metabolic adaptations taking place in the brain after ischemia.

A Single Bout of High-Intensity Interval Training Reduces Awareness of Subsequent Hypoglycemia in Patients With Type 1 Diabetes.

PubMed

Rooijackers, Hanne M; Wiegers, Evita C; van der Graaf, Marinette; Thijssen, Dick H; Kessels, Roy P C; Tack, Cees J; de Galan, Bastiaan E

2017-07-01

High-intensity interval training (HIIT) has gained increasing popularity in patients with diabetes. HIIT acutely increases plasma lactate levels. This may be important, since the administration of lactate during hypoglycemia suppresses symptoms and counterregulation while preserving cognitive function. We tested the hypothesis that, in the short term, HIIT reduces awareness of hypoglycemia and attenuates hypoglycemia-induced cognitive dysfunction. In a randomized crossover trial, patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), patients with impaired awareness of hypoglycemia (IAH), and healthy participants ( n = 10 per group) underwent a hyperinsulinemic-hypoglycemic (2.6 mmol/L) clamp, either after a HIIT session or after seated rest. Compared with rest, HIIT reduced symptoms of hypoglycemia in patients with NAH but not in healthy participants or patients with IAH. HIIT attenuated hypoglycemia-induced cognitive dysfunction, which was mainly driven by changes in the NAH subgroup. HIIT suppressed cortisol and growth hormone responses, but not catecholamine responses to hypoglycemia. The present findings demonstrate that a single HIIT session rapidly reduces awareness of subsequent hypoglycemia in patients with type 1 diabetes and NAH, but does not in patients with IAH, and attenuates hypoglycemia-induced cognitive dysfunction. The role of exercise-induced lactate in mediating these effects, potentially serving as an alternative fuel for the brain, should be further explored. © 2017 by the American Diabetes Association.

Glycogenolysis in astrocytes supports blood-borne glucose channeling not glycogen-derived lactate shuttling to neurons: evidence from mathematical modeling.

PubMed

DiNuzzo, Mauro; Mangia, Silvia; Maraviglia, Bruno; Giove, Federico

2010-12-01

In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (∼1.5:1) neuronal versus astrocytic activation-induced Na(+) influx ratio, ∼12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na(+) influx ratio to 190:65 mmol/L (∼3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current 'thinking paradigm'. This might be critical in subcellular domains during functional conditions associated with fast energetic demands.

Glycogenolysis in astrocytes supports blood-borne glucose channeling not glycogen-derived lactate shuttling to neurons: evidence from mathematical modeling

PubMed Central

DiNuzzo, Mauro; Mangia, Silvia; Maraviglia, Bruno; Giove, Federico

2010-01-01

In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (∼1.5:1) neuronal versus astrocytic activation-induced Na+ influx ratio, ∼12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na+ influx ratio to 190:65 mmol/L (∼3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current ‘thinking paradigm'. This might be critical in subcellular domains during functional conditions associated with fast energetic demands. PMID:20827264

The effect of long chain polyunsaturated fatty acid supplementation on intelligence in low birth weight infant during lactation: A meta-analysis

PubMed Central

Song, Yuan; Liu, Ya; Pan, Yun; Yuan, Xiaofeng; Chang, Pengyu; Tian, Yuan; Cui, Weiwei

2018-01-01

Background Low birth weight infant (LBWIs) are prone to mental and behavioural problems. As an important constituent of the brain and retina, long chain polyunsaturated fatty acids are essential for foetal infant mental and visual development. The effect of lactation supplemented with long chain polyunsaturated fatty acids (LCPUFA) on the improvement of intelligence in low birth weight children requires further validation. Methods In this study, a comprehensive search of multiple databases was performed to identify studies focused the association between intelligence and long chain polyunsaturated fatty acid supplementation in LBWIs. Studies that compared the Bayley Scales of Infant Development (BSID) or the Wechsler Abbreviated Scale of Intelligence for Children (WISC) scores between LBWIs who were supplemented and controls that were not supplemented with LCPUFA during lactation were selected for inclusion in the meta-analysis. Results The main outcome was the mean difference in the mental development index (MDI) and psychomotor development index (PDI) of the BSID and the full scale intelligence quotient (FSIQ), verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ) of the WISC between LBWIs and controls. Our findings indicated that the mean BSID or WISC scores in LBWIs did not differ between the supplemented groups and controls. Conclusion This meta-analysis does not reveal that LCPUFA supplementation has a significant impact on the level of intelligence in LBWIs. PMID:29634752

Insecticides applied to a nursery colony of little brown bats (Myotis lucifugus): lethal concentrations in brain tissues

USGS Publications Warehouse

Clark, D.R.; Kunz, T.H.; Kaiser, T.E.

1978-01-01

-Forty-six Myotis lucifugus were collected in May and June 1974 at a nursery colony in Hillsborough County, New Hampshire, that had been sprayed with DDT and chlordane in August and September 1973. When collected, 27 bats were alive, two were convulsing, and 17 were dead. Brains, carcasses, and milk and masticated insects from stomachs were analyzed for organochlorine insecticides and polychlorinated biphenyls (PCB's). ...Concentrations of chemical residues in brains of surviving bats were compared with those of dead and convulsing bats. These comparisons indicated that DDT was the cause of death. Lethal brain concentrations of DDT in adult females averaged 24.52 parts per million (ppm) and suggested that adult M. lucifugus are approximately twice as sensitive to DDT as are adult laboratory rats and mice. Juvenile bats were about 1.5 times more sensitive than adult bats....Large chemical residues were present in milk. We found a statistically significant relationship between declines in carcass residues in lactating females and uterine regression for six of 10 toxicants. Among juveniles, there were corresponding, significant increases (for nine of 10 toxicants) in carcass levels of residues correlated with increasing age (growth of forearm).

Detecting activity-evoked pH changes in human brain

PubMed Central

Magnotta, Vincent A.; Heo, Hye-Young; Dlouhy, Brian J.; Dahdaleh, Nader S.; Follmer, Robin L.; Thedens, Daniel R.; Welsh, Michael J.; Wemmie, John A.

2012-01-01

Localized pH changes have been suggested to occur in the brain during normal function. However, the existence of such pH changes has also been questioned. Lack of methods for noninvasively measuring pH with high spatial and temporal resolution has limited insight into this issue. Here we report that a magnetic resonance imaging (MRI) strategy, T1 relaxation in the rotating frame (T1ρ), is sufficiently sensitive to detect widespread pH changes in the mouse and human brain evoked by systemically manipulating carbon dioxide or bicarbonate. Moreover, T1ρ detected a localized acidosis in the human visual cortex induced by a flashing checkerboard. Lactate measurements and pH-sensitive 31P spectroscopy at the same site also identified a localized acidosis. Consistent with the established role for pH in blood flow recruitment, T1ρ correlated with blood oxygenation level-dependent contrast commonly used in functional MRI. However, T1ρ was not directly sensitive to blood oxygen content. These observations indicate that localized pH fluctuations occur in the human brain during normal function. Furthermore, they suggest a unique functional imaging strategy based on pH that is independent of traditional functional MRI contrast mechanisms. PMID:22566645

Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin.

PubMed

Yokoyama, Shota; Tsuji, Hideyuki; Hiraoka, Sachiko; Nishihara, Masayuki

2016-01-01

Metformin is a biguanaide antidiabetic drug used worldwide, and its effectiveness and benefits have already been established. However, the safety of high doses of metformin in Japanese patients, especially in elderly patients with a decreased renal function, remains unclear. Among the side effects of metformin, lactate acidosis is the most problematic due to a high mortality rate. Therefore, we assessed plasma lactate levels in metformin-treated patients to identify independent risk factors for hyperlactemia. 290 outpatients receiving various doses of metformin at our hospital were enrolled between March and July 2014. Serum electrolytes, Cre (creatinine), BUN (blood urea nitrogen), UA (uric acid), HbA1c (hemoglobin A1c), and lactate levels were investigated. Lactate levels did not significantly differ between the elderly (≥75 years) and non-elderly (<75 years) groups. Patients in the elderly group had a significantly lower daily metformin dose and estimated glomerular filtration rate (eGFR), compared with the non-elderly group (both p<0.005). Between with and without hyperlactemia groups, no significant differences were observed in either Cre or age. On the other hand, patients with hyperlactemia had a significantly higher dose of metformin than those without hyperlactemia (p<0.05). In this study, we found that old age and mildly impaired kidney function were not associated with increased lactate levels, and that a higher dose of metformin may be an independent risk factor for elevated lactate levels in Japanese patients.

Blood lactate levels in 31 female dogs with pyometra

PubMed Central

Hagman, Ragnvi; Reezigt, Bert Jan; Bergström Ledin, Hanna; Karlstam, Erika

2009-01-01

Background Canine pyometra is a life-threatening disease common in countries where spaying of dogs is not routinely performed. The disease is associated with endotoxemia, sepsis, systemic inflammatory response syndrome (SIRS) and a 3–4% mortality rate. Blood lactate analysis is clinically valuable in predicting prognosis and survival, evaluating tissue perfusion and treatment response in human and veterinary critical care settings. The aims of the present study were to investigate 1) the blood lactate levels of female dogs with pyometra by a hand-held analyser and 2) if these levels are related with the clinical status or other biochemical or hematological disorders. Methods In total 31 female dogs with pyometra admitted for surgical ovariohysterectomy and 16 healthy female control dogs were included in the present study. A complete physical examination including SIRS-status determination was performed. Blood samples for lactate concentrations, hematological and biochemical parameters, acid-base and blood gas analysis and other laboratory parameters were collected and subsequently analysed. The diagnosis pyometra was verified with histopathological examination of the uterus and ovaries. Increased hospitalisation length and presence of SIRS were used as indicators of outcome. Results In the pyometra group the median blood lactate level was 1,6 mmol l-1 (range <0.8–2.7 mmol l-1). In the control group the median lactate level was 1,2 mmol l-1 (range <0.8–2.1 mmol l-1). Of the 31 bitches 19 (61%) fulfilled 2 or more criteria for SIRS at inclusion, 10 bitches (32%) fulfilled 3 of the SIRS criteria whereas none accomplished more than 3 criteria. Lactate levels did not differ significantly between the pyometra and control group, or between the SIRS positive and SIRS negative dogs with pyometra. Increased lactate concentration (>2.5 mmol l-1) was demonstrated in one female dog with pyometra (3%), and was not associated with longer hospitalisation or presence of SIRS. Lactate measurement was not indicative of peritonitis. None of the bitches died during or within two months of the hospital stay. The measurements of temperature, heart rate, respiratory rate, percentage bandforms of neutrophilic granulocytes, α2-globulins, creatinin, pvCO2, TCO2 and base excess showed significant differences between the SIRS positive and the SIRS negative pyometra cases. Conclusion Increased blood lactate concentrations were demonstrated in 3% (1/31), and SIRS was present in 61% (19/31) of the female dogs with pyometra. Preoperative lactate levels were not related with presence of SIRS or prolonged hospitalisation. Lactate measurement was not indicative of peritonitis. The value of a single and repeated lactate analysis in more severely affected cases remains to be determined. PMID:19134167

Repeated high-intensity interval exercise shortens the positive effect on executive function during post-exercise recovery in healthy young males.

PubMed

Tsukamoto, Hayato; Suga, Tadashi; Takenaka, Saki; Tanaka, Daichi; Takeuchi, Tatsuya; Hamaoka, Takafumi; Isaka, Tadao; Ogoh, Shigehiko; Hashimoto, Takeshi

2016-06-01

A single bout of aerobic exercise improves executive function (EF), but only for a short period. Compared with a single bout of aerobic exercise, we recently found that high-intensity interval exercise (HIIE) could maintain a longer improvement in EF. However, the mechanism underlying the effect of different exercise modes on the modifications of EF remains unclear. The purpose of the current investigation was to test our hypothesis that the amount of exercise-induced lactate production and its accumulation affects human brain function during and after exercise, thereby affecting post-exercise EF. Ten healthy male subjects performed cycle ergometer exercise. The HIIE protocol consisted of four 4-min bouts at 90% peak VO2 with a 3-min active recovery period at 60% peak VO2. The amount of lactate produced during exercise was manipulated by repeating the HIIE twice with a resting period of 60min between the 1st HIIE and 2nd HIIE. To evaluate EF, a color-word Stroop task was performed, and reverse-Stroop interference scores were obtained. EF immediately after the 1st HIIE was significantly improved compared to that before exercise, and the improved EF was sustained during 40min of the post-exercise recovery. However, for the 2nd HIIE, the improved EF was sustained for only 10min of the post-exercise recovery period, despite the performance of the same exercise. In addition, during and following HIIE, the glucose and lactate accumulation induced by the 2nd HIIE was significantly lower than that induced by the 1st HIIE. Furthermore, there was an inverse relationship between lactate and EF by plotting the changes in lactate levels against changes in EF from pre-exercise during the late phase of post-exercise recovery. These findings suggested the possibility that repeated bouts of HIIE, which decreases lactate accumulation, may dampen the positive effect of exercise on EF during the post-exercise recovery. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Glucose metabolism transporters and epilepsy: only GLUT1 has an established role.

PubMed

Hildebrand, Michael S; Damiano, John A; Mullen, Saul A; Bellows, Susannah T; Oliver, Karen L; Dahl, Hans-Henrik M; Scheffer, Ingrid E; Berkovic, Samuel F

2014-02-01

The availability of glucose, and its glycolytic product lactate, for cerebral energy metabolism is regulated by specific brain transporters. Inadequate energy delivery leads to neurologic impairment. Haploinsufficiency of the glucose transporter GLUT1 causes a characteristic early onset encephalopathy, and has recently emerged as an important cause of a variety of childhood or later-onset generalized epilepsies and paroxysmal exercise-induced dyskinesia. We explored whether mutations in the genes encoding the other major glucose (GLUT3) or lactate (MCT1/2/3/4) transporters involved in cerebral energy metabolism also cause generalized epilepsies. A cohort of 119 cases with myoclonic astatic epilepsy or early onset absence epilepsy was screened for nucleotide variants in these five candidate genes. No epilepsy-causing mutations were identified, indicating that of the major energetic fuel transporters in the brain, only GLUT1 is clearly associated with generalized epilepsy. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

PubMed

Donnino, Michael W; Andersen, Lars W; Chase, Maureen; Berg, Katherine M; Tidswell, Mark; Giberson, Tyler; Wolfe, Richard; Moskowitz, Ari; Smithline, Howard; Ngo, Long; Cocchi, Michael N

2016-02-01

To determine if intravenous thiamine would reduce lactate in patients with septic shock. Randomized, double-blind, placebo-controlled trial. Two US hospitals. Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014. Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge. The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047). Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time.

Relationship among blood indicators of lipomobilization and hepatic function during early lactation in high-yielding dairy cows

PubMed Central

Muiño, Rodrigo; Pereira, Víctor; Campos, Rómulo; Benedito, José Luis

2011-01-01

Blood indicators are used as a tool to diagnose metabolic disorders. The present work was conducted to study the relationships among blood indicators of lipomobilization and hepatic function in high-yielding dairy cows. Two groups of Holstein cows were studied: 27 early lactation cows and 14 mid lactation cows from four different herds with similar husbandry characteristics in Galicia, Spain. Blood samples were obtained to measure beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA), triglycerides (TG), and the activity of aspartate transaminase (AST) and gamma-glutamyl transferase. Cows in early lactation had higher levels of BHB and NEFA than mid lactation cows. High lipomobilization (NEFA > 400 µmol/L) was detected in 67% and 7% of early lactation and mid lactation cows, respectively, while subclinical ketosis (BHB > 1.2 mmol/L) was detected in 41% and 28% of the early lactation and lactation cows, respectively. TG concentrations were low in all cows suffering subclinical ketosis and in 61% of the cows with high lipomobilization. During early lactation, 30% of cows suffered hepatic lipidosis as detected by levels of AST. Compromised hepatic function was observed in early lactation cows as shown by lower concentrations of glucose, total protein, and urea. PMID:21897097

Hyperpolarized 13C MR Markers of Renal Tumor Aggressiveness

DTIC Science & Technology

2015-12-01

production in two human glioblastoma xenograft models where the blood–brain barrier (BBB) was disrupted relative to normal brain, suggesting that HP...rodent mammary adenocarcinoma and murine lymphoma xenografts ) has shown ample conversion to leucine.98 In this preclinical study, SNR and contrast were...4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner, Oncogene 33 (2013) 4433–4441. Real

Computational modelling of the piglet brain to simulate near-infrared spectroscopy and magnetic resonance spectroscopy data collected during oxygen deprivation.

PubMed

Moroz, Tracy; Banaji, Murad; Robertson, Nicola J; Cooper, Chris E; Tachtsidis, Ilias

2012-07-07

We describe a computational model to simulate measurements from near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS) in the piglet brain. Piglets are often subjected to anoxic, hypoxic and ischaemic insults, as experimental models for human neonates. The model aims to help interpret measurements and increase understanding of physiological processes occurring during such insults. It is an extension of a previous model of circulation and mitochondrial metabolism. This was developed to predict NIRS measurements in the brains of healthy adults i.e. concentration changes of oxyhaemoglobin and deoxyhaemoglobin and redox state changes of cytochrome c oxidase (CCO). We altered and enhanced the model to apply to the anaesthetized piglet brain. It now includes metabolites measured by (31)P-MRS, namely phosphocreatine, inorganic phosphate and adenosine triphosphate (ATP). It also includes simple descriptions of glycolysis, lactate dynamics and the tricarboxylic acid (TCA) cycle. The model is described, and its simulations compared with existing measurements from piglets during anoxia. The NIRS and MRS measurements are predicted well, although this requires a reduction in blood pressure autoregulation. Predictions of the cerebral metabolic rate of oxygen consumption (CMRO(2)) and lactate concentration, which were not measured, are given. Finally, the model is used to investigate hypotheses regarding changes in CCO redox state during anoxia.

Fetal and neonatal iron deficiency but not copper deficiency increases vascular complexity in the developing rat brain

PubMed Central

Bastian, Thomas W.; Santarriaga, Stephanie; Nguyen, Thu An; Prohaska, Joseph R.; Georgieff, Michael K.; Anderson, Grant W.

2015-01-01

Objectives Anemia caused by nutritional deficiencies, such as iron and copper deficiencies, is a global health problem. Iron and copper deficiencies have their most profound effect on the developing fetus/infant, leading to brain development deficits and poor cognitive outcomes. Tissue iron depletion or chronic anemia can induce cellular hypoxic signaling. In mice, chronic hypoxia induces a compensatory increase in brain blood vessel outgrowth. We hypothesized that developmental anemia, due to iron or copper deficiencies, induces angiogenesis/vasculogenesis in the neonatal brain. Methods To test our hypothesis, three independent experiments were performed where pregnant rats were fed iron- or copper-deficient diets from gestational day 2 through mid-lactation. Effects on the neonatal brain vasculature were determined using qPCR to assess mRNA levels of angiogenesis/vasculogenesis-associated genes and GLUT1 immunohistochemistry (IHC) to assess brain blood vessel density and complexity. Results Iron deficiency, but not copper deficiency, increased mRNA expression of brain endothelial cell- and angiogenesis/vasculogenesis-associated genes (i.e. Glut1, Vwf, Vegfa, Ang2, Cxcl12, and Flk1) in the neonatal brain, suggesting increased cerebrovascular density. Iron deficiency also increased hippocampal and cerebral cortical blood vessel branching by 62% and 78%, respectively. Discussion This study demonstrates increased blood vessel complexity in the neonatal iron-deficient brain, which is likely due to elevated angiogenic/vasculogenic signaling. At least initially, this is probably an adaptive response to maintain metabolic substrate homeostasis in the developing iron-deficient brain. However, this may also contribute to long-term neurodevelopmental deficits. PMID:26177275

Reduced brain/serum glucose ratios predict cerebral metabolic distress and mortality after severe brain injury.

PubMed

Kurtz, Pedro; Claassen, Jan; Schmidt, J Michael; Helbok, Raimund; Hanafy, Khalid A; Presciutti, Mary; Lantigua, Hector; Connolly, E Sander; Lee, Kiwon; Badjatia, Neeraj; Mayer, Stephan A

2013-12-01

The brain is dependent on glucose to meet its energy demands. We sought to evaluate the potential importance of impaired glucose transport by assessing the relationship between brain/serum glucose ratios, cerebral metabolic distress, and mortality after severe brain injury. We studied 46 consecutive comatose patients with subarachnoid or intracerebral hemorrhage, traumatic brain injury, or cardiac arrest who underwent cerebral microdialysis and intracranial pressure monitoring. Continuous insulin infusion was used to maintain target serum glucose levels of 80-120 mg/dL (4.4-6.7 mmol/L). General linear models of logistic function utilizing generalized estimating equations were used to relate predictors of cerebral metabolic distress (defined as a lactate/pyruvate ratio [LPR] ≥ 40) and mortality. A total of 5,187 neuromonitoring hours over 300 days were analyzed. Mean serum glucose was 133 mg/dL (7.4 mmol/L). The median brain/serum glucose ratio, calculated hourly, was substantially lower (0.12) than the expected normal ratio of 0.40 (brain 2.0 and serum 5.0 mmol/L). In addition to low cerebral perfusion pressure (P = 0.05) and baseline Glasgow Coma Scale score (P < 0.0001), brain/serum glucose ratios below the median of 0.12 were independently associated with an increased risk of metabolic distress (adjusted OR = 1.4 [1.2-1.7], P < 0.001). Low brain/serum glucose ratios were also independently associated with in-hospital mortality (adjusted OR = 6.7 [1.2-38.9], P < 0.03) in addition to Glasgow Coma Scale scores (P = 0.029). Reduced brain/serum glucose ratios, consistent with impaired glucose transport across the blood brain barrier, are associated with cerebral metabolic distress and increased mortality after severe brain injury.

Immune activation in lactating dams alters sucklings' brain cytokines and produces non-overlapping behavioral deficits in adult female and male offspring: A novel neurodevelopmental model of sex-specific psychopathology.

PubMed

Arad, Michal; Piontkewitz, Yael; Albelda, Noa; Shaashua, Lee; Weiner, Ina

2017-07-01

Early immune activation (IA) in rodents, prenatal through the mother or early postnatal directly to the neonate, is widely used to produce behavioral endophenotypes relevant to schizophrenia and depression. Given that maternal immune response plays a crucial role in the deleterious effects of prenatal IA, and lactation is a critical vehicle of immunological support to the neonate, we predicted that immune activation of the lactating dam will produce long-term abnormalities in the sucklings. Nursing dams were injected on postnatal day 4 with the viral mimic poly-I:C (4mg/kg) or saline. Cytokine assessment was performed in dams' plasma and milk 2h, and in the sucklings' hippocampus, 6h and 24h following poly-I:C injection. Male and female sucklings were assessed in adulthood for: a) performance on behavioral tasks measuring constructs considered relevant to schizophrenia (selective attention and executive control) and depression (despair and anhedonia); b) response to relevant pharmacological treatments; c) brain structural changes. Maternal poly-I:C injection caused cytokine alterations in the dams' plasma and milk, as well as in the sucklings' hippocampus. Lactational poly-I:C exposure led to sex-dimorphic (non-overlapping) behavioral abnormalities in the adult offspring, with male but not female offspring exhibiting attentional and executive function abnormalities (manifested in persistent latent inhibition and slow reversal) and hypodopaminergia, and female but not male offspring exhibiting despair and anhedonia (manifested in increased immobility in the forced swim test and reduced saccharine preference) and hyperdopaminergia, mimicking the known sex-bias in schizophrenia and depression. The behavioral double-dissociation predicted distinct pharmacological profiles, recapitulating the pharmacology of negative/cognitive symptoms and depression. In-vivo imaging revealed hippocampal and striatal volume reductions in both sexes, as found in both disorders. This is the first evidence for the emergence of long-term behavioral and brain abnormalities after lactational exposure to an inflammatory agent, supporting a causal link between early immune activation and disrupted neuropsychodevelopment. That such exposure produces schizophrenia- or depression-like phenotype depending on sex, resonates with notions that risk factors are transdiagnostic, and that sex is a susceptibility factor for neurodevelopmental psychopathologies. Copyright © 2017 Elsevier Inc. All rights reserved.

Changes in Plasma Progesterone Levels in the Caudal Vena Cava and the Jugular Vein and Luteinizing Hormone Secretion Pattern After Feeding in Lactating and Non-lactating Dairy Cows

PubMed Central

ENDO, Natsumi; NAGAI, Kiyosuke; TANAKA, Tomomi; KAMOMAE, Hideo

2012-01-01

Abstract The present study was designed to assess progesterone profiles at the secreted (caudal vena cava) and circulating levels (jugular vein) and luteinizing hormone (LH) secretion pattern in lactating and non-lactating cows with reference to feeding. Four lactating and four non-lactating cycling Holstein cows were examined. Blood samples were collected simultaneously from the caudal vena cava (via a catheter inserted from the coccygeal vein) and the jugular vein every 15 min for 12 h (0500–1700 h) during the functional luteal phase. Cows were fed 50% of the daily diet 6 h after the start of blood sampling. During the 12-h sampling period, mean progesterone concentrations in the caudal vena cava did not differ between lactating and non-lactating cows (49.0 ± 2.9 and 53.3 ± 3.7 ng/ml; mean ± SE), whereas mean progesterone concentrations in the jugular vein in lactating cows were higher than those in non-lactating cows (6.4 ± 0.1 and 5.6 ± 0.1 ng/ml, P < 0.001). Lactating cows had a higher frequency of LH pulses than non-lactating cows (7.0 ± 0.7 and 4.3 ± 0.9 pulses/12 h, P<0.05). The influence of feeding was not observed on LH profiles but was observed on progesterone profiles in both veins. Progesterone concentrations in the caudal vena cava increased after feeding in both groups. Progesterone concentrations in the jugular vein decreased after feeding in lactating cows but not in non-lactating cows. These results indicate the difference in feeding-related changes in progesterone dynamics between lactating and non-lactating cows. PMID:23171608

Cerebral Gluconeogenesis and Diseases

PubMed Central

Yip, James; Geng, Xiaokun; Shen, Jiamei; Ding, Yuchuan

2017-01-01

The gluconeogenesis pathway, which has been known to normally present in the liver, kidney, intestine, or muscle, has four irreversible steps catalyzed by the enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Studies have also demonstrated evidence that gluconeogenesis exists in brain astrocytes but no convincing data have yet been found in neurons. Astrocytes exhibit significant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 activity, a key mechanism for regulating glycolysis and gluconeogenesis. Astrocytes are unique in that they use glycolysis to produce lactate, which is then shuttled into neurons and used as gluconeogenic precursors for reduction. This gluconeogenesis pathway found in astrocytes is becoming more recognized as an important alternative glucose source for neurons, specifically in ischemic stroke and brain tumor. Further studies are needed to discover how the gluconeogenesis pathway is controlled in the brain, which may lead to the development of therapeutic targets to control energy levels and cellular survival in ischemic stroke patients, or inhibit gluconeogenesis in brain tumors to promote malignant cell death and tumor regression. While there are extensive studies on the mechanisms of cerebral glycolysis in ischemic stroke and brain tumors, studies on cerebral gluconeogenesis are limited. Here, we review studies done to date regarding gluconeogenesis to evaluate whether this metabolic pathway is beneficial or detrimental to the brain under these pathological conditions. PMID:28101056

Dexamethasone prevents hypoxia/ischemia-induced reductions in cerebral glucose utilization and high-energy phosphate metabolites in immature brain.

PubMed

Tuor, U I; Yager, J Y; Bascaramurty, S; Del Bigio, M R

1997-11-01

We examined the potential importance of dexamethasone-mediated alterations in energy metabolism in providing protection against hypoxic-ischemic brain damage in immature rats. Seven-day-old rats (n = 165) that had been treated with dexamethasone (0.1 mg/kg, i.p.) or vehicle were assigned to control or hypoxic-ischemic groups (unilateral carotid artery occlusion plus 2-3 h of 8% oxygen at normothermia). The systemic availability of alternate fuels such as beta-hydroxybutyrate, lactate, pyruvate, and free fatty acids was not altered by dexamethasone treatment, and, except for glucose, brain levels were also unaffected. At the end of hypoxia, levels of cerebral high-energy phosphates (ATP and phosphocreatine) were decreased in vehicle- but relatively preserved in dexamethasone-treated animals. The local cerebral metabolic rate of glucose utilization (lCMRgl) was decreased modestly under control conditions in dexamethasone-treated animals, whereas cerebral energy use measured in a model of decapitation ischemia did not differ significantly between groups. The lCMRgl increased markedly during hypoxia-ischemia (p < 0.05) and remained elevated throughout ischemia in dexamethasone- but not vehicle-treated groups, indicating an enhanced glycolytic flux with dexamethasone treatment. Thus, dexamethasone likely provides protection against hypoxic-ischemic damage in immature rats by preserving cerebral ATP secondary to a maintenance of glycolytic flux.

Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

PubMed Central

Berggren, Kiersten L.; Chen, Jianfang; Fox, Julia; Miller, Jonathan; Dodds, Lindsay; Dugas, Bryan; Vargas, Liset; Lothian, Amber; McAllum, Erin; Volitakis, Irene; Roberts, Blaine; Bush, Ashley I.; Fox, Jonathan H.

2015-01-01

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in huntingtin (htt) protein. Dysregulation of brain iron homeostasis, oxidative stress and neurodegeneration are consistent features of the HD phenotype. Therefore, environmental factors that exacerbate oxidative stress and iron dysregulation may potentiate HD. Iron supplementation in the human population is common during infant and adult-life stages. In this study, iron supplementation in neonatal HD mice resulted in deterioration of spontaneous motor running activity, elevated levels of brain lactate and oxidized glutathione consistent with increased energetic dysfunction and oxidative stress, and increased striatal and motor cortical neuronal atrophy, collectively demonstrating potentiation of the disease phenotype. Oxidative stress, energetic, and anatomic markers of degeneration were not affected in wild-type littermate iron-supplemented mice. Further, there was no effect of elevated iron intake on disease outcomes in adult HD mice. We have demonstrated an interaction between the mutant huntingtin gene and iron supplementation in neonatal HD mice. Findings indicate that elevated neonatal iron intake potentiates mouse HD and promotes oxidative stress and energetic dysfunction in brain. Neonatal-infant dietary iron intake level may be an environmental modifier of human HD. PMID:25703232

Basal levels of metabolic activity are elevated in Genetic Absence Epilepsy Rats from Strasbourg (GAERS): measurement of regional activity of cytochrome oxidase and lactate dehydrogenase by histochemistry.

PubMed

Dufour, Franck; Koning, Estelle; Nehlig, Astrid

2003-08-01

The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are considered an isomorphic, predictive, and homologous model of human generalized absence epilepsy. It is characterized by the expression of spike-and-wave discharges in the thalamus and cortex. In this strain, basal regional rates of cerebral glucose utilization measured by the quantitative autoradiographic [(14)C]2-deoxyglucose technique display a widespread consistent increase compared to a selected strain of genetically nonepileptic rats (NE). In order to verify whether these high rates of glucose metabolism are paralleled by elevated activities of the enzymes of the glycolytic and tricarboxylic acid cycle pathways, we measured by histochemistry the regional activity of the two key enzymes of glucose metabolism, lactate dehydrogenase (LDH) for the anaerobic pathway and cytochrome oxidase (CO) for the aerobic pathway coupled to oxidative phosphorylation. CO and LDH activities were significantly higher in GAERS than in NE rats in 24 and 28 of the 30 brain regions studied, respectively. The differences in CO and LDH activity between both strains were widespread, affected all brain systems studied, and ranged from 12 to 63%. The data of the present study confirm the generalized increase in cerebral glucose metabolism in GAERS, occurring both at the glycolytic and at the oxidative step. However, they still do not allow us to understand why the ubiquitous mutation(s) generates spike-and-wave discharges only in the thalamocortical circuit.

Effects of Maternal Behavior Induction and Pup Exposure on Neurogenesis in Adult, Virgin Female Rats

PubMed Central

Furuta, Miyako; Bridges, Robert S.

2009-01-01

The states of pregnancy and lactation bring about a range of physiological and behavioral changes in the adult mammal that prepare the mother to care for her young. Cell proliferation increases in the subventricular zone (SVZ) of the female rodent brain during both pregnancy and lactation when compared to that in cycling, diestrous females. In the present study, the effects of maternal behavior induction and pup exposure on neurogenesis in nulliparous rats were examined in order to determine whether maternal behavior itself, independent of pregnancy and lactation, might affect neurogenesis. Adult, nulliparous, Sprague-Dawley, female rats were exposed daily to foster young in order to induce maternal behavior. Following the induction of maternal behavior each maternal subject plus females that were exposed to pups for a comparable number of test days, but did not display maternal behavior, and subjects that had received no pup exposure were injected with bromodeoxyuridine (BrdU, 90 mg/kg, i.v.). Brain sections were double-labeled for BrdU and the neural marker, NeuN, to examine the proliferating cell population. Increases in the number of double-labeled cells were found in the maternal virgin brain when compared with the number of double-labeled cells present in non-maternal, pup-exposed nulliparous rats and in females not exposed to young. No changes were evident in the dentate gyrus of the hippocampus as a function of maternal behavior. These data indicate that in nulliparous female rats maternal behavior itself is associated with the stimulation of neurogenesis in the SVZ. PMID:19712726

Serratia marcescens meningitis: epidemiology, prognostic factors and treatment outcomes.

PubMed

Wu, Yen-Mu; Hsu, Po-Chang; Yang, Chien-Chang; Chang, Hong-Jyun; Ye, Jung-Jr; Huang, Ching-Tai; Lee, Ming-Hsun

2013-08-01

Serratia marcescens is a rare pathogen of central nervous system infections. This study was to investigate the epidemiology, prognostic factors, and treatment outcomes of S. marcescens meningitis. This retrospective analysis included 33 patients with culture-proven S. marcescens meningitis hospitalized between January 2000 and June 2011. Of the 33 patients enrolled, only one did not receive neurosurgery before the onset of S. marcescens meningitis. Patients with S. marcescens meningitis had higher ratios of brain solid tumors (54.5%) and neurosurgery (97.0%) with a mortality rate of 15.2%. The mean interval between the first neurosurgical procedure and the diagnosis of meningitis was 17.1 days (range, 4-51 days). Only one third-generation cephalosporin-resistant S. marcescens isolate was recovered from the patients' cerebrospinal fluid (CSF) specimens. Compared with the favorable outcome group (n = 20), the unfavorable outcome group (n = 13) had a higher percentage of brain solid tumors, more intensive care unit stays, and higher Sequential Organ Failure Assessment score, CSF lactate and serum C-reactive protein concentrations at diagnosis of meningitis. Under the multiple regression analysis, CSF lactate concentration ≥2-fold the upper limit of normal (ULN) was independently associated with unfavorable outcomes (odds ratio, 7.20; 95% confidence interval, 1.08-47.96; p = 0.041). S. marcescens meningitis is highly associated with neurosurgical procedures for brain solid tumors. CSF lactate concentration ≥2x ULN may predict an unfavorable outcome. Its mortality is not high and empiric treatment with parenteral third-generation cephalosporins may have a satisfactory clinical response. Copyright © 2012. Published by Elsevier B.V.

Gray bats and pollution in Missouri and northern Alabama

USGS Publications Warehouse

Clark, D.R.; Bunck, C.M.; Cromartie, E.; LaVal, R.K.; Tuttle, M.D.

1981-01-01

Gray bats died with lethal brain concentrations of dieldrin and rising levels of heptachlor epoxide in 1976, 1977, and 1978 at Bat Caves No. 2-3, Franklin County, Missouri. The colony disappeared in 1979. Dieldrin was banned in 1974 and 1981 was the last year for heptachlor use in Missouri. The State is recommendiing three organophosphates (chlorpyrifos or Dursban, dyfonate or Fonophos, and ethoprop or Mocap) as substitutes for heptachlor. All three compounds have excellent records in the environment. Analyses of insects collected where bats of this colony fed showed beetles, particularly rove beetles (Staphylinidae), to be the most heavily contaminated part of the bat's diet. Lactation concentrated these residues so that levels in milk were approximately 30 times those in the insect diet. Gray bats found dead in caves in northern Alabama showed DDD (a DDT derivative) contamination. Bats from the colony at Cave Springs Cave on the Wheeler National Wildlife Refuge contained up to 29 ppm DDD in their brains, but this is probably less than one-half the lethal level. Bats from other colonies contained less. The DDD contamination enters the Terinessee River just above the Wheeler Refuge and is seen in gray bat colonies as far as 60 miles downriver.

The perinatal effects of maternal caffeine intake on fetal and neonatal brain levels of testosterone, estradiol, and dihydrotestosterone in rats.

PubMed

Karaismailoglu, S; Tuncer, M; Bayrak, S; Erdogan, G; Ergun, E L; Erdem, A

2017-08-01

Testosterone, estradiol, and dihydrotestosterone are the main sex steroid hormones responsible for the organization and sexual differentiation of brain structures during early development. The hypothalamo-pituitary-adrenocortical axis, adrenal cells, and gonads play a key role in the production of sex steroids and express adenosine receptors. Caffeine is a non-selective adenosine antagonist; therefore, it can modulate metabolic pathways in these tissues. Besides, the proportion of pregnant women that consume caffeine is ∼60%. That is why the relationship between maternal caffeine consumption and fetal development is important. Therefore, we aimed to investigate this modulatory effect of maternal caffeine consumption on sex steroids in the fetal and neonatal brain tissues. Pregnant rats were treated with a low (0.3 g/L) or high (0.8 g/L) dose of caffeine in their drinking water during pregnancy and lactation. The testosterone, estradiol, and dihydrotestosterone levels in the frontal cortex and hypothalamus were measured using radioimmunoassay at embryonic day 19 (E19), birth (PN0), and postnatal day 4 (PN4). The administration of low-dose caffeine increased the body weight in PN4 male and female rats and anogenital index in PN4 males. The administration of high-dose caffeine decreased the adrenal weight in E19 male rats and increased testosterone levels in the frontal cortex of E19 female rats and the hypothalamus of PN0 male rats. Maternal caffeine intake during pregnancy affects sex steroid levels in the frontal cortex and hypothalamus of the offspring. This concentration changes of the sex steroids in the brain may influence behavioral and neuroendocrine functions at some point in adult life.

Hemorrhagic shock shifts the serum cytokine profile from pro- to anti-inflammatory after experimental traumatic brain injury in mice.

PubMed

Shein, Steven L; Shellington, David K; Exo, Jennifer L; Jackson, Travis C; Wisniewski, Stephen R; Jackson, Edwin K; Vagni, Vincent A; Bayır, Hülya; Clark, Robert S B; Dixon, C Edward; Janesko-Feldman, Keri L; Kochanek, Patrick M

2014-08-15

Secondary insults, such as hemorrhagic shock (HS), worsen outcome from traumatic brain injury (TBI). Both TBI and HS modulate levels of inflammatory mediators. We evaluated the addition of HS on the inflammatory response to TBI. Adult male C57BL6J mice were randomized into five groups (n=4 [naïve] or 8/group): naïve; sham; TBI (through mild-to-moderate controlled cortical impact [CCI] at 5 m/sec, 1-mm depth), HS; and CCI+HS. All non-naïve mice underwent identical monitoring and anesthesia. HS and CCI+HS underwent a 35-min period of pressure-controlled hemorrhage (target mean arterial pressure, 25-27 mm Hg) and a 90-min resuscitation with lactated Ringer's injection and autologous blood transfusion. Mice were sacrificed at 2 or 24 h after injury. Levels of 13 cytokines, six chemokines, and three growth factors were measured in serum and in five brain tissue regions. Serum levels of several proinflammatory mediators (eotaxin, interferon-inducible protein 10 [IP-10], keratinocyte chemoattractant [KC], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1alpha [MIP-1α], interleukin [IL]-5, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor [G-CSF]) were increased after CCI alone. Serum levels of fewer proinflammatory mediators (IL-5, IL-6, regulated upon activation, normal T-cell expressed, and secreted, and G-CSF) were increased after CCI+HS. Serum level of anti-inflammatory IL-10 was significantly increased after CCI+HS versus CCI alone. Brain tissue levels of eotaxin, IP-10, KC, MCP-1, MIP-1α, IL-6, and G-CSF were increased after both CCI and CCI+HS. There were no significant differences between levels after CCI alone and CCI+HS in any mediator. Addition of HS to experimental TBI led to a shift toward an anti-inflammatory serum profile--specifically, a marked increase in IL-10 levels. The brain cytokine and chemokine profile after TBI was minimally affected by the addition of HS.

Fructose-1,6-Bisphospate does not preserve ATP in hypoxic-ischemic neonatal cerebrocortical slices

PubMed Central

Liu, Jia; Hirai, Kiyoshi; Litt, Lawrence

2008-01-01

Fructose-1,6-bisphosphate (FBP), an endogenous intracellular metabolite in glycolysis, was found in many preclinical studies to be neuroprotective during hypoxia-ischemia (HI) when administered exogenously. We looked for HI neuroprotection from FBP in a neonatal rat brain slice model, using 14.1 Tesla 1H /31P/13C NMR spectroscopy of perchloric acid slice extracts to ask: 1) if FBP preserves high energy phosphates during HI; and 2) if exogenous [1-13C]FBP enters cells and is glycolytically metabolized to [3-13C]lactate. We also asked: 3) if substantial superoxide production occurs during and after HI, thinking such might be treatable by exogenous FBP's antioxidant effects. Superfused P7 rat cerebrocortical slices (350μm) were treated with 2 mM FBP before and during 30 min of HI, and then given four hours of recovery with an FBP-free oxygenated superfusate. Slices were removed before HI, at the end of HI, and at 1 and 4 hours after HI. FBP did not improve high energy phosphate levels or change 1H metabolite profiles. Large increases in [3-13C]lactate were seen with 13C NMR, but the lactate fractional enrichment was always (1.1±0.5)%, implying that all of lactate's 13C was natural abundance 13C, that none was from metabolism of 13C-FBP. FBP had no effect on the fluorescence of ethidium produced from superoxide oxidation of hydroethidine. Compared to control slices, ethidium fluorescence was 25% higher during HI and 50% higher at the end of recovery. Exogenous FBP did not provide protection or enter glycolysis. Its use as an antioxidant might be worth studying at higher FBP concentrations. PMID:18725216

Gender-specific desensitization of group I metabotropic glutamate receptors after maternal l-glutamate intake during lactation.

PubMed

López-Zapata, Antonio; León-Navarro, David Agustín; Crespo, María; Martín, Mairena

2018-04-22

In the present work we have studied the effect of maternal intake of l-Glutamate (l-Glu) (1 g/L) during lactation on group I mGluR transduction pathway in brain plasma membrane from 15 days-old neonates. Results obtained have shown that maternal l-glutamate intake did not significantly affect neither weights of pups nor negative geotaxis reflex, an index of neurobehavioral development, but increased l-Glu plasma level in both male and female neonates. In male neonates, maternal l-Glu intake evoked a loss of mGluR 1 whereas no variation on mGluR 5 was observed as revealed by Western-blotting assay. The loss of mGlu 1 R was accompanied by a decrease on l-Glu-stimulated phospholipase C activity suggesting, therefore, a loss of group I mGluR functionality. Concerning female neonates, no variations were detected neither mGluR 1 nor mGluR 5 and group I mGluR functionality was also preserved. Copyright © 2018 ISDN. Published by Elsevier Ltd. All rights reserved.

Phosphorylation status of pyruvate dehydrogenase distinguishes metabolic phenotypes of cultured rat brain astrocytes and neurons.

PubMed

Halim, Nader D; Mcfate, Thomas; Mohyeldin, Ahmed; Okagaki, Peter; Korotchkina, Lioubov G; Patel, Mulchand S; Jeoung, Nam Ho; Harris, Robert A; Schell, Michael J; Verma, Ajay

2010-08-01

Glucose metabolism in nervous tissue has been proposed to occur in a compartmentalized manner with astrocytes contributing largely to glycolysis and neurons being the primary site of glucose oxidation. However, mammalian astrocytes and neurons both contain mitochondria, and it remains unclear why in culture neurons oxidize glucose, lactate, and pyruvate to a much larger extent than astrocytes. The objective of this study was to determine whether pyruvate metabolism is differentially regulated in cultured neurons versus astrocytes. Expression of all components of the pyruvate dehydrogenase complex (PDC), the rate-limiting step for pyruvate entry into the Krebs cycle, was determined in cultured astrocytes and neurons. In addition, regulation of PDC enzymatic activity in the two cell types via protein phosphorylation was examined. We show that all components of the PDC are expressed in both cell types in culture, but that PDC activity is kept strongly inhibited in astrocytes through phosphorylation of the pyruvate dehydrogenase alpha subunit (PDH alpha). In contrast, neuronal PDC operates close to maximal levels with much lower levels of phosphorylated PDH alpha. Dephosphorylation of astrocytic PDH alpha restores PDC activity and lowers lactate production. Our findings suggest that the glucose metabolism of astrocytes and neurons may be far more flexible than previously believed. (c) 2010 Wiley-Liss, Inc.

Emergence of delayed behavioral effects in offspring mice exposed to low levels of mercury vapor during the lactation period.

PubMed

Yoshida, Minoru; Watanabe, Chiho; Honda, Akiko; Satoh, Masahiko; Yasutake, Akira

2013-02-01

This study examined the emergence of delayed behavioral effects in offspring mice exposed to low levels of mercury vapor (Hg(0)) during the lactation period. Female offspring of mice were repeatedly exposed to Hg(0) at 0.057 mg/m(3), similar to the current threshold value (TLV), for 24 hr until the 20(th) day postpartum. The behavioral effects were evaluated with locomotor activity in the open field (OPF), learning activity in the passive avoidance response (PA) and spatial learning ability in the Morris water maze (MM) at the ages of 3 and 15 months. Hg(0)-exposed mice did not differ from controls in the three behavioral measurements at 3 months of age, and no neurobehavioral effects were observed. On the other hand, the mice exhibited significantly more central locomotion in the OPF task when tested at 15 months of age, but no abnormality in other behavioral performance. Immediately after postnatal exposure, the brain mercury concentration of offspring was about 150 times that of the control, in which the concentrations were approximately 0.4 µg/g. The results indicate that mice exposed to Hg(0) at concentrations around TLV during the developing period resulted in the emergence of delayed behavioral effects at a later stage in life.

Astrocyte - neuron lactate shuttle may boost more ATP supply to the neuron under hypoxic conditions - in silico study supported by in vitro expression data

PubMed Central

2011-01-01

Background Neuro-glial interactions are important for normal functioning of the brain as well as brain energy metabolism. There are two major working models - in the classical view, both neurons and astrocytes can utilize glucose as the energy source through oxidative metabolism, whereas in the astrocyte-neuron lactate shuttle hypothesis (ANLSH) it is the astrocyte which can consume glucose through anaerobic glycolysis to pyruvate and then to lactate, and this lactate is secreted to the extracellular space to be taken up by the neuron for further oxidative degradation. Results In this computational study, we have included hypoxia-induced genetic regulation of these enzymes and transporters, and analyzed whether the ANLSH model can provide an advantage to either cell type in terms of supplying the energy demand. We have based this module on our own experimental analysis of hypoxia-dependent regulation of transcription of key metabolic enzymes. Using this experimentation-supported in silico modeling, we show that under both normoxic and hypoxic conditions in a given time period ANLSH model does indeed provide the neuron with more ATP than in the classical view. Conclusions Although the ANLSH is energetically more favorable for the neuron, it is not the case for the astrocyte in the long term. Considering the fact that astrocytes are more resilient to hypoxia, we would propose that there is likely a switch between the two models, based on the energy demand of the neuron, so as to maintain the survival of the neuron under hypoxic or glucose-and-oxygen-deprived conditions. PMID:21995951

Analysis of neuron-astrocyte metabolic cooperation in the brain of db/db mice with cognitive decline using 13C NMR spectroscopy.

PubMed

Zheng, Hong; Zheng, Yongquan; Wang, Dan; Cai, Aimin; Lin, Qiuting; Zhao, Liangcai; Chen, Minjiang; Deng, Mingjie; Ye, Xinjian; Gao, Hongchang

2017-01-01

Type 2 diabetes has been linked to cognitive impairment, but its potential metabolic mechanism is still unclear. The present study aimed to explore neuron-astrocyte metabolic cooperation in the brain of diabetic (db/db, BKS.Cg-m +/+ Leprdb/J) mice with cognitive decline using 13 C NMR technique in combination with intravenous [2- 13 C]-acetate and [3- 13 C]-lactate infusions. We found that the 13 C-enrichment from [2- 13 C]-acetate into tricarboxylic acid cycle intermediate, succinate, was significantly decreased in db/db mice with cognitive decline compared with wild-type (WT, C57BLKS/J) mice, while an opposite result was obtained after [3- 13 C]-lactate infusion. Relative to WT mice, db/db mice with cognitive decline had significantly lower 13 C labeling percentages in neurotransmitters including glutamine, glutamate, and γ-aminobutyric acid after [2- 13 C]-acetate infusion. However, [3- 13 C]-lactate resulted in increased 13 C-enrichments in neurotransmitters in db/db mice with cognitive decline. This may indicate that the disturbance of neurotransmitter metabolism occurred during the development of cognitive decline. In addition, a reduction in 13 C-labeling of lactate and an increase in gluconeogenesis were found from both labeled infusions in db/db mice with cognitive decline. Therefore, our results suggest that the development of cognitive decline in type 2 diabetes may be implicated to an unbalanced metabolism in neuron-astrocyte cooperation and an enhancement of gluconeogenesis. © The Author(s) 2016.

Astrocyte-neuron lactate shuttle may boost more ATP supply to the neuron under hypoxic conditions--in silico study supported by in vitro expression data.

PubMed

Genc, Seda; Kurnaz, Isil A; Ozilgen, Mustafa

2011-10-13

Neuro-glial interactions are important for normal functioning of the brain as well as brain energy metabolism. There are two major working models--in the classical view, both neurons and astrocytes can utilize glucose as the energy source through oxidative metabolism, whereas in the astrocyte-neuron lactate shuttle hypothesis (ANLSH) it is the astrocyte which can consume glucose through anaerobic glycolysis to pyruvate and then to lactate, and this lactate is secreted to the extracellular space to be taken up by the neuron for further oxidative degradation. In this computational study, we have included hypoxia-induced genetic regulation of these enzymes and transporters, and analyzed whether the ANLSH model can provide an advantage to either cell type in terms of supplying the energy demand. We have based this module on our own experimental analysis of hypoxia-dependent regulation of transcription of key metabolic enzymes. Using this experimentation-supported in silico modeling, we show that under both normoxic and hypoxic conditions in a given time period ANLSH model does indeed provide the neuron with more ATP than in the classical view. Although the ANLSH is energetically more favorable for the neuron, it is not the case for the astrocyte in the long term. Considering the fact that astrocytes are more resilient to hypoxia, we would propose that there is likely a switch between the two models, based on the energy demand of the neuron, so as to maintain the survival of the neuron under hypoxic or glucose-and-oxygen-deprived conditions.

Effective Treatment of Traumatic Brain Injury in Rowett Nude Rats with Stromal Vascular Fraction Transplantation.

PubMed

Berman, Sean; Uhlendorf, Toni L; Berman, Mark; Lander, Elliot B

2018-06-18

Traumatic brain injury (TBI) affects 1.9 million Americans, including blast TBI that is the signature injury of the Iraq and Afghanistan wars. Our project investigated whether stromal vascular fraction (SVF) can assist in post-TBI recovery. We utilized strong acoustic waves (5.0 bar) to induce TBI in the cortex of adult Rowett Nude (RNU) rats. One hour post-TBI, harvested human SVF (500,000 cells suspended in 0.5 mL lactated Ringers) was incubated with Q-Tracker cell label and administered into tail veins of RNU rats. For comparison, we utilized rats that received SVF 72 h post-TBI, and a control group that received lactated Ringers solution. Rotarod and water maze assays were used to monitor motor coordination and spatial memories. Rats treated immediately after TBI showed no signs of motor skills and memory regression. SVF treatment 72 h post-TBI enabled the rats maintain their motor skills, while controls treated with lactated Ringers were 25% worse statistically in both assays. Histological analysis showed the presence of Q-dot labeled human cells near the infarct in both SVF treatment groups; however, labeled cells were twice as numerous in the one hour group. Our study suggests that immediate treatment with SVF would serve as potential therapeutic agents in TBI.

Serum Lactate Predicts Adverse Outcomes in Emergency Department Patients With and Without Infection.

PubMed

Oedorf, Kimie; Day, Danielle E; Lior, Yotam; Novack, Victor; Sanchez, Leon D; Wolfe, Richard E; Kirkegaard, Hans; Shapiro, Nathan I; Henning, Daniel J

2017-02-01

Lactate levels are increasingly used to risk stratify emergency department (ED) patients with and without infection. Whether a serum lactate provides similar prognostic value across diseases is not fully elucidated. This study assesses the prognostic value of serum lactate in ED patients with and without infection to both report and compare relative predictive value across etiologies. We conducted a prospective, observational study of ED patients displaying abnormal vital signs (AVS) (heart rate ≥130 bpm, respiratory rate ≥24 bpm, shock index ≥1, and/or systolic blood pressure <90 mmHg). The primary outcome, deterioration, was a composite of acute renal failure, non-elective intubation, vasopressor administration or in-hospital mortality. Of the 1,152 patients with AVS who were screened, 488 patients met the current study criteria: 34% deteriorated and 12.5% died. The deterioration rate was 88/342 (26%, 95% CI: 21 - 30%) for lactate < 2.5 mmol/L, 47/90 (52%, 42 - 63%) for lactate 2.5 - 4.0 mmol/L, and 33/46 (72%, 59 - 85%) for lactate >4.0mmol/L. Trended stratified lactate levels were associated with deterioration for both infected (p<0.01) and non-infected (p<0.01) patients. In the logistic regression models, lactate > 4mmol/L was an independent predictor of deterioration for patients with infection (OR 4.8, 95% CI: 1.7 - 14.1) and without infection (OR 4.4, 1.7 - 11.5). Lactate levels can risk stratify patients with AVS who have increased risk of adverse outcomes regardless of infection status.

Microbiota Is Involved in Post-resection Adaptation in Humans with Short Bowel Syndrome.

PubMed

Gillard, Laura; Mayeur, Camille; Robert, Véronique; Pingenot, Isabelle; Le Beyec, Johanne; Bado, André; Lepage, Patricia; Thomas, Muriel; Joly, Francisca

2017-01-01

Short bowel syndrome (SBS) is characterized by severe intestinal malabsorption following restrictive surgery. The objective of this study was to determine the functional contribution of SBS-microbiota after resection. It is well-known that SBS-microbiota displayed specific features with a prevalence of Lactobacillus, a low amount of some anaerobic microbes ( Clostridium leptum ) and an accumulation of fecal lactate in some patients. Patients with jejuno-colonic anastomosis were stratified according to the presence of lactate in their feces and, we observe that the lactate-producing bacteria were predominant in the sub-group of patients accumulating fecal lactate. One case of D-encephalopathy crisis occurred when the D-lactate isoform accumulated in the feces and plasma bicarbonate levels decreased. The fecal sample at the time of the encephalopathy was transferred to germ free rats (SBS-H rats). The SBS-H microbiota conserved some characteristics of the SBS donnor, predominated by lactate-producing bacteria (mainly Lactobacillus ), a low level of lactate-consuming bacteria and undetectable C. leptum . However, lactate did not accumulate in feces of recipient rats and the D-encephalopathy was not reproduced in SBS-H rats. This suggests that the intact small bowel of the recipient rats protected them from lactate accumulation and that D-lactate encephalopathy can occur only in the absence of small intestine. After fecal transfer, we also show that gnotobiotic rats exhibited high levels of circulating GLP-1 and ghrelin, two hormones that are known to be induced in SBS patients. Therefore, the microbiota of SBS is a reservoir of biological signals involved in post-resection adaptation.

Microbiota Is Involved in Post-resection Adaptation in Humans with Short Bowel Syndrome

PubMed Central

Gillard, Laura; Mayeur, Camille; Robert, Véronique; Pingenot, Isabelle; Le Beyec, Johanne; Bado, André; Lepage, Patricia; Thomas, Muriel; Joly, Francisca

2017-01-01

Short bowel syndrome (SBS) is characterized by severe intestinal malabsorption following restrictive surgery. The objective of this study was to determine the functional contribution of SBS-microbiota after resection. It is well-known that SBS-microbiota displayed specific features with a prevalence of Lactobacillus, a low amount of some anaerobic microbes (Clostridium leptum) and an accumulation of fecal lactate in some patients. Patients with jejuno-colonic anastomosis were stratified according to the presence of lactate in their feces and, we observe that the lactate-producing bacteria were predominant in the sub-group of patients accumulating fecal lactate. One case of D-encephalopathy crisis occurred when the D-lactate isoform accumulated in the feces and plasma bicarbonate levels decreased. The fecal sample at the time of the encephalopathy was transferred to germ free rats (SBS-H rats). The SBS-H microbiota conserved some characteristics of the SBS donnor, predominated by lactate-producing bacteria (mainly Lactobacillus), a low level of lactate-consuming bacteria and undetectable C. leptum. However, lactate did not accumulate in feces of recipient rats and the D-encephalopathy was not reproduced in SBS-H rats. This suggests that the intact small bowel of the recipient rats protected them from lactate accumulation and that D-lactate encephalopathy can occur only in the absence of small intestine. After fecal transfer, we also show that gnotobiotic rats exhibited high levels of circulating GLP-1 and ghrelin, two hormones that are known to be induced in SBS patients. Therefore, the microbiota of SBS is a reservoir of biological signals involved in post-resection adaptation. PMID:28469580

Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children

PubMed Central

2014-01-01

Background Cerebrospinal fluid (CSF) lactate is a potential biomarker for bacterial meningitis in children. To this end, we performed a single-center retrospective cohort study of children from Sao Paulo, Brazil, with CSF pleocytosis to evaluate the ability of CSF lactate to distinguish between children with bacterial and aseptic meningitis. We determined the optimum cutoff point for CSF lactate using receiver-operator curve (ROC) analysis. Findings We identified 451 children of whom 40 (9%) had bacterial meningitis. Children with bacterial meningitis had a higher median CSF lactate level [9.6 mmol/l, interquartile range (IQR) 3.2-38.5 mmol/l bacterial meningitis vs. 2.0 mmol/l, IQR 1.2-2.8 mmol/l aseptic meningitis]. A CSF lactate cutoff point of 3.0 mmol/l had a sensitivity of 95% [95% confidence interval (CI) 83-99%), specificity of 94% (95% CI 90-96%) and negative predictive value of 99.3% (95% CI 97.7-99.9%) for bacterial meningitis. Conclusions In combination with a validated meningitis clinical prediction rule, the CSF lactate level can be used to distinguish between bacterial and aseptic meningitis in children with CSF pleocytosis. PMID:24576334

Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children.

PubMed

Mekitarian Filho, Eduardo; Horita, Sérgio Massaru; Gilio, Alfredo Elias; Nigrovic, Lise E

2014-02-27

Cerebrospinal fluid (CSF) lactate is a potential biomarker for bacterial meningitis in children. To this end, we performed a single-center retrospective cohort study of children from Sao Paulo, Brazil, with CSF pleocytosis to evaluate the ability of CSF lactate to distinguish between children with bacterial and aseptic meningitis. We determined the optimum cutoff point for CSF lactate using receiver-operator curve (ROC) analysis. We identified 451 children of whom 40 (9%) had bacterial meningitis. Children with bacterial meningitis had a higher median CSF lactate level [9.6 mmol/l, interquartile range (IQR) 3.2-38.5 mmol/l bacterial meningitis vs. 2.0 mmol/l, IQR 1.2-2.8 mmol/l aseptic meningitis]. A CSF lactate cutoff point of 3.0 mmol/l had a sensitivity of 95% [95% confidence interval (CI) 83-99%), specificity of 94% (95% CI 90-96%) and negative predictive value of 99.3% (95% CI 97.7-99.9%) for bacterial meningitis. In combination with a validated meningitis clinical prediction rule, the CSF lactate level can be used to distinguish between bacterial and aseptic meningitis in children with CSF pleocytosis.

Abandoned prairie vole mothers show normal maternal care but altered emotionality: Potential influence of the brain corticotropin-releasing factor system.

PubMed

Bosch, Oliver J; Pohl, Tobias T; Neumann, Inga D; Young, Larry J

2018-04-02

When fathers leave the family, mothers are at increased risk of developing depression and anxiety disorders. In biparental, socially monogamous prairie voles (Microtus ochrogaster), sudden bond disruption increases passive stress-coping, indicative of depressive-like behavior, and acts as chronic stressor in both males and females. However, the consequences of separation in lactating prairie vole mothers are unknown. In the present study, following 18 days of cohousing, half of the prairie vole pairs were separated by removing the male. In early lactation, maternal care was unaffected by separation, whereas anxiety-related behavior and passive stress-coping were significantly elevated in separated mothers. Separation significantly increased corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus under basal conditions, similar to levels of paired females after acute exposure to forced swim stress. A second cohort of lactating prairie voles was infused intracerebroventricularly with either vehicle or the CRF receptor antagonist D-Phe just prior to behavioral testing. The brief restraining during acute infusion significantly decreased arched back nursing in vehicle-treated paired and separated groups, whereas in the D-Phe-treated separated group the behavior was not impaired. Furthermore, in the latter, anxiety-related behavior and passive stress-coping were normalized to levels similar to vehicle-treated paired mothers. In conclusion, maternal investment is robust enough to withstand loss of the partner, whereas the mother's emotionality is affected, which may be - at least partly - mediated by a CRF-dependent mechanism. This animal model has potential for mechanistic studies of behavioral and physiological consequences of partner loss in single mothers. Copyright © 2017 Elsevier B.V. All rights reserved.

Correlation of the association of serum lactate, random blood sugar, and revised trauma score as predictors of outcome in hemodynamically unstable abdominal emergencies.

PubMed

Allwell-Brown, E; Afuwape, O O; Ayandipo, O; Alonge, T

2016-01-01

Elevated levels of serum lactate and glucose during resuscitation have been demonstrated to be predictors of morbidity and mortality in hemodynamically unstable patients with surgical abdominal conditions. However, the rate of return to normal levels of both lactate and blood glucose may be better predictors of mortality and morbidity. The aims of this study are: (I) To determine the pattern of serum lactate and glucose changes in patients with surgical abdominal conditions requiring resuscitation within 48 hours of presentation. (II) To correlate the predictive capability of these two independent parameters. (III) To correlate the predictive values of these parameters with the revised trauma score (RTS). This is a prospective observational study conducted over three months. The patients admitted by the general surgery division requiring resuscitation from shock was included in this study. Resuscitation was carried out with crystalloids. The estimation of serum lactate and glucose levels was done at presentation (0 hours), 12, 24 and 48 hours after admission. The revised trauma score (RTS) was calculated for each patient at presentation and at 12, 24 and 48 hours subsequently. The patients were followed up four weeks or when death occurred within four weeks of presentation. Forty four patients were recruited in the study. There were seven mortalities. The mean serum levels of Plasma glucose and lactate of all the patients were elevated at presentation in the emergency department. Survival was better with a return to normal serum lactate within 12 hours. On the other hand the random plasma glucose (RPG) levels may not be useful in prognosticating patients. However a combination of serum lactate, RTS (at 24 and 48 hours) and RPG at 48 hours may improve predictive parameters in trauma related cases.

[Breast-feeding (part II): Lactation inhibition--Guidelines for clinical practice].

PubMed

Marcellin, L; Chantry, A A

2015-12-01

Provide guidelines for clinical use of non-pharmacological and pharmacological treatments of inhibition of lactation and the management of the weaning. Systematically review of the literature between 1972 and May 2015 from the databases Medline, Google Scholar, Cochrane Library, and the international recommendations about inhibition of lactation with establishment of levels of evidence (LE) and grades of recommendation. The available data on the effectiveness of non-pharmacological measures are limited, with very low levels of evidence that fail to make recommendations (Professional consensus). Pharmacological treatments for inhibition of lactation should not be given routinely to women who do not wish to breast-feed (Professional consensus). For women aware of the risks of pharmacological treatments of inhibition of lactation, lisuride and cabergolin are the preferred drugs (Professional consensus). Because of potentially serious adverse effects, bromocriptin is contraindicated in inhibiting lactation (Professional consensus). Available data on management of lactation weaning fail to provide recommendation and no treatment is recommended (Professional consensus). Bromocriptin is contraindicated in the treatment of inhibiting lactation. Women who do not wish to breast-feed have to be informed of the benefits and disadvantages of the pharmacological treatment for inhibition of lactation. Copyright © 2015. Published by Elsevier Masson SAS.

The effect of lactational mastitis on the macronutrient content of breast milk.

PubMed

Say, Birgul; Dizdar, Evrim Alyamaç; Degirmencioglu, Halil; Uras, Nurdan; Sari, Fatma Nur; Oguz, Suna; Canpolat, Fuat Emre

2016-07-01

Mastitis in lactating mothers reduces milk production and alters the cellular composition of milk. Changes occurring in the mammary gland during the inflammatory response are believed to increase the permeability of the blood-milk barrier. This study examined the effect of mastitis during lactation on the macronutrient content of breast milk. The study was conducted at Zekai Tahir Burak Maternity Teaching Hospital. Transitional breast milk samples were obtained from term lactating mothers with or without mastitis. Milk protein, fat, carbohydrate, and energy levels were measured using a mid-infrared human milk analyzer. The study recruited 30 term lactating mothers: 15 mothers diagnosed with mastitis and 15 healthy mothers. The characteristics of the mothers in both groups were similar. Fat, carbohydrate, and energy levels were statistically lower in the milk samples of mothers with mastitis compared with the mothers without mastitis. Lactational mastitis was associated with lower breast milk fat, carbohydrate, and energy levels. The local inflammatory response induced by cytokines and increased blood-milk barrier permeability might account for the changes in the fat, carbohydrate, and energy levels of human milk. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Alterations of neurotransmitter norepinephrine and gamma-aminobutyric acid correlate with murine behavioral perturbations related to bisphenol A exposure.

PubMed

Ogi, Hiroshi; Itoh, Kyoko; Ikegaya, Hiroshi; Fushiki, Shinji

2015-09-01

Humans are commonly exposed to endocrine-disrupting chemical bisphenol A (BPA), giving rise to concern over the psychobehavioral effects of BPA. The aim of this study was to investigate the effects of prenatal and lactational BPA exposure on neurotransmitters, including norepinephrine (NE), gamma-aminobutyric acid (GABA) and glutamate (Glu), and to assess the association with behavioral phenotypes. C57BL/6J mice were orally administered with BPA (500 μg/bwkg/day) or vehicle daily from embryonic day 0 to postnatal week 3 (P3W), through their dams. The IntelliCage behavioral experiments were conducted from P11W to P15W. At around P14-16W, NE, GABA and Glu levels in nine brain regions were measured by high performance liquid chromatography. Furthermore, the associations between the neurotransmitter levels and the behavioral indices were statistically analyzed. In females exposed to BPA, the GABA and Glu levels in almost all regions, and the NE levels in the cortex, hypothalamus and thalamus were higher than those in the controls. In males exposed to BPA, the GABA levels in the amygdala and hippocampus showed lower values, while Glu levels were higher in some regions, compared with the controls. In regard to the associations, the number of "diurnal corner visits without drinking" was correlated with the NE levels in the cortex and thalamus in females. The "nocturnal corner visit duration without drinking" was correlated with the GABA level in the hippocampus in males. These results suggest that prenatal and lactational exposure to low doses of BPA might modulate the NE, GABA and Glu systems, resulting in behavioral alterations. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Trpc2-deficient lactating mice exhibit altered brain and behavioral responses to bedding stimuli.

PubMed

Hasen, Nina S; Gammie, Stephen C

2011-03-01

The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2(-/-) knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female. Copyright © 2010 Elsevier B.V. All rights reserved.

Low plasma magnesium is associated with impaired brain metabolism in neonates with hypoxic-ischaemic encephalopathy.

PubMed

Chakkarapani, Elavazhagan; Chau, Vann; Poskitt, Kenneth J; Synnes, Anne; Kwan, Eddie; Roland, Elke; Miller, Steven P

2016-09-01

To determine the association between lowest plasma magnesium concentration and brain metabolism, and whether magnetic resonance imaging brain injury patterns moderated the association in hypoxic-ischemic encephalopathy. In 131 early (day-of-life 3) and 65 late (day-of-life 10) scans of term encephalopathic infants born between 2004 and 2012, we examined the association of lowest plasma magnesium (until day-of-life 3) on basal ganglia and white matter peak metabolite ratios on magnetic resonance spectroscopy independent of covariates, stratified by the predominant patterns of injury (normal, basal nuclei/total, watershed, multifocal) using multiple linear regression. Lowest plasma magnesium was associated with lower white matter N-acetyl-aspartate/choline in the multifocal pattern on early scan (regression-coefficient, β: 0.13; 95% CI: 0.04, 0.22) and in the basal nuclei/total pattern on late scan (β: 0.08; 95% CI: 0.02, 0.15), and was negatively associated with basal ganglia lactate/N-acetyl-aspartate (β: -0.16; 95% CI: -0.05, -0.28) and lactate/choline (β: -0.1; 95% CI: -0.03, -0.17) ratio in the basal nuclei/total pattern on late scan independent of hypomagnesaemia correction, cooling and postmenstrual age at scan. Lowest plasma magnesium was not associated with metabolite ratios in other brain injury patterns. In infants with hypoxic-ischaemic encephalopathy, predominant patterns of brain injury moderated the association between lowest plasma magnesium in the first three days of life and impaired brain metabolism. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Abnormal brain development in newborns with congenital heart disease.

PubMed

Miller, Steven P; McQuillen, Patrick S; Hamrick, Shannon; Xu, Duan; Glidden, David V; Charlton, Natalie; Karl, Tom; Azakie, Anthony; Ferriero, Donna M; Barkovich, A James; Vigneron, Daniel B

2007-11-08

Congenital heart disease in newborns is associated with global impairment in development. We characterized brain metabolism and microstructure, as measures of brain maturation, in newborns with congenital heart disease before they underwent heart surgery. We studied 41 term newborns with congenital heart disease--29 who had transposition of the great arteries and 12 who had single-ventricle physiology--with the use of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before cardiac surgery. We calculated the ratio of N-acetylaspartate to choline (which increases with brain maturation), the ratio of lactate to choline (which decreases with maturation), average diffusivity (which decreases with maturation), and fractional anisotropy of white-matter tracts (which increases with maturation). We compared these findings with those in 16 control newborns of a similar gestational age. As compared with control newborns, those with congenital heart disease had a decrease of 10% in the ratio of N-acetylaspartate to choline (P=0.003), an increase of 28% in the ratio of lactate to choline (P=0.08), an increase of 4% in average diffusivity (P<0.001), and a decrease of 12% in white-matter fractional anisotropy (P<0.001). Preoperative brain injury, as seen on MRI, was not significantly associated with findings on MRS or DTI. White-matter injury was observed in 13 newborns with congenital heart disease (32%) and in no control newborns. Term newborns with congenital heart disease have widespread brain abnormalities before they undergo cardiac surgery. The imaging findings in such newborns are similar to those in premature newborns and may reflect abnormal brain development in utero. Copyright 2007 Massachusetts Medical Society.

Transcriptome Analysis Identifies Key Metabolic Changes in the Hooded Seal (Cystophora cristata) Brain in Response to Hypoxia and Reoxygenation

PubMed Central

Czech-Damal, Nicole U.; Folkow, Lars P.

2017-01-01

The brain of diving mammals tolerates low oxygen conditions better than the brain of most terrestrial mammals. Previously, it has been demonstrated that the neurons in brain slices of the hooded seal (Cystophora cristata) withstand hypoxia longer than those of mouse, and also tolerate reduced glucose supply and high lactate concentrations. This tolerance appears to be accompanied by a shift in the oxidative energy metabolism to the astrocytes in the seal while in terrestrial mammals the aerobic energy production mainly takes place in neurons. Here, we used RNA-Seq to compare the effect of hypoxia and reoxygenation in vitro on brain slices from the visual cortex of hooded seals. We saw no general reduction of gene expression, suggesting that the response to hypoxia and reoxygenation is an actively regulated process. The treatments caused the preferential upregulation of genes related to inflammation, as found before e.g. in stroke studies using mammalian models. Gene ontology and KEGG pathway analyses showed a downregulation of genes involved in ion transport and other neuronal processes, indicative for a neuronal shutdown in response to a shortage of O2 supply. These differences may be interpreted in terms of an energy saving strategy in the seal's brain. We specifically analyzed the regulation of genes involved in energy metabolism. Hypoxia and reoxygenation caused a similar response, with upregulation of genes involved in glucose metabolism and downregulation of the components of the pyruvate dehydrogenase complex. We also observed upregulation of the monocarboxylate transporter Mct4, suggesting increased lactate efflux. Together, these data indicate that the seal brain responds to the hypoxic challenge by a relative increase in the anaerobic energy metabolism. PMID:28046118

Protective role of Kv7 channels in oxygen and glucose deprivation-induced damage in rat caudate brain slices

PubMed Central

Barrese, Vincenzo; Taglialatela, Maurizio; Greenwood, Iain A; Davidson, Colin

2015-01-01

Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since Kv7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The Kv7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The Kv7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an ~6-fold decrease in Kv7.2 transcript, while levels of mRNAs encoding for other Kv7 subunits were unaffected; western blot experiments showed a parallel reduction in Kv7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for Kv7.2 in modulating ischemia-evoked caudate damage. PMID:25966943

Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates.

PubMed

Ben-Ari, Yehezkel; Tyzio, Roman; Nehlig, Astrid

2011-09-01

Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that γ-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mm), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal "control" conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl(-)](i)) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl(-)](i) that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

The lactate paradox revisited in lowlanders during acclimatization to 4100 m and in high-altitude natives

PubMed Central

van Hall, G; Lundby, C; Araoz, M; Calbet, J A L; Sander, M; Saltin, B

2009-01-01

Chronic hypoxia has been proposed to induce a closer coupling in human skeletal muscle between ATP utilization and production in both lowlanders (LN) acclimatizing to high altitude and high-altitude natives (HAN), linked with an improved match between pyruvate availability and its use in mitochondrial respiration. This should result in less lactate being formed during exercise in spite of the hypoxaemia. To test this hypothesis six LN (22–31 years old) were studied during 15 min warm up followed by an incremental bicycle exercise to exhaustion at sea level, during acute hypoxia and after 2 and 8 weeks at 4100 m above sea level (El Alto, Bolivia). In addition, eight HAN (26–37 years old) were studied with a similar exercise protocol at altitude. The leg net lactate release, and the arterial and muscle lactate concentrations were elevated during the exercise in LN in acute hypoxia and remained at this higher level during the acclimatization period. HAN had similar high values; however, at the moment of exhaustion their muscle lactate, ADP and IMP content and Cr/PCr ratio were higher than in LN. In conclusion, sea-level residents in the course of acclimatization to high altitude did not exhibit a reduced capacity for the active muscle to produce lactate. Thus, the lactate paradox concept could not be demonstrated. High-altitude natives from the Andes actually exhibit a higher anaerobic energy production than lowlanders after 8 weeks of acclimatization reflected by an increased muscle lactate accumulation and enhanced adenine nucleotide breakdown. PMID:19139048

Pregnancy swimming causes short- and long-term neuroprotection against hypoxia-ischemia in very immature rats.

PubMed

Sanches, Eduardo Farias; Durán-Carabali, Luz Elena; Tosta, Andrea; Nicola, Fabrício; Schmitz, Felipe; Rodrigues, André; Siebert, Cassiana; Wyse, Angela; Netto, Carlos

2017-09-01

BackgroundHypoxia-ischemia (HI) is a major cause of neurological damage in preterm newborn. Swimming during pregnancy alters the offspring's brain development. We tested the effects of swimming during pregnancy in the very immature rat brain.MethodsFemale Wistar rats (n=12) were assigned to the sedentary (SE, n=6) or the swimming (SW, n=6) group. From gestational day 0 (GD0) to GD21 the rats in the SW group were made to swim for 20 min/day. HI on postnatal day (PND) 3 rats caused sensorimotor and cognitive impairments. Animals were distributed into SE sham (SESH), sedentary HIP3 (SEHI), swimming sham (SWSH), and swimming HIP3 (SWHI) groups. At PND4 and PND5, Na + /K + -ATPase activity and brain-derived neurotrophic factor (BDNF) levels were assessed. During lactation and adulthood, neurological reflexes, sensorimotor, anxiety-related, and cognitive evaluations were made, followed by histological assessment at PND60.ResultsAt early stages, swimming caused an increase in hippocampal BDNF levels and in the maintenance of Na + /K + -ATPase function in the SWHI group. The SWHI group showed smaller lesions and the preservation of white matter tracts. SEHI animals showed a delay in reflex maturation, which was reverted in the SWHI group. HIP3 induced spatial memory deficits and hypomyelination in SEHI rats, which was reverted in the SWHI group.ConclusionSwimming during pregnancy neuroprotected the brains against HI in very immature neonatal rats.

Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures.

PubMed

Magner, Martin; Szentiványi, Karol; Svandová, Ivana; Ješina, Pavel; Tesařová, Markéta; Honzík, Tomáš; Zeman, Jiří

2011-03-01

Increased lactate is an important biochemical marker in diagnosis of children with suspicion of mitochondrial disorders. A diagnostic dilemma may originate if analyses are performed after seizures, when the increased lactate levels may be considered to result from the seizures. To address this problem, we ascertained the diagnostic value of lactate and alanine in blood (B) and cerebrospinal fluid (CSF) in children with mitochondrial disorders (n = 24), epilepsy (n = 32), psychomotor retardation (n = 23), meningitis (n = 12) and meningism (n = 16). Lactate concentration was measured using a spectrophotometric method. Amino acids in serum and CSF were analyzed by ion exchange chromatography with ninhydrin detection. Average blood and CSF-lactate levels were significantly higher in children with mitochondrial disorders (3.87 ± 0.48 and 4.43 ± 0.55 mmol/l) and meningitis (2.77 ± 0.45 and 8.58 ± 1.08 mmol/l) than in children with epilepsy (1.72 ± 0.13 and 1.62 ± 0.04 mmol/l), psychomotor retardation (1.79 ± 1.40 and 1.68 ± 0.06 mmol/l) or meningism (1.70 ± 0.13 and 1.64 ± 0.07 mmol/l). Blood and CSF-alanine levels were also higher in children with mitochondrial disorders (558 ± 44 and 51 ± 8 μmol/l) than in children with epilepsy (327 ± 23 and 27 ± 3 μmol/l) or psychomotor retardation (323 ± 27 and 26 ± 3 μmol/l). The CSF-lactate levels of children with epilepsy were similar whether the samples were obtained 3 ± 0.6 h after an attack of brief seizures or from children without history of recent seizures. Elevated cerebrospinal fluid lactate level is a reliable marker pointing to mitochondrial origin of disease, even in children who have recently suffered short-lasting seizures. Some children with mitochondrial disorders manifest only mild or intermittent elevation of lactate levels. Copyright © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Fatty acids in energy metabolism of the central nervous system.

PubMed

Panov, Alexander; Orynbayeva, Zulfiya; Vavilin, Valentin; Lyakhovich, Vyacheslav

2014-01-01

In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain's energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcile β-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups.

Fatty Acids in Energy Metabolism of the Central Nervous System

PubMed Central

Orynbayeva, Zulfiya; Vavilin, Valentin; Lyakhovich, Vyacheslav

2014-01-01

In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain's energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcile β-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups. PMID:24883315

Impaired hippocampal glucose metabolism during and after flurothyl-induced seizures in mice: Reduced phosphorylation coincides with reduced activity of pyruvate dehydrogenase.

PubMed

McDonald, Tanya S; Borges, Karin

2017-07-01

To determine changes in glucose metabolism and the enzymes involved in the hippocampus ictally and postictally in the acute mouse flurothyl seizure model. [U- 13 C]-Glucose was injected (i.p.) prior to, or following a 5 min flurothyl-induced seizure. Fifteen minutes later, mice were killed and the total metabolite levels and % 13 C enrichment were analyzed in the hippocampal formation using gas chromatography-mass spectrometry. Activities of key metabolic and antioxidant enzymes and the phosphorylation status of pyruvate dehydrogenase were measured, along with lipid peroxidation. During seizures, total lactate levels increased 1.7-fold; however, [M + 3] enrichment of both lactate and alanine were reduced by 30% and 43%, respectively, along with a 28% decrease in phosphofructokinase activity. Postictally the % 13 C enrichments of all measured tricarboxylic acid (TCA) cycle intermediates and the amino acids were reduced by 46-93%. At this time, pyruvate dehydrogenase (PDH) activity was 56% of that measured in controls, and there was a 1.9-fold increase in the phosphorylation of PDH at ser232. Phosphorylation of PDH is known to decrease its activity. Here, we show that the increase of lactate levels during flurothyl seizures is from a source other than [U- 13 C]-glucose, such as glycogen. Surprisingly, although we saw a reduction in phosphofructokinase activity during the seizure, metabolism of [U- 13 C]-glucose into the TCA cycle seemed unaffected. Similar to our recent findings in the chronic phase of the pilocarpine model, postictally the metabolism of glucose by glycolysis and the TCA cycle was impaired along with reduced PDH activity. Although this decrease in activity may be a protective mechanism to reduce oxidative stress, which is observed in the flurothyl model, ATP is critical to the recovery of ion and neurotransmitter balance and return to normal brain function. Thus we identified promising novel strategies to enhance energy metabolism and recovery from seizures. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Dairy fat blends high in α-linolenic acid are superior to n-3 fatty-acid-enriched palm oil blends for increasing DHA levels in the brains of young rats.

PubMed

Du, Qin; Martin, Jean-Charles; Agnani, Genevieve; Pages, Nicole; Leruyet, Pascale; Carayon, Pierre; Delplanque, Bernadette

2012-12-01

Achieving an appropriate docosahexaenoic acid (DHA) status in the neonatal brain is an important goal of neonatal nutrition. We evaluated how different dietary fat matrices improved DHA content in the brains of both male and female rats. Forty rats of each gender were born from dams fed over gestation and lactation with a low α-linolenic acid (ALA) diet (0.4% of fatty acids) and subjected for 6 weeks after weaning to a palm oil blend-based diet (10% by weight) that provided either 1.5% ALA or 1.5% ALA and 0.12% DHA with 0.4% arachidonic acid or to an anhydrous dairy fat blend that provided 1.5% or 2.3% ALA. Fatty acids in the plasma, red blood cells (RBCs) and whole brain were determined by gas chromatography. The 1.5% ALA dairy fat was superior to both the 1.5% ALA palm oil blends for increasing brain DHA (14.4% increase, P<.05), and the 2.3% ALA dairy blend exhibited a further increase that could be ascribed to both an ALA increase and n-6/n-3 ratio decrease. Females had significantly higher brain DHA due to a gender-to-diet interaction, with dairy fats attenuating the gender effect. Brain DHA was predicted with a better accuracy by some plasma and RBC fatty acids when used in combination (R(2) of 0.6) than when used individually (R(2)=0.47 for RBC n-3 docosapentaenoic acid at best). In conclusion, dairy fat blends enriched with ALA appear to be an interesting strategy for achieving optimal DHA levels in the brain of postweaning rats. Human applications are worth considering. Copyright © 2012 Elsevier Inc. All rights reserved.

Heritability of methane emissions from dairy cows over a lactation measured on commercial farms.

PubMed

Pszczola, M; Rzewuska, K; Mucha, S; Strabel, T

2017-11-01

Methane emission is currently an important trait in studies on ruminants due to its environmental and economic impact. Recent studies were based on short-time measurements on individual cows. As methane emission is a longitudinal trait, it is important to investigate its changes over a full lactation. In this study, we aimed to estimate the heritability of the estimated methane emissions from dairy cows using Fourier-transform infrared spectroscopy during milking in an automated milking system by implementing the random regression method. The methane measurements were taken on 485 Polish Holstein-Friesian cows at 2 commercial farms located in western Poland. The overall daily estimated methane emission was 279 g/d. Genetic variance fluctuated over the course of lactation around the average level of 1,509 (g/d), with the highest level, 1,866 (g/d), at the end of the lactation. The permanent environment variance values started at 2,865 (g/d) and then dropped to around 846 (g/d) at 100 d in milk (DIM) to reach the level of 2,444 (g/d) at the end of lactation. The residual variance was estimated at 2,620 (g/d). The average repeatability was 0.25. The heritability level fluctuated over the course of lactation, starting at 0.23 (SE 0.12) and then increasing to its maximum value of 0.3 (SE 0.08) at 212 DIM and ending at the level of 0.27 (SE 0.12). Average heritability was 0.27 (average SE 0.09). We have shown that estimated methane emission is a heritable trait and that the heritability level changes over the course of lactation. The observed changes and low genetic correlations between distant DIM suggest that it may be important to consider the period in which methane phenotypes are collected.

Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.

PubMed

Ding, Fan; Yao, Jia; Rettberg, Jamaica R; Chen, Shuhua; Brinton, Roberta Diaz

2013-01-01

We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3-15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6-9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.

Minimally invasive monitoring of skeletal muscle hypermetabolism induced by the phosphodiesterase-III-inhibitor milrinone and sodium fluoride.

PubMed

Schuster, Frank; Johannsen, Stephan; Roewer, Norbert; Anetseder, Martin

2013-04-01

We hypothesized that the phosphodiesterase-III-inhibitor milrinone and the non-specific G-protein activator sodium fluoride increase the skeletal muscular lactate levels as a sign of a hypermetabolic response. With approval of the local animal care committee Sprague-Dawley rats were killed and artificially perfused either with Ringer's solution or sodium fluoride 110 mM, while milrinone 1.32 mM or Ringer's solution at 1 μl/min was applied via microdialysis probes in both hind limbs. Lactate was measured spectrophotometrically in the dialysate. Baseline lactate levels before drug application did not differ between hind limbs. Local infusion of milrinone via microdialysis did not significantly increase intramuscular lactate concentrations compared with the Ringer control group. Muscular perfusion with sodium fluoride resulted in a significant increase of lactate and was potentiated by combination with local milrinone. Phosphodiesterase-III-inhibition alone does not significantly influence the lactate levels in skeletal muscle of sacrificed rats. Sodium fluoride infusion leads to an intramuscular lactate increase, which was further potentiated by local inhibition of phosphodiesterase-III. The fluoride-mediated hypermetabolic response following sodium fluoride could be a possible explanation for the observed myotoxic adverse effects in individuals treated by fluoride-containing agents. © 2012 The Authors. JPP © 2012. Royal Pharmaceutical Society.

Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes

PubMed Central

Neumann, I D; Johnstone, H A; Hatzinger, M; Liebsch, G; Shipston, M; Russell, J A; Landgraf, R; Douglas, A J

1998-01-01

The responsiveness of the rat hypothalamo-pituitary-adrenal (HPA) axis and hypothalamo-neurohypophysial system (HNS) to emotional (elevated plus-maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophin-releasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy-related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress-induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stress-induced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg−1, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nm, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography. [125I] CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. Anxiety-related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus-maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved. PMID:9490853

Computational modelling of the piglet brain to simulate near-infrared spectroscopy and magnetic resonance spectroscopy data collected during oxygen deprivation

PubMed Central

Moroz, Tracy; Banaji, Murad; Robertson, Nicola J.; Cooper, Chris E.; Tachtsidis, Ilias

2012-01-01

We describe a computational model to simulate measurements from near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS) in the piglet brain. Piglets are often subjected to anoxic, hypoxic and ischaemic insults, as experimental models for human neonates. The model aims to help interpret measurements and increase understanding of physiological processes occurring during such insults. It is an extension of a previous model of circulation and mitochondrial metabolism. This was developed to predict NIRS measurements in the brains of healthy adults i.e. concentration changes of oxyhaemoglobin and deoxyhaemoglobin and redox state changes of cytochrome c oxidase (CCO). We altered and enhanced the model to apply to the anaesthetized piglet brain. It now includes metabolites measured by 31P-MRS, namely phosphocreatine, inorganic phosphate and adenosine triphosphate (ATP). It also includes simple descriptions of glycolysis, lactate dynamics and the tricarboxylic acid (TCA) cycle. The model is described, and its simulations compared with existing measurements from piglets during anoxia. The NIRS and MRS measurements are predicted well, although this requires a reduction in blood pressure autoregulation. Predictions of the cerebral metabolic rate of oxygen consumption (CMRO2) and lactate concentration, which were not measured, are given. Finally, the model is used to investigate hypotheses regarding changes in CCO redox state during anoxia. PMID:22279158

Myoclonic epilepsy with ragged-red fibers without increased lactate levels.

PubMed

Kimura, Shigemi; Ozasa, Shiro; Nakamura, Kyoko; Nomura, Keiko; Kosuge, Hirofumi

2009-07-01

Myoclonic epilepsy associated with ragged-red fibers is one of the mitochondrial encephalomyopathies. Pathogenic mitochondrial DNA mutations have been identified in the mitochondrial transfer RNA (tRNA)(Lys) at positions 8344 and 8356. Characteristics of myoclonic epilepsy associated with ragged-red fibers include myoclonic epilepsy, generalized epilepsy, hearing loss, exercise intolerance, lactic acidosis, and ragged-red fibers. The elevated lactate level is one of the most important symptoms needed to make a diagnosis of mitochondrial encephalomyopathy. In the present case, however, myoclonic epilepsy was associated with ragged-red fibers but without increased lactate levels. Therefore, myoclonic epilepsy associated with ragged-red fibers should be suspected in a patient who has myoclonic epilepsy that is difficult to control with antiepileptic medications and who has other symptoms of mitochondrial disease, such as mental retardation, even if the patient's lactate level is normal.

Inhibition of lactation.

PubMed

Llewellyn-Jones, D

1975-01-01

The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

The effect of lactation length on greenhouse gas emissions from the national dairy herd.

PubMed

Wall, E; Coffey, M P; Pollott, G E

2012-11-01

Many governments have signed up to greenhouse gas emission (GHGE) reduction programmes under their national climate change obligations. Recently, it has been suggested that the use of extended lactations in dairy herds could result in reduced GHGE. Dairy GHGE were modelled on a national basis and the model was used to compare emissions from lactations of three different lengths (305, 370 and 440 days), and a current 'base' scenario on the basis of maintaining current milk production levels. In addition to comparing GHGE from the average 'National Herd' under these scenarios, results were used to investigate how accounting for lactations of different lengths might alter the estimation of emissions calculated from the National Inventory methodology currently recommended by Intergovernmental Panel on Climate Change. Data for the three lactation length scenarios were derived from nationally recorded dairy performance information and used in the GHGE model. Long lactations required fewer milking cows and replacements to maintain current milk yield levels than short ones, but GHGEs were found to rise from 1214 t of CO2 equivalent (CE)/farm per year for lactations of 305 days to 1371 t CE/farm per year for 440-day lactations. This apparent anomaly can be explained by the less efficient milk production (kg milk produced per kg cow weight) found in later lactation, a more pronounced effect in longer lactations. The sensitivity of the model to changes in replacement rate, persistency and level of milk yield was investigated. Changes in the replacement rate from 25% to 20% and in persistency by −10% to +20% resulted in very small changes in GHGE. Differences in GHGE due to the level of milk yield were much more dramatic with animals in the top 10% for yield, producing about 25% less GHGE/year than the average animal. National Inventory results were investigated using a more realistic spread of lactation lengths than recommended for such calculations using emissions calculated in the first part of the study. Current UK emission calculations based on the National Inventory were 329 Gg of methane per year from the dairy herd. Using the national distribution of lactation lengths, this was found to be an underestimate by about 10%. This work showed that the current rise in lactation length or a move towards calving every 18 months would increase GHGE by 7% to 14% compared with the current scenario, assuming the same milk yield in all models. Increased milk yield would have a much greater effect on reducing GHGE than changes to lactation length, replacement rate or persistency. National Inventory methodology appears to underestimate GHGE when the distribution of lactation lengths is considered and may need revising to provide more realistic figures.

Bidirectional Control of Blood Flow by Astrocytes: A Role for Tissue Oxygen and Other Metabolic Factors.

PubMed

Gordon, Grant R J; Howarth, Clare; MacVicar, Brian A

2016-01-01

Altering cerebral blood flow through the control of cerebral vessel diameter is critical so that the delivery of molecules important for proper brain functioning is matched to the activity level of neurons. Although the close relationship of brain glia known as astrocytes with cerebral blood vessels has long been recognized, it is only recently that these cells have been demonstrated to translate information on the activity level and energy demands of neurons to the vasculature. In particular, astrocytes respond to elevations in extracellular glutamate as a consequence of synaptic transmission through the activation of group 1 metabotropic glutamate receptors. These Gq-protein coupled receptors elevate intracellular calcium via IP3 signaling. A close examination of astrocyte endfeet calcium signals has been shown to cause either vasoconstriction or vasodilation. Common to both vasomotor responses is the generation of arachidonic acid in astrocytes by calcium sensitive phospholipase A2. Vasoconstriction ensues from the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid, while vasodilation ensues from the production of epoxyeicosatrienoic acids or prostaglandins. Factors that determine whether constrictor or dilatory pathways predominate include brain oxygen, lactate, adenosine as well as nitric oxide. Changing the oxygen level itself leads to many downstream changes that facilitate the switch from vasoconstriction at high oxygen to vasodilation at low oxygen. These findings highlight the importance of astrocytes as sensors of neural activity and metabolism to coordinate the delivery of essential nutrients via the blood to the working cells.

Long-chain polyunsaturated fatty acids decline rapidly in milk from mothers delivering extremely preterm indicating the need for supplementation.

PubMed

Nilsson, Anders K; Löfqvist, Chatarina; Najm, Svetlana; Hellgren, Gunnel; Sävman, Karin; Andersson, Mats X; Smith, Lois E H; Hellström, Ann

2018-06-01

Our aim was to perform an in-depth analysis of the composition of fatty acids in milk from mothers delivering extremely preterm babies. We investigated longitudinal changes in milk fatty acid profiles and the relationship between several types of fatty acids, including omega-3 and omega-6. Milk samples were collected at three stages of lactation from 78 mothers who delivered at less than 28 weeks of pregnancy at the Sahlgrenska University Hospital, Gothenburg, Sweden, from April 2013 to September 2015. Fatty acid composition was analysed by gas chromatography-mass spectrometry. A reduction in long-chain polyunsaturated fatty acids (LCPUFAs) was observed during the lactation period. The concentrations of arachidonic acid and docosahexaenoic acid declined from medians of 0.34 to 0.22 mol% and 0.29 to 0.15 mol%, respectively, between postnatal day 7 and a postmenstrual age of 40 weeks. Strong correlations were found between the intermediates of several classes of fatty acids, including omega-3, omega-6 and omega-9. A rapid reduction in LCPUFA content in the mother's milk during the lactation period emphasises the importance of fatty acid supplementation to infants born extremely preterm, at least during the period corresponding to the third trimester, when rapid development of the brain and adipose tissue requires high levels of LCPUFAs. ©2018 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.

N-acetylcysteine supplementation controls total antioxidant capacity, creatine kinase, lactate, and tumor necrotic factor-alpha against oxidative stress induced by graded exercise in sedentary men.

PubMed

Leelarungrayub, Donrawee; Khansuwan, Raphiphat; Pothongsunun, Prapas; Klaphajone, Jakkrit

2011-01-01

Aim of this study was to evaluate the effects of short-term (7 days) N-acetylcysteine (NAC) at 1,200 mg daily supplementation on muscle fatigue, maximal oxygen uptake (VO(2max)), total antioxidant capacity (TAC), lactate, creatine kinase (CK), and tumor necrotic factor-alpha (TNF-α). Twenty-nine sedentary men (13 controls; 16 in the supplement group) from a randomized control were included. At before and after supplementation, fatigue index (FI) was evaluated in the quadriceps muscle, and performed a graded exercise treadmill test to induce oxidative stress, and as a measure of VO(2max). Blood samples were taken before exercise and 20 minutes after it at before and after supplementation, to determine TAC, CK, lactate, and TNF-α levels. Results showed that FI and VO(2max) increased significantly in the supplement group. After exercise decreased the levels of TAC and increased lactate, CK, and TNF-α of both groups at before supplementation. After supplementation, lactate, CK, and TNF-α levels significantly increased and TAC decreased after exercise in the control group. Whereas the TAC and lactate levels did not change significantly, but CK and TNF-α increased significantly in the supplement group. Therefore, this results showed that NAC improved the muscle fatigue, VO(2max), maintained TAC, controlled lactate production, but had no influence on CK and TNF-α.

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

PubMed

Wilkins, Heather M; Harris, Janna L; Carl, Steven M; E, Lezi; Lu, Jianghua; Eva Selfridge, J; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M; Michaelis, Mary L; Michaelis, Elias K; Brooks, William M; Swerdlow, Russell H

2014-12-15

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock

PubMed Central

2010-01-01

Background Lactate clearance, a surrogate for the magnitude and duration of global tissue hypoxia, is used diagnostically, therapeutically and prognostically. This study examined the association of early lactate clearance with selected inflammatory, coagulation, apoptosis response biomarkers and organ dysfunction scores in severe sepsis and septic shock. Methods Measurements of serum arterial lactate, biomarkers (interleukin-1 receptor antagonist, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, intercellular adhesion molecule-1, high mobility group box-1, D-Dimer and caspase-3), and organ dysfunction scores (Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Multiple Organ Dysfunction Score, and Sequential Organ Failure Assessment) were obtained in conjunction with a prospective, randomized study examining early goal-directed therapy in severe sepsis and septic shock patients presenting to the emergency department (ED). Lactate clearance was defined as the percent change in lactate levels after six hours from a baseline measurement in the ED. Results Two-hundred and twenty patients, age 65.0 +/- 17.1 years, were examined, with an overall lactate clearance of 35.5 +/- 43.1% and in-hospital mortality rate of 35.0%. Patients were divided into four quartiles of lactate clearance, -24.3 +/- 42.3, 30.1 +/- 7.5, 53.4 +/- 6.6, and 75.1 +/- 7.1%, respectively (p < 0.01). The mean levels of all biomarkers and organ dysfunction scores over 72 hours were significantly lower with higher lactate clearance quartiles (p < 0.01). There was a significant decreased in-hospital, 28-day, and 60-day mortality in the higher lactate clearance quartiles (p < 0.01). Conclusions Early lactate clearance as a surrogate for the resolution of global tissue hypoxia is significantly associated with decreased levels of biomarkers, improvement in organ dysfunction and outcome in severe sepsis and septic shock. PMID:20181046

Clinical utility of serum lactate levels for differential diagnosis of generalized tonic-clonic seizures from psychogenic nonepileptic seizures and syncope.

PubMed

Doğan, Ebru Apaydın; Ünal, Ali; Ünal, Aslıhan; Erdoğan, Çağla

2017-10-01

The differential diagnosis of generalized tonic-clonic seizures (GTCS), psychogenic nonepileptic seizures (PNES), and syncope constitutes a major challenge. Misdiagnosis rates up to 20 to 30% are reported in the literature. To assess the clinical utility of serum lactate levels for differentiation of GTCS, PNES, and syncope based on gender differences. Data from 270 patients were evaluated retrospectively. Only patients ≥18 years old with the final diagnosis of GTCS, PNES, or syncope in their chart were recruited. Serum lactate levels were measured in the first 2h of the index event. Serum lactate levels in patients with GTCS (n=157) were significantly higher than in the patients with PNES (n=25) (p<0.001) and syncope (n=88) (p<0.001). When compared with the females, serum lactate levels in patients with GTCS were significantly higher in the male subgroup (p=0.004). In male patients the ROC analysis yielded a serum lactate value of 2.43mmol/l with a sensitivity of 0.85 and a specificity of 0.88 as the optimal cut-off value to distinguish GTCS from other events. The ROC analysis for the AUC yielded a high estimate of 0.94 (95% confidence interval: 0.91-0.98). When a cut-off value of 2.43mmol/l was chosen for the females, which was an optimal value for male patients, the specificity was 0.85, however, the sensitivity was 0.64. We propose that serum lactate level when measured in the first 2h after the index event has a high clinical utility in the differential diagnosis of GTCS, PNES, and syncope. With concomitant clinical signs and physical examination findings besides neuroimaging and EEG, elevated levels of lactate should be taken into account when evaluating a patient with impaired consciousness. On the other hand, the suggested cut-off value 2.43mmol/l might not have a discriminative effect between GTCS, PNES, and syncope in female patients. This finding should be verified in a prospectively designed study with a larger patient population. Copyright © 2017 Elsevier Inc. All rights reserved.

Data describing lack of effects of 17α-ethinyl estradiol on mammary gland morphology in female mice exposed during pregnancy and lactation.

PubMed

LaPlante, Charlotte D; Vandenberg, Laura N

2017-10-01

Ethinyl estradiol (EE) is a synthetic estrogen used in pharmaceutical contraceptives. In many studies evaluating estrogenic endocrine disruptors, EE is used as a positive control for estrogenicity. However, the effects of EE often differ from the effects of other xenoestrogens, suggesting that these other compounds might act via distinct mechanisms. Reported here are data describing the effect of low doses of EE during pregnancy and lactation on the morphology of the lactating mammary gland in CD-1 mice. The data suggest that these low doses have few if any discernable effects on mammary gland morphology. Alterations to cell proliferation and the expression of estrogen receptor (ER)α were also not observed. These companion data were collected from the same females analyzed for effects of EE on maternal behavior and brain recently published in Reproductive Toxicology (Catanese & Vandenberg, 2017).

Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory.

PubMed

Gould, Joanna M; Smith, Phoebe J; Airey, Chris J; Mort, Emily J; Airey, Lauren E; Warricker, Frazer D M; Pearson-Farr, Jennifer E; Weston, Eleanor C; Gould, Philippa J W; Semmence, Oliver G; Restall, Katie L; Watts, Jennifer A; McHugh, Patrick C; Smith, Stephanie J; Dewing, Jennifer M; Fleming, Tom P; Willaime-Morawek, Sandrine

2018-06-25

Maternal protein malnutrition throughout pregnancy and lactation compromises brain development in late gestation and after birth, affecting structural, biochemical, and pathway dynamics with lasting consequences for motor and cognitive function. However, the importance of nutrition during the preimplantation period for brain development is unknown. We have previously shown that maternal low-protein diet (LPD) confined to the preimplantation period (Emb-LPD) in mice, with normal nutrition thereafter, is sufficient to induce cardiometabolic and locomotory behavioral abnormalities in adult offspring. Here, using a range of in vivo and in vitro techniques, we report that Emb-LPD and sustained LPD reduce neural stem cell (NSC) and progenitor cell numbers at E12.5, E14.5, and E17.5 through suppressed proliferation rates in both ganglionic eminences and cortex of the fetal brain. Moreover, Emb-LPD causes remaining NSCs to up-regulate the neuronal differentiation rate beyond control levels, whereas in LPD, apoptosis increases to possibly temper neuron formation. Furthermore, Emb-LPD adult offspring maintain the increase in neuron proportion in the cortex, display increased cortex thickness, and exhibit short-term memory deficit analyzed by the novel-object recognition assay. Last, we identify altered expression of fragile X family genes as a potential molecular mechanism for adverse programming of brain development. Collectively, these data demonstrate that poor maternal nutrition from conception is sufficient to cause abnormal brain development and adult memory loss.

Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.

PubMed

Takimoto, Masaki; Hamada, Taku

2014-05-01

The brain is capable of oxidizing lactate and ketone bodies through monocarboxylate transporters (MCTs). We examined the protein expression of MCT1, MCT2, MCT4, glucose transporter 1 (GLUT1), and cytochrome-c oxidase subunit IV (COX IV) in the rat brain within 24 h after a single exercise session. Brain samples were obtained from sedentary controls and treadmill-exercised rats (20 m/min, 8% grade). Acute exercise resulted in an increase in lactate in the cortex, hippocampus, and hypothalamus, but not the brainstem, and an increase in β-hydroxybutyrate in the cortex alone. After a 2-h exercise session MCT1 increased in the cortex and hippocampus 5 h postexercise, and the effect lasted in the cortex for 24 h postexercise. MCT2 increased in the cortex and hypothalamus 5-24 h postexercise, whereas MCT2 increased in the hippocampus immediately after exercise, and remained elevated for 10 h postexercise. Regional upregulation of MCT2 after exercise was associated with increases in brain-derived neurotrophic factor and tyrosine-related kinase B proteins, but not insulin-like growth factor 1. MCT4 increased 5-10 h postexercise only in the hypothalamus, and was associated with increased hypoxia-inducible factor-1α expression. However, none of the MCT isoforms in the brainstem was affected by exercise. Whereas GLUT 1 in the cortex increased only at 18 h postexercise, COX IV in the hippocampus increased 10 h after exercise and remained elevated for 24 h postexercise. These results suggest that acute prolonged exercise induces the brain region-specific upregulation of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.

Hemodynamic, ventilatory, and biochemical responses of panic patients and normal controls with sodium lactate infusion and spontaneous panic attacks.

PubMed

Gaffney, F A; Fenton, B J; Lane, L D; Lake, C R

1988-01-01

Hemodynamic, ventilatory, and biochemical variables were measured in ten healthy adults and ten panic patients during infusion of 0.5 mol/L of sodium lactate. Physical activity, fitness level, and ambulatory electrocardiograms were also recorded. Lactate infusion doubled cardiac output, increased blood lactate levels by sixfold, and produced hypernatremia, hypocalcemia, and decreased serum bicarbonate levels in both groups but raised arterial pressure only in the patients. The patients hyperventilated before and during the infusion. Physiological responses and somatic complaints with the infusion differed little between the groups, but emotional complaints were six times more frequent among the panic patients. Eight patients but no control subjects interpreted their symptoms as a panic attack. Heart rate increased with only 14 of 31 recorded spontaneous outpatient panic attacks. Sodium lactate infusions appear to produce panic by mimicking the physiology of spontaneous panic. Treatment with cardioactive agents is not indicated in the absence of cardiopulmonary or autonomic nervous system abnormalities.

Initial blood lactate correlates with carboxyhemoglobin and clinical severity in carbon monoxide poisoned patients.

PubMed

Cervellin, Gianfranco; Comelli, Ivan; Rastelli, Gianni; Picanza, Alessandra; Lippi, Giuseppe

2014-12-01

The aim of this study was to assess the role of blood lactate levels at admission in carbon monoxide (CO)-poisoned patients for establishing severity of poisoning and short term prognosis. All cases of CO poisoning visited in the emergency department during the years 2012 and 2013 were retrieved from the hospital database. The concentration of COHb and lactate was assessed in arterial blood in all patients with suspected CO poisoning, along with the plasma concentration of troponin I (TnI). The control population for TnI results consisted in 125 blood donors. Twenty three (61%) out of 38 CO-poisoned patients underwent hyperbaric oxygen (HBO) treatment, and 10 (26%) were admitted to a hospital ward. A significant correlation was found between lactate and COHb (r=0.54; p<0.001), and between lactate and TnI (r=0.44; p=0.001). A significant correlation was also found between COHb and TnI (r=0.38; p=0.020). Blood lactate levels were higher in patients treated with HBO and hospital admission. In multivariate analysis, none of the parameters was associated with HBO treatment, whereas increased value of blood lactate (p=0.036) was the only significant predictor of hospital admission. Twenty five (66%) patients had detectable TnI levels compared to 13% controls (p<0.001), whereas 16% CO-poisoned patients had TnI levels >99th percentile compared to 2% controls (p=0.003). The odds ratio for detectable TnI and TnI >99th percentile in CO-poisoned patients were 13.1 (p<0.001) and 7.6 (p=0.006), respectively. Initial blood lactate level may be useful for risk stratification of CO-poisoned patients, especially for predicting hospitalization. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Abnormal Neurological Responses in Young Adult Offspring Caused by Excess Omega-3 Fatty Acid (Fish Oil) Consumption by the Mother during Pregnancy and Lactation

PubMed Central

Church, M. W.; Jen, K-L. C.; Jackson, D. A.; Adams, B. R.; Hotra, J. W.

2009-01-01

Consuming omega-3 fatty acids (ω-3 FA) during pregnancy and lactation benefits fetal and infant brain development and might reduce the severity of preterm births by prolonging pregnancy. However, diets that are relatively rich in ω-3 FA can adversely affect fetal and infant development and the auditory brainstem response (ABR), a measure of brain development and sensory function. We previously examined the offspring of female rats fed excessive, adequate or deficient amounts of ω-3 FA during pregnancy and lactation. The 24-day-old offspring in the Excess group, compared to the Control group, had postnatal growth retardation and poor hearing acuity and prolonged neural transmission times as evidenced by the ABR. The Deficient group was intermediate. The current study followed these offspring to see if these poor outcomes persisted into young adulthood. Based on prior findings, we hypothesized that the Excess and Deficient offspring would “catch-up” to the Control offspring by young adulthood. Female Wistar rats received one of the three diet conditions from day 1 of pregnancy through lactation. The three diets were the Control ω-3 FA condition (ω-3/ω-6 ratio ~ 0.14), the Excess ω-3 FA condition (ω-3/ω-6 ratio ~ 14.0) and Deficient ω-3 FA condition (ω-3/ω-6 ratio ~ 0% ratio). The Control diet contained 7 % soybean oil; whereas the Deficient and Excess ω-3 FA diets contained 7% safflower oil and 7% fish oil, respectively. One male and female offspring per litter were ABR-tested as young adults using tone pip stimuli of 2, 4, 8 and 16 kHz. The postnatal growth retardation and prolonged neural transmission times in the Excess and Deficient pups had dissipated by young adulthood. In contrast, the Excess group had elevated ABR thresholds (hearing loss) at all tone pip frequencies in comparison to the Control and Deficient groups. The Deficient group had worse ABR thresholds than the Control group in response to the 8 kHz tone pips only. The Excess group also had ABR amplitude-intensity profiles suggestive of hyperacusis. These results are consistent with the Barker hypothesis concerning the fetal and neonatal origins of adult diseases. Thus, consuming diets that are excessively rich or deficient in ω-3 FA during pregnancy and lactation seems inadvisable because of risks for long-lasting adverse effects on brain development and sensory function. PMID:18834936

Increased densities of monocarboxylate transport protein MCT1 after chronic administration of nicotine in rat brain.

PubMed

Canis, Martin; Mack, Brigitte; Gires, Olivier; Maurer, Martin H; Kuschinsky, Wolfgang; Duembgen, Lutz; Duelli, Roman

2009-08-01

Chronic administration of nicotine is followed by a general stimulation of brain metabolism that results in a distinct increase of glucose transport protein densities for Glut1 and Glu3, and local cerebral glucose utilization (LCGU). This increase of LCGU might be paralleled by an enhanced production of lactate. Therefore, the question arose as to whether chronic nicotine infusion is accompanied by increased local densities of monocarboxylate transporter MCT1 in the brain. Secondly, we inquired whether LCGU might be correlated with local densities of MCT1 during normal conditions and after chronic nicotine infusion. Nicotine was given subcutaneously for 1 week by osmotic mini-pumps and local densities of MCT1 were measured by immunoautoradiographic methods in cryosections of rat brains. MCT1 density was significantly increased in 21 of 32 brain structures investigated (median increase 15.0+/-3.6%). Immunohistochemical stainings of these substructures revealed an over-expression of MCT1 within endothelial cells and astrocytes of treated animals. A comparison of 23 MCT1 densities with LCGU measured in the same structures in a previous study revealed a partial correlation between both parameters under control conditions and after chronic nicotine infusion. 10 out of 23 brain areas, which showed a significant increase of MCT1 density due to chronic nicotine infusion, also showed a significant increase of LCGU. In summary, our data show that chronic nicotine infusion induces a moderate increase of local and global density of MCT1 in defined brain structures. However, in terms of brain topologies and substructures this phenomenon did partially match with increased LCGU. It is concluded that MCT1 transporters were upregulated during chronic nicotine infusion at the level of brain substructures and, at least partially, independently of LCGU.

Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients

PubMed Central

2012-01-01

Introduction Daily interruption of sedation (IS) has been implemented in 30 to 40% of intensive care units worldwide and may improve outcome in medical intensive care patients. Little is known about the benefit of IS in acutely brain-injured patients. Methods This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2) during IS trials. Results Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics were not considered safe on 28 days (34%). An increase in the FOUR Score (Full Outline of UnResponsiveness score) was observed in 50% of IS-trials by a median of three (two to four) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one-third of IS-trials the trial had to be stopped due to an ICP-crisis (> 20 mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in PbtO2 (P < 0.05), including 67% with critical values of PbtO2 < 20 mmHg, a tendency to brain metabolic distress (P < 0.07) was observed. Conclusions Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome the clinical benefit. PMID:23186037

Biomarkers, lactate, and clinical scores as outcome predictors in systemic poisons exposures.

PubMed

Lionte, C; Sorodoc, V; Tuchilus, C; Cimpoiesu, D; Jaba, E

2017-07-01

Acute exposure to systemic poisons represents an important challenge in clinical toxicology. We aimed to analyze the potential role of cardiac biomarkers, routine laboratory tests, and clinical scores as morbidity and in-hospital mortality predictors in patients intoxicated with various systemic poisons. We conducted a prospective study on adults acutely exposed to systemic poisons. We determined the PSS, Glasgow Coma Scale (GCS), and we performed electrocardiogram, laboratory tests, lactate and cardiac biomarkers (which were reassessed 4 h, respectively 6 h later). Of 120 patients included, 45% developed complications, 19.2% had a poor outcome, and 5% died. Multivariate logistic regression sustained lactate (odds ratio (OR) 1.58; confidence interval (CI) 95%: 0.97-2.59; p 0.066), MB isoenzyme of creatine kinase (6h-CKMB; OR 1.08; CI 95%: 1.02-1.16; p 0.018) as predictors for a poor outcome. A GCS < 10 (OR 0.113; CI 95%: 0.019-0.658; p 0.015) and 4h-lactate (OR 4.87; CI 95%: 0.79-29.82; p 0.087) predicted mortality after systemic poisons exposure. Receiver operating characteristic analysis showed that brain natriuretic peptide (area under the curve (AUC), 0.96; CI 95%: 0.92-0.99; p < 0.001), lactate (AUC, 0.91; CI 95%: 0.85-0.97; p < 0.001), and 6h-CKMB have good discriminatory capacity for predicting a poor outcome. In conclusion, these biomarkers, lactate, and GCS can be used to predict morbidity and mortality after systemic poisons exposure.

Assessment of brain metabolite correlates of adeno-associated virus-mediated over-expression of human alpha-synuclein in cortical neurons by in vivo (1) H-MR spectroscopy at 9.4 T.

PubMed

Cuellar-Baena, Sandra; Landeck, Natalie; Sonnay, Sarah; Buck, Kerstin; Mlynarik, Vladimir; In 't Zandt, René; Kirik, Deniz

2016-06-01

In this study, we used proton-localized spectroscopy ((1) H-MRS) for the acquisition of the neurochemical profile longitudinally in a novel rat model of human wild-type alpha-synuclein (α-syn) over-expression. Our goal was to find out if the increased α-syn load in this model could be linked to changes in metabolites in the frontal cortex. Animals injected with AAV vectors encoding for human α-syn formed the experimental group, whereas green fluorescent protein expressing animals were used as the vector-treated control group and a third group of uninjected animals were used as naïve controls. Data were acquired at 2, 4, and 8 month time points. Nineteen metabolites were quantified in the MR spectra using LCModel software. On the basis of 92 spectra, we evaluated any potential gender effect and found that lactate (Lac) levels were lower in males compared to females, while the opposite was observed for ascorbate (Asc). Next, we assessed the effect of age and found increased levels of GABA, Tau, and GPC+PCho. Finally, we analyzed the effect of treatment and found that Lac levels (p = 0.005) were specifically lower in the α-syn group compared to the green fluorescent protein and control groups. In addition, Asc levels (p = 0.05) were increased in the vector-injected groups, whereas glucose levels remained unchanged. This study indicates that the metabolic switch between glucose-lactate could be detectable in vivo and might be modulated by Asc. No concomitant changes were found in markers of neuronal integrity (e.g., N-acetylaspartate) consistent with the fact that α-syn over-expression in cortical neurons did not result in neurodegeneration in this model. We acquired the neurochemical profile longitudinally in a rat model of human wild-type alpha-synuclein (α-syn) over-expression in cortical neurons. We found that Lactate levels were reduced in the α-syn group compared to the control groups and Ascorbate levels were increased in the vector-injected groups. No changes were found in markers of neuronal integrity consistent with the fact that α-syn over-expression did not result in frank neurodegeneration. © 2016 International Society for Neurochemistry.

Early colonization of functional groups of microbes in the infant gut.

PubMed

Pham, Van T; Lacroix, Christophe; Braegger, Christian P; Chassard, Christophe

2016-07-01

The colonization of the infant gut is crucial for early life development. Although the composition and diversity of the infant gut microbiota (GM) has been well described at a taxonomic level, functional aspects of this ecosystem remain unexplored. In the infant gut, lactate is produced by a number of bacteria and plays an important role in the trophic chain of the fermentation process. However, little is known about the lactate-utilizing bacteria (LUB) community in infants and their impact on gut health. By combining culture-based and molecular methods, we intensively studied LUB in fecal samples of 40 healthy infants on both taxonomic and functional levels. We demonstrated metabolic cross-feeding of lactate and identified keystone species specified for lactate utilization. The interactions of such species and their metabolic outcome could have direct impacts on infant health, either beneficial (production of short chain fatty acids) or detrimental (accumulation of hydrogen or hydrogen sulfide). We identified mode of delivery as a strong determinant for lactate-producing and -utilizing bacteria levels. These findings present the early establishment of GM with a novel perspective and emphasize the importance of lactate utilization in infancy. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

Are arterial, muscle and working limb lactate exchange data obtained on men at altitude consistent with the hypothesis of an intracellular lactate shuttle?

PubMed

Brooks, G A

1999-01-01

The "Lactate Shuttle" Hypothesis posits that lactate removal requires exchange among producing and consuming cells. The "Intra-cellular Lactate Shuttle" hypothesis posits that lactate exchange occurs among compartments within cells, and that mitochondria are the major sites of cellular lactate disposal. Thus, cells with high mitochondrial densities (cardiocytes, myocytes, hepatocytes) are those which participate in lactate clearance. The model of an Intracellular Lactate Shuttle recognizes that the Keq for LDH is 3.6 x 10(4) M-1; thus, glycolysis results in cytosolic lactate production regardless of the intracellular PO2. The model also requires presence of a mitochondrial monocarboxylate transporter (MCT) that allows uptake of lactate as well as pyruvate, and intra-mitochondrial LDH whose function is linked to the ETC, and which permits lactate-->pyruvate conversion and oxidation. Recently, we have shown that liver, heart and muscle mitochondria readily oxidize lactate and contain LDH and MCT1. Accordingly, we have concluded that lactate is the predominant monocarboxylate oxidized by mitochondria in vivo. The model of an "Intra-cellular Lactate Shuttle" is consistent with many of the observations on men at sea level and altitude. The observations include: oxidation is the primary fate of lactate disposal during rest and exercise; lactate production and oxidation occur simultaneously within resting and working muscle; increasing [lactate]a increases muscle lactate extraction, and that by increasing SaO2 acclimatization reduces blood [lactate].

Are Prolactin Levels Linked to Suction Pressure?

PubMed

Zhang, Feng; Xia, Haiou; Shen, Meiyun; Li, Xia; Qin, Ling; Gu, Hongmei; Xu, Xujuan

2016-11-01

Suction pressure has been reported to be a key driving force of lactation. An infant's sucking at its mother's breasts is the major stimulus to post-natal prolactin (PRL) secretion, and PRL is the essential hormone for lactation and milk production. It is unknown what role suction pressure has in PRL secretion and milk supply postnatally. To explore the relationship between the suction pressure, PRL level, lactation, and milk supply in breastfeeding mother-infant dyads. Healthy women with normal full-term infants were enrolled (n = 122). Data collection included suction pressure, PRL level, and the mother's perception of both the onset of her lactation and her milk supply at 1 month. Suction pressure was measured with a pressure sensor connected to a tube placed alongside the nipple. The chemiluminescence method was used to quantify maternal serum PRL level both before and after a breastfeed to explore the effect of suckling on PRL increment. The mother's perception of the onset of her lactation was evaluated by the mother's sense of fullness in her breast. The mother's perception of milk supply was evaluated by using the H&H Lactation Scale. Data from 117 participants were included in this analysis. Low suction pressure, a shorter gestational age, a high pre-gestational body mass index (BMI), and high infant birth weight were associated with a smaller than average PRL increment. High suction pressure, longer sucking duration, and a low gestational weight gain were related to a mother's perception of an earlier onset of her lactation. However, low suction pressure, a high frequency of giving formula, a small PRL increment, and the mother's perception of a later onset of her lactation were correlated with her perception of an insufficient milk supply. Suction pressure varied directly with the post-natal PRL increment. Suction pressure was associated with the timing of the mother's perception of her lactation. Strong suction pressure by the infant is likely to enhance the mother's confidence in her lactation. Additionally, sucking duration, frequency of giving formula, maternal BMI, and infant birth weight played a role in early breastfeeding success.

Alterations in brain glucose utilization accompanying elevations in blood ethanol and acetate concentrations in the rat.

PubMed

Pawlosky, Robert J; Kashiwaya, Yoshihiro; Srivastava, Shireesh; King, Michael T; Crutchfield, Calvin; Volkow, Nora; Kunos, George; Li, Ting-Kai; Veech, Richard L

2010-02-01

Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Rats were infused with solutions of sodium acetate, ethanol, or saline containing (13)C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs' cycle, acyl-coenzyme A (CoA) compounds, and amino acids. Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of (13)C-glucose into the brain compared to controls and the concentration of brain (13)C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg(2+) in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, alpha-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD(+)]/[NADH] was lower, the free mitochondrial [NAD(+)]/[NADH] and [CoQ]/[CoQH(2)] were oxidized and the DeltaG' of ATP lowered by acetate infusion from -61.4 kJ to -59.9 kJ/mol. Animals with elevated levels of blood ethanol or acetate had decreased (13)C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in (13)C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in DeltaG' of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form.

Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

PubMed Central

Pawlosky, Robert J.; Kashiwaya, Yoshihiro; Srivastava, Shireesh; King, Michael T.; Crutchfield, Calvin; Volkow, Nora; Kunos, George; Li, Ting-Kai; Veech, Richard L.

2010-01-01

Background Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Methods Rats were infused with solutions of sodium acetate, ethanol, or saline containing 13C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs’ cycle, acyl-coenzyme A (CoA) compounds, and amino acids. Results Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of 13C-glucose into the brain compared to controls and the concentration of brain 13C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg2+ in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, α-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD+]/[NADH] was lower, the free mitochondrial [NAD+]/[NADH] and [CoQ]/[CoQH2] were oxidized and the ΔG′ of ATP lowered by acetate infusion from −61.4 kJ to −59.9 kJ/mol. Conclusions Animals with elevated levels of blood ethanol or acetate had decreased 13C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in 13C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in ΔG′ of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form. PMID:19951290

Maternal obesity and high-fat diet program offspring metabolic syndrome.

PubMed

Desai, Mina; Jellyman, Juanita K; Han, Guang; Beall, Marie; Lane, Robert H; Ross, Michael G

2014-09-01

We determined the potential programming effects of maternal obesity and high-fat (HF) diet during pregnancy and/or lactation on offspring metabolic syndrome. A rat model of maternal obesity was created using an HF diet prior to and throughout pregnancy and lactation. At birth, pups were cross-fostered, thereby generating 4 paradigms of maternal diets during pregnancy/lactation: (1) control (Con) diet during pregnancy and lactation (Con/Con), (2) HF during pregnancy and lactation (HF/HF), (3) HF during pregnancy alone (HF/Con), and (4) HF during lactation alone (Con/HF). Maternal phenotype during pregnancy and the end of lactation evidenced markedly elevated body fat and plasma corticosterone levels in HF dams. In the offspring, the maternal HF diet during pregnancy alone programmed increased offspring adiposity, although with normal body weight, whereas the maternal HF diet during lactation increased both body weight and adiposity. Metabolic disturbances, particularly that of hyperglycemia, were apparent in all groups exposed to the maternal HF diet (during pregnancy and/or lactation), although differences were apparent in the manifestation of insulin resistant vs insulin-deficient phenotypes. Elevated systolic blood pressure was manifest in all groups, implying that exposure to an obese/HF environment is disadvantageous for offspring health, regardless of pregnancy or lactation periods. Nonetheless, the underlying mechanism may differ because offspring that experienced in utero HF exposure had increased corticosterone levels. Maternal obesity/HF diet has a marked impact on offspring body composition and the risk of metabolic syndrome was dependent on the period of exposure during pregnancy and/or lactation. Copyright © 2014 Mosby, Inc. All rights reserved.

Fluid resuscitation with isotonic or hypertonic saline solution avoids intraneural calcium influx after traumatic brain injury associated with hemorrhagic shock.

PubMed

Balbino, Marcos; Capone Neto, Antonio; Prist, Ricardo; Ferreira, Alice Teixeira; Poli-de-Figueiredo, Luiz F

2010-04-01

Calcium is one of the triggers involved in ischemic neuronal death. Because hypotension is a strong predictor of outcome in traumatic brain injury (TBI), we tested the hypothesis that early fluid resuscitation blunts calcium influx in hemorrhagic shock associated to TBI. Fifteen ketamine-halothane anesthetized mongrel dogs (18.7 kg +/- 1.4 kg) underwent unilateral cryogenic brain injury. Blood was shed in 5 minutes to a target mean arterial pressure of 40 mm Hg to 45 mm Hg and maintained at these levels for 20 minutes (shed blood volume = 26 mL/kg +/- 7 mL/kg). Animals were then randomized into three groups: CT (controls, no fluid resuscitation), HS (7.5% NaCl, 4 mL/kg, in 5 minutes), and LR (lactate Ringer's, 33 mL/kg, in 15 minutes). Twenty minutes later, a craniotomy was performed and cerebral biopsies were obtained next to the lesion ("clinical penumbra") and from the corresponding contralateral side ("lesion's mirror") to determine intracellular calcium by fluorescence signals of Fura-2-loaded cells. Controls remained hypotensive and in a low-flow state, whereas fluid resuscitation improved hemodynamic profile. There was a significant increase in intracellular calcium in the injured hemisphere in CT (1035 nM +/- 782 nM), compared with both HS (457 nM +/- 149 nM, p = 0.028) and LR (392 nM +/- 178 nM, p = 0.017), with no differences between HS and LR (p = 0.38). Intracellular calcium at the contralateral, uninjured hemisphere was 438 nM +/- 192 nM in CT, 510 nM +/- 196 nM in HS, and 311 nM +/- 51 nM in LR, with no significant differences between them. Both small volume hypertonic saline and large volume lactated Ringer's blunts calcium influx in early stages of TBI associated to hemorrhagic shock. No fluid resuscitation strategy promotes calcium influx and further neural damage.

The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring

PubMed Central

Wu, Wei-Li; Adams, Catherine E.; Stevens, Karen E.; Chow, Ke-Huan; Freedman, Robert; Patterson, Paul H.

2015-01-01

Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of α7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective α7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal spleen-placenta-fetal brain axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (IL-6) and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of IL-6 in Chrna7 mutant mice. We found that the basal level of IL-6 was higher in Chrna7 mutant fetal brain, which suggests that α7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7+/− offspring. The Chrna7+/− offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that α7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA. PMID:25683697

Three-Dimensional Magnetic Resonance Spectroscopic Imaging of Brain and Prostate Cancer1

PubMed Central

Kurhanewicz, John; Vigneron, Daniel B; Nelson, Sarah J

2000-01-01

Abstract Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical “window” to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy. PMID:10933075

Selenium and Antioxidant Status in Dairy Cows at Different Stages of Lactation.

PubMed

Gong, Jian; Xiao, Min

2016-05-01

Thirty-five multiparous Holstein cows averaging 550 ± 50 kg of body weight and in 2 to 4 parity were divided into three groups according to lactation stage (group A: nine cows from 4 to 1 weeks prepartum; group B: 11 cows from 1 to 30 days postpartum; group C: 15 cows from 30 to 100 days postpartum). Selenium concentration, malondialdehyde (MDA) level, glutathione peroxidase (GSH-Px) activity, thioredoxin reductase (TrxR) activity, and total antioxidant status (TAS) in serum were determined to evaluate selenium and antioxidant status in dairy cows at different stages of lactation. The results showed that mean serum selenium concentration, MDA level, and GSH-Px activity of cows in early lactation increased significantly (P < 0.05) when compared with cows in the dry period and peak lactation. Conversely, serum TrxR activity and TAS declined during this period (P < 0.05). The increase of serum MDA level during early lactation indicate that the reactive oxygen species, including lipid hydroperoxides, increase in this period, thus placing the cows at a greater risk of oxidative stress. The significant decrease in TrxR activity that is accompanied with a decrease in TAS during early lactation suggests that dairy cows have low antioxidant defense in this period and TrxR may be an important antioxidant defense mechanism in transition dairy cows.

MCT1 and MCT4 Expression and Lactate Flux Activity Increase During White and Brown Adipogenesis and Impact Adipocyte Metabolism.

PubMed

Petersen, Charlotte; Nielsen, Mette D; Andersen, Elise S; Basse, Astrid L; Isidor, Marie S; Markussen, Lasse K; Viuff, Birgitte M; Lambert, Ian H; Hansen, Jacob B; Pedersen, Stine F

2017-10-12

Adipose tissue takes up glucose and releases lactate, thereby contributing significantly to systemic glucose and lactate homeostasis. This implies the necessity of upregulation of net acid and lactate flux capacity during adipocyte differentiation and function. However, the regulation of lactate- and acid/base transporters in adipocytes is poorly understood. Here, we tested the hypothesis that adipocyte thermogenesis, browning and differentiation are associated with an upregulation of plasma membrane lactate and acid/base transport capacity that in turn is important for adipocyte metabolism. The mRNA and protein levels of the lactate-H + transporter MCT1 and the Na + ,HCO 3 - cotransporter NBCe1 were upregulated in mouse interscapular brown and inguinal white adipose tissue upon cold induction of thermogenesis and browning. MCT1, MCT4, and NBCe1 were furthermore strongly upregulated at the mRNA and protein level upon differentiation of cultured pre-adipocytes. Adipocyte differentiation was accompanied by increased plasma membrane lactate flux capacity, which was reduced by MCT inhibition and by MCT1 knockdown. Finally, in differentiated brown adipocytes, glycolysis (assessed as ECAR), and after noradrenergic stimulation also oxidative metabolism (OCR), was decreased by MCT inhibition. We suggest that upregulation of MCT1- and MCT4-mediated lactate flux capacity and NBCe1-mediated HCO 3 - /pH homeostasis are important for the physiological function of mature adipocytes.

Renal Cortical Pyruvate Depletion during AKI

PubMed Central

Johnson, Ali C.M.; Becker, Kirsten

2014-01-01

Pyruvate is a key intermediary in energy metabolism and can exert antioxidant and anti-inflammatory effects. However, the fate of pyruvate during AKI remains unknown. Here, we assessed renal cortical pyruvate and its major determinants (glycolysis, gluconeogenesis, pyruvate dehydrogenase [PDH], and H2O2 levels) in mice subjected to unilateral ischemia (15–60 minutes; 0–18 hours of vascular reflow) or glycerol-induced ARF. The fate of postischemic lactate, which can be converted back to pyruvate by lactate dehydrogenase, was also addressed. Ischemia and glycerol each induced persistent pyruvate depletion. During ischemia, decreasing pyruvate levels correlated with increasing lactate levels. During early reperfusion, pyruvate levels remained depressed, but lactate levels fell below control levels, likely as a result of rapid renal lactate efflux. During late reperfusion and glycerol-induced AKI, pyruvate depletion corresponded with increased gluconeogenesis (pyruvate consumption). This finding was underscored by observations that pyruvate injection increased renal cortical glucose content in AKI but not normal kidneys. AKI decreased PDH levels, potentially limiting pyruvate to acetyl CoA conversion. Notably, pyruvate therapy mitigated the severity of AKI. This renoprotection corresponded with increases in cytoprotective heme oxygenase 1 and IL-10 mRNAs, selective reductions in proinflammatory mRNAs (e.g., MCP-1 and TNF-α), and improved tissue ATP levels. Paradoxically, pyruvate increased cortical H2O2 levels. We conclude that AKI induces a profound and persistent depletion of renal cortical pyruvate, which may induce additional injury. PMID:24385590

[Case of interval form of carbon monoxide poisoning without increased carboxyhemoglobin level diagnosed by characteristic MR spectroscopy findings].

PubMed

Kamisawa, Tomoko; Ikawa, Masamichi; Hamano, Tadanori; Nagata, Miwako; Kimura, Hirohiko; Yoneda, Makoto

2014-01-01

A 67-year-old man living alone was admitted for acute disturbance of consciousness during winter. He presented with semicoma, a decorticate posture, and exaggerated tendon reflexes of the limbs, but brainstem reflexes were intact. The carboxyhemoglobin (COHb) level was normal in arterial blood gas on admission, and protein in cerebrospinal fluid was increased without pleocytosis. Brain MRI showed diffuse T2 high intensities in the deep white matter bilaterally without a contrast effect and abnormal T1 intensity in the pallidum. (1)H-MR spectroscopy (MRS) of the white matter lesion demonstrated findings suggesting demyelination as an increased choline peak, enhanced anaerobic metabolism as increased lactate and lipids peaks, and reduced neurons as a decreased N-acetylaspartate peak, which corresponded to delayed encephalopathy due to the interval form of carbon monoxide (CO) poisoning. The possibility of CO exposure due to coal briquette use 2 weeks before the symptomatic onset was indicated by his family, so he was diagnosed with CO poisoning. His consciousness slightly improved with corticosteroid therapy and repetitive hyperbaric oxygen therapy, but brain MRI and MRS findings did not improve. Characteristic MRS findings of leukoencephalopathy are helpful for diagnosing the interval form of CO poisoning in the case of a normal COHb level.

Milk trace elements in lactating cows environmentally exposed to higher level of lead and cadmium around different industrial units.

PubMed

Patra, R C; Swarup, D; Kumar, P; Nandi, D; Naresh, R; Ali, S L

2008-10-01

The present investigation was carried out to assess the trace mineral profile of milk from lactating cows reared around different industrial units and to examine the effect of blood and milk concentration of lead and cadmium on copper, cobalt, zinc and iron levels in milk. Respective blood and milk samples were collected from a total of 201 apparently healthy lactating cows above 3 years of age including 52 cows reared in areas supposed to be free from pollution. The highest milk lead (0.85+/-0.11 microg/ml) and cadmium (0.23+/-0.02 microg/ml) levels were recorded in lactating cows reared around lead-zinc smelter and steel manufacturing plant, respectively. Significantly (P<0.05) higher concentration of milk copper, cobalt, zinc and iron compared to control animals was recorded in cows around closed lead cum operational zinc smelter. Analysis of correlation between lead and other trace elements in milk from lactating cows with the blood lead level>0.20 microg/ml (n=79) revealed a significant negative correlations between milk iron and milk lead (r=-0.273, P=0.015). However, such trend was not recorded with blood lead level<0.20 microg/ml (n=122). The milk cobalt concentration was significantly correlated (r=0.365, P<0.001) with cadmium level in milk and the highest milk cadmium (>0.10 to 0.39 microg/ml) group had significantly (P<0.05) increased milk cobalt. It is concluded that increased blood and milk lead or cadmium level as a result of natural exposure of lactating cows to these environmental toxicants significantly influences trace minerals composition of milk and such alterations affect the milk quality and nutritional values.

Astrocyte-neuron lactate transport is required for long-term memory formation

PubMed Central

Suzuki, Akinobu; Stern, Sarah A.; Bozdagi, Ozlem; Huntley, George W.; Walker, Ruth H.; Magistretti, Pierre J.; Alberini, Cristina M.

2011-01-01

SUMMARY We report that in the rat hippocampus learning leads to a significant increase in extracellular lactate levels, which derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in-vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation. PMID:21376239

Glucose metabolism in different regions of the rat brain under hypokinetic stress influence

NASA Technical Reports Server (NTRS)

Konitzer, K.; Voigt, S.

1980-01-01

Glucose metabolism in rats kept under long term hypokinetic stress was studied in 7 brain regions. Determination was made of the regional levels of glucose, lactate, glutamate, glutamine, aspartate, gamma-aminobutyrate and the incorporation of C-14 from plasma glucose into these metabolites, in glycogen and protein. From the content and activity data the regional glucose flux was approximated quantitatively. Under normal conditions the activity gradient cortex and frontal pole cerebellum, thalamus and mesencephalon, hypothalamus and pons and medulla is identical with that of the regional blood supply (measured with I131 serum albumin as the blood marker). Within the first days of immobilization a functional hypoxia occurred in all brain regions and the utilization of cycle amino acids for protein synthesis was strongly diminished. After the first week of stress the capillary volumes of all regions increased, aerobic glucose metabolism was enhanced (factors 1.3 - 2.0) and the incorporation of glucose C-14 via cycle amino acids into protein was considerably potentiated. The metabolic parameters normalized between the 7th and 11th week of stress. Blood supply and metabolic rate increased most in the hypothalamus.

[Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

PubMed

Ichikawa, Hiroo

2016-02-01

Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels.

Lactate Profile During Greco-Roman Wrestling Matchx

PubMed Central

Karnincic, Hrvoje; Tocilj, Zoran; Uljevic, Ognjen; Erceg, Marko

2009-01-01

The objective of this study was to determine and compare lactate profile of two groups of Greco-Roman wrestlers with different competences and training experience. Study was conducted on 10 wrestles that were members of Croatian national team and 10 wrestlers that were members of Wrestling club Split. Lactate samples were collected at four intervals during control fights that were held according to international wrestling rules of World wrestling federation FILA. Values of lactate increased as competition progressed, and they were highest at the end of the match for both groups of wrestlers. According to this study there were no significant differences in lactate between two groups at the end of the match, while significant differences were noted during the match. The information about lactate profile presented in this study can be used by coaches and wrestlers to develop condition programs. Key Points There were no significant differences in lactate concentrations at the end of the match between two proficiency levels of wrestlers. More proficient (elite) wrestlers raise lactates gradually through the wrestling match while less proficient (club) wrestlers raise it abruptly at the end of the first bout. Both groups of wrestlers are unable to sustain same level of activity through the match suggesting that they are utilizing too much energy from anaerobic glycolysis. PMID:24474881

[Diagnostic value of detection of blood levels of lactate, pyruvate and 2,3-diphosphoglycerate in children with diabetes mellitus].

PubMed

Marchenko, L F; Baturin, A A; Terent'eva, E A

1991-01-01

Measurements were made of lactate, pyruvate and 2,3-diphosphoglycerate in 69 children admitted to the hospital in a state of diabetic ketoacidosis of different intensity. Depending on the intensity of metabolic abnormalities, the content of lactate and pyruvate was found to be increased, whereas that of 2,3-diphosphoglycerate to be lowered. Measurements of the content of lactate and the lactate/pyruvate ratio enables carrying out differential diagnosis between the ketoacidotic and lactacidotic varieties of diabetic coma.

Cross-generational trans fat intake facilitates mania-like behavior: oxidative and molecular markers in brain cortex.

PubMed

Trevizol, F; Roversi, Kr; Dias, V T; Roversi, K; Barcelos, R C S; Kuhn, F T; Pase, C S; Golombieski, R; Veit, J C; Piccolo, J; Pochmann, D; Porciúncula, L O; Emanuelli, T; Rocha, J B T; Bürger, M E

2015-02-12

Since that fast food consumption have raised concerns about people's health, we evaluated the influence of trans fat consumption on behavioral, biochemical and molecular changes in the brain-cortex of second generation rats exposed to a model of mania. Two successive generations of female rats were supplemented with soybean oil (SO, rich in n-6 FA, control group), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans FA) from pregnancy, lactation to adulthood, when male rats from 2nd generation received amphetamine (AMPH-4 mg/kg-i.p., once a day, for 14 days) treatment. AMPH increased locomotor index in all animals, which was higher in the HVF group. While the FO group showed increased n-3 polyunsaturated fatty acid (PUFA) incorporation and reduced n-6/n-3 PUFA ratio, HVF allowed trans fatty acid (TFA) incorporation and increased n-6/n-3 PUFA ratio in the brain-cortex. In fact, the FO group showed minor AMPH-induced hyperactivity, decreased reactive species (RS) generation per se, causing no changes in protein carbonyl (PC) levels and dopamine transporter (DAT). FO supplementation showed molecular changes, since proBDNF was increased per se and reduced by AMPH, decreasing the brain-derived neurotrophic factor (BDNF) level following drug treatment. Conversely, HVF was related to increased hyperactivity, higher PC level per se and higher AMPH-induced PC level, reflecting on DAT, whose levels were decreased per se as well as in AMPH-treated groups. In addition, while HVF increased BDNF-mRNA per se, AMPH reduced this value, acting on BDNF, whose level was lower in the same AMPH-treated experimental group. ProBDNF level was influenced by HVF supplementation, but it was not sufficient to modify BDNF level. These findings reinforce that prolonged consumption of trans fat allows TFA incorporation in the cortex, facilitating hyperactive behavior, oxidative damages and molecular changes. Our study is a warning about cross-generational consumption of processed food, since high trans fat may facilitate the development of neuropsychiatric conditions, including bipolar disorder (BD). Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

[Effect of a new derivative of glutamic and apovincaminic acids on brain metabolism in post-ischemic period].

PubMed

Makarova, L M; Prikhod'ko, M A; Pogorelyĭ, V E; Skachilova, S Ia; Mirzoian, R S

2014-01-01

Neuroprotective properties of the new derivative of glutamic and apovincaminic acids, ethyl -(3-alpha,16-alpha)-eburnamenin-14-carbopxylate of 2-aminopentadionic acid (LHT 1-02) were studied on a model of acute brain ischemia in cats. LHT 1-02 has proved to be more effective than the reference drugs vinpocetin and glycine in preventing the reperfusive damage, which was manifested by decreased postischemic hyperglycemia, activated utilization of oxygen in the brain, and suppressed postischemic metabolic lactate acidosis. Thus, the results of this comparative study show expediency of further investigations of LHT 1 - 02 as a potential neuroprotective drug.

Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis

PubMed Central

Russell, Vivienne A; Oades, Robert D; Tannock, Rosemary; Killeen, Peter R; Auerbach, Judith G; Johansen, Espen B; Sagvolden, Terje

2006-01-01

Background Current concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD. The hypothesis We propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing). Testing the hypothesis Multi-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under conditions that vary in duration, complexity, speed, and reinforcement; 2) Use of sensitive neuroimaging techniques such as diffusion tensor imaging, magnetic resonance spectroscopy, electroencephalography or magnetoencephalopathy to quantify developmental changes in myelination in ADHD as a potential basis for the delayed maturation of brain function and coordination, and 3) Investigation of the prevalence of genetic markers for factors that regulate energy metabolism (lactate, glutamate, glucose transporters, glycogen synthase, glycogen phosphorylase, glycolytic enzymes), release of glutamate from synaptic terminals and glutamate-stimulated lactate production (SNAP25, glutamate receptors, adenosine receptors, neurexins, intracellular Ca2+), as well as astrocyte function (α1, α2 and β-adrenoceptors, dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin). Implications of the hypothesis The hypothesis extends existing theories of ADHD by proposing a physiological basis for specific aspects of the ADHD phenotype – namely frequent, transient and impairing fluctuations in functioning, particularly during performance of speeded, effortful tasks. The immediate effects of deficient ATP production and slow restoration of ionic gradients across membranes of rapidly firing neurons have implications for daily functioning: For individuals with ADHD, performance efficacy would be enhanced if repetitive and lengthy effortful tasks were segmented to reduce concurrent demands for speed and accuracy of response (introduction of breaks into lengthy/effortful activities such as examinations, motorway driving, assembly-line production). Also, variations in task or modality and the use of self- rather than system-paced schedules would be helpful. This would enable energetic demands to be distributed to alternate neural resources, and energy reserves to be re-established. Longer-term effects may manifest as reduction in regional brain volumes since brain areas with the highest energy demand will be most affected by a restricted energy supply and may be reduced in size. Novel forms of therapeutic agent and delivery system could be based on factors that regulate energy production and myelin synthesis. Since the phenomena and our proposed basis for it are not unique to ADHD but also manifests in other disorders, the implications of our hypotheses may be relevant to understanding and remediating these other conditions as well. PMID:16925830

Patterns of variation in glycogen, free glucose and lactate in organs of supercooled hatchling painted turtles (Chrysemys picta).

PubMed

Packard, Mary J; Packard, Gary C

2005-08-01

Hatchling painted turtles (Chrysemys picta) typically spend their first winter of life in a shallow, subterranean hibernaculum (the natal nest), where they may be exposed for extended periods to ice and cold. The key to their survival seems to be to avoid freezing and to sustain a state of supercooling. As temperature declines below 0 degrees C, however, the heart of an unfrozen turtle beats progressively slower, the diminished perfusion of peripheral tissues with blood induces a functional hypoxia, and anaerobic glycolysis assumes ever greater importance as a source of ATP. We hypothesized that diminished circulatory function in supercooled turtles also reduces the delivery of metabolic substrates to peripheral tissues from central stores in the liver, so that the tissues depend increasingly on endogenous stores to fuel their metabolism. We discovered in the current investigation that part of the glycogen reserve in hearts and brains of hatchlings is mobilized during the first 10 days of exposure to -6 degrees C but that glucose from hepatic glycogen supports metabolism of the organs thereafter. Hatchlings that were held at -6 degrees C for 10 days and then at +3 degrees C for another 10 days were able to reconstitute some of the reserve of glycogen in heart and liver but not the glycogen reserve in brain. Patterns of accumulation of lactate in individual organs were very similar to those reported for whole animals in a companion study, and point to a high degree of reliance on anaerobic metabolism at -6 degrees C and to a lesser degree of reliance on anaerobiosis at higher subzero temperatures. Lactate had returned to baseline levels in organs of animals that were held for 10 days at -6 degrees C and for another 10 days at +3 degrees C, but free glucose remained elevated. Indeed, carbohydrate metabolism probably does not return to the pre-exposure state in any of the major organs until well after the exposure to subzero temperatures has ended, circulatory sufficiency has been restored, and aerobic respiration has fully supplanted anaerobic respiration as a source of ATP.

Endogenous and dietary lipids influencing feed intake and energy metabolism of periparturient dairy cows.

PubMed

Kuhla, B; Metges, C C; Hammon, H M

2016-07-01

The high metabolic priority of the mammary gland for milk production, accompanied by limited feed intake around parturition results in a high propensity to mobilize body fat reserves. Under these conditions, fuel selection of many peripheral organs is switched, for example, from carbohydrate to fat utilization to spare glucose for milk production and to ensure partitioning of tissue- and dietary-derived nutrients toward the mammary gland. For example, muscle tissue uses nonesterified fatty acids (NEFA) but releases lactate and amino acids in a coordinated order, thereby providing precursors for milk synthesis or hepatic gluconeogenesis. Tissue metabolism and in concert, nutrient partitioning are controlled by the endocrine system involving a reduction in insulin secretion and systemic insulin sensitivity and orchestrated changes in plasma hormones such as insulin, adiponectin, insulin growth factor-I, growth hormone, glucagon, leptin, glucocorticoids, and catecholamines. However, the endocrine system is highly sensitive and responsive to an overload of fatty acids no matter if excessive NEFA supply originates from exogenous or endogenous sources. Feeding a diet containing rumen-protected fat from late lactation to calving and beyond exerts similar negative effects on energy intake, glucose and insulin concentrations as does a high extent of body fat mobilization around parturition in regard to the risk for ketosis and fatty liver development. High plasma NEFA concentrations are thought not to act directly at the brain level, but they increase the energy charge of the liver which is, signaled to the brain to diminish feed intake. Cows differing in fat mobilization during the transition phase differ in their hepatic energy charge, whole body fat oxidation, glucose metabolism, plasma ghrelin, and leptin concentrations and in feed intake several week before parturition. Hence, a high lipid load, no matter if stored, mobilized or fed, affects the endocrine system, metabolism, and feed intake, and increases the risk for metabolic disorders. Future research should focus on a timely parallel increase in feed intake and milk yield during early lactation to reduce the impact of body fat on feed intake, metabolic health, and negative energy balance. Copyright © 2015 Elsevier Inc. All rights reserved.

Assessment of stress in effect to pyrethroid insecticides, λ-cyhalothrin and cypermethrin, in a freshwater fish, Channa punctatus (BLOCH).

PubMed

Kumar, A; Sharma, B; Pandey, R S

2012-12-22

The present study was planned to see the changes in the levels of different biochemical stress markers such as the level of lipid peroxidation and the specific activities of lactate dehydrogenase (LDH), acid and alkaline phosphatases in different organs such as brain, liver, kidney, gills and muscle of a freshwater muddy fish, Channa punctatus in effect to pyrethroid insecticides, cypermethrin and λ-cyhalothrin treated for 96 h. The results showed significant increase in the levels of lipid peroxidation as well as the activities of LDH, acid and alkaline phosphatases in a dose dependent manner. The remarkable increase in the levels of these stress biomarkers indicates strong stress inducing potential of these insecticides in fishes. The importance of the current study lies in indicating the potential risk of muddy freshwater fishes due to strong soil binding property of pyrethroids along with their slow metabolism in fishes as compared to that of mammals.

Effects of hyperglycemia and effects of ketosis on cerebral perfusion, cerebral water distribution, and cerebral metabolism.

PubMed

Glaser, Nicole; Ngo, Catherine; Anderson, Steven; Yuen, Natalie; Trifu, Alexandra; O'Donnell, Martha

2012-07-01

Diabetic ketoacidosis (DKA) may cause brain injuries in children. The mechanisms responsible are difficult to elucidate because DKA involves multiple metabolic derangements. We aimed to determine the independent effects of hyperglycemia and ketosis on cerebral metabolism, blood flow, and water distribution. We used magnetic resonance spectroscopy to measure ratios of cerebral metabolites (ATP to inorganic phosphate [Pi], phosphocreatine [PCr] to Pi, N-acetyl aspartate [NAA] to creatine [Cr], and lactate to Cr) and diffusion-weighted imaging and perfusion-weighted imaging to assess cerebral water distribution (apparent diffusion coefficient [ADC] values) and cerebral blood flow (CBF) in three groups of juvenile rats (hyperglycemic, ketotic, and normal control). ATP-to-Pi ratio was reduced in both hyperglycemic and ketotic rats in comparison with controls. PCr-to-Pi ratio was reduced in the ketotic group, and there was a trend toward reduction in the hyperglycemic group. No significant differences were observed in NAA-to-Cr or lactate-to-Cr ratio. Cortical ADC was reduced in both groups (indicating brain cell swelling). Cortical CBF was also reduced in both groups. We conclude that both hyperglycemia and ketosis independently cause reductions in cerebral high-energy phosphates, CBF, and cortical ADC values. These effects may play a role in the pathophysiology of DKA-related brain injury.

Impaired cerebral development in fetuses with congenital cardiovascular malformations: Is it the result of inadequate glucose supply?

PubMed

Rudolph, Abraham M

2016-08-01

Cerebral development may be impaired in fetuses with congenital cardiovascular malformations, particularly hypoplastic left heart syndrome (HLHS) and aortopulmonary transposition (APT). The decreased cerebral arterial pusatility index observed in some of these fetuses led to the belief that cerebral vascular resistance was reduced as a result of arterial hypoxemia and cerebral hypoxia is thought to be responsible for impaired cerebral growth. However, other hemodynamic factors could affect pulsatility index. I propose that cerebral blood flow is reduced in fetuses with HLHS and that reduced glucose, rather than oxygen, delivery interferes with cerebral development. This is based on the fact that most of these fetuses do not have lactate accumulation in the brain.In fetuses with APT, umbilical venous blood, containing oxygen and glucose derived across the placenta, is distributed to the lungs and lower body; venous blood, with low oxygen and glucose content, is delivered to the ascending aorta and brain. Oxygen and glucose delivery may further be reduced by decreased cerebral blood flow resulting from run-off of aortic blood through the ductus arteriosus to the pulmonary circulation during diastole. In APT fetuses, lack of lactate in the brain also supports my proposal that glucose deficiency interferes with cerebral development.

Effects of early serotonin programming on behavior and central monoamine concentrations in an avian model

USDA-ARS?s Scientific Manuscript database

Serotonin (5-HT) acts as a neurogenic compound in the developing brain; however serotonin altering drugs such as SSRIs are often prescribed to pregnant and lactating mothers. Early agonism of 5-HT receptors could alter the development of serotonergic circuitry, altering neurotransmission and behavio...

Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes.

PubMed

Barshad, Gilad; Blumberg, Amit; Cohen, Tal; Mishmar, Dan

2018-06-14

Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA)- and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic coregulation is poorly understood. To address this question, we analyzed ∼8500 RNA-seq experiments from 48 human body sites. Despite well-known variation in mitochondrial activity, quantity, and morphology, we found overall positive mtDNA-nDNA OXPHOS genes' co-expression across human tissues. Nevertheless, negative mtDNA-nDNA gene expression correlation was identified in the hypothalamus, basal ganglia, and amygdala (subcortical brain regions, collectively termed the "primitive" brain). Single-cell RNA-seq analysis of mouse and human brains revealed that this phenomenon is evolutionarily conserved, and both are influenced by brain cell types (involving excitatory/inhibitory neurons and nonneuronal cells) and by their spatial brain location. As the "primitive" brain is highly oxidative, we hypothesized that such negative mtDNA-nDNA co-expression likely controls for the high mtDNA transcript levels, which enforce tight OXPHOS regulation, rather than rewiring toward glycolysis. Accordingly, we found "primitive" brain-specific up-regulation of lactate dehydrogenase B ( LDHB ), which associates with high OXPHOS activity, at the expense of LDHA , which promotes glycolysis. Analyses of co-expression, DNase-seq, and ChIP-seq experiments revealed candidate RNA-binding proteins and CEBPB as the best regulatory candidates to explain these phenomena. Finally, cross-tissue expression analysis unearthed tissue-dependent splice variants and OXPHOS subunit paralogs and allowed revising the list of canonical OXPHOS transcripts. Taken together, our analysis provides a comprehensive view of mito-nuclear gene co-expression across human tissues and provides overall insights into the bi-genomic regulation of mitochondrial activities. © 2018 Barshad et al.; Published by Cold Spring Harbor Laboratory Press.

Lactic acidosis in vivo: testing the link between lactate generation and H+ accumulation in ischemic mouse muscle

PubMed Central

Marcinek, David J.; Kushmerick, Martin J.

2010-01-01

The link between lactate generation and cellular acidosis has been questioned based on the possibility of H+ generation, independent of lactate production during glycolysis under physiological conditions. Here we test whether glycolytic H+ generation matches lactate production over a physiological pH and lactate range using ischemia applied to the hindlimb of a mouse. We measured the H+ generation and ATP level in vivo using 31P-magnetic resonance spectroscopy and chemically determined intracellular lactate level in the hindlimb muscles. No significant change was found in ATP content by chemical analysis (P > 0.1), in agreement with the stoichiometric decline in phosphocreatine (20.2 ± 1.2 mM) vs. rise in Pi (18.7 ± 2.0 mM), as measured by 31P-magnetic resonance spectroscopy. A substantial drop in pH from 7.0 to 6.7 and lactate accumulation to 25 mM were found during 25 min of ischemia. The rise in H+ generation closely agreed with the accumulation of lactate, as shown by a close correlation with a slope near identity (0.98; r2 = 0.86). This agreement between glycolytic H+ production and elevation of lactate is confirmed by an analysis of the underlying reactions involved in glycolysis in vivo and supports the concept of lactic acidosis under conditions that substantially elevate lactate and drop pH. However, this link is expected to fail with conditions that deplete phosphocreatine, leading to net ATP hydrolysis and nonglycolytic H+ generation. Thus both direct measurements and an analysis of the stoichiometry of glycolysis in vivo support lactate acidosis as a robust concept for physiological conditions of the muscle cell. PMID:20133437

NT-pro Brain Natriuretic Peptide Levels and the Risk of Death in the Cooperative Study of Sickle Cell Disease

PubMed Central

Machado, Roberto F.; Hildesheim, Mariana; Mendelsohn, Laurel; Remaley, Alan T.; Kato, Gregory J.; Gladwin, Mark T.

2011-01-01

Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160 ng/l was present in 27.6 % of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0.001), high lactate dehydrogenase (P<0.001), and high total bilirubin levels (P<0.007). A NT-proBNP level ≥160 ng/l was an independent predictor of mortality (RR 6.24, 95% CI 2.9–13.3, P<0.0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population. PMID:21689089

NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease.

PubMed

Machado, Roberto F; Hildesheim, Mariana; Mendelsohn, Laurel; Remaley, Alan T; Kato, Gregory J; Gladwin, Mark T

2011-08-01

Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160ng/l was present in 27·6% of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0·001), high lactate dehydrogenase (P<0·001), and high total bilirubin levels (P<0·007). A NT-proBNP level ≥160ng/l was an independent predictor of mortality (RR 6·24, 95% CI 2·9-13·3, P<0·0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population. © 2011 Blackwell Publishing Ltd.

Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's.

PubMed

Ding, Fan; Yao, Jia; Zhao, Liqin; Mao, Zisu; Chen, Shuhua; Brinton, Roberta Diaz

2013-01-01

Previously, we demonstrated that reproductive senescence in female triple transgenic Alzheimer's (3×TgAD) mice was paralleled by a shift towards a ketogenic profile with a concomitant decline in mitochondrial activity in brain, suggesting a potential association between ovarian hormone loss and alteration in the bioenergetic profile of the brain. In the present study, we investigated the impact of ovariectomy and 17β-estradiol replacement on brain energy substrate availability and metabolism in a mouse model of familial Alzheimer's (3×TgAD). Results of these analyses indicated that ovarian hormones deprivation by ovariectomy (OVX) induced a significant decrease in brain glucose uptake indicated by decline in 2-[(18)F]fluoro-2-deoxy-D-glucose uptake measured by microPET-imaging. Mechanistically, OVX induced a significant decline in blood-brain-barrier specific glucose transporter expression, hexokinase expression and activity. The decline in glucose availability was accompanied by a significant rise in glial LDH5 expression and LDH5/LDH1 ratio indicative of lactate generation and utilization. In parallel, a significant rise in ketone body concentration in serum occurred which was coupled to an increase in neuronal MCT2 expression and 3-oxoacid-CoA transferase (SCOT) required for conversion of ketone bodies to acetyl-CoA. In addition, OVX-induced decline in glucose metabolism was paralleled by a significant increase in Aβ oligomer levels. 17β-estradiol preserved brain glucose-driven metabolic capacity and partially prevented the OVX-induced shift in bioenergetic substrate as evidenced by glucose uptake, glucose transporter expression and gene expression associated with aerobic glycolysis. 17β-estradiol also partially prevented the OVX-induced increase in Aβ oligomer levels. Collectively, these data indicate that ovarian hormone loss in a preclinical model of Alzheimer's was paralleled by a shift towards the metabolic pathway required for metabolism of alternative fuels in brain with a concomitant decline in brain glucose transport and metabolism. These findings also indicate that estrogen plays a critical role in sustaining brain bioenergetic capacity through preservation of glucose metabolism.

In vitro effects of bicarbonate and bicarbonate-lactate buffered peritoneal dialysis solutions on mesothelial and neutrophil function.

PubMed

Topley, N; Kaur, D; Petersen, M M; Jörres, A; Williams, J D; Faict, D; Holmes, C J

1996-02-01

The inclusion of bicarbonate in the formulation of peritoneal dialysis solutions may avoid the in vitro impairment of certain cell functions seen with acidic lactate-based fluids. The supranormal physiological levels of HCO3- and PCO2 inherent in such formulations may, however, not be biocompatible. This study compared the in vitro biocompatibility of a pH 5.2 lactate-based formulation with formulations containing either 40 mM lactate at pH 7.4, 38 mM HCO3- at pH 6.8 (PCO2 at approximately 240 mm Hg) or 7.4 (PCO2 at approximately 60 mm Hg), and 25 mM HCO3- plus 15 mM lactate at pH 6.8 (PCO2 at approximately 160 mm Hg) or 7.4 (PCO2 at approximately 40 mm Hg). Significant release of lactate dehydrogenase or decreases in ATP content by human peritoneal mesothelial cells (HPMC) and human peripheral polymorphonuclear leukocytes (PMN) after a 30-min exposure to each test solution was only seen with the pH 5.2 lactate-based fluid. The ATP content of HPMC exposed to this fluid returned to control levels after 30 min of recovery in M199 control medium but showed a trend toward decreasing ATP content at 240 min. Similarly, interleukin (IL)-1 beta-induced IL-6 synthesis by HPMC was also only significantly reduced by the pH 5.2 lactate solution. PMN chemiluminescence was unaffected by 30-min exposure to all test solutions except for the pH 5.2 lactate formulation. Staphylococcus epidermidis phagocytosis was reduced to between 46 to 57% of control with all test solutions except the pH 5.2 lactate solution, which further suppressed the chemiluminescence response to 17% of control. These data suggest that short exposure to supranormal physiological levels of HCO3- and PCO2 does not impair HPMC or PMN viability and function. Furthermore, neutral pH lactate-containing solutions show equivalent biocompatibility to bicarbonate-based ones.

Fitting milk production curves through nonlinear mixed models.

PubMed

Piccardi, Monica; Macchiavelli, Raúl; Funes, Ariel Capitaine; Bó, Gabriel A; Balzarini, Mónica

2017-05-01

The aim of this work was to fit and compare three non-linear models (Wood, Milkbot and diphasic) to model lactation curves from two approaches: with and without cow random effect. Knowing the behaviour of lactation curves is critical for decision-making in a dairy farm. Knowledge of the model of milk production progress along each lactation is necessary not only at the mean population level (dairy farm), but also at individual level (cow-lactation). The fits were made in a group of high production and reproduction dairy farms; in first and third lactations in cool seasons. A total of 2167 complete lactations were involved, of which 984 were first-lactations and the remaining ones, third lactations (19 382 milk yield tests). PROC NLMIXED in SAS was used to make the fits and estimate the model parameters. The diphasic model resulted to be computationally complex and barely practical. Regarding the classical Wood and MilkBot models, although the information criteria suggest the selection of MilkBot, the differences in the estimation of production indicators did not show a significant improvement. The Wood model was found to be a good option for fitting the expected value of lactation curves. Furthermore, the three models fitted better when the subject (cow) random effect was considered, which is related to magnitude of production. The random effect improved the predictive potential of the models, but it did not have a significant effect on the production indicators derived from the lactation curves, such as milk yield and days in milk to peak.

SYNAPTOSOMAL LACTATE DEHYDROGENASE ISOENZYME COMPOSITION IS SHIFTED TOWARD AEROBIC FORMS IN PRIMATE BRAIN EVOLUTION

PubMed Central

Duka, Tetyana; Anderson, Sarah M.; Collins, Zachary; Raghanti, Mary Ann; Ely, John J.; Hof, Patrick R.; Wildman, Derek E.; Goodman, Morris; Grossman, Lawrence I.; Sherwood, Chet C.

2014-01-01

With the evolution of a relatively large brain size in haplorhine primates (i.e., tarsiers, monkeys, apes and humans), there have been associated changes in the molecular machinery that delivers energy to the neocortex. Here we investigated variation in lactate dehydrogenase (LDH) expression and isoenzyme composition of the neocortex and striatum in primates using quantitative Western blotting and isoenzyme analysis of total homogenates and synaptosomal fractions. Analysis of isoform expression revealed that LDH in the synaptosomal fraction from both forebrain regions shifted towards a predominance of the heart-type, aerobic isoforms, LDHB, among haplorhines as compared to strepsirrhines (i.e., lorises and lemurs), while in total homogenate of neocortex and striatum there was no significant difference in the LDH isoenzyme composition between the primate suborders. The largest increase occurred in synapse-associated LDH-B expression in the neocortex, displaying an especially remarkable elevation in the ratio of LDH-B to LDH-A in humans. The phylogenetic variation in LDH-B to LDH-A ratio was correlated with species typical brain mass, but not encephalization quotient. A significant LDHB increase in the sub-neuronal fraction from haplorhine neocortex and striatum suggests a relatively higher rate of aerobic glycolysis that is linked to synaptosomal mitochondrial metabolism. Our results indicate that there is differential composition of LDH isoenzymes and metabolism in synaptic terminals that evolved in primates to meet increased energy requirements in association with brain enlargement. PMID:24686273

Blocking Lactate Export by Inhibiting the Myc Target MCT1 Disables Glycolysis and Glutathione Synthesis

PubMed Central

Doherty, Joanne R.; Yang, Chunying; Scott, Kristen E. N.; Cameron, Michael D.; Fallahi, Mohammad; Li, Weimin; Hall, Mark A.; Amelio, Antonio L.; Mishra, Jitendra K.; Li, Fangzheng; Tortosa, Mariola; Genau, Heide Marika; Rounbehler, Robert J.; Lu, Yunqi; Dang, Chi. V.; Kumar, K. Ganesh; Butler, Andrew A.; Bannister, Thomas D.; Hooper, Andrea T.; Unsal-Kacmaz, Keziban; Roush, William R.; Cleveland, John L.

2014-01-01

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1, and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, and reductions in glucose transport, and in levels of ATP, NADPH and glutathione. Reductions in glutathione then lead to increases in hydrogen peroxide, mitochondrial damage and, ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies. PMID:24285728

Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis.

PubMed

Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N; Cameron, Michael D; Fallahi, Mohammad; Li, Weimin; Hall, Mark A; Amelio, Antonio L; Mishra, Jitendra K; Li, Fangzheng; Tortosa, Mariola; Genau, Heide Marika; Rounbehler, Robert J; Lu, Yunqi; Dang, Chi V; Kumar, K Ganesh; Butler, Andrew A; Bannister, Thomas D; Hooper, Andrea T; Unsal-Kacmaz, Keziban; Roush, William R; Cleveland, John L

2014-02-01

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.

Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease.

PubMed

Coelho, Flávia Gomes de Melo; Vital, Thays Martins; Stein, Angelica Miki; Arantes, Franciel José; Rueda, André Veloso; Camarini, Rosana; Teodorov, Elizabeth; Santos-Galduróz, Ruth Ferreira

2014-01-01

Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well-documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using a controlled design, twenty-one patients with AD (76.3 ± 6.2 years) and eighteen healthy older adults (74.6 ± 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p = 0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity.

Early changes in coagulation profiles and lactate levels in patients with septic shock undergoing extracorporeal membrane oxygenation

PubMed Central

Kim, Hyoung Soo; Cheon, Dae Young; Ha, Sang Ook; Han, Sang Jin; Kim, Hyun-Sook; Lee, Sun Hee; Kim, Sung Gyun

2018-01-01

Background To investigate the impact of coagulation profiles and lactate levels in patients with septic shock undergoing extracorporeal membrane oxygenation (ECMO). Methods A retrospective analysis of coagulation profiles, including disseminated intravascular coagulation (DIC) score, before and during 48 h of ECMO support [on day 0 (pre-ECMO), day 1, and day 2], was conducted in patients with septic shock undergoing ECMO. Results A total of 37 patients were included, and 15 (40.5%) patients survived. The initial DIC scores did not change in either the pre-ECMO overt-DIC (n=15) or non-overt-DIC (n=22) group after ECMO commencement. However, the DIC scores were significantly higher, at all three time-points, in non-survivors than in survivors. Additionally, the lactate levels improved considerably in the pre-ECMO non-overt-DIC group and in survivors during ECMO support, but not in the pre-ECMO overt DIC group or non-survivors. On a multivariate analysis, the pre-ECMO DIC score was significantly associated with hospital death [odds ratio (OR), 3.935; 95% confidence interval (CI), 1.170–13.230]. Receiver operating characteristic (ROC) curves revealed that the combination of pre-ECMO DIC score plus lactate level was the best predictor of hospital death (area under the curve, 0.879; 0.771–0.987); patients with combined scores >9.35 (the optimal cut-off) exhibited a three-fold higher mortality rate than did those with lower scores (81.8% vs. 26.7%, P=0.001). Conclusions During the early period of ECMO support, the coagulation profiles and lactate levels exhibited different trajectories in survivors and non-survivors. Furthermore, the pre-ECMO DIC score plus lactate level was the best predictor of hospital death. PMID:29707291

The Effects of Direct Oxygen Supply During Static Cold Preservation of Rat Livers: An Experimental Study.

PubMed

Zumrutdal, Emin; Karateke, Faruk; Eser, Pınar Eylem; Turan, Umit; Ozyazici, Sefa; Sozutek, Alper; Gulkaya, Mustafa; Kunt, Mevlut

2016-12-01

We aimed to determine the biochemical and histopathologic effects of direct oxygen supply to the preservation fluid of static cold storage system with a simple method on rat livers. Sixteen rats were randomly divided into 2 groups: the control group, which contained Ringer's lactate as preservation fluid; and the oxygen group, which contained oxygen and Ringer's lactate for preservation. Each liver was placed in a bag containing 50 mL Ringer's lactate and placed in ice-filled storage containers. One hundred percent oxygen supplies were given via a simple, inexpensive system created in our laboratory, to the livers in oxygen group. We obtained samples for histopathologic evaluation in the 12th hour. In addition, 3 mL of preservation fluid was subjected to biochemical analysis at 0, sixth, and twelfth hours. Aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and pH levels were measured from the preservation fluid. In oxygen-supplemented group, the acceleration speed of increase in alanine aminotransferase and lactate dehydrogenase levels at sixth hour and lactate dehydrogenase, alanine aminotransferase, and lactate dehydrogenase levels at 12th hour were statistically significantly reduced. In histopathologic examination, all parameters except ballooning were statistically significantly better in the oxygen-supplemented group. This simple system for oxygenation of liver tissues during static cold storage was shown to be effective with good results in biochemical and histopathologic assessments. Because this is a simple, inexpensive, and easily available method, larger studies are warranted to evaluate its effects (especially in humans).

Responses of blood pressure and lactate levels to various aquatic exercise movements in postmenopausal women.

PubMed

Chien, K-Y; Chen, W-C; Kan, N-W; Hsu, M-C; Lee, S-L

2015-12-01

Middle-aged and elderly women represent the main attending group in head-out aquatic exercise (HOAE). Blood pressure (BP) significantly increases both during water immersion and aquatic walking. Based on risk concerns, it is important to evaluate BP responses in postmenopausal women doing HOAE. The aim of this study was to determine BP, lactate levels, and rating of perceived exertion (RPE) changes associated with performing 3 different movements at 3 levels of exercise intensity in water. Twelve postmenopausal women (59.9±0.6 years old) participated in 3 aquatic trials involving running (RU), rocking (RO), and scissor kicks (SK) on separate days. Systolic BP, mean arterial pressure (MAP), lactate levels, RPE, and motion cadence were measured at rest; upon reaching 50%, 65%, and 80% of heart rate reserve for 6 minutes; and 10 and 30 minutes after exercise. Under similar RPE responses at 3 levels of intensity, SK resulted in higher systolic BP, MAP, and lactate levels than RO at 10 minutes after exercise (P<0.05) and the lowest motion cadence (P<0.05). RO resulted in the lowest MAP and diastolic BP responses during exercise (P<0.05). RU resulted in lower responses of lactate levels at high exercise intensity (P<0.05). RO resulted in lower diastolic BP and MAP responses compared with RU and SK during exercise. These findings suggest that RO movement in aquatic exercises is more suitable for people at high risk for cardiovascular disease.

Dynamic Changes in Cytosolic ATP Levels in Cultured Glutamatergic Neurons During NMDA-Induced Synaptic Activity Supported by Glucose or Lactate.

PubMed

Lange, Sofie C; Winkler, Ulrike; Andresen, Lars; Byhrø, Mathilde; Waagepetersen, Helle S; Hirrlinger, Johannes; Bak, Lasse K

2015-12-01

We have previously shown that synaptic transmission fails in cultured neurons in the presence of lactate as the sole substrate. Thus, to test the hypothesis that the failure of synaptic transmission is a consequence of insufficient energy supply, ATP levels were monitored employing the ATP biosensor Ateam1.03YEMK. While inducing synaptic activity by subjecting cultured neurons to two 30 s pulses of NMDA (30 µM) with a 4 min interval, changes in relative ATP levels were measured in the presence of lactate (1 mM), glucose (2.5 mM) or the combination of the two. ATP levels reversibly declined following NMDA-induced neurotransmission activity, as indicated by a reversible 10-20 % decrease in the response of the biosensor. The responses were absent when the NMDA receptor antagonist memantine was present. In the presence of lactate alone, the ATP response dropped significantly more than in the presence of glucose following the 2nd pulse of NMDA (approx. 10 vs. 20 %). Further, cytosolic Ca(2+) homeostasis during NMDA-induced synaptic transmission is partially inhibited by verapamil indicating that voltage-gated Ca(2+) channels are activated. Lastly, we showed that cytosolic Ca(2+) homeostasis is supported equally well by both glucose and lactate, and that a pulse of NMDA causes accumulation of Ca(2+) in the mitochondrial matrix. In summary, we have shown that ATP homeostasis during neurotransmission activity in cultured neurons is supported by both glucose and lactate. However, ATP homeostasis seems to be negatively affected by the presence of lactate alone, suggesting that glucose is needed to support neuronal energy metabolism during activation.

myo-Inositol metabolism during lactation and development in the rat. The prevention of lactation-induced fatty liver by dietary myo-inositol.

PubMed

Burton, L E; Wells, W W

1976-11-01

Effects of dietary myo-inositol deprivation were examined during prenatal and postnatal development and during lactation in the rat. The deficient diet contained no detectable myo-inositol while the supplemented diet contained 0.5% (w/w) myo-inositol while the supplemented diet ct contained 0.5% (w/w) myo-inositol at the expense of sucrose. Both diets contained 25% casein, adequate amounts of all known vitamins, choline, and essential fatty acids as well as 0.5% (w/w) phthalylsulfathiazole to depress myo-inositol contribution to the diet by microorganisms. Pregnant rats of the Holtzman strain were fed the respective diets during gestation and lactation, and pups were fed the corresponding diet after weaning until 3 months of age. There were no significant differen-es in body weight between experimental groups. Supplementation of the diet with myo-inositol significanly increased the levels of myo-inositol in plasma, liver, kidney, and intestine of pups at all ages examined, and significantly increased the levels of myo-inositol in the milk and mammary tissue during lactation. During lactation, the myo-inositol deprived dams developed severe fatty livers (31% w/w) characterized by diminished phosphatidyl-inositol (50%) and total phospholipid phosphorus (57%) levels as compared with controls. After weaning, the liver lipid content of the myo-inositol deprived dams returned to normal (4.5%). The data suggest that a possible threshold level of free myo-inositol (approximately 0.15 mumoles/g lipid-free tissue) was required to prevent fatty liver in lactating dams under these dietary conditions. Effects of the deficient diet on fertility were also examined. Based on sperm count and production of offspring, there were no differnences between the experimental and control males. Females of both groups showed equal ability to produce offspring.

Evaluation of a novel 5-group classification system of sepsis by vasopressor use and initial serum lactate in the emergency department.

PubMed

Swenson, Kai E; Dziura, James D; Aydin, Ani; Reynolds, Jesse; Wira, Charles R

2018-03-01

Prognostication in sepsis is limited by disease heterogeneity, and measures to risk-stratify patients in the proximal phases of care lack simplicity and accuracy. Hyperlactatemia and vasopressor dependence are easily identifiable risk factors for poor outcomes. This study compares incidence and hospital outcomes in sepsis based on initial serum lactate level and vasopressor use in the emergency department (ED). In a retrospective analysis of a prospectively identified dual-center ED registry, patients with sepsis were categorized by ED vasopressor use and initial serum lactate level. Vasopressor-dependent patients were categorized as dysoxic shock (lactate >4.0 mmol/L) and vasoplegic shock (≤4.0 mmol/L). Patients not requiring vasopressors were categorized as cryptic shock major (lactate >4.0 mmol/L), cryptic shock minor (>2.0 and ≤4.0 mmol/L), and sepsis without lactate elevation (≤2.0 mmol/L). Of 446 patients included, 4.9% (n = 22) presented in dysoxic shock, 11.7% (n = 52) in vasoplegic shock, 12.1% (n = 54) in cryptic shock major, 30.9% (n = 138) in cryptic shock minor, and 40.4% (n = 180) in sepsis without lactate elevation. Group mortality rates at 28 days were 50.0, 21.1, 18.5, 12.3, and 7.2%, respectively. After adjusting for potential confounders, odds ratios for mortality at 28 days were 15.1 for dysoxic shock, 3.6 for vasoplegic shock, 3.8 for cryptic shock major, and 1.9 for cryptic shock minor, when compared to sepsis without lactate elevation. Lactate elevation is associated with increased mortality in both vasopressor dependent and normotensive infected patients presenting to the emergency department (ED). Cryptic shock mortality (normotension + lactate >4 mmol/L) is equivalent to vasoplegic shock mortality (vasopressor requirement + lactate <4 mmol/L) in our population. The odds of normotensive, infected patients decompensating is three to fourfold higher with hyperlactemia. The proposed Sepsis-3 definitions exclude an entire group of high-risk ED patients. A simple classification in the ED by vasopressor requirement and initial lactate level may identify high-risk subgroups of sepsis. This study may inform prognostication and triage decisions in the proximal phases of care.

A protocol for resuscitation of severe burn patients guided by transpulmonary thermodilution and lactate levels: a 3-year prospective cohort study.

PubMed

Sánchez, Manuel; García-de-Lorenzo, Abelardo; Herrero, Eva; Lopez, Teresa; Galvan, Beatriz; Asensio, María; Cachafeiro, Lucia; Casado, Cesar

2013-08-15

The use of urinary output and vital signs to guide initial burn resuscitation may lead to suboptimal resuscitation. Invasive hemodynamic monitoring may result in over-resuscitation. This study aimed to evaluate the results of a goal-directed burn resuscitation protocol that used standard measures of mean arterial pressure (MAP) and urine output, plus transpulmonary thermodilution (TPTD) and lactate levels to adjust fluid therapy to achieve a minimum level of preload to allow for sufficient vital organ perfusion. We conducted a three-year prospective cohort study of 132 consecutive critically burned patients. These patients underwent resuscitation guided by MAP (>65 mmHg), urinary output (0.5 to 1 ml/kg), TPTD and lactate levels. Fluid therapy was adjusted to achieve a cardiac index (CI) >2.5 L/minute/m² and an intrathoracic blood volume index (ITBVI) >600 ml/m2, and to optimize lactate levels. Statistical analysis was performed using mixed models. We also used Pearson or Spearman methods and the Mann-Whitney U-test. A total of 98 men and 34 women (mean age, 48 ± 18 years) was studied. The mean total body surface area (TBSA) burned was 35% ± 22%. During the early resuscitation phase, lactate levels were elevated (2.58 ± 2.05 mmol/L) and TPTD showed initial hypovolemia by the CI (2.68 ± 1.06 L/minute/m²) and the ITBVI (709 ± 254 mL/m²). At 24 to 32 hours, the CI and lactic levels were normalized, although the ITBVI remained below the normal range (744 ± 276 ml/m²). The mean fluid rate required to achieve protocol targets in the first 8 hours was 4.05 ml/kg/TBSA burned, which slightly increased in the next 16 hours. Patients with a urine output greater than or less than 0.5 ml/kg/hour did not show differences in heart rate, mean arterial pressure, CI, ITBVI or lactate levels. Initial hypovolemia may be detected by TPTD monitoring during the early resuscitation phase. This hypovolemia might not be reflected by blood pressure and hourly urine output. An adequate CI and tissue perfusion can be achieved with below-normal levels of preload. Early resuscitation guided by lactate levels and below-normal preload volume targets appears safe and avoids unnecessary fluid input.

Lactational changes in concentration and distribution of ganglioside molecular species in human breast milk from Chinese mothers.

PubMed

Ma, Lin; Liu, Xihong; MacGibbon, Alastair K H; Rowan, Angela; McJarrow, Paul; Fong, Bertram Y

2015-11-01

Gangliosides play a critical role in human brain development and function. Human breast milk (HBM) is an important dietary source of gangliosides for the growing infant. In this study, ganglioside concentrations were measured in the breast milk from a cross-sectional sample of Chinese mothers over an 8-month lactation period. The average total ganglioside concentration increased from 13.1 mg/l during the first month to 20.9 mg/l by 8 months of lactation. The average concentration during the typically solely breast-feeding period of 1‒6 months was 18.9 mg/l. This is the first study to report the relative distribution of the individual ganglioside molecular species through lactation for any population group. The ganglioside molecular species are made up of different fatty acid moieties that influence the physical properties of these gangliosides, and hence affect their function. The GM(3) molecular species containing long-chain acyl fatty acids had the most prominent changes, increasing in both concentration and relative distribution. The equivalent long-chain acyl fatty acid GD(3) molecular species typically decreased in concentration and relative distribution. The lactational trends for both concentration and relative distribution for the very long-chain acyl fatty acid molecular species were more varied. The major GM(3) and GD(3) molecular species during lactation were d40:1 and d42:1, respectively. An understanding of ganglioside molecular species distribution in HBM is essential for accurate application of mass spectrometry methods for ganglioside quantification.

Acute mercury exposition of virgin, pregnant, and lactating rats: Histopathological kidney and liver evaluations.

PubMed

Oliveira, Vitor Antunes; Favero, Gaia; Stacchiotti, Alessandra; Giugno, Lorena; Buffoli, Barbara; de Oliveira, Claudia Sirlene; Lavazza, Antonio; Albanese, Massimo; Rodella, Luigi Fabrizio; Pereira, Maria Ester; Rezzani, Rita

2017-05-01

This work investigated the effects of mercury chloride (HgCl 2 ) acute exposure on virgin, pregnant and lactating rats by determination of renal and hepatic morphological and ultrastructural parameters and the expression of oxidative stress and stress tolerance markers, due to kidney and liver are the organs that more accumulate inorganic mercury. Adult Wistar rats virgin (90 days old), pregnant (18 th gestation day) and lactating (7 th lactation day) were injected once with HgCl 2 (5 mg/kg) or saline (controls). We observed that HgCl 2 exposure of virgin rats caused significant inflammatory infiltration and severe morphological variations, like glomeruli atrophy, dilatation of Bowman's capsule, tubular degeneration and hepatocytes alteration. Moreover, virgin rats presented mitochondrial modification, important oxidative stress and increase in stress tolerance proteins at both kidney and liver level, compared with virgin controls. In detail, virgin rats exposed to HgCl 2 presented significantly elevated level of inducible nitric oxide synthase, heat shock protein 27 and glucose regulated proteins 75 expressions at both renal tubular and hepatocytes level, respect untreated virgin rats. Interestingly, pregnant and lactating rats exposed to HgCl 2 presented weak renal and liver morphological alterations, showing weak inflammatory infiltration and no significant difference in structural mitochondrial transmembrane protein, oxidative stress markers and stress tolerance proteins expressions respect controls (virgin, pregnant and lactating rats). Although, both control and HgCl 2 -exposed pregnant and lactating rats showed renal glomeruli greater in diameter respect virgin rats. In conclusion, we believe that virgin rats are more sensitive to HgCl 2 toxicity respect pregnant and lactating rats. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1500-1512, 2017. © 2016 Wiley Periodicals, Inc.

Effect of incorporation of calcium lactate on physico-chemical, textural, and sensory properties of restructured buffalo meat loaves

PubMed Central

Irshad, A.; Sharma, B. D.; Ahmed, S. R.; Talukder, S.; Malav, O. P.; Kumar, Ashish

2016-01-01

Aim: The present study was conducted to develop a functional meat product by fortifying calcium (in the form of calcium lactate) with restructured buffalo meat loaf (RBML). Materials and Methods: Deboned buffalo meat obtained from the carcass of adult female buffalo within 5-6 h of slaughter and stored under frozen condition. Calcium fortified RBML were prepared by replacing the lean buffalo meat with calcium lactate powder at 0%, 1%, 1.25%, and 1.5% level through the pre-standardized procedure. The developed products were evaluated for physico-chemical properties, proximate composition, calcium concentration (mg/100 g), water activity (aw), Lovibond® tintometer color units, texture profile analysis (TPA), and sensory qualities as per-standard procedures. Results: Of the various product quality parameters evaluated, cooking yield (%), product pH, moisture (%), protein (%), fat (%), and water activity (aw) decreases significantly with increasing level of calcium lactate. Calcium content of fortified functional RBMLs was 135.02, 165.73, and 203.85 mg/100 g as compared to 6.48 mg/100 g in control. Most of the sensory scores at 1% and 1.25% levels of calcium lactate in treatment products remained comparable among themselves and control product, with a gradual decline. Conclusions: The present study concluded that 1.25% calcium lactate was the optimum level for the fortification of calcium in RBML without affecting the textural and sensory properties which could meet out 15% of recommended dietary allowance for calcium. PMID:27051201

Effect of incorporation of calcium lactate on physico-chemical, textural, and sensory properties of restructured buffalo meat loaves.

PubMed

Irshad, A; Sharma, B D; Ahmed, S R; Talukder, S; Malav, O P; Kumar, Ashish

2016-02-01

The present study was conducted to develop a functional meat product by fortifying calcium (in the form of calcium lactate) with restructured buffalo meat loaf (RBML). Deboned buffalo meat obtained from the carcass of adult female buffalo within 5-6 h of slaughter and stored under frozen condition. Calcium fortified RBML were prepared by replacing the lean buffalo meat with calcium lactate powder at 0%, 1%, 1.25%, and 1.5% level through the pre-standardized procedure. The developed products were evaluated for physico-chemical properties, proximate composition, calcium concentration (mg/100 g), water activity (aw), Lovibond(®) tintometer color units, texture profile analysis (TPA), and sensory qualities as per-standard procedures. Of the various product quality parameters evaluated, cooking yield (%), product pH, moisture (%), protein (%), fat (%), and water activity (aw) decreases significantly with increasing level of calcium lactate. Calcium content of fortified functional RBMLs was 135.02, 165.73, and 203.85 mg/100 g as compared to 6.48 mg/100 g in control. Most of the sensory scores at 1% and 1.25% levels of calcium lactate in treatment products remained comparable among themselves and control product, with a gradual decline. The present study concluded that 1.25% calcium lactate was the optimum level for the fortification of calcium in RBML without affecting the textural and sensory properties which could meet out 15% of recommended dietary allowance for calcium.

Effect of Swimming on the Production of Aldosterone in Rats

PubMed Central

Wang, Paulus S.; Jian, Cai-Yun; Yeh, Yung-Hsing; Chen, Yi-An; Wang, Kai-Lee; Lin, Yi-Chun; Chang, Ling-Ling; Wang, Guei-Jane; Wang, Shyi-Wu

2014-01-01

It has been demonstrated that exercise is one of the stresses known to increase the aldosterone secretion. Both potassium and angiotensin II (Ang II) levels are shown to be correlated with aldosterone production during exercise, but the mechanism is still unclear. In an in vivo study, male rats were catheterized via right jugular vein (RJV), and divided into four groups namely water immersion, swimming, lactate infusion (13 mg/kg/min) and pyruvate infusion (13 mg/kg/min) groups. Each group was treated for 10 min. Blood samples were collected at 0, 10, 15, 30, 60 and 120 min from RJV after administration. In an in vitro study, rat zona glomerulosa (ZG) cells were challenged by lactate (1–10 mM) in the presence or absence of Ang II (10−8 M) for 60 min. The levels of aldosterone in plasma and medium were measured by radioimmunoassay. Cell lysates were analyzed by immunoblotting assay. After exercise and lactate infusion, plasma levels of aldosterone and lactate were significantly higher than those in the control group. Swimming for 10 min significantly increased the plasma Ang II levels in male rats. Administration of lactate plus Ang II significantly increased aldosterone production and enhanced protein expression of steroidogenic acute regulatory protein (StAR) in ZG cells. These results demonstrated that acute exercise led to the increase of both aldosterone and Ang II secretion, which is associated with lactate action on ZG cells and might be dependent on the activity of renin-angiotensin system. PMID:25289701

Early Decline in Glucose Transport and Metabolism Precedes Shift to Ketogenic System in Female Aging and Alzheimer's Mouse Brain: Implication for Bioenergetic Intervention

PubMed Central

Ding, Fan; Yao, Jia; Rettberg, Jamaica R.; Chen, Shuhua; Brinton, Roberta Diaz

2013-01-01

We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3–15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6–9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain. PMID:24244584

Astrocyte-neuron lactate transport is required for long-term memory formation.

PubMed

Suzuki, Akinobu; Stern, Sarah A; Bozdagi, Ozlem; Huntley, George W; Walker, Ruth H; Magistretti, Pierre J; Alberini, Cristina M

2011-03-04

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluation of urinary S100B protein level and lactate/creatinine ratio for early diagnosis and prognostic prediction of neonatal hypoxic-ischemic encephalopathy.

PubMed

Liu, Li; Zheng, Chong-Xun; Peng, Shu-Feng; Zhou, Hong-Yan; Su, Zu-You; He, Li; Ai, Ting

2010-01-01

Early identification and prevention of hypoxic-ischemic encephalopathy (HIE) in newborns may reduce neonatal mortality and neurological dysfunction. To analyze the diagnostic and prognostic values of urinary S100B level and lactate/creatinine ratio in newborns with HIE. Seventy-eight full-term newborns with HIE and 25 normal newborns were enrolled. The Neonatal Behavioral Neurological Assessment (NBNA) and Developmental Screening Test were scored. The concentration of urinary S100B protein was determined using the S100B enzyme-linked immunosorbent assay and the levels of urinary lactate and creatinine were measured with the enzyme colorimetric method. Urinary S100B level on days 1-3 after birth and lactate/creatinine ratio on day 1 were significantly higher in newborns with HIE than those in the control group. Both indexes were positively correlated with the clinical grading of HIE. A cutoff value for the S100B level of 0.47 microg/l on day 3 after birth had a sensitivity of 90% and specificity of 92% for prediction of HIE. A lactate/creatinine ratio of more than 0.55 on day 1 showed the highest sensitivity (92%) and specificity (90%). A combination of both indexes improved the sensitivity and specificity to 99 and 97%, respectively. A negative correlation of both lactate/creatinine ratio on day 1 and S100B level on days 1-3 after birth with the NBNA score was identified on days 3, 7 and 14 after birth. The Developmental Screening Test score of 36 newborns with HIE within 6 months after birth showed that 65% of infants with moderate and high HIE had an abnormal developmental quotient. These data suggest that early measurement of both S100B level and lactate/creatinine ratio in the urine of newborns with HIE is a practical convenient and sensitive way to improve diagnosis on the third day of life and prognostic prediction of HIE. Copyright 2009 S. Karger AG, Basel.

Effect of LED phototherapy on blood lactate level in Taekwondo contest

NASA Astrophysics Data System (ADS)

Park, H. C.; Lee, B. K.; Lee, S. J.; Lim, S.

2017-02-01

The effect of LED phototherapy on blood lactate level in the muscle was studied. A 450cm2 large red and near infrared LED pad with its irradiance of 10mW/cm2 was applied for 10 minutes to brachial muscle and quadriceps muscle of thigh to the participants before and after the Taekwondo contest. Blood samples from the participants were taken at 5 minutes after the competition and 10 minutes after the recovery. The test results showed that the LED therapy (LEDT) before and after the competition had a significant effect on the decrease of blood lactate level of the participants.

Neuron-glia metabolic coupling and plasticity.

PubMed

Magistretti, Pierre J

2006-06-01

The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiological principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography (PET). Astrocytes play a central role in neurometabolic coupling, and the basic mechanism involves glutamate-stimulated aerobic glycolysis; the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase triggers glucose uptake and processing via glycolysis, resulting in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fuelling of the neuronal energy demands associated with synaptic transmission. An operational model, the 'astrocyte-neuron lactate shuttle', is supported experimentally by a large body of evidence, which provides a molecular and cellular basis for interpreting data obtained from functional brain imaging studies. In addition, this neuron-glia metabolic coupling undergoes plastic adaptations in parallel with adaptive mechanisms that characterize synaptic plasticity. Thus, distinct subregions of the hippocampus are metabolically active at different time points during spatial learning tasks, suggesting that a type of metabolic plasticity, involving by definition neuron-glia coupling, occurs during learning. In addition, marked variations in the expression of genes involved in glial glycogen metabolism are observed during the sleep-wake cycle, with in particular a marked induction of expression of the gene encoding for protein targeting to glycogen (PTG) following sleep deprivation. These data suggest that glial metabolic plasticity is likely to be concomitant with synaptic plasticity.

Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism.

PubMed

Rowlands, Benjamin D; Lau, Chew Ling; Ryall, James G; Thomas, Donald S; Klugmann, Matthias; Beart, Philip M; Rae, Caroline D

2015-07-01

Silent information regulators (SIRTs) have been shown to deacetylate a range of metabolic enzymes, including those in glycolysis and the Krebs cycle, and thus alter their activity. SIRTs require NAD(+) for their activity, linking cellular energy status to enzyme activity. To examine the impact of SIRT1 modulation on oxidative metabolism, this study tests the effect of ligands that are either SIRT-activating compounds (resveratrol and SRT1720) or SIRT inhibitors (EX527) on the metabolism of (13)C-enriched substrates by guinea pig brain cortical tissue slices with (13)C and (1)H nuclear magnetic resonance spectroscopy. Resveratrol increased lactate labeling but decreased incorporation of (13)C into Krebs cycle intermediates, consistent with effects on AMPK and inhibition of the F0/F1-ATPase. By testing with resveratrol that was directly applied to astrocytes with a Seahorse analyzer, increased glycolytic shift and increased mitochondrial proton leak resulting from interactions of resveratrol with the mitochondrial electron transport chain were revealed. SRT1720, by contrast, stimulated incorporation of (13)C into Krebs cycle intermediates and reduced incorporation into lactate, although the inhibitor EX527 paradoxically also increased Krebs cycle (13)C incorporation. In summary, the various SIRT1 modulators show distinct acute effects on oxidative metabolism. The strong effects of resveratrol on the mitochondrial respiratory chain and on glycolysis suggest that caution should be used in attempts to increase bioavailability of this compound in the CNS. © 2015 Wiley Periodicals, Inc.

Docosahexaenoic Acid and Neurodevelopmental Outcomes of Term Infants.

PubMed

Meldrum, Suzanne; Simmer, Karen

2016-01-01

Docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, is essential for normal brain development. DHA is found predominantly in seafood, fish oil, breastmilk and supplemented formula. DHA intake in Western countries is often below recommendations. Observational studies have demonstrated an association between DHA intake in pregnancy and neurodevelopment of offspring but cannot fully adjust for confounding factors that influence child development. Randomised clinical trials of DHA supplementation during pregnancy and/or lactation, and of term infants, have not shown a consistent benefit nor harm on neurodevelopment of healthy children born at term. The evidence does not support DHA supplementation of healthy pregnant and lactating women, nor healthy infants. © 2016 S. Karger AG, Basel.

Derivation and Validation of Predictive Factors for Clinical Deterioration after Admission in Emergency Department Patients Presenting with Abnormal Vital Signs Without Shock

PubMed Central

Henning, Daniel J.; Oedorf, Kimie; Day, Danielle E.; Redfield, Colby S.; Huguenel, Colin J.; Roberts, Jonathan C.; Sanchez, Leon D.; Wolfe, Richard E.; Shapiro, Nathan I.

2015-01-01

Introduction Strategies to identify high-risk emergency department (ED) patients often use markedly abnormal vital signs and serum lactate levels. Risk stratifying such patients without using the presence of shock is challenging. The objective of the study is to identify independent predictors of in-hospital adverse outcomes in ED patients with abnormal vital signs or lactate levels, but who are not in shock. Methods We performed a prospective observational study of patients with abnormal vital signs or lactate level defined as heart rate ≥130 beats/min, respiratory rate ≥24 breaths/min, shock index ≥1, systolic blood pressure <90mm/Hg, or lactate ≥4mmole/L. We excluded patients with isolated atrial tachycardia, seizure, intoxication, psychiatric agitation, or tachycardia due to pain (ie: extremity fracture). The primary outcome was deterioration, defined as development of acute renal failure (creatinine 2× baseline), non-elective intubation, vasopressor requirement, or mortality. Independent predictors of deterioration after hospitalization were determined using logistic regression. Results Of 1,152 consecutive patients identified with abnormal vital signs or lactate level, 620 were excluded, leaving 532 for analysis. Of these, 53/532 (9.9±2.5%) deteriorated after hospital admission. Independent predictors of in-hospital deterioration were: lactate >4.0mmol/L (OR 5.1, 95% CI [2.1–12.2]), age ≥80 yrs (OR 1.9, CI [1.0–3.7]), bicarbonate <21mEq/L (OR 2.5, CI [1.3–4.9]), and initial HR≥130 (OR 3.1, CI [1.5–6.1]). Conclusion Patients exhibiting abnormal vital signs or elevated lactate levels without shock had significant rates of deterioration after hospitalization. ED clinical data predicted patients who suffered adverse outcomes with reasonable reliability. PMID:26759655

Nutritional strategies to cope with reduced litter weight gain and total tract digestibility in lactating sows.

PubMed

Álvarez-Rodríguez, J; Mir, L; Seradj, A R; Morazán, H; Balcells, J; Babot, D

2017-10-01

Twelve lactating sows were used to evaluate the effects of reducing dietary crude protein (CP) (14% vs. 12%) and increasing neutral detergent fibre (NDF) levels (18% vs. 22%) on litter performance, total tract apparent digestibility and manure composition in a 4 × 4 latin square arrangement during a 36-day lactation period. Diets were isoenergetic (2.9 Mcal ME/kg) and had similar total lysine content (0.9%). In addition, a second aim was to compare a reference external marker method (Cr 2 O 3 ) with an internal feed marker [acid-insoluble ash (AIA)] for the calculation of apparent total tract digestibility of nutrients in lactating sows. The reduction of dietary CP level in lactating sows had no effect on either live-weight or backfat thickness or apparent total tract digestibility of nutrients. However, the piglets' average daily gain (ADG) was reduced in low dietary CP diets, which suggests that sows reduced milk production due to an underestimation of certain essential amino acid requirements (e.g. valine). The increase of dietary NDF level did not affect sow and litter performance. Nevertheless, the total tract apparent digestibility of organic matter, CP and carbohydrates was reduced, and ether extract digestion was increased in high NDF compared to normal NDF diets equally balanced for ME and lysine content. The coefficients of total tract apparent digestibility of nutrients in lactating sows were greater when using AIA compared to Cr 2 O 3 marker, regardless of dietary CP or NDF level, but their coefficients of variation were lower in the former than in the latter. In lactating sows, a trade-off between litter performance and nutrient digestion is established when reducing dietary CP or increasing NDF levels while maintaining similar lysine content through synthetic amino acids and balancing metabolizable energy through dietary fat sources. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: comparison with valproic acid autistic model.

PubMed

Ali, Elham H A; Elgoly, Amany H Mahmoud

2013-10-01

The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800 mg/kg b.wt) at the 12.5 days of gestation. Butyl paraben was orally and subcutaneously administered (200 mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3 days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism. © 2013 Elsevier Inc. All rights reserved.

Arctigenin Treatment Protects against Brain Damage through an Anti-Inflammatory and Anti-Apoptotic Mechanism after Needle Insertion

PubMed Central

Song, Jie; Li, Na; Xia, Yang; Gao, Zhong; Zou, Sa-feng; Kong, Liang; Yao, Ying-Jia; Jiao, Ya-Nan; Yan, Yu-Hui; Li, Shao-Heng; Tao, Zhen-Yu; Lian, Guan; Yang, Jing-Xian; Kang, Ting-Guo

2016-01-01

Convection enhanced delivery (CED) infuses drugs directly into brain tissue. Needle insertion is required and results in a stab wound injury (SWI). Subsequent secondary injury involves the release of inflammatory and apoptotic cytokines, which have dramatic consequences on the integrity of damaged tissue, leading to the evolution of a pericontusional-damaged area minutes to days after in the initial injury. The present study investigated the capacity for arctigenin (ARC) to prevent secondary brain injury and the determination of the underlying mechanism of action in a mouse model of SWI that mimics the process of CED. After CED, mice received a gavage of ARC from 30 min to 14 days. Neurological severity scores (NSS) and wound closure degree were assessed after the injury. Histological analysis and immunocytochemistry were used to evaluated the extent of brain damage and neuroinflammation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to detect universal apoptosis. Enzyme-linked immunosorbent assays (ELISA) was used to test the inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10) and lactate dehydrogenase (LDH) content. Gene levels of inflammation (TNF-α, IL-6, and IL-10) and apoptosis (Caspase-3, Bax and Bcl-2) were detected by reverse transcription-polymerase chain reaction (RT-PCR). Using these, we analyzed ARC’s efficacy and mechanism of action. Results: ARC treatment improved neurological function by reducing brain water content and hematoma and accelerating wound closure relative to untreated mice. ARC treatment reduced the levels of TNF-α and IL-6 and the number of allograft inflammatory factor (IBA)- and myeloperoxidase (MPO)-positive cells and increased the levels of IL-10. ARC-treated mice had fewer TUNEL+ apoptotic neurons and activated caspase-3-positive neurons surrounding the lesion than controls, indicating increased neuronal survival. Conclusions: ARC treatment confers neuroprotection of brain tissue through anti-inflammatory and anti-apoptotic effects in a mouse model of SWI. These results suggest a new strategy for promoting neuronal survival and function after CED to improve long-term patient outcome. PMID:27445818

Perioperative erythropoietin protects the CNS against ischemic lesions in patients after open heart surgery.

PubMed

Lakič, Nikola; Mrak, Miha; Šušteršič, Miha; Rakovec, Peter; Bunc, Matjaž

2016-12-01

The aim of this study was to establish erythropoietin as a protective factor against brain ischemia during open heart surgery. A total of 36 consecutive patients scheduled for revascularization heart surgery were included in the study. Of the patients 18 received 3 intravenous doses of recombinant human erythropoietin (rHuEpo, 24,000 IU) and 18 patients received a placebo. Magnetic resonance imaging (MRI) to detect new brain ischemic lesions was performed. Additionally, S100A, S100B, neuron-specific enolase A and B (NSE-A and B) and the concentration of antibodies against N‑methyl-D-aspartate receptors (NMDAR) to identify new neurological complications were determined. Patients who received rHuEpo showed no postoperative ischemic changes in the brain on MRI images. In the control group 5 (27.8 %) new ischemic lesions were found. The NMDAR antibody concentration, S100A, S100B and NSE showed no significant differences between the groups for new cerebral ischemia. High levels of lactate before and after external aortic compression (p = 0.022 and p = 0.048, respectively) and duration of operation could predict new ischemic lesions (p = 0.009). The addition of rHuEpo reduced the formation of lesions detectable by MRI in the brain and could be used clinically as neuroprotection in cardiac surgery.