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Sample records for neurotoxic catecholamine metabolite

  1. Symptomatic pheochromocytoma with normal urinary catecholamine metabolites.

    PubMed

    Zianni, Dimitra; Tzanela, Marinella; Klimopoulos, Serafim; Thalassinos, N C

    2004-01-01

    A 61-year old female presented with paroxysmal hypertension and a 4.5cm left adrenal mass on CT scan. Repeated measurements of 24-hour urinary fractionated metanephrines, total catecholamines and vanillylmandelic acid (VMA) were within normal range. A further scintigraphic study with (131)I -metaiodobenzylguanidine ((131)I-MIBG) revealed selective concentration of the radiotracer, corresponding to the CT mass. After adequate preoperative treatment, successful surgical excision of the tumor was performed and the pathological examination confirmed the diagnosis of a cystic pheochromocytoma with a 2cm solid tumor. On reevaluation three months later using (131)I-MIBG, no evidence of remaining or recurrent disease was found. The patient, off any antihypertensive medication, reported mild recurrent hypertension and panic attacks that were adequately controlled with antidepressants. This is a rare case of a symptomatic pheochromocytoma without elevated urine catecholamines and metanephrines. According to the literature, plasma free metanephrines would be the ideal test for biochemical detection of the tumor. However, in the event that they are not available and there is a high clinical suspicion for the presence of pheochromocytoma, as in our patient, we suggest performance of a functional nuclear medicine study, such as (131)I-MIBG, to confirm the clinical diagnosis.

  2. The metabolites of catecholamines in urine of patients irradiated therapeutically.

    PubMed

    Pericić, D; Deanović, Z

    1976-04-01

    The metabolites of catecholamines were determined in 24-hour urine samples of patients with genital carcinoma and treated by radio therapy. The patients were irradiated first with gamma-rays of radium and then with X-rays. The radium sources (80 mCi) were placed intracavitarily for 46 hours twice within 2 weeks. X-irradiation (800 R daily), applied 1 month after radium treatment, was delivered on four abdominal fields over 15 days. The quantities of excreted catecholamine metabolites during irradiation were compared with control values (obtained before irradiation) in the same patients. Gamma-irradiation provoked a significant increase in the excretion of 3-methoxy-4-hydroxy-mandelic acid, metadrenaline and normetadrenaline, as well as of homovanillic acid, whereas X-irradiation provoked only a significant increase in the excretion of free 3-methoxy-4-hydroxy-phenylglycol. The increased excretion might be explained: (1) in the case of radium application, by direct radiation-induced release of catecholamines from the peripheral symphathetic nerves; (2) in the case of X-irradiation, by putting in the motion the complex of early neuroendocrine reactions via irradiated adrenal medulla.

  3. ALTERATION OF CATECHOLAMINES IN PHOECHROMOCYTOMA (PC12) CELLS IN VITRO BY THE METABOLITES OF CHLOROTRIAZINE HERBICIDE

    EPA Science Inventory

    The effects of four major chlorotriazine metabolites on the constitutive synthesis of the catecholamines dopamine (DA) and norepinephrine (NE) were examined using undifferentiated PC12 cells. NE release and intracellular DA and NE concentrations were quantified following treatme...

  4. Neurogenic hypertension associated with an excessively high excretion rate of catecholamine metabolites.

    PubMed Central

    Funck-Brentano, C; Pagny, J Y; Menard, J

    1987-01-01

    A 60 year old hypertensive patient suffered several cerebral infarctions. A phaeochromocytoma was suspected because the excretion rates of vanillylmandelic acid and its methoxy derivatives were raised and the patient had hypertensive crises. No tumour was found, however, by 131mI-iodobenzylguanidine scintigraphy and computed tomography of the abdomen. Moreover, the enhanced orthostatic plasma catecholamine response suggested that the high excretion rates of catecholamine metabolites were more likely to be caused by the syndrome of raised catecholamines after cerebrovascular accidents than a phaeochromocytoma. A phaeochromocytoma should not be diagnosed within several months of cerebral infarction without first excluding the possibility of a hyperadrenergic state induced by cerebral infarction. PMID:3593621

  5. Increased biogenic catecholamine and metabolite levels in two patients with malignant catatonia.

    PubMed

    Nisijima, Koichi

    2013-01-01

    The pathophysiology of malignant catatonia, a rare life-threatening psychiatric syndrome, has not yet been elucidated. This paper reports on two patients with malignant catatonia who showed elevated urinary or plasma catecholamine levels. Patient 1 had high catecholamine and metabolite levels in a 24-hour urine sample, and patient 2 had elevated plasma catecholamine levels. These findings indicate the presence of peripheral sympathetic nervous system hyperactivity in malignant catatonia. Symptoms of autonomic dysfunction, including tachycardia, labile blood pressure, and diaphoresis, are typical features of malignant catatonia and may be related to the increased levels of biogenic amines in these cases. Although the findings in the present study cannot entirely explain the pathophysiology of malignant catatonia, they do indicate that hyperactivity of the sympathetic nervous system may be involved in the pathology of this condition.

  6. Catecholamines 101

    PubMed Central

    2010-01-01

    This review of clinical catecholamine neurochemistry is based on the Streeten Memorial Lecture at the 19th annual meeting of the American Autonomic Society and lectures at a satellite of the 6th Congress of the International Society of Autonomic Neuroscience. Here I provide historical perspective, describe sources and meanings of plasma levels of catecholamines and their metabolites, present a model of a sympathetic noradrenergic neuron that conveys how particular aspects of sympathetic nervous function affect plasma levels of catecholamines and their metabolites, and apply the model to understand plasma neurochemical patterns associated with some drugs and disease states. PMID:20623313

  7. [Catecholamines and their metabolites in children with Asperger and Kanner syndromes].

    PubMed

    Gorina, A S; Kolesnichenko, L S; Mikhnovich, V I

    2011-01-01

    Children with Asperger and Kanner syndromes in the stable state demonstrate similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine and by an increase in dopamine and homovanylic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanylic acid, epinephrine and MHPG. Only in children with Kanner syndrome in the aggravated state plasma MHPG increases, excretion of tyrosine decreases and excretion of normetanephrine increases. The observed imbalance in dopamine and epinephrine/norepinephrine systems justifies combined analysis of changes in catecholamines and their metabolites levels as the most informative approach in the study of the effect of autistic disorders.

  8. Spectroscopic study on the inclusion complexes of β-cyclodextrin with selected metabolites of catecholamines

    NASA Astrophysics Data System (ADS)

    Korytkowska-Wałach, Anna; Dubrawska, Beata; Śmiga-Matuszowicz, Monika; Bieg, Tadeusz

    2017-01-01

    Inclusion complexes formed between β-cyclodextrin (β-CD) and metabolites of catecholamines, i.e. vanillylmandelic acid (VMA), homovanillic acid (HVA) as well as vanillin (VA) were studied using NMR spectroscopy. Due to the importance of these compounds for the diagnosis tumours of the sympathoadrenal system, hydrogels containing β-CD moieties for enhancing entrapping metabolites of catecholamine from aqueous solutions are located in the area of our interest. Stoichiometry and association constants of the complexes of β-CD with VMA, HVA and VA respectively were determined by using continuous variation and 1H NMR titration methods. Significant discrepancies were pointed out depending on used referencing method. In this study water solution of 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt as an external reference was used to avoid errors in the determination of association constants. β-CD formed the most stable complexes with VA and HVA molecules whilst smallest value of association constant was determined for the VMA/β-CD complex. Two-dimensional rotating-frame Overhauser effect spectroscopy (2D ROESY) allowed to establish definite information on the molecular structures of the complexes formed. Geometry of the latter was proposed basing on contour plots of the 2D ROESY spectra, which also indicated two possibilities of complexed molecule arrangement into β-cyclodextrin interior. The values of determined association constants are in good agreement with postulated geometry of the complexes. Value of association constant determined for inclusion complexes of β-cyclodextrin with homovanillic acid an vanillin indicates the strongest binding of molecules among investigated complexes, so it was finally concluded that β-CD moiety introduced into hydrogel network could be effective for homovanillic acid and vanillin entrapping.

  9. Neurotoxicity of Ecstasy metabolites in rat cortical neurons, and influence of hyperthermia.

    PubMed

    Capela, João Paulo; Meisel, Andreas; Abreu, Artur Reis; Branco, Paula Sério; Ferreira, Luísa Maria; Lobo, Ana Maria; Remião, Fernando; Bastos, Maria Lurdes; Carvalho, Félix

    2006-01-01

    3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There is growing evidence that the MDMA neurotoxic profile may be highly dependent on both its hepatic metabolism and body temperature. Metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, both of which are catechols that can undergo oxidation to the corresponding ortho-quinones. In the presence of glutathione (GSH), ortho-quinones may be conjugated with GSH to form glutathionyl adducts. In this study, we evaluated the neurotoxicity of MDMA and three of its metabolites obtained by synthesis, N-Me-alpha-MeDA, alpha-MeDA, and 5-(GSH)-alpha-MeDA [5-(glutathion-S-yl)-alpha-methyldopamine] in rat cortical neuronal serum-free cultures under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Cell viability was assessed, and the mechanism of cell death was also evaluated. Our study shows that these metabolites are more neurotoxic [5-(GSH)-alpha-MeDA being the most toxic] than the parent compound MDMA. The neurotoxicity of MDMA metabolites was partially prevented by the antioxidants N-acetylcystein and also, in a minor extent, by alpha-phenyl-N-tert-butyl nitrone. All the tested compounds induced apoptotic cell death in cortical neurons, and their neurotoxic effect was potentiated under hyperthermic conditions. These data suggest that MDMA metabolites, especially under hyperthermic conditions, contribute to MDMA-induced neurotoxicity.

  10. The Metabolic Fate of ortho-Quinones Derived from Catecholamine Metabolites.

    PubMed

    Ito, Shosuke; Yamanaka, Yuta; Ojika, Makoto; Wakamatsu, Kazumasa

    2016-01-27

    ortho-Quinones are produced in vivo through the oxidation of catecholic substrates by enzymes such as tyrosinase or by transition metal ions. Neuromelanin, a dark pigment present in the substantia nigra and locus coeruleus of the brain, is produced from dopamine (DA) and norepinephrine (NE) via an interaction with cysteine, but it also incorporates their alcoholic and acidic metabolites. In this study we examined the metabolic fate of ortho-quinones derived from the catecholamine metabolites, 3,4-dihydroxyphenylethanol (DOPE), 3,4-dihydroxyphenylethylene glycol (DOPEG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylmandelic acid (DOMA). The oxidation of catecholic substrates by mushroom tyrosinase was followed by UV-visible spectrophotometry. HPLC analysis after reduction with NaBH₄ or ascorbic acid enabled measurement of the half-lives of ortho-quinones and the identification of their reaction products. Spectrophotometric examination showed that the ortho-quinones initially formed underwent extensive degradation at pH 6.8. HPLC analysis showed that DOPE-quinone and DOPEG-quinone degraded with half-lives of 15 and 30 min at pH 6.8, respectively, and >100 min at pH 5.3. The major product from DOPE-quinone was DOPEG which was produced through the addition of a water molecule to the quinone methide intermediate. DOPEG-quinone yielded a ketone, 2-oxo-DOPE, through the quinone methide intermediate. DOPAC-quinone and DOMA-quinone degraded immediately with decarboxylation of the ortho-quinone intermediates to form 3,4-dihydroxybenzylalcohol (DHBAlc) and 3,4-dihydroxybenzaldehyde (DHBAld), respectively. DHBAlc-quinone was converted to DHBAld with a half-life of 9 min, while DHBAld-quinone degraded rapidly with a half-life of 3 min. This study confirmed the fact that ortho-quinones from DOPE, DOPEG, DOPAC and DOMA are converted to quinone methide tautomers as common intermediates, through proton rearrangement or decarboxylation. The unstable quinone

  11. Accumulation of neurotoxic thioether metabolites of 3,4-(+/-)-methylenedioxymethamphetamine in rat brain.

    PubMed

    Erives, Gladys V; Lau, Serrine S; Monks, Terrence J

    2008-01-01

    The serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-alpha-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA (20 mg/kg s.c.) at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-alpha-MeDA thioether metabolites in striatal dialysate. The area under the curve (AUC)(0-300 min) for 5-(glutathion-S-yl)-N-Me-alpha-MeDA increased 33% between the first and fourth injections and essentially doubled for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA. Likewise, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC(0-300 min) for both 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (35%) and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (85%), probably because processes for their elimination become saturated. Indeed, the elimination half-life of 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA increased by 53 and 28%, respectively, between the first and third doses. Finally, although the C(max) values for the monothioether conjugates were essentially unchanged after each injection, the values increased by 38 and approximately 50% for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA, respectively, between the first and fourth injections. The data indicate that neurotoxic metabolites of MDMA may accumulate in brain after

  12. Diurnal Profiles of Melatonin Synthesis-Related Indoles, Catecholamines and Their Metabolites in the Duck Pineal Organ

    PubMed Central

    Lewczuk, Bogdan; Ziółkowska, Natalia; Prusik, Magdalena; Przybylska-Gornowicz, Barbara

    2014-01-01

    This study characterizes the diurnal profiles of ten melatonin synthesis-related indoles, the quantitative relations between these compounds, and daily variations in the contents of catecholamines and their metabolites in the domestic duck pineal organ. Fourteen-week-old birds, which were reared under a 12L:12D cycle, were killed at two-hour intervals. The indole contents were measured using HPLC with fluorescence detection, whereas the levels of catecholamines and their metabolites were measured using HPLC with electrochemical detection. All indole contents, except for tryptophan, showed significant diurnal variations. The 5-hydroxytryptophan level was approximately two-fold higher during the scotophase than during the photophase. The serotonin content increased during the first half of the photophase, remained elevated for approximately 10 h and then rapidly decreased in the middle of the scotophase. N-acetylserotonin showed the most prominent changes, with a more than 15-fold increase at night. The melatonin cycle demonstrated only an approximately 5-fold difference between the peak and nadir. The 5-methoxytryptamine content was markedly elevated during the scotophase. The 5-hydroxyindole acetic acid, 5-hydroxytryptophol, 5-methoxyindole acetic acid and 5-methoxytryptophol profiles were analogous to the serotonin rhythm. The norepinephrine and dopamine contents showed no significant changes. The DOPA, DOPAC and homovanillic acid levels were higher during the scotophase than during the photophase. Vanillylmandelic acid showed the opposite rhythm, with an elevated level during the daytime. PMID:25032843

  13. Evaluation of the effects of zilpateral hydrochloride supplementation on catecholamin response and other blood metabolites following a combined corticotropin releasing hormone and vasopressin challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The stress response of cattle supplemented with zilpaterol hydrochloride (ZH) has become a topic due to anecdotal claims of supplemented cattle responding poorly to stress. This study was designed to determine if differences exist in the catecholamine and blood metabolite response of ZH-supplemente...

  14. Catechol O-methyltransferase and monoamine oxidase A genotypes, and plasma catecholamine metabolites in bipolar and schizophrenic patients.

    PubMed

    Zumárraga, Mercedes; Dávila, Ricardo; Basterreche, Nieves; Arrue, Aurora; Goienetxea, Biotza; Zamalloa, María I; Erkoreka, Leire; Bustamante, Sonia; Inchausti, Lucía; González-Torres, Miguel A; Guimón, José

    2010-01-01

    Metabolites of dopamine and norepinephrine measured in the plasma have long been associated with symptomatic severity and response to treatment in schizophrenic, bipolar and other psychiatric patients. Plasma concentrations of catecholamine metabolites are genetically regulated. The genes encoding enzymes that are involved in the synthesis and degradation of these monoamines are candidate targets for this genetic regulation. We have studied the relationship between the Val158Met polymorphism in catechol O-methyltransferase gene, variable tandem repeat polymorphisms in the monoamine oxidase A gene promoter, and plasma concentrations of 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid in healthy control subjects as well as in untreated schizophrenic and bipolar patients. We found that the Val158Met substitution in catechol O-methyltransferase gene influences the plasma concentrations of homovanillic and 3,4-dihydroxyphenylacetic acids. Although higher concentrations of plasma homovanillic acid were found in the high-activity ValVal genotype, this mutation did not affect the plasma concentration of 3-methoxy-4-hydroxyphenylglycol. 3,4-dihydroxyphenylacetic acid concentrations were higher in the low-activity MetMet genotype. Interestingly, plasma values 3-methoxy-4-hydroxyphenylglycol were greater in schizophrenic patients and in bipolar patients than in healthy controls. Our results are compatible with the previously reported effect of the Val158Met polymorphism on catechol O-methyltransferase enzymatic activity. Thus, our results suggest that this polymorphism, alone or associated with other polymorphisms, could have an important role in the genetic control of monoamine concentration and its metabolites.

  15. Plasma levels of brain derived-neurotrophic factor and catecholamine metabolites are increased during active phase of psychotic symptoms in CNS lupus: a case report.

    PubMed

    Ikenouchi, Atsuko; Yoshimura, Reiji; Ikemura, Naomi; Utsunomiya, Kensuke; Mitoma, Masae; Nakamura, Jun

    2006-09-30

    In the present study, the authors reported a case of systemic lupus erythematosus (SLE) with central nervous system involvement (CNS lupus). The authors also longitudinally investigated plasma levels of brain-derived neurotrophic factor (BDNF) and catecholamine metabolites in the patient, and found that plasma levels of BDNF, 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were raised in accordance with the severity of psychotic symptoms in this case of CNS lupus. These results suggest that it is useful to measure plasma levels of BDNF and the catecholamine metabolites in order to predict the severity of psychotic symptoms in CNS lupus and to provide a differential diagnosis from that of steroid-induced psychosis.

  16. Comparative neurochemical profile of 3,4-methylenedioxymethamphetamine and its metabolite alpha-methyldopamine on key targets of MDMA neurotoxicity.

    PubMed

    Escubedo, E; Abad, S; Torres, I; Camarasa, J; Pubill, D

    2011-01-01

    The neurotoxicity of MDMA or "Ecstasy" in rats is selectively serotonergic, while in mice it is both dopaminergic and serotonergic. MDMA metabolism may play a key role in this neurotoxicity. The function of serotonin and dopamine transporter and the effect of MDMA and its metabolites on them are essential to understand MDMA neurotoxicity. The aim of the present study was to investigate and compare the effects of MDMA and its metabolite alpha-methyldopamine (MeDA) on several molecular targets, mainly the dopamine and serotonin transporter functionality, to provide evidence for the role of this metabolite in the neurotoxicity of MDMA in rodents. MeDA had no affinity for the serotonin transporter but competed with serotonin for its uptake. It had no persistent effects on the functionalism of the serotonin transporter, in contrast to the effect of MDMA. Moreover, MeDA inhibited the uptake of dopamine into the serotonergic terminal and also MAO(B) activity. MeDA inhibited dopamine uptake with a lower IC(50) value than MDMA. After drug washout, the inhibition by MeDA persisted while that of MDMA was significantly reduced. The effect of MDMA on the dopamine transporter is related with dopamine release from vesicular stores, as this inhibition disappeared in reserpine-treated animals. However, the effect of MeDA seems to be a persistent conformational change of this transporter. Moreover, in contrast with MDMA, MeDA did not show affinity for nicotinic receptors, so no effects of MeDA derived from these interactions can be expected. The metabolite reduced cell viability at lower concentrations than MDMA. Apoptosis plays a key role in MDMA induced cellular toxicity but necrosis is the major process involved in MeDA cytotoxicity. We conclude that MeDA could protect against the serotonergic lesion induced by MDMA but potentiate the dopaminergic lesion as a result of the persistent blockade of the dopamine transporter induced this metabolite.

  17. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor.

    PubMed

    Bunzow, J R; Sonders, M S; Arttamangkul, S; Harrison, L M; Zhang, G; Quigley, D I; Darland, T; Suchland, K L; Pasumamula, S; Kennedy, J L; Olson, S B; Magenis, R E; Amara, S G; Grandy, D K

    2001-12-01

    The trace amine para-tyramine is structurally and functionally related to the amphetamines and the biogenic amine neurotransmitters. It is currently thought that the biological activities elicited by trace amines such as p-tyramine and the psychostimulant amphetamines are manifestations of their ability to inhibit the clearance of extracellular transmitter and/or stimulate the efflux of transmitter from intracellular stores. Here we report the discovery and pharmacological characterization of a rat G protein-coupled receptor that stimulates the production of cAMP when exposed to the trace amines p-tyramine, beta-phenethylamine, tryptamine, and octopamine. An extensive pharmacological survey revealed that psychostimulant and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of the catecholamine neurotransmitters are also good agonists at the rat trace amine receptor 1 (rTAR1). These results suggest that the trace amines and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are potent rTAR1 agonists suggests that the effects of these widely used drugs may be mediated in part by this receptor as well as their previously characterized targets, the neurotransmitter transporter proteins.

  18. Catecholamines - urine

    MedlinePlus

    Dopamine-urine test; Epinephrine-urine test; Adrenalin-urine test; Urine metanephrine; Normetanephrine; Norepinephrine-urine test; Urine catecholamines; VMA; HVA; Metanephrine; Homovanillic acid (HVA)

  19. Cerebrospinal fluid levels of catecholamines and its metabolites in Parkinson's disease: Effect of L-DOPA treatment and changes in levodopa-induced dyskinesia.

    PubMed

    Andersen, A D; Blaabjerg, M; Binzer, M; Kamal, A; Thagesen, H; Kjaer, T W; Stenager, E; Gramsbergen, J B

    2017-02-28

    Levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to L-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily L-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID (PD-LID, n=8)) as compared to non-dyskinetic PD patients receiving L-DOPA (PD-L, n=6), or not receiving L-DOPA (PD-N, n=7) as well as non-PD controls (n=16). PD patients were clinically assessed using the Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1-2 hours after oral intake of L-DOPA or other anti-Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (1) decreased levels of dihydroxyphenylacetic acid and homovanillic acid in PD patients not receiving L-DOPA (2) higher DA levels in LID as compared to controls (3) higher DA/L-DOPA and lower DOPAC/DA ratio's in LID as compared to PDL and (4) an age-dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non-DA cells and deficient DA re-uptake in PD-LID. Monitoring DA and DOPAC in CSF of L-DOPA-treated PD patients may help identify patients at risk of developing LID. This article is protected by copyright. All rights reserved.

  20. Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder.

    PubMed

    Savitz, Jonathan; Drevets, Wayne C; Smith, Chelsey M; Victor, Teresa A; Wurfel, Brent E; Bellgowan, Patrick S F; Bodurka, Jerzy; Teague, T Kent; Dantzer, Robert

    2015-01-01

    Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.

  1. Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder.

    PubMed

    Meier, Timothy B; Drevets, Wayne C; Wurfel, Brent E; Ford, Bart N; Morris, Harvey M; Victor, Teresa A; Bodurka, Jerzy; Teague, T Kent; Dantzer, Robert; Savitz, Jonathan

    2016-03-01

    Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p<0.01) and BA32 (p<0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p<0

  2. Detection of a novel neurotoxic metabolite of Parkinson's disease-related neurotoxin, 1-benzyl-1,2,3,4- tetrahydroisoquinoline.

    PubMed

    Kotake, Yaichiro; Sekiya, Yoko; Okuda, Katsuhiro; Ohta, Shigeru

    2014-01-01

    Naturally occurring low-molecular weight compounds with a chemical structure like that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline(1BnTIQ), are candidates for the endogenous neurotoxins that cause Parkinson's disease (PD). 1BnTIQ is an endogenous amine in human CSF and increases in the CSF of patients with PD. It inhibits complex Iand elicits PD-like behavioral abnormalities in monkey and mouse. In this study, we searched metabolites of 1BnTIQ by rat liver S9 using liquid chromatography-tandem mass spectrometry, and identified a dehydrated metabolite, 1-benzyl-3,4-dihydroisoquinoline (1BnDIQ). 1BnDIQ was identified by corresponding mass spectra and precursor ion scans in authentic and complete enzyme samples. Multiple reaction monitoring analysis showed microsome-dependent 1BnDIQ production. We previously reported that 1BnDIQ is more toxic than 1BnTIQ in cytotoxicity study in SH-SY5Y neuroblastoma cells. In addition, 1BnTIQ is reported to pass through the blood-brain barrier of the rat brain, and 1BnDIQ is supposed to be more lipophilic than 1BnTIQ. 1BnDIQ may easily reach the brain, and it might contribute to PD-related neurotoxicity.

  3. Pharmacological studies confirm neurotoxic metabolite(s) produced by the bloom-forming Cylindrospermopsis raciborskii in Hungary.

    PubMed

    Vehovszky, Á; Kovács, A W; Farkas, A; Győri, J; Szabó, H; Vasas, G

    2015-05-01

    A rapid cyanobacterial bloom of Cylindrospermopsis raciborskii (3.2 × 10(4) filaments/mL) was detected early November, 2012, in the Fancsika pond (East Hungary). The strong discoloration of water was accompanied by a substantial fish mortality (even dead cats were seen on the site), raising the possibility of some toxic metabolites in the water produced by the bloom-forming cyanobacteria (C. raciborskii). The potential neuronal targets of the toxic substances in the bloom sample were studied on identified neurons (RPas) in the central nervous system of Helix pomatia. The effects of the crude aqueous extracts of the Fancsika bloom sample (FBS) and the laboratory isolate of C. raciborskii from the pond (FLI) were compared with reference samples: C. raciborskii ACT 9505 (isolated in 1995 from Lake Balaton, Hungary), the cylindrospermopsin producer AQS, and the neurotoxin (anatoxin-a, homoanatoxin-a) producer Oscillatoria sp. (PCC 6506) strains. Electrophysiological tests showed that both FBS and FLI samples as well the ACT 9505 extracts modulate the acetylcholine receptors (AChRs) of the neurons, evoking ACh agonist effects, then inhibiting the ACh-evoked neuronal responses. Dose-response data suggested about the same range of toxicity of FBS and FLI samples (EC50  = 0.397 mg/mL and 0.917 mg/mL, respectively) and ACT 9505 extracts (EC50  = 0.734 mg/mL). The extract of the neurotoxin-producing PCC 6506 strain, however, proved to be the strongest inhibitor of the ACh responses on the same neurons (EC50  = 0.073 mg/mL). The presented results demonstrated an anatoxin-a-like cholinergic inhibitory effects of cyanobacterial extracts (both the environmental FBS sample, and the laboratory isolate, FLI) by some (yet unidentified) toxic components in the matrix of secondary metabolites. Previous pharmacological studies of cyanobacterial samples collected in other locations (Balaton, West Hungary) resulted in similar conclusions; therefore, we cannot exclude that

  4. Neurotoxic metabolites of ''commercial hexane'' in the urine of shoe factory workers

    SciTech Connect

    Perbellini, L.; Brugnone, F.; Gaffuri, E.

    1981-12-01

    Urinary metabolites were tested in 41 shoe-factory workers exposed to a mixture of 10 solvents among which ''commercial hexane'' was the prevailing component. Cyclohexanol, 2-methyl-2-pentanol, 3-methyl-2-pentanol, and trichloroethanol were determined in connection with exposure to cyclohexane, 2-methylpentane, 3-methylpentane, and trichloroethylene, respectively. 2-Hexanol, 2,5-hexanedione, 2,5-dimethylfuran, and gamma-valerolactone were all determined in connection with n-hexane exposure only. 2,5-Hexanedione was the principal n-hexane metabolite found in the workers' urine. This finding of the experimentally proven neurotoxin 2,5-hexanedione in the urine of shoe-factory workers exposed to ''commercial hexane'' is consistent with the idea that this compound is responsible for the development of neuropathy in this group of individuals.

  5. Arsenic metabolites affect expression of the neurofilament and tau genes: an in-vitro study into the mechanism of arsenic neurotoxicity.

    PubMed

    Vahidnia, A; van der Straaten, R J H M; Romijn, F; van Pelt, J; van der Voet, G B; de Wolff, F A

    2007-09-01

    Neurological studies indicate that the central (CNS) and peripheral nervous system (PNS) may be affected by arsenic (As). As-exposed patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison to healthy subjects. As may play a role in the disruption of neuroskeletal integrity, but the mechanisms by which it exerts a toxic effect on the peripheral and central nervous system are still unclear. In the present study, we examined the neurotoxic effects of various arsenic metabolites (iAs(III), iAs(V), MMA(V) and DMA(V)) on two different cell lines derived from the peripheral (ST-8814) and central (SK-N-SH) nervous system. The effects of the arsenic metabolites were examined on the relative quantification levels of the cytoskeletal genes, neurofilament-light (NEFL), neurofilament-medium (NEF3), neurofilament-heavy (NEFH) and microtubule-associated protein-tau (MAPT), using real-time PCR. Our results show that iAs(III) and iAs(V) have no significant effects on either cell lines. On the other hand, MMA(V) and DMA(V) cause significant changes in expression levels of NEF3 and NEFL genes, while the expression level of the NEFH gene is significantly increased in both cell lines.

  6. Attention deficit disorder symptoms and urine catecholamines.

    PubMed

    Rogeness, G A; Maas, J W; Javors, M A; Macedo, C A; Fischer, C; Harris, W R

    1989-03-01

    The symptoms of hyperactivity, impulsivity, and concentration deficits associated with attention deficit disorder (ADD) may be related, in part, to alterations in dopaminergic and noradrenergic functioning. In this study we correlate the above symptoms with 24-hour urinary catecholamines and their metabolites in emotionally disturbed boys divided into two groups based on their plasma dopamine-beta-hydroxylase (DBH) activities and also divided into the following diagnostic groups: conduct disorder, undersocialized; conduct disorder, socialized; and subjects without conduct disorder. Boys in the low DBH group showed significant correlations between the ADD symptoms and the biochemical measures. The low DBH group may be more genetically homogeneous with regard to catecholamine function, making relationships between catecholamine function and behavior more visible. The group of boys with conduct disorder, socialized had higher 24-hour urinary norepinephrine and vanillylmandelic acid output. The relationship between monoamines and their metabolites appeared to differ among diagnostic groups.

  7. Catecholamines in shock.

    PubMed

    Alho, A; Jäättelä, A; Lahdensuu, M; Rokkanen, P; Avikainen, V; Karaharju, E; Tervo, T; Lepistö, P

    1977-06-01

    The role of endogenous catecholamines in various clinical shock and stress states is reviewed; the effects, especially on the peripheral circulation, of catecholamine secretion are the same independent of the cause. Risks of using sympathomimetic agents in the treatment of shock are evaluated. A prolonged noradrenaline activity is to be expected in surgical stress states, e.g. multiple injuries, fat embolism syndrome, burns and infections; therapeutic approaches to minimize the sympathoadrenal activity are outlined.

  8. Acrylamide neurotoxicity.

    PubMed

    Erkekoglu, Pinar; Baydar, Terken

    2014-02-01

    Acrylamide, a food contaminant, belongs to a large class of structurally similar toxic chemicals, 'type-2 alkenes', to which humans are widely exposed. Besides, occupational exposure to acrylamide has received wide attention through the last decades. It is classified as a neurotoxin and there are three important hypothesis considering acrylamide neurotoxicity: inhibition of kinesin-based fast axonal transport, alteration of neurotransmitter levels, and direct inhibition of neurotransmission. While many researchers believe that exposure of humans to relatively low levels of acrylamide in the diet will not result in clinical neuropathy, some neurotoxicologists are concerned about the potential for its cumulative neurotoxicity. It has been shown in several studies that the same neurotoxic effects can be observed at low and high doses of acrylamide, with the low doses simply requiring longer exposures. This review is focused on the neurotoxicity of acrylamide and its possible outcomes.

  9. PHEOCHROMOCYTOMA: A CATECHOLAMINE AND OXIDATIVE STRESS DISORDER

    PubMed Central

    Pacak, Karel

    2012-01-01

    The WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla — an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Almost all pheochromocytomas and paragangliomas produce catecholamines. The concentrations of catecholamines in pheochromocytoma tissues are enormous, potentially creating a volcano that can erupt at any time. Significant eruptions result in catecholamine storms called “attacks” or “spells”. Acute catecholamine crisis can strike unexpectedly, leaving traumatic memories of acute medical disaster that champions any intensive care unit. A very well-defined genotype-biochemical phenotype relationship exists, guiding proper and cost-effective genetic testing of patients with these tumors. Currently, the production of norepinephrine and epinephrine is optimally assessed by the measurement of their O-methylated metabolites, normetanephrine or metanephrine, respectively. Dopamine is a minor component, but some paragangliomas produce only this catecholamine or this together with norepinephrine. Methoxytyramine, the O-methylated metabolite of dopamine, is the best biochemical marker of these tumors. In those patients with equivocal biochemical results, a modified clonidine suppression test coupled with the measurement of plasma normetanephrine has recently been introduced. In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations. Oxidative stress results from a significant imbalance between levels of prooxidants, generated during oxidative phosphorylation, and antioxidants. The gradual accumulation of prooxidants due to metabolic oxidative stress results in proto

  10. Protective activities of Vaccinium antioxidants with potential relevance to mitochondrial dysfunction and neurotoxicity.

    PubMed

    Yao, Yu; Vieira, Amandio

    2007-01-01

    Both the neurotransmitter dopamine (DA) and a neurotoxic metabolite, 6-hydroxy DA, can be oxidized to generate hydrogen peroxide and other reactive species (ROS). ROS promote oxidative stress and have been implicated in dopaminergic neurodegeneration, e.g., Parkinson's disease (PD). There is also evidence for a relation between catecholamine-mediated oxidative damage in dopaminergic neurons and the effects of these neurotransmitters on the redox state of cytochrome c (Cytc). In neurons and other cells, oxidative stress may be enhanced by abnormal release of Cytc and other mitochondrial proteins into the cytoplasm. Cytc release can result in apoptosis; but sub-apoptogenic-threshold release can also occur, and may be highly damaging in the presence of DA metabolites. Loss of mitochondrial membrane integrity, a pathological situation of relevance to several aging-related neurodegenerative disorders including PD, contributes to release of Cytc; and the level of such release is known to be indicative of the extent of mitochondrial dysfunction. In this context, we have used a Cytc-enhanced 6-hydroxy DA oxidation reaction to gauge dietary antioxidant activities. Anthocyanin-rich preparations of Vaccinium species (Vaccinium myrtillus, Vaccinium corymbosum, and Vaccinium oxycoccus) as well as a purified glycosylated anthocyanidin were compared. The most potent inhibition of oxidation was observed with V. myrtillus preparation: 50% inhibition with 7 microM of total anthocyanins. This activity was 1.5-4 times higher than that for the other preparations or for the purified anthocyanin. Ascorbate (Vitamin C), at up to 4-fold higher concentrations, did not result in significant inhibition in this assay. Antioxidant activity in the assay correlated strongly (r2>0.91, P<0.01) with reported Vaccinium content of anthocyanins and total cyanidins, but not quercetin or myricetin. The results provide evidence for the high potency of anthocyanins towards a potentially neurotoxic reaction

  11. Plasma catecholamine activity in chronic lead poisoning

    SciTech Connect

    deCastro, F.J.

    1990-04-01

    Plasma catecholamines where measured in 15 children with chronic lead poisoning and 15 matched controls by radioimmunassay. The data suggest that plasma catecholamines (norepinephrine and epinphrine) were significantly elevated in chronic lead poisoning. Plasma catecholamine elevation may well be important in the clinical finding of hyperactivity and hypertension associated with chronic lead poisoning.

  12. Unexpected changes in urinary catecholamines and vanillylmandelic acid following rape assault.

    PubMed

    Ende, N; Gertner, S B; Socha, B

    1990-03-01

    Although psychological changes are recognized to occur in rape assault survivors there is no information on the biochemical changes in these victims. This study compares urinary catecholamines and metabolites in 17 rape victims to two female control groups (one of which engaged in normal sexual intercourse and the other did not). We found, in the rape victims, unexpected changes in the excretion pattern of catecholamines and metabolites as compared to the various control groups. The most significant difference was the dramatic increase in urinary conjugated dopamine (P less than 0.01) in the rape victims which remained elevated for over 24 hr. Urinary vanillylmandelic acid (VMA) rose significantly in rape assault victims when compared to the normal control group. The VMA levels in rape victims were significantly lower, however, than in the women who had undergone (normal) sexual intercourse (P less than 0.01). Urinary free epinephrine showed a marked decline and remained depressed for over 24 hr in the rape assault victims (P less than 0.01) compared to normal controls. Some possible reasons for these patterns in catecholamines and metabolite excretion are suggested. These changes may be of importance in the poststress syndrome that occurs following the rape assault. In summary, a different profile of catecholamine and metabolite excretion patterns was found in rape compared to normal sexual intercourse. The enhanced dopamine excretion is contrary to the expected change of enhanced epinephrine secretion in severe stress.

  13. Effects of mental workload and caffeine on catecholamines and blood pressure compared to performance variations.

    PubMed

    Papadelis, Christos; Kourtidou-Papadeli, Chrysoula; Vlachogiannis, Emmanouil; Skepastianos, Petros; Bamidis, Panayiotis; Maglaveras, Nikos; Pappas, Kostantinos

    2003-02-01

    Caffeine is characterised as a central nervous system stimulant, also affecting metabolic and cardiovascular functions. A number of studies have demonstrated an effect of caffeine on the excretion of catecholamines and their metabolites. Urinary epinephrine and norepinephrine have been shown to increase after caffeine administration. Similar trends were observed in our study in adrenaline (ADR) and noradrenaline (NORADR) levels and additionally a dose dependent effect of caffeine. The effect of caffeine on cognitive performance, blood pressure, and catecholamines was tested under resting conditions and under mental workload. Each subject performed the test after oral administration of 1 cup and then 3 cups of coffee. Root mean square error (RMSE) for the tracking task was continuously monitored. Blood pressure was also recorded before and after each stage of the experiment. Catecholamines were collected and measured for three different conditions as: at rest, after mental stress alone, after one dose of caffeine under stress, and after triple dose of caffeine under stress. Comparison of the performance of each stage with the resting conditions revealed statistically significant differences between group of smokers/coffee drinkers compared with the other two groups of non-coffee drinkers/non-smokers and non-smokers/coffee drinkers. There was no statistically significant difference between the last two groups. There was an increase of urine adrenaline with 1 cup of coffee and statistically significant increase of urine noradrenaline. Both catecholamines were significantly increased with triple dose of caffeine. Mental workload increased catecholamines. There was a dose dependent effect of caffeine on catecholamines.

  14. Effect of microgravity on plasma catecholamine responses to stressors during space flight.

    PubMed

    Kvetnansky, R; Macho, L; Koska, J; Pacak, K; Hoff, T; Ksinantova, L; Noskov, V B; Kobzev, E; Grigoriev, A I; Vigas, M

    2001-07-01

    The effect of microgravity on the sympathicoadrenal system (SAS) activity in humans and animals has not yet been clarified. Our previous studies suggested that the SAS activity, evaluated by circulating and/or urinary catecholamine (CA) levels in astronauts during space flights, was found to be rather unchanged. However, CA levels were measured in astronauts only at rest conditions. The aim of the present study was to investigate effect of microgravity during space flight and post-flight readaptation on responsiveness of the SAS to somatic and psychic stressors evaluated by levels of catecholamines and their metabolite in the blood of the Slovak cosmonaut during his stay on board the space station Mir.

  15. Alteration of catecholamine concentrations in rat testis after methamphetamine exposure.

    PubMed

    Janphet, S; Nudmamud-Thanoi, S; Thanoi, S

    2017-03-01

    Methamphetamine (METH) is an illicit drug that can lead to changes in catecholamines in the brain. It also has substantial effects on reproductive function. We investigated whether rat models of METH abuse could induce changes in the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), in testis. Four groups of rats received vehicle, acute dose (AB), escalating dose (ED) or ED with an acute high dose (ED-binge) METH. DOPAC, NE and DHPG were determined using HPLC. DOPAC was significantly increased in the AB while NE was significantly decreased in the ED-binge. DHPG was also significantly decreased in the ED and ED-binge. METH induces alterations of DOPAC, NE and DHPG testicular concentrations that may result in male reproductive dysfunction.

  16. Neurotoxicity of ecstasy (MDMA): an overview.

    PubMed

    Sarkar, Sumit; Schmued, Larry

    2010-08-01

    "Ecstasy" (MDMA) is a powerful hallucinogenic drug which has raised concern worldwide because of its high abuse liability. A plethora of studies have demonstrated that MDMA has the potential to induce neurotoxicity both in human and laboratory animals. Although research on MDMA has been carried out by many different laboratories, the mechanism underlying MDMA induced toxicity has not been fully elucidated. MDMA has the ability to reduce serotonin levels in terminals of axons in the cortex of rats and mice. Recently we have shown that it also has the potential to produce degenerate neurons in discrete areas of the brain such as insular and parietal cortex, thalamus, tenia tecta and bed nucleus of stria terminalis (BST). Acute effects of MDMA can result in a constellation of changes including arrthymias, hypertension, hyperthermia, serotonin (5-HT) syndrome, liver problems, seizures and also long lasting neurocognitive impairments including mood disturbances. In human MDMA abusers, there is evidence for reduction of serotonergic biochemical markers. Several factors may contribute to the MDMA-induced neurotoxicity, especially hyperthermia. Other factors potentially influencing MDMA toxicity include monoamine oxidase metabolism of dopamine and serotonin, nitric oxide generation, glutamate excitotoxicity, serotonin 2A receptor agonism and the formation of MDMA neurotoxic metabolites. In this review we will cover the following topics: pharmacological mechanisms, metabolic pathways and acute effects in laboratory animals, as well as in humans, with special attention on the mechanism and pathology of MDMA induced neurotoxicity.

  17. Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders.

    PubMed

    Goldstein, David S; Kopin, Irwin J; Sharabi, Yehonatan

    2014-12-01

    Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the "catecholaldehyde hypothesis" for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

  18. Arsenic neurotoxicity--a review.

    PubMed

    Vahidnia, A; van der Voet, G B; de Wolff, F A

    2007-10-01

    Arsenic (As) is one of the oldest poisons known to men. Its applications throughout history are wide and varied: murder, make-up, paint and even as a pesticide. Chronic As toxicity is a global environmental health problem, affecting millions of people in the USA and Germany to Bangladesh and Taiwan. Worldwide, As is released into the environment by smelting of various metals, combustion of fossil fuels, as herbicides and fungicides in agricultural products. The drinking water in many countries, which is tapped from natural geological resources, is also contaminated as a result of the high level of As in groundwater. The environmental fate of As is contamination of surface and groundwater with a contaminant level higher than 10 particle per billion (ppb) as set by World Health Organization (WHO). Arsenic exists in both organic and inorganic species and either form can also exist in a trivalent or pentavalent oxidation state. Long-term health effects of exposure to these As metabolites are severe and highly variable: skin and lung cancer, neurological effects, hypertension and cardiovascular diseases. Neurological effects of As may develop within a few hours after ingestion, but usually are seen in 2-8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain-Barré syndrome. The predominant clinical features of neuropathy are paresthesias, numbness and pain, particularly in the soles of the feet. Electrophysiological studies performed on patients with As neuropathy have revealed a reduced nerve conduction velocity, typical of those seen in axonal degeneration. Most of the adverse effects of As, are caused by inactivated enzymes in the cellular energy pathway, whereby As reacts with the thiol groups of proteins and enzymes and inhibits their catalytic activity. Furthermore, As-induced neurotoxicity, like many other neurodegenerative diseases, causes changes in cytoskeletal protein composition and hyperphosphorylation

  19. Catecholamine metabolism in a psychoactive cactus.

    PubMed

    Keller, W J; Yeary, R A

    1980-04-01

    The Dona Ana cactus, Coryphantha macromeris (Engelm.) Br. and R. and its runyonii (Br. and R.) L. Benson variety are being promoted as natural and legal psychedelic agents with about one-fifth potency of peyote [Lophophora williamsii (Lem.) Coult.]. Like peyote, Dona Ana produces and accumulates various methylated catecholamine derivatives. Of these phenethylamines, normacromerine (N-methyl-3,4-dimethoxy-beta-hydroxyphenethylamine) is by far the most abundant and has been shown to affect animal behavior in such a way as to suggest psychoactivity. It has been demonstrated that the catecholamines epinephrine and norepinephrine occur naturally in C. macromeris var. runyonii and serve as biosynthetic intermediates in normacromerine biosynthesis. Catecholamine precursors and derivatives have also been shown to be part of the metabolic pathway leading to the formation of normacromerine in Dona Ana. Normacromerine appears to be the end product of catecholamine metabolism since recent studies have revealed that very little of this compound is metabolized once it has been formed by the cactus. Completed research of this type has allowed the comparison of catecholamine metabolism leading to the formation of a mind-altering drug in a cactus plant and the metabolism of catecholamines in humans. These data together with evidence from future research will allow biochemical analogies which may suggest etiologies for certain types of mental illness.

  20. Neurotoxicity and Behavior

    EPA Science Inventory

    Neurotoxicity is important to consider as a component of occupational and environmental safety and health programs. The failure to do so has contributed to a number of cases in which workers, consumers of manufactured products, and people exposed in the environment were irreparab...

  1. Pattern of elevation of urine catecholamines in intracerebral haemorrhage.

    PubMed

    Hamann, G F; Strittmatter, M; Hoffmann, K H; Holzer, G; Stoll, M; Keshevar, T; Moili, R; Wein, K; Schimrigk, K

    1995-01-01

    Autonomic nervous system dysfunction is a common complication of severe intracranial disease. The aim of this study was to reveal the autonomic changes in patients suffering from acute intracerebral haemorrhage (ICH). 25 patients with spontaneous ICH within 24 hours of onset of symptoms were included. All patients were treated with standardised medical management and the meta- and normetanephrines were detected by high performance liquid chromatography (HPLC) in 24-hour urine every day. The mean level of normetanephrine (709 +/- 579 micrograms/day) and metanephrine (244 +/- 161 mg/day) were significantly elevated in comparison with a control group, p < or = 0.01. The norepinephrine elevation was of greater diagnostic and prognostic importance. Maximum urinary catecholamine metabolite levels occurred between day 3 to 10 after the bleeding. Normetanephrines correlated with the prognosis and the complications of ICH: intraventricular involvement resulted in significantly elevated normetanephrine levels (896 +/- 520 micrograms/day versus 311 +/- 78 micrograms/day) p < or = 0.01. Patients with a great volume of haematoma developed severe autonomic dysregulation (normetanephrines 1114 +/- 493 micrograms/day), whereas patients with smaller haematoma did not (339 +/- 125 micrograms/day) p < or = 0.0001; patients with bad outcome (1014 +/- 620 mg/day) had higher levels of normetanephrines than those with a good prognosis (322 +/- 110 micrograms/day) p < or = 0.001. A close relationship to elevated intracranial pressure was established. This study demonstrated the feasibility of detecting autonomic nervous system dysfunction in neurological intensive care patients by means of examination of the metabolites of the catecholamines in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Tyrosine - Effects on catecholamine release

    NASA Technical Reports Server (NTRS)

    Acworth, Ian N.; During, Matthew J.; Wurtman, Richard J.

    1988-01-01

    Tyrosine administration elevates striatal levels of dopamine metabolites in animals given treatments that accelerate nigrostriatal firing, but not in untreated rats. We examined the possibility that the amino acid might actually enhance dopamine release in untreated animals, but that the technique of measuring striatal dopamine metabolism was too insensitive to demonstrate such an effect. Dopamine release was assessed directly, using brain microdialysis of striatal extracellular fluid. Tyrosine administration (50-200 mg/kg IP) did indeed cause a dose related increase in extracellular fluid dopamine levels with minor elevations in levels of DOPAC and HVA, its major metabolites, which were not dose-related. The rise in dopamine was short-lived, suggesting that receptor-mediated feedback mechanisms responded to the increased dopamine release by diminishing neuronal firing or sensitivity to tyrosine. These observations indicate that measurement of changes in striatal DOPAC and HVA, if negative, need not rule out increases in nigrostriatal dopamine release.

  3. Functionally active ganglioneuroma with increased plasma and urinary catecholamines and positive iodine 131-meta-iodobenzylguanidine scintigraphy

    SciTech Connect

    Clerico, A.; Jenkner, A.; Castello, M.A.; Ciofetta, G.; Lucarelli, C.; Codini, M. )

    1991-01-01

    Ganglioneuromas are usually considered not to be functionally active. Studies of their catecholamine excretory pattern and of their imaging by means of the adrenergic tracing agent 131-I-MIBG have been therefore sparse. We report on a case of secretory ganglioneuroma, as demonstrated by the increased urinary excretion of the catecholamine metabolites HVA and VMA, increased plasma dopamine and epinephrine levels, and positive 131-I-MIBG scintigraphy. We must therefore be aware that a functionally active tumor is not necessarily a neuroblastoma, and that the diagnosis should be biopsy proven.

  4. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression.

    PubMed

    Bhatia, Pankaj; Singh, Nirmal

    2015-12-01

    Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression.

  5. Nitric oxide neurotoxicity.

    PubMed

    Dawson, V L; Dawson, T M

    1996-06-01

    Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent L-arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO-), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constituents including proteins, DNA and lipids. The inherent biochemical and physiological characteristics of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.

  6. Clinical catecholamine neurochemistry: a legacy of Julius Axelrod.

    PubMed

    Goldstein, David S; Eisenhofer, Graeme; Kopin, Irwin J

    2006-01-01

    1. Discoveries, insights, and concepts that Julius Axelrod introduced about the disposition and metabolism of catecholamines provided the scientific basis and spurred the development of clinical catecholamine neurochemistry. 2. Here, we provide examples of this aspect of Axelrod's scientific legacy.

  7. Noncholinergic control of adrenal catecholamine secretion.

    PubMed Central

    Livett, B G; Marley, P D

    1993-01-01

    It has been known for over 70 years that adrenal catecholamine secretion can be modulated or elicited by noncholinergic neurotransmitters and hormones. However, our understanding of the cellular mechanisms by which these agents produce their effects and the physiological conditions under which they act are not well characterised. Here we briefly review the mechanisms by which one such agent (the neuropeptide substance P) modulates the cholinergic secretory response of adrenal chromaffin cells, and another agent (angiotensin II) elicits catecholamine secretion independently of the cholinergic innervation. PMID:7507911

  8. The Dipeptides Ile-Tyr and Ser-Tyr Exert Distinct Effects on Catecholamine Metabolism in the Mouse Brainstem

    PubMed Central

    Moriyasu, Kazuki; Ichinose, Takashi; Nakahata, Akane; Tanaka, Mitsuru; Matsui, Toshiro; Furuya, Shigeki

    2016-01-01

    Catecholamine synthesis and transmission in the brain are influenced by the availability of Tyr in the body. In this study, we compared the effects of oral administration of Tyr-containing dipeptides Ile-Tyr, Ser-Tyr, and Tyr-Pro with Tyr alone on catecholamine metabolism in the mouse brainstem. Among these dipeptides, Ile-Tyr administration led to increases in dopamine, the dopamine metabolites homovanillic acid, and 3,4-dihydroxyphenylacetic acid, compared to administration of Ser-Tyr, Tyr-Pro, or Tyr alone. In comparison, administration of Ser-Tyr induced significantly increasing noradrenaline turnover, while Tyr-Pro administration suppressed dopamine turnover. Therefore, oral administration of Ile-Tyr, Ser-Tyr, and Tyr-Pro differentially affected metabolism of dopamine and noradrenaline. These observations strongly suggest that Tyr-containing dipeptides exert distinct effects on catecholamine metabolism in the brainstem when ingested orally. PMID:26981137

  9. Catecholamines and cognition after traumatic brain injury

    PubMed Central

    Jenkins, Peter O.; Mehta, Mitul A.

    2016-01-01

    Cognitive problems are one of the main causes of ongoing disability after traumatic brain injury. The heterogeneity of the injuries sustained and the variability of the resulting cognitive deficits makes treating these problems difficult. Identifying the underlying pathology allows a targeted treatment approach aimed at cognitive enhancement. For example, damage to neuromodulatory neurotransmitter systems is common after traumatic brain injury and is an important cause of cognitive impairment. Here, we discuss the evidence implicating disruption of the catecholamines (dopamine and noradrenaline) and review the efficacy of catecholaminergic drugs in treating post-traumatic brain injury cognitive impairments. The response to these therapies is often variable, a likely consequence of the heterogeneous patterns of injury as well as a non-linear relationship between catecholamine levels and cognitive functions. This individual variability means that measuring the structure and function of a person’s catecholaminergic systems is likely to allow more refined therapy. Advanced structural and molecular imaging techniques offer the potential to identify disruption to the catecholaminergic systems and to provide a direct measure of catecholamine levels. In addition, measures of structural and functional connectivity can be used to identify common patterns of injury and to measure the functioning of brain ‘networks’ that are important for normal cognitive functioning. As the catecholamine systems modulate these cognitive networks, these measures could potentially be used to stratify treatment selection and monitor response to treatment in a more sophisticated manner. PMID:27256296

  10. Localization of pheochromocytoma by selective venous catheterization and assay of plasma catecholamines.

    PubMed Central

    Davies, R. A.; Patt, N. L.; Sole, M. J.

    1979-01-01

    The diagnosis of pheochromocytoma rests primarily on determination of the 24-hour urinary excretion of catecholamines and their metabolites. In most cases nephrotomography and selective arteriography or venography, or both, are sufficient to localize the tumour. Selective venous catheterization and the assay of plasma catecholamines should be considered for pheochromocytoma localization in: (a) patients in whom standard techniques fail to localize the tumour; (b) patients who exhibit idiosyncratic reactions to the angiographic contrast materials; (c) young patients or patients with familial pheochromocytoma, including those with multiple neurofibromatosis or multiple endocrine adenomatosis, type 2; (d) patients with recurrent, malignant, or suspected multicentric or extra-adrenal tumours; and (e) patients excreting only norepinephrine in the urine. The validity of the results is particularly dependent on the skill with which venous catheterization is carried out. PMID:436033

  11. Neurotoxicity of metals.

    PubMed

    Caito, Samuel; Aschner, Michael

    2015-01-01

    Metals are frequently used in industry and represent a major source of toxin exposure for workers. For this reason governmental agencies regulate the amount of metal exposure permissible for worker safety. While essential metals serve physiologic roles, metals pose significant health risks upon acute and chronic exposure to high levels. The central nervous system is particularly vulnerable to metals. The brain readily accumulates metals, which under physiologic conditions are incorporated into essential metalloproteins required for neuronal health and energy homeostasis. Severe consequences can arise from circumstances of excess essential metals or exposure to toxic nonessential metal. Herein, we discuss sources of occupational metal exposure, metal homeostasis in the human body, susceptibility of the nervous system to metals, detoxification, detection of metals in biologic samples, and chelation therapeutic strategies. The neurologic pathology and physiology following aluminum, arsenic, lead, manganese, mercury, and trimethyltin exposures are highlighted as classic examples of metal-induced neurotoxicity.

  12. Neurotoxicity of organomercurial compounds.

    PubMed

    Sanfeliu, Coral; Sebastià, Jordi; Cristòfol, Rosa; Rodríguez-Farré, Eduard

    2003-01-01

    Mercury is a ubiquitous contaminant, and a range of chemical species is generated by human activity and natural environmental change. Elemental mercury and its inorganic and organic compounds have different toxic properties, but all them are considered hazardous in human exposure. In an equimolecular exposure basis, organomercurials with a short aliphatic chain are the most harmful compounds and they may cause irreversible damage to the nervous system. Methylmercury (CH(3)Hg(+)) is the most studied following the neurotoxic outbreaks identified as Minamata disease and the Iraq poisoning. The first description of the CNS pathology dates from 1954. Since then, the clinical neurology, the neuropathology and the mechanisms of neurotoxicity of organomercurials have been widely studied. The high thiol reactivity of CH(3)Hg(+), as well as all mercury compounds, has been suggested to be the basis of their harmful biological effects. However, there is clear selectivity of CH(3)Hg(+) for specific cell types and brain structures, which is not yet fully understood. The main mechanisms involved are inhibition of protein synthesis, microtubule disruption, increase of intracellular Ca(2+) with disturbance of neurotransmitter function, oxidative stress and triggering of excitotoxicity mechanisms. The effects are more damaging during CNS development, leading to alterations of the structure and functionality of the nervous system. The major source of CH(3)Hg(+) exposure is the consumption of fish and, therefore, its intake is practically unavoidable. The present concern is on the study of the effects of low level exposure to CH(3)Hg(+) on human neurodevelopment, with a view to establishing a safe daily intake. Recommendations are 0.4 micro g/kg body weight/day by the WHO and US FDA and, recently, 0.1 micro g/kg body weight/day by the US EPA. Unfortunately, these levels are easily attained with few meals of fish per week, depending on the source of the fish and its position in the

  13. Plasma catecholamine concentrations associated with cerebral vasospasm.

    PubMed

    Loach, A B; Benedict, C R

    1980-03-01

    Plasma concentrations of adrenaline and noradrenaline were measured sequentially over the immediate post-operative period following clipping of an intracranial aneurysm in 11 patients. Those patients who developed local cerebral vasospasm showed a sustained rise in plasma catecholamines, particularly noradrenaline, whilst those patients who developed generalised cerebral vasospasm showed early peaks of very high concentrations of adrenaline and noradrenaline which preceded radiological evidence of generalized vasospam.

  14. Neurotoxicity and risk assessment of brominated and alternative flame retardants.

    PubMed

    Hendriks, Hester S; Westerink, Remco H S

    2015-01-01

    Brominated flame retardants (BFRs) are widely used chemicals that prevent or slow the onset and spreading of fire. Unfortunately, many of these compounds pose serious threats for human health and the environment, indicating an urgent need for safe(r) and less persistent alternative flame retardants (AFRs). As previous research identified the nervous system as a sensitive target organ, the neurotoxicity of past and present flame retardants is reviewed. First, an overview of the neurotoxicity of BFRs in humans and experimental animals is provided, and some common in vitro neurotoxic mechanisms of action are discussed. The combined epidemiological and toxicological studies clearly underline the need for replacing BFRs. Many potentially suitable AFRs are already in use, despite the absence of a full profile of their environmental behavior and toxicological properties. To prioritize the suitability of some selected halogenated and non-halogenated organophosphorous flame retardants and inorganic halogen-free flame retardants, the available neurotoxic data of these AFRs are discussed. The suitability of the AFRs is rank-ordered and combined with human exposure data (serum concentrations, breast milk concentrations and house dust concentrations) and physicochemical properties (useful to predict e.g. bioavailability and persistence in the environment) for a first semi-quantitative risk assessment of the AFRs. As can be concluded from the reviewed data, several BFRs and AFRs share some neurotoxic effects and modes of action. Moreover, the available neurotoxicity data indicate that some AFRs may be suitable substitutes for BFRs. However, proper risk assessment is hampered by an overall scarcity of data, particularly regarding environmental persistence, human exposure levels, and the formation of breakdown products and possible metabolites as well as their toxicity. Until these data gaps in environmental behavioral and toxicological profiles are filled, large scale use of

  15. Neurotransmitter alterations in PTSD: catecholamines and serotonin.

    PubMed

    Southwick, S M; Paige, S; Morgan, C A; Bremner, J D; Krystal, J H; Charney, D S

    1999-10-01

    In this chapter we review trauma-related studies involving epinephrine (E), norepinephrine (NE), and serotonin (5-HT). Central catecholamine neurons seem to play a critical role in level of alertness, vigilance, orienting, selective attention, memory, fear conditioning, and cardiovascular responses to life-threatening stimuli. Evidence of catecholamine dysregulation in post-traumatic stress disorder (PTSD) includes exaggerated increases in heart rate and blood pressure when exposed to visual and auditory reminders of trauma, elevated 24-hour urine catecholamine excretion, decreased platelet alpha-2 adrenergic receptor number, exaggerated behavioral, cardiovascular, and biochemical responses to IY yohimbine, decreased cortical brain metabolism secondary to IV yohimbine, and clinical efficacy of adrenergic blocking agents. Serotonin seems to play numerous roles in the central nervous system, including regulation of sleep, aggression, appetite, cardiovascular and respiratory activity, motor output, anxiety, mood, neuroendocrine secretion, and analgesia. Evidence of serotonergic dysregulation in PTSD includes frequent symptoms of aggression, impulsivity, depression and suicidality, decreased platelet paroxetine binding, blunted prolactin response to fenfluramine, exaggerated reactivity to m-chloro-phenyl-piperazine, and clinical efficacy of serotonin reuptake inhibitors. It has been suggested that alterations in NE, E, and 5-HT may have relevance for symptoms commonly seen in survivors with PTSD, including hypervigilance, exaggerated startle, irritability, impulsivity, aggression, intrusive memories, depressed mood, and suicidality.

  16. Improved solid-phase extraction and liquid chromatography with electrochemical detection of urinary catecholamines and 5-S-L-cysteinyl-L-dopa.

    PubMed

    Huang, T H; Wall, J; Kabra, P

    1988-10-28

    We describe a rapid, precise, accurate liquid chromatographic procedure for determining urinary catecholamines and 5-S-L-cysteinyl-L-dopa. The catecholamines (norepinephrine, epinephrine, and dopamine) and 5-S-L-cysteinyl-L-dopa are extracted from 1.0 ml of urine together with internal standards, by using a Bond-Elut strong cation-exchange (SCX) and an affinity phenylboronic acid (PBA) extraction column in series. The eluate obtained from PBA column is then chromatographed on a reversed-phase C18 column with a mobile phase containing pentane- and heptanesulfonate as ion-pair reagents. The detection is achieved with an amperometric detector set at an oxidation potential of +0.55 V. The chromatography is complete is less than 8 min for catecholamines and less than 5 min for cysteinyldopa. The method can measure less than 2 micrograms/l for catecholamines and 5 micrograms/l for cysteinyldopa. Analytical recoveries of catecholamines and cysteinyldopa added to urine pool ranged from 90-107%. Between run coefficient of variation ranged from 4.7 to 8%. None of the drugs and catecholamines metabolites tested interfered with the assay.

  17. New advances in the biochemical diagnosis of pheochromocytoma: moving beyond catecholamines.

    PubMed

    Lenders, Jacques W M; Pacak, Karel; Eisenhofer, Graeme

    2002-09-01

    Pheochromocytomas are dangerous tumors that, although a rare cause of hypertension, require consideration among large numbers of patients. The resulting low prevalence of the tumor among tested populations and the inadequacies of commonly used biochemical tests make excluding or confirming the tumor an often difficult and time-consuming task. Recognition that catecholamines are metabolized to free metanephrines within pheochromocytoma tumor cells, and that this process is independent of catecholamine release, provides a rationale for use of these metabolites in the biochemical diagnosis of pheochromocytoma. Here we briefly review the history of biochemical diagnosis of pheochromocytoma in relation to recent data about the diagnostic utility of plasma free metanephrines for detection of these tumors. Measurements of urinary or plasma catecholamines have reasonable sensitivity for detection of most pheochromocytomas, particularly those in patients with sustained hypertension. False-negative test results can, however, occur in asymptomatic patients tested because of an adrenal incidentaloma or a familial predisposition for pheochromocytoma, or when sampling is carried out between episodes of paroxysmal hypertension. Measurements of urinary total metanephrines or vanillylmandelic acid are less reliable and are of little value as initial screening tests. In contrast, measurements of plasma concentrations or free metanephrines or 24-hour urinary outputs of fractionated normetanephrine and metanephrine almost always reveal the tumor. Although, both tests have similarly high sensitivity, the relatively low specificity of urinary fractionated metanephrines means that pheochromocytomas can be more efficiently excluded or confirmed using measurements of plasma free metanephrines.

  18. Guidelines for Neurotoxicity Risk Assessment

    EPA Pesticide Factsheets

    These Guidelines set forth principles and procedures to guide EPA scientists in evaluating environmental contaminants that may pose neurotoxic risks, and inform Agency decision makers and the public about these procedures.

  19. INTRACELLULAR SIGNALING AND DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    A book chapter in ?Molecular Toxicology: Transcriptional Targets? reviewed the role of intracellular signaling in the developmental neurotoxicity of environmental chemicals. This chapter covered a number of aspects including the development of the nervous system, role of intrace...

  20. [Hyperhomocysteinemia: atherothrombosis and neurotoxicity].

    PubMed

    Fridman, O

    1999-01-01

    The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation

  1. Neurotoxic Shellfish Poisoning

    PubMed Central

    Watkins, Sharon M.; Reich, Andrew; Fleming, Lora E.; Hammond, Roberta

    2008-01-01

    Neurotoxic shellfish poisoning (NSP) is caused by consumption of molluscan shellfish contaminated with brevetoxins primarily produced by the dinoflagellate, Karenia brevis. Blooms of K. brevis, called Florida red tide, occur frequently along the Gulf of Mexico. Many shellfish beds in the US (and other nations) are routinely monitored for presence of K. brevis and other brevetoxin-producing organisms. As a result, few NSP cases are reported annually from the US. However, infrequent larger outbreaks do occur. Cases are usually associated with recreationally-harvested shellfish collected during or post red tide blooms. Brevetoxins are neurotoxins which activate voltage-sensitive sodium channels causing sodium influx and nerve membrane depolarization. No fatalities have been reported, but hospitalizations occur. NSP involves a cluster of gastrointestinal and neurological symptoms: nausea and vomiting, paresthesias of the mouth, lips and tongue as well as distal paresthesias, ataxia, slurred speech and dizziness. Neurological symptoms can progress to partial paralysis; respiratory distress has been recorded. Recent research has implicated new species of harmful algal bloom organisms which produce brevetoxins, identified additional marine species which accumulate brevetoxins, and has provided additional information on the toxicity and analysis of brevetoxins. A review of the known epidemiology and recommendations for improved NSP prevention are presented. PMID:19005578

  2. Plasma catecholamines during an ultrarapid heroin detoxification.

    PubMed

    Macedo, T R; Relvas, J; Fontes Ribeiro CA; Pacheco, F; Morgadinho, M T; Pinto, C M; Gomes, P C; Ventura, M; Henriques, V; Nunes, S V; Ruis, G R; Ramalheira, C; Boto, I; Vale, L L

    2000-09-01

    The adrenergic system has long been known to be activated in a situation of stress and thus during opiate withdrawal. A method for detoxification that decreases the stimulation of the sympathetic nervous system will prevent changes of catecholamine levels. Some of such methods have been developed. One of them uses direct transition from heroin to oral naltrexone after deep sedation with midazolam in conjunction with naloxone, droperidol, ondansetron, and clonidine treatment for 24 hours. Can such method prevent adrenergic changes? Moreover, 5-HT has been related to mood disorders. This study aims to determine plasma catecholamines and 5-HT before heroin withdrawal, during the day of the withdrawal, and at the ends of the first day, the first week, and the first 6 months. Forty-three patients with more than 6 years of drug abuse volunteered to seek help to detoxify. After clinical evaluation, blood samples were taken. Plasma catecholamines were isolated by standard alumina procedures and measured by high-performance liquid chromatography with electrochemical detection. Only for NE was there a significant decrease in the day of heroin withdrawal with deep sedation, followed the next day by an increase. During the following days, NE plasma concentrations returned slowly to basal levels. Epinephrine and dopamine plasma levels did not significantly change. Platelet 5-HT levels progressively decreased from the day before detoxification until the last period of observation. We also found that there were no abrupt changes in cardiovascular functions. In conclusion, our results suggest that this type of ultrarapid opiate detoxification prevents the dramatic activation of the autonomic nervous system.

  3. [The brain catecholamines during domestication of the silver fox Vulpes fulvus].

    PubMed

    Nikulina, E M

    1990-01-01

    Studies have been made on the content of catecholamines (noradrenaline and dopamine) as well as metabolites of dopamine (3,4-dihydroxyphenylacetic and homovanillic acids) in the brain structures of silver foxes which differ in their handling reactions. The level of noradrenaline was found to be significantly higher in the anterior hypothalamus of domesticated animals; no differences in noradrenaline content were found in the frontal cortex, hippocamp, posterior hypothalamus and midbrain in animals from aggressive and domesticated groups. Dopamine content was higher in the tuberculum olfactorium of domesticated animals, being lower in the striatum and n. accumbens. Metabolite level remained unaffected which is presumably due to changes in dopamine synthesis in the investigated structures. It was concluded that domestication of animals favours the specimens with an altered state of catecholaminergic system of the brain.

  4. A test of the catecholamines hypothesis for an acute exercise-cognition interaction.

    PubMed

    McMorris, T; Collard, K; Corbett, J; Dicks, M; Swain, J P

    2008-03-01

    The purpose of the study was to examine the usage of norepinephrine (NE) and dopamine (DA) in the brain when exercising while simultaneously undertaking cognitive tests. Plasma concentrations of the NE metabolite 3-methoxy 4-hydroxyphenylglycol (MHPG) and the DA metabolite homovanillic acid (HVA) showed a linear increase from rest to exercising at 40% and 80% maximum power output (W.max) while simultaneously undertaking cognitive tasks (random number generation (RNG) and response time). Delta plasma concentrations of MHPG and HVA at each exercise intensity while undertaking cognitive tasks and while exercising without cognitive tasks did not differ. Taking blood samples at 0, 1, 3, and 5 min following cessation of exercise did not affect results. Regression correlations showed that delta MHPG and HVA plasma concentrations at the 1 and 3 min sampling times were strong predictors of delta RNG, response time and movement time. Reaction time at 80% W.max significantly increased, while movement time at 80% W.max significantly decreased. It was concluded that these results provide no support for a direct effect of increased catecholamines concentrations on cognitive performance during exercise. The regression data suggest that there is some relationship between exercise, catecholamines concentrations and cognition.

  5. Urinary catecholamine levels and gingivitis in children.

    PubMed

    Vanderas, A P; Kavvadia, K; Papagiannoulis, L

    1998-05-01

    This study investigated the relationship between gingivitis and emotionally stressful states measured by the urinary catecholamines in children. Three-hundred and fourteen (314) children, boys and girls, aged 6 to 8 years were included in the study. Gingivitis was recorded by the gingival bleeding index and dental plaque by the plaque control record index. Proximal decayed surfaces, faulty restorations, and stainless steel crowns were diagnosed clinically and radiographically. Information concerning systemic and socioeconomic factors was collected by a questionnaire. A 24-hour urine sample was collected for each subject and analyzed by the HPLC technique to assay the catecholamine content. The multiple-regression analysis was carried out to test whether gingivitis was affected by the studied variables. The 95% probability was used. The results showed that epinephrine, norepinephrine, and dopamine did not have a significant association with gingival index. Dental plaque and proximal decayed surfaces significantly affected gingivitis. Of the socioeconomic factors, mother's education had a significant association with gingivitis when all factors were included in the analysis. The data suggest that emotionally stressful states may not increase the probability of developing gingivitis in children of this age.

  6. Urinary catecholamine levels and bruxism in children.

    PubMed

    Vanderas, A P; Menenakou, M; Kouimtzis, T; Papagiannoulis, L

    1999-02-01

    This study was performed to test the hypothesis that emotionally stressful states measured by the urinary catecholamines may affect the development of bruxism. Three hundred and fourteen children, boys and girls, aged 6-8 years were included in this study. Bruxism was recorded by a clinical examination and an interview. Positive evidence of this parafunction was defined as the presence of both historical and clinical indicators. Information concerning systemic and socio-economic factors was collected by a questionnaire. A 24-h urine sample was collected for each subject and analysed by the high performance liquid chromatography technique to assay the catecholamine content. Of the total of 273 children who had a complete 24-h urine sample, 167 were identified to be with and without positive evidence of bruxism. The logistic multiple-regression analysis was carried out to test whether the presence of bruxism was affected by the variables studied; 95% probability was used. The results showed that epinephrine and dopamine had a significant and strong association with bruxism. The data therefore provide support for the concept that emotional stress is a prominent factor in the development of bruxing behaviour.

  7. Intraoperative hypertensive crisis due to a catecholamine-secreting esthesioneuroblastoma

    PubMed Central

    Salmasi, Vafi; Schiavi, Adam; Binder, Zev A.; Ruzevick, Jacob; Orr, Brent A.; Burger, Peter C.; Ball, Douglas W.; Blitz, Ari M.; Koch, Wayne M.; Ishii, Masaru; Gallia, Gary L.

    2015-01-01

    Background Although uncommon, esthesioneuroblastomas may produce clinically significant amounts of catecholamines. Methods We report a patient with a catecholamine-secreting esthesioneuroblastoma who developed intraoperative hypertensive crisis. Results A patient with history of hypertension was referred to our skull base center for management of a residual esthesioneuroblastoma. A staged endonasal endoscopic approach was planned. At the conclusion of the first stage, a hypertensive crisis occurred. Work-up revealed elevated levels of serum and urinary catecholamines. The patient was treated with alpha adrenoceptor blockade prior to the second stage. Serum catecholamine levels following this second stage were normal. On immunohistochemical analysis, the tumor cells were found to be positive for tyrosine hydroxylase, the rate limiting enzyme in cathecholamine synthesis, and achaete-scute homologue 1, a transcription factor essential in the development of olfactory and sympathetic neurons. Conclusion Catecholamine production should be considered in the differential of unexpected extreme hypertension during surgical resection of esthesioneuroblastoma. PMID:25352487

  8. Nanomechanics of Poly(catecholamine) Coatings in Aqueous Solutions.

    PubMed

    Lim, Chanoong; Huang, Jun; Kim, Sunjin; Lee, Haeshin; Zeng, Hongbo; Hwang, Dong Soo

    2016-03-01

    Mussel-inspired self-polymerized catecholamine coatings have been widely utilized as a versatile coating strategy that can be applied to a variety of substrates. For the first time, nanomechanical measurements and an evaluation of the contribution of primary amine groups to poly(catecholamine) coatings have been conducted using a surface-forces apparatus. The adhesive strength between the poly(catecholamine) layers is 30-times higher than that of a poly(catechol) coating. The origin of the strong attraction between the poly(catecholamine) layers is probably due to surface salt displacement by the primary amine, π-π stacking (the quadrupole-quadrupole interaction of indolic crosslinks), and cation-π interactions (the monopole-quadrupole interaction between positively charged amine groups and the indolic crosslinks). The contribution of the primary amine group to the catecholamine coating is vital for the design and development of mussel-inspired catechol-based coating materials.

  9. Catecholamines promote Actinobacillus pleuropneumoniae growth by regulating iron metabolism.

    PubMed

    Li, Lu; Chen, Zhaohui; Bei, Weicheng; Su, Zhipeng; Huang, Qi; Zhang, Liang; Chen, Huanchun; Zhou, Rui

    2015-01-01

    Catecholamines are host stress hormones that can induce the growth of many bacteria by facilitating iron utilization and/or regulate the expression of virulence genes through specific hormone receptors. Whether these two responsive pathways are interconnected is unknown. In our previous study, it was found that catecholamines can regulate the expression of a great number of genes of Actinobacillus pleuropneumoniae, an important swine respiratory pathogen. However, bacterial growth was not affected by catecholamines in rich medium. In this study, it was discovered that catecholamines affected A. pleuropneumoniae growth in chemically defined medium (CDM). We found that serum inhibited A. pleuropneumoniae growth in CDM, while epinephrine, norepinephrine and dopamine promoted A. pleuropneumoniae growth in the CDM containing serum. The known bacterial hormone receptor QseC didn't play roles in this process. Ion-supplementation and transcriptome analysis indicated that serum addition resulted in iron-restricted conditions which were alleviated by the addition of catecholamines. Transferrin, one of the components in serum, inhibited the growth of A. pleuropneumoniae in CDM, an effect reversed by addition of catecholamines in a TonB2-dependent manner. Our data demonstrate that catecholamines promote A. pleuropneumoniae growth by regulating iron-acquisition and metabolism, which is independent of the adrenergic receptor QseC.

  10. Phenotypic screening for developmental neurotoxicity ...

    EPA Pesticide Factsheets

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific

  11. Cadmium and Its Neurotoxic Effects

    PubMed Central

    Wang, Bo; Du, Yanli

    2013-01-01

    Cadmium (Cd) is a heavy metal that has received considerable concern environmentally and occupationally. Cd has a long biological half-life mainly due to its low rate of excretion from the body. Thus, prolonged exposure to Cd will cause toxic effect due to its accumulation over time in a variety of tissues, including kidneys, liver, central nervous system (CNS), and peripheral neuronal systems. Cd can be uptaken from the nasal mucosa or olfactory pathways into the peripheral and central neurons; for the latter, Cd can increase the blood brain barrier (BBB) permeability. However, mechanisms underlying Cd neurotoxicity remain not completely understood. Effect of Cd neurotransmitter, oxidative damage, interaction with other metals such as cobalt and zinc, estrogen-like, effect and epigenetic modification may all be the underlying mechanisms. Here, we review the in vitro and in vivo evidence of neurotoxic effects of Cd. The available finding indicates the neurotoxic effects of Cd that was associated with both biochemical changes of the cell and functional changes of central nervous system, suggesting that neurotoxic effects may play a role in the systemic toxic effects of the exposure to Cd, particularly the long-term exposure. PMID:23997854

  12. Biomarkers, mechanisms, and potential prevention of catecholamine neuron loss in Parkinson disease.

    PubMed

    Goldstein, David S

    2013-01-01

    This chapter is on biomarkers, mechanisms, and potential treatment of catecholamine neuron loss in Parkinson disease (PD). PD is characterized by a movement disorder from loss of nigrostriatal dopamine neurons. An intense search is going on for biomarkers of the disease process. Theoretically, cerebrospinal fluid (CSF) levels of the deaminated DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), should be superior to other neurochemical indices of loss of central dopamine. CSF DOPAC is low in PD-even in patients with recent onset of Parkinsonism. Cardiac norepinephrine depletion is as severe as the loss of putamen dopamine. PD importantly involves nonmotor manifestations, including anosmia, dementia, REM behavior disorder, and orthostatic hypotension, and all of these nonmotor features are associated with neuroimaging evidence for cardiac sympathetic denervation, which seems to occur independently of the movement disorder and striatal dopaminergic lesion. Analogy to a bank robber's getaway car conveys the catecholaldehyde hypothesis, according to which buildup of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the immediate product of the action of monoamine oxidase on cytosolic dopamine, causes or contributes to the death of dopamine neurons. Decreased vesicular uptake of dopamine and decreased DOPAL detoxification by aldehyde dehydrogenase (ALDH) determine this buildup. Vesicular uptake is also markedly decreased in the heart in PD. Multiple factors influence vesicular uptake and ALDH activity. Evidence is accruing for aging-related induction of positive feedback loops and an autotoxic final common pathway in the death of catecholamine neurons, mediated by metabolites produced continuously in neuronal life. The catecholaldehyde hypothesis also leads to testable experimental therapeutic ideas.

  13. Neurotoxic thioether adducts of 3,4-methylenedioxymethamphetamine identified in human urine after ecstasy ingestion.

    PubMed

    Perfetti, Ximena; O'Mathúna, Brian; Pizarro, Nieves; Cuyàs, Elisabet; Khymenets, Olha; Almeida, Bruno; Pellegrini, Manuela; Pichini, Simona; Lau, Serrine S; Monks, Terrence J; Farré, Magí; Pascual, Jose Antonio; Joglar, Jesús; de la Torre, Rafael

    2009-07-01

    3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and a serotonergic neurotoxicant in animal models and possibly humans. The underlying mechanism of neurotoxicity involves the formation of reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced neurotoxicity is mediated via the formation of bioreactive metabolites. In particular, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently cause the formation of glutathione and N-acetylcysteine conjugates, which retain the ability to redox cycle and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) and 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) in human urine of 15 recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 h after MDMA ingestion approximately 0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and catechol-O-methyltransferase expression, the combination of which are major determinants of steady-state levels of HHMA and 4-hydroxy-3-methoxyamphetamine, probably explain the interindividual variability seen in the recovery of N-Ac-5-Cys-HHMA and N-Ac-5-Cys-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to neurotoxicity in humans.

  14. Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases.

    PubMed

    Goldstein, David S; Holmes, Courtney; Kopin, Irwin J; Sharabi, Yehonatan

    2011-08-01

    Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies - cytoplasmic inclusions containing α-synuclein protein aggregates - in the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH; also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons. We used 6-[18F]-dopamine (18F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal 18F-DA was followed by assessment of arterial plasma levels of the 18F-DA metabolite 18F-dihydroxyphenylacetic acid (18F-DOPAC). The ratio of myocardial 18F-DA to arterial 18F-DOPAC provided an index of vesicular uptake. Tracer concentrations were measured in patients with PD with or without orthostatic hypotension (PD+OH, PD-No-OH); in patients with pure autonomic failure (PAF, a Lewy body disease without parkinsonism); in patients with multiple system atrophy (MSA, a non-Lewy body synucleinopathy); and in normal controls. Patients with PD+OH or PAF had decreased vesicular 18F-DA uptake and accelerated 18F-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial 18F-DA uptake. We conclude that sympathetic denervation in Lewy body diseases is associated with decreased vesicular uptake of neuronal catecholamines, suggesting that vesicular monoamine transport is impaired. Vesicular uptake may constitute a novel target for diagnosis, treatment, and prevention.

  15. THE NUMBER OF CATECHOLAMINE STORAGE GRANULES IN ADRENAL MEDULLA

    DTIC Science & Technology

    A method is described for counting the catecholamine-containing heavy granules of adrenal glands. There are 5.0 ! 0.8 (S. E.) x 10 to the 12th power... granules /gram wet weight of fowl adrenal gland. Individual heavy granules contain about 8 million molecules of catecholamines (1.4 x 10 to the 17th...power mole). Reference to published electron microphotographs of adrenal medulla cells allows estimation of the average volume of heavy granules and

  16. Reversible catecholamine-induced cardiomyopathy due to pheochromocytoma: case report.

    PubMed

    Satendra, Milan; de Jesus, Cláudia; Bordalo e Sá, Armando L; Rosário, Luís; Rocha, José; Bicha Castelo, Henrique; Correia, Maria José; Nunes Diogo, António

    2014-03-01

    Pheochromocytoma is a tumor originating from chromaffin tissue. It commonly presents with symptoms and signs of catecholamine excess, such as hypertension, tachycardia, headache and sweating. Cardiovascular manifestations include catecholamine-induced cardiomyopathy, which may present as severe left ventricular dysfunction and congestive heart failure. We report a case of pheochromocytoma which was diagnosed following investigation of dilated cardiomyopathy. We highlight the dramatic symptomatic improvement and reversal of cardiomyopathy, with recovery of left ventricular function after treatment.

  17. Local Anesthetic-Induced Neurotoxicity

    PubMed Central

    Verlinde, Mark; Hollmann, Markus W.; Stevens, Markus F.; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

    2016-01-01

    This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. PMID:26959012

  18. Developmental neurotoxicity of industrial chemicals.

    PubMed

    Grandjean, P; Landrigan, P J

    2006-12-16

    Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

  19. Multiple mechanisms of PCB neurotoxicity

    SciTech Connect

    Carpenter, D.O.; Stoner, C.T.; Lawrence, D.A.

    1996-12-31

    Polychlorinated biphenyls (PCBs) have been implicated in cancer, but many of the symptoms in humans exposed to PCBs are related to the nervous system and behavior. We demonstrated three different direct mechanisms whereby PCBs are neurotoxic in rats. By using flow cytometry, we demonstrated that the orthosubstituted PCB congener 2,4,4{prime}, but neither TCDD nor the coplanar PCB congener 3,4,5,3{prime},4{prime}, causes rapid death of cerebellar granule cells. The ortho-substituted congener 2,4,4{prime} reduced long-term potentiation, an indicator of cognitive potential, in hippocampal brain slices, but a similar effect was observed for the coplanar congener 3,4,3{prime},4{prime}, indicating that this effect may be caused by both ortho- and coplanar congeners by mechanisms presumably not mediated via the Ah receptor. It was previously shown that some ortho-substituted PCB congeners cause a reduction in levels of the neurotransmitter dopamine, and we present in vitro and in vivo evidence that this is due to reduction of synthesis of dopamine via inhibition of the enzyme tyrosine hydroxylase. Thus, PCBs have a variety of mechanisms of primary neurotoxicity, and neurotoxicity is a characteristic of ortho-substituted, non-dioxin-like congeners as well as some coplanar congeners. The relative contribution of each of these mechanisms to the loss of cognitive function in humans exposed to PCBs remains to be determined. 42 refs., 3 figs., 1 tab.

  20. Occupational Neurotoxic Diseases in Taiwan

    PubMed Central

    Liu, Chi-Hung; Huang, Chu-Yun

    2012-01-01

    Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization. PMID:23251841

  1. Xylamine, a ligand for the catecholamine transporter

    SciTech Connect

    Waggaman, L.A.

    1985-01-01

    Previous studies have established xylamine (N-2'-chloro-ethyl-N-ethyl-2-methylbenzylamine) irreversibly inhibits neuronal norepinephrine uptake with no concomitant effect on other neurotransmitter systems. Since xylamine is thought to alkylate transport-associated sites in the plasma membrane of noradrenergic neurons, so the loss of endogenous norepinephrine may be a consequence of neuronal membrane damage resulting from the alkylation of membrane components. In these studies, xylamine, under in vitro conditions, irreversibly inhibited both neuronal norepinephrine and dopamine uptake in the rat cortex and striatum, respectively. The efficacy of xylamine as a neuronal dopamine uptake inhibitor appeared to depend on its ability to access dopaminergic neurons during tissue exposure to the drug. In sympathetically innervated peripheral tissues, (/sup 3/H)xylamine was accumulated in noradrenergic neurons in a carrier-dependent manner. Although the data suggested that xylamine was interacting with the norepinephrine uptake carrier, (/sup 3/H)xylamine exposure to isolated synaptic membranes from superior cervical ganglia revealed a large proportion of (/sup 3/H)xylamine binding that was not associated with the noradrenergic transporter. For a closer characterization of xylamine binding in synaptic membranes, brain tissue was chosen as a more practical source of these membranes. While these experiments did not meet with great success, xylamine remains potentially useful as a ligand for identifying the catecholamine transporter, particularly in conjunction with procedures for protein purification and reconstitution.

  2. Selective blockade of nicotinic acetylcholine receptors by pimobendan, a drug for the treatment of heart failure: reduction of catecholamine secretion and synthesis in adrenal medullary cells.

    PubMed

    Toyohira, Yumiko; Kubo, Tatsuhiko; Watanabe, Miyabi; Uezono, Yasuhito; Ueno, Susumu; Shinkai, Koji; Tsutsui, Masato; Izumi, Futoshi; Yanagihara, Nobuyuki

    2005-02-01

    Pimobendan, a Ca(2+) sensitizer, is used clinically in the treatment of chronic heart failure. Although chronic heart failure is associated with activation of the sympathetic nervous system, it remains unknown whether pimobendan affects the function of sympathetic neurons and the adrenal medulla. Here, we report the inhibitory effects of pimobendan on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Pimobendan decreased the catecholamine secretion (IC(50)=29.5 microM) elicited by carbachol, an agonist at nicotinic acetylcholine receptors, but not that elicited by veratridine, an activator of voltage-dependent Na(+) channels, or by high K(+), an activator of voltage-dependent Ca(2+) channels. Pimobendan also inhibited carbachol-induced influx of (22)Na(+) (IC(50)=25.9 microM) and (45)Ca(2+) (IC(50)=26.0 microM), but not veratridine-induced (22)Na(+) influx or high K(+)-induced (45)Ca(2+) influx. The reduction of catecholamine secretion caused by pimobendan was not overcome by increasing the concentration of carbachol. UD-CG 212, an active metabolite of pimobendan, lowered carbachol-induced catecholamine secretion with a concentration/inhibition curve similar to that of pimobendan. In experiments in situ, pimobendan suppressed both basal and carbachol-stimulated (14)C-catecholamine synthesis (IC(50)=5.3 and 4.9 microM) from [(14)C] tyrosine [but not from L: -3, 4-dihydroxyphenyl [3-(14)C] alanine ([(14)C]DOPA)], as well as tyrosine hydroxylase activity (IC(50)=3.8 and 4.3 microM). These findings suggest that pimobendan inhibits carbachol-induced catecholamines secretion and synthesis through suppression of nicotinic acetylcholine receptors.

  3. Correlation between catecholamine levels and outcome in patients with severe head trauma.

    PubMed

    Salehpoor, F; Bazzazi, A M; Estakhri, R; Zaheri, M; Asghari, B

    2010-08-01

    Some studies have shown that catecholamines and the changes in their levels during and after head trauma can be useful in predicting the outcome in head trauma patients. The goal of this study is to search for a probable relation between urine levels of catecholamines and prognosis in patients with severe head trauma. Fifty four patients with severe head trauma Glasgow Coma Scale (GCS < or = 8) on admission time were recruited in Imam Reza Hospital within one. These patients were included when having no major accompanying trauma in other organs. Twenty four hour urine was collected after admission and levels of metanephrine and nor-metanephrine were measured. The relation between urine levels of these metabolites with final outcome and also with GCS at admission, 24, 48 h and 1 week after admission and discharge time and Glasgow Outcome Scale (GOS) were studied. Fifty two patients, 48 males and 4 females with a mean age of 32.3 +/- 14.7 (3-72) years were included. The main underlying etiologies were motorcycle (46.2%) and car accidents (25%). Diffuse axonal injury, brain contusion and subdural hematoma were three main diagnoses (28.8, 17.3 and 15.4% of the cases, respectively). 19 (36.5%) of the patients expired within the study period. The mean level of metanephrine and normetanephrine in urine were 207.9 +/- 200.5 and 330.2 +/- 218.4 microg in 24 h, respectively. There was no meaningful relation between urine levels of these metabolites and any of GCS and GOS. There was also no meaningful relation between these parameters and final prognosis in patients.

  4. Pyrilamine inhibits nicotine-induced catecholamine secretion.

    PubMed

    Kim, Dong-Chan; Yun, So Jeong; Park, Yong-Soo; Jun, Dong-Jae; Kim, Dongjin; Jiten Singh, N; Kim, Sanguk; Kim, Kyong-Tai

    2014-07-01

    Function of nicotine, which induces activation of all parts of the body including our brain, has been receiving much attention for a long period of time and also been actively studied by researchers for its pharmacological actions in the central nervous system. The modulation of nicotine concentration and the inhibition of nicotine binding on target receptors in the brain are the key factors for smoking addiction therapy. In previous studies showed that influx of nicotine at the blood-brain barrier was through the pyrilamine-sensitive organic cation transporters. But the direct interacting mechanism of pyrilamine on the nicotine binding target receptors has not yet been clarified. The aim of the present study is to investigate the direct binding mechanisms of a pyrilamine on the nicotinic acetylcholine receptors (nAChRs). We found that pyrilamine shares the same ligand binding pocket of nicotine (NCT) on nAChRs but interacts with more amino acid residues than NCT does. The extended part of pyrilamine interacts with additional residues in the ligand binding pocket of nAChRs which are located nearby the entrance of the binding pocket. The catecholamine (CA) secretion induced by nAChR agonist (NCT') was significantly inhibited by the pyrilamine pretreatment. Real time carbon-fiber amperometry confirmed the inhibition of the NCT'-induced exocytosis by pyrilamine in a single cell level. We also found that pyrilamine inhibited the NCT'-induced [Ca(2+)]i. In contrast, pyrilamine did not affect the increase in calcium induced by high K(+). Overall, these data suggest that pyrilamine directly docks into the ligand binding site of nAChRs and specifically inhibits the nAChR-mediated effects thereby causing inhibition of CA secretion. Therefore, pyrilamine may play an important role to explore new treatments to aid smoking cessation.

  5. RISK CHARACTERIZATION OF PERSISTENT NEUROTOXIC CONTAMINANTS

    EPA Science Inventory

    Neurotoxicity is an adverse change in structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent. Thousands of chemicals have been estimated to have neurotoxic potential. Many persistent and bioaccumulat...

  6. Immobilized Catecholamine and Cocaine Effects on Contractility of Cardiac Muscle

    PubMed Central

    Venter, J. Craig; Ross, John; Dixon, Jack E.; Mayer, Steven E.; Kaplan, Nathan O.

    1973-01-01

    Isoproterenol, norepinephrine, and epinephrine covalently bound to glass beads exert a positive inotropic effect on isometrically contracting papillary muscles from cats. Immobilized isoproterenol maintains increases in force and velocity of contraction for more than 5 hr. 1 μM Cocaine potentiates the action of immobilized norepinephrine, isoproterenol, and epinephrine, but not of isoproterenol in solution. The data presented indicate that the effects of immobilized catecholamines are not due to their coming off the glass. The effects observed with cocaine and immobilized catecholamines are not altered by prior treatment of the muscle with reserpine. These results suggest that the major site of catecholamine action is on receptors located on the extended surface of myocardial cells and a post-junctional site for cocaine potentiation. Images PMID:4515619

  7. [Catecholamine response to the Wingate test in untrained women].

    PubMed

    Vincent, Sophie; Gratas-Delamarche, Arlette; Berthon, Phanélie Marie; Zouhal, Hassane; Jacob, Christophe; Bentue-Ferrer, Danièle; Delamarche, Paul

    2003-10-01

    Supramaximal exercises are well known to induce a severe stress on the adrenal medulla and nervous sympathetic system. This stress induces increased plasma catecholamines concentrations. The responses of catecholamines to supramaximal exercises in women are still not well characterized and have been studied mostly in trained subjects. Hence the aim of the present study was to evaluate plasma catecholamine responses to a Wingate test in young and untrained women (n = 6) and men (n = 7). Venous plasma catecholamine concentrations were determined by HPLC, at rest, at the end of the warm-up and of the exercise, and during recovery (5, 10, 20, and 30 mn). Our results failed to show any significant difference in resting catecholamine concentrations ([A]p: 0.41 +/- 0.05 vs. 0.45 +/- 0.05 nmol. L-1; [NA]p: 3.28 +/- 0.68 vs. 2.58 +/- 0.26 nmol.L-1), kinetics, and maximal plasma catecholamine concentrations (Amax: 4.47 +/- 1.08 vs. 3.31 +/- 0.63 nmol.L-1; NAmax: 18.05 +/- 1.11 vs. 14.01 +/- 2.02 nmol.L-1) in response to the Wingate test between women and men, respectively. The Amax/NAmax ratio used as an index of adrenal medulla sensitivity to sympathetic input was also similar between genders. In conclusion, this study was able to demonstrate, in untrained subjects, that gender did not alder the sympatho-adrenergic response induced by a severe stress.

  8. Catecholamines: Mediator of the Hypermetabolic Response to Thermal Injury

    PubMed Central

    Wilmore, Douglas W.; Long, James M.; Mason, Arthur D.; Skreen, Robert W.; Pruitt, Basil A.

    1974-01-01

    Hypermetabolism characterizes the metabolic response to thermal injury and the extent of energy production is positively related to the rate of urinary catecholamine excretion. Alpha and beta adrenergic blockade decreased metabolism from 69.6 ± 5.3 Kcal/m2/hr to 57.4 ± 5.2 (p < 0.01), and infusion of 6 µgm epinephrine/minute in normal man significantly increased metabolic rate. Twenty noninfected burned adults with a mean burn size of 45% total body surface (range 7-84%) and four normal controls were studied in an environmental chamber at two or more temperatures between 19 and 33 C with vapor pressure constant at 11.88 mm Hg. All burn patients were hypermetabolic at all temperatures studied and their core and mean skin temperatures were significantly elevated above control values. Between 25 and 33 C ambient, metabolism was unchanged in controls and burns of less than 40% total body surface (48.9 ± 4.6 Kcal/m2/hr vs. 48.9 ± 4.5), but metabolic rate decreased in larger burns in the warmer environment (72.0 ± 1.9 vs. 65.8 ± 1.7, p < 0.001). At 21 C, metabolism and catecholamines increased, except in four nonsurvivors who became hypothermic with decreased catechol elaboration. Metabolic rate in ten patients with bacteremia was below predicted levels while catecholamines were markedly elevated suggesting interference with tissue uptake of the neurohormonal transmitters. Feeding burn patients or administering glucose and insulin improved nitrogen retention and altered substrate flow but did not significantly reduce urinary catecholamines or metabolic rate. Burned patients are internally warm, not externally cold, and catecholamines appear to mediate their increased heat production. Hypermetabolism may be modified by ambient temperature, infection, and pharmacologic means. Alterations in hypothalamic function due to injury, resulting in increased catecholamine elaboration, would explain the metabolic response to thermal injury. PMID:4412350

  9. Neurotoxicity

    MedlinePlus

    ... Strategy Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ... Information Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ...

  10. Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity.

    PubMed

    Bai, F; Lau, S S; Monks, T J

    1999-12-01

    Direct injection of either 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) or 3,4-(+/-)-methylenedioxyamphetamine (MDA) into the brain fails to reproduce the serotonergic neurotoxicity seen following peripheral administration. The serotonergic neurotoxicity of MDA and MDMA therefore appears to be dependent upon the generation of a neurotoxic metabolite, or metabolites, the identity of which remains unclear. alpha-Methyldopamine (alpha-MeDA) is a major metabolite of both MDA and MDMA. We have shown that intracerebroventricular (icv) injection of 2,5-bis(glutathion-S-yl)-alpha-methyldopamine [2, 5-bis(glutathion-S-yl)-alpha-MeDA] causes decreases in serotonin concentrations in the striatum, cortex, and hippocampus, and neurobehavioral effects similar to those seen following MDA and MDMA administration. In contrast, although 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S-yl)-alpha-MeDA] and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine [5-(N-acetylcystein-S-yl)-alpha-MeDA] produce neurobehavioral changes similar to those seen with MDA and MDMA, and acute changes in brain 5-HT and dopamine concentrations, neither conjugate caused long-term decreases in 5-HT concentrations. We now report that direct intrastriatal or intracortical administration of 5-(glutathion-S-yl)-alpha-MeDA (4 x 200 or 4 x 400 nmol), 5-(N-acetylcystein-S-yl)-alpha-MeDA (4 x 7 or 4 x 20 nmol), and 2, 5-bis(glutathion-S-yl)-alpha-MeDA (4 x 150 or 4 x 300 nmol) causes significant decreases in striatal and cortical 5-HT concentrations (7 days following the last injection). Interestingly, intrastriatal injection of 5-(glutathion-S-yl)-alpha-MeDA or 2, 5-bis(glutathion-S-yl)-alpha-MeDA, but not 5-(N-acetylcystein-S-yl)-alpha-methyldopamine, also caused decreases in 5-HT concentrations in the ipsilateral cortex. The same pattern of changes was seen when the conjugates were injected into the cortex. The effects of the thioether conjugates of alpha-MeDA were confined to 5-HT nerve terminal fields

  11. Studies on the metabolism of catecholamines in the central nervous system of the mouse

    PubMed Central

    Ceasar, P.M.; Hague, P.; Sharman, D.F.; Werdinius, B.

    1974-01-01

    1 The distribution of the metabolites of noradrenaline, 1-(3,4-dihydroxyphenyl)ethane-1,2-diol (DOPEG) and 1-(4-hydroxy-3-methoxyphenyl)ethane-1,2-diol (MOPEG), in the brain of the mouse has been investigated. 2 The rate of disappearance of the metabolites after inhibition of the enzyme monoamine oxidase has been used to estimate their turnover rates in the mouse hypothalamus. It was concluded that the turnover of DOPEG was much faster than that of MOPEG. 3 When mice were treated with reserpine dissolved in 5% ascorbic acid solution there was an increase in the hypothalamic concentration of both MOPEG and DOPEG. However, similar increases in the concentrations of the two metabolites were seen when the animals were treated with 5% ascorbic acid solution alone. 4 The administration of tropolone, an inhibitor of the enzyme catechol-O-methyl transferase, resulted in an increase in the concentration of DOPEG. 5 Mice, exposed to a temperature of -15° C showed increased hypothalamic concentrations of both DOPEG and MOPEG. 6 The rates of formation in the mouse striatum of 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), acidic metabolites of dopamine, were compared with the turnover rate of dopamine, estimated from the rate at which this catecholamine disappears after treatment with α-methyl-p-tyrosine. It was concluded that the estimate of dopamine turnover obtained by this method is likely to be too large because of the compensatory feedback mechanism which is thought to play a role in the metabolism of dopamine in the brain. PMID:4141637

  12. Biomarkers of adult and developmental neurotoxicity

    SciTech Connect

    Slikker, William

    2005-08-07

    Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. A multidisciplinary approach is necessary to assess adult and developmental neurotoxicity due to the complex and diverse functions of the nervous system. The overall strategy for understanding developmental neurotoxicity is based on two assumptions: (1) significant differences in the adult versus the developing nervous system susceptibility to neurotoxicity exist and they are often developmental stage dependent; (2) a multidisciplinary approach using neurobiological, including gene expression assays, neurophysiological, neuropathological, and behavioral function is necessary for a precise assessment of neurotoxicity. Application of genomic approaches to developmental studies must use the same criteria for evaluating microarray studies as those in adults including consideration of reproducibility, statistical analysis, homogenous cell populations, and confirmation with non-array methods. A study using amphetamine to induce neurotoxicity supports the following: (1) gene expression data can help define neurotoxic mechanism(s) (2) gene expression changes can be useful biomarkers of effect, and (3) the site-selective nature of gene expression in the nervous system may mandate assessment of selective cell populations.

  13. Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations

    PubMed Central

    Bohár, Zsuzsanna; Toldi, József; Fülöp, Ferenc; Vécsei, László

    2015-01-01

    Kynurenines are the products of tryptophan metabolism. Among them, kynurenine and kynurenic acid are generally thought to have neuroprotective properties, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are considered neurotoxic. They participate in immunoregulation and inflammation and possess pro- or anti-excitotoxic properties, and their involvement in oxidative stress has also been suggested. Consequently, it is not surprising that kynurenines have been closely related to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. More information about the less-known metabolites, picolinic and cinnabarinic acid, evaluation of new receptorial targets, such as aryl-hydrocarbon receptors, and intensive research on the field of the immunomodulatory function of kynurenines delineated the high importance of this pathway in general homeostasis. Emerging knowledge about the kynurenine pathway provides new target points for the development of therapeutical solutions against neurodegenerative diseases. PMID:25938971

  14. Neurotoxicity of manganese oxide nanomaterials

    NASA Astrophysics Data System (ADS)

    Stefanescu, Diana M.; Khoshnan, Ali; Patterson, Paul H.; Hering, Janet G.

    2009-11-01

    Manganese (Mn) toxicity in humans has been observed as manganism, a disease that resembles Parkinson's disease. The mechanism of Mn toxicity and the chemical forms that may be responsible for its neurotoxicity are not well understood. We examined the toxicity of Mn oxide nanomaterials in a neuronal precursor cell model, using the MTS assay to evaluate mitochondrial function in living cells and the LDH assay to quantify the release of the enzyme lactate dehydrogenase as a result of damage to the cell membrane. Both assays show that the toxicity of Mn is dependent on the type of Mn oxide nanomaterial and its concentration as well as on the state of cell differentiation. Following exposure to Mn oxide nanomaterials, reactive oxygen species (ROS) are generated, and flow cytometry experiments suggest that cell death occurred through apoptosis. During exposure to Mn oxide nanomaterials, increased levels of the transcription factor NF-κB (which mediates the cellular inflammatory response) were observed.

  15. Delayed treatment of hemoglobin neurotoxicity.

    PubMed

    Regan, Raymond F; Rogers, Bret

    2003-01-01

    Hemoglobin is an oxidative neurotoxin that may contribute to cell injury after CNS trauma and hemorrhagic stroke. Prior studies have demonstrated that concomitant treatment with iron-chelating antioxidants prevents its neurotoxicity. However, the efficacy of these agents when applied hours after hemoglobin has not been determined, and is the subject of the present investigation. Consistent with prior observations, an increase in reactive oxygen species generation, detected by 2',7'-dichlorofluorescin oxidation, was observed when mixed neuronal/astrocyte cultures prepared from mouse cortex were exposed to hemoglobin alone. However, this oxidative stress developed slowly. A significant increase in the dichlorofluorescein signal compared with control, untreated cultures was not observed until four hours after addition of hemoglobin, and was followed by loss of membrane integrity and propidium iodide staining. Treating cultures with the 21-aminosteroid U74500A or the ferric iron chelator deferoxamine four hours after initiating hemoglobin treatment markedly attenuated reactive oxygen species production within 2 h. Continuous exposure to 5 micro M hemoglobin for 24 h resulted in death of about three-quarters of neurons, without injuring astrocytes. Most neuronal loss was prevented by concomitant treatment with U74500A; its effect was not significantly attenuated if treatment was delayed for 2-4 h, and it still prevented over half of neuronal death if treatment was delayed for 8 h. Similar neuroprotection was produced by delayed treatment with deferoxamine or the lipid-soluble iron chelator phenanthroline. None of these agents had any effect on neuronal death when added to cultures 12 h after hemoglobin. These results suggest that hemoglobin is a potent but slowly-acting neurotoxin. The delayed onset of hemoglobin neurotoxicity may make it an attractive target for therapeutic intervention.

  16. Improved Quantification of Plasma Catecholamines by the Radioenzymic Kit Method.

    DTIC Science & Technology

    1982-11-01

    TLC zones to scintillation vials, (g) elution of the metanephrines from the silica gel, followed by their oxidation to 3H- vanillin , (h) extraction of...the 3H- vanillin into scintillation counting fluid, (i) measurement of the radioactivity of each vial, and (j) calculation of catecholamine

  17. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  18. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  19. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  20. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  1. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  2. Molecular Profiling: Catecholamine Modulation of Gene Expression in Enteropathogenic Bacteria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Investigations of the enteric pathogens Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium and Vibrio parahaemolyticus have demonstrated that these bacteria can respond to the presence of catecholamines, including norepinephrine and/or epinephrine, in their environment by modulating g...

  3. Reduced catecholamine response to exercise in amenorrheic athletes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies have found an array of endocrine disturbances related to energy deprivation in women with functional hypothalamic amenorrhea. Purpose: We examined the catecholamine response to exercise in five eumenorrheic (EU) and five amenorrheic (AM) athletes, matched by age (mean T SEM: EU = 29.8 T 2.5 ...

  4. Catecholamines and related o-diphenols in cockroach hemolymph and cuticle during sclerotization and melanization: comparative studies on the order Dictyoptera.

    PubMed

    Czapla, T H; Hopkins, T L; Kramer, K J

    1990-01-01

    Catecholamines and related o-diphenols extracted from the cuticle and hemolymph of adult cockroaches during sclerotization and pigmentation of the cuticle were analyzed by reverse phase HPLC with electrochemical detection. At ecdysis, dopamine (DA) o-conjugates predominated in the hemolymph of Periplaneta americana, P. australasiae, P. fuliginosa, P. brunnea, and Blatta orientalis (Blattidae); Blattella germanica (Blattellidae); and Gromphadorhina portentosa and Blaberus craniifer (Blaberidae). N-Acetyldopamine (NADA) conjugates were second in abundance in these species, but were major in the hemolymph of the other blaberoid species, Leucophaea maderae and Nauphoeta cinerea. After ecdysis NADA became the major hemolymph catecholamine in all species as DA decreased rapidly. N-beta-Alanyldopamine (NBAD) concentrations in the hemolymph remained low in all species, although NBAD and its metabolite, N-beta-alanylnorepinephrine (NBANE), were generally the major catecholamines in tanning cuticle. Catechol (1,2-dihydroxybenzene) occurred mainly as a conjugate(s) at high levels in the hemolymph of nymphs and adults of all blattid species. Only trace amounts were detected in B. germanica and Cryptocercus punctulatus (Cryptocercidae), and none was found in any of the blaberoid species. High concentrations of NBANE and NBAD accumulated in tanning cuticle of B. germanica, G. portentosa, and all blattid species, whereas NADA and DA predominated in cuticle from the other blaberoid species, particularly L. maderae and N. cinerea. However, cockroaches as a group appear to utilize both the N-acetyl and N-beta-alanyl catecholamines for stabilization of the exoskeleton. The Blattidae differed most from the other families in having considerably higher concentrations of catecholamines in hemolymph and cuticle, as well as the large amounts of catechol conjugates in the hemolymph.

  5. Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy IngestionS⃞

    PubMed Central

    Perfetti, Ximena; O'Mathúna, Brian; Pizarro, Nieves; Cuyàs, Elisabet; Khymenets, Olha; Almeida, Bruno; Pellegrini, Manuela; Pichini, Simona; Lau, Serrine S.; Monks, Terrence J.; Farré, Magí; Pascual, Jose Antonio; Joglar, Jesús; de la Torre, Rafael

    2009-01-01

    3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and a serotonergic neurotoxicant in animal models and possibly humans. The underlying mechanism of neurotoxicity involves the formation of reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced neurotoxicity is mediated via the formation of bioreactive metabolites. In particular, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently cause the formation of glutathione and N-acetylcysteine conjugates, which retain the ability to redox cycle and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) and 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) in human urine of 15 recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 h after MDMA ingestion ∼0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and catechol-O-methyltransferase expression, the combination of which are major determinants of steady-state levels of HHMA and 4-hydroxy-3-methoxyamphetamine, probably explain the interindividual variability seen in the recovery of N-Ac-5-Cys-HHMA and N-Ac-5-Cys-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to neurotoxicity in humans. PMID:19349378

  6. A vicious cycle of acute catecholamine cardiomyopathy and circulatory collapse secondary to pheochromocytoma.

    PubMed

    Otusanya, Olufisayo; Goraya, Harmeen; Iyer, Priyanka; Landi, Kristen; Tibb, Amit; Msaouel, Pavlos

    2015-10-01

    Acute catecholamine cardiomyopathy is an uncommon, life-threatening manifestation of pheochromocytoma. The massive release of catecholamines from the adrenal medulla and their toxic effects on the coronary vessels and the cardiac myocytes play a significant role in the pathogenesis of cardiomyopathy in patients with pheochromocytoma. Severe manifestations, such as acute catecholamine cardiomyopathy, may be the initial presentation, especially in unsuspected and untreated pheochromocytoma cases. The clinical course of catecholamine-induced cardiomyopathy is unpredictable as patients may rapidly deteriorate into circulatory collapse and multisystem crisis. We report a case of a 25-year-old man who presented with catecholamine-induced cardiomyopathy.

  7. ASSESSING HIPPOCAMPAL CHANGES INDICATIVE OF NEUROTOXIC EFFECTS.

    EPA Science Inventory

    Subtle changes in cognitive function are often the earliest indication of neurotoxic effects in humans. The hippocampus is a large forebrain structure subserving specific kinds of information encoding and consolidation in humans and other animals. Because of it laminar structur...

  8. EVALUATION OF POTENTIAL DEVELOPMENTAL NEUROTOXICITY OF ORGANOTINS.

    EPA Science Inventory

    Organotins, including monomethyltin (MMT), dimethyltin (DMT), and dibutyltin (DBT), are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for developmental neurotoxic effects were raised by published findi...

  9. Strategies for enhancing catecholamine-mediated neurotransmission

    NASA Technical Reports Server (NTRS)

    Wurtman, Richard J.

    1992-01-01

    Major findings made during this project period included the following observations: changes in tyrosine availability do affect brain dopamine release, as assessed by in vivo microdialysis, but that neuronal feedback mechanisms limit the durations of this effect except when dopaminergic neurotransmission has been deficient; the circulating hormone TRH markedly stimulates brain dopamine release, an effect probably mediated by its diketopiperazine metabolite; the amount of circulating L-dopa which enters the brain is both enhanced by carbohydrate consumption and suppressed by protein intake (both nutritional effects can be damaging, inasmuch as a sudden rush of L-dopa into the brain can facilitate dyskinesias, while the inhibition of brain L-dopa uptake by proteins suppresses its conversion to brain dopamine; an appropriate mixture of dietary proteins and carbohydrates can obviate both effects); serotonin release from superfused hypothalamic slices is a linear function of available tryptophan levels throughout the normal dynamic range; the daily rhythm in plasma melatonin levels is abnormal both in the sudden infant death syndrome and in women with secondary amenorrhea; tyrosine can potentiate the anorectic effects of widely-used sympathomimetic drugs; newly-described COMT inhibitors can enhance brain dopamine release in vivo; and a cell culture system, based on Y-79 (retinoblast) cells, exists in which melatonin reliably suppresses dopamine release.

  10. Hypercalcemic effect of catecholamines and its prevention by thyrocalcitonin.

    PubMed

    Hsu, W H; Cooper, C W

    1975-12-18

    Earlier work by others has shown that the catecholamines, epinephrine and isoproterenol, can raise blood calcium levels in parathyroidectomized but not intact rats, and can restrict the hypocalcemic effect of injected thyrocalcitonin (TCT). The present findings support this earlier work, further showing that such catecholamines can produce hypercalcemia in rats after removal of the thyroid gland by acute thyroparathyroidectomy (TPTX) and indicating that these drugs may raise blood calcium by mobilizing calcium from bone. Rats were fasted overnight, subjected to TPTX and concurrently injected with adrenergic agonist or antagonist drugs alone or in combination. Epinephrine, isoproterenol, and the beta-2 adrenergic agonist, salbutamol, in doses greater than or equal to 1 mg/kg raised blood calcium from low normal levels (approximately 9-10 mg/100 ml) by 1.5 to 2 mg/100 ml (p less than 0.01). Hypercalcemia was apparent by 1 hour after injection and lasted for 1-4 hours. The extent of Ca elevation was dose-related. Pretreatment of rats with the alpha-adrenergic antagonist, phenoxybenzamine, enhanced the effect of epinephrine while pretreatment with the beta-antagonist, propranolol, reduced the effect of isoproterenol. The more selective beta-2 antagonist, butoxamine, but not the beta-1 antagonist, practolol, also reduced the hypercalcemic effect of isoproterenol in TPTX rats. These results suggest that catecholamine-induced hypercalcemia in TPTX rats is mediated by beta-2 adrenergic receptors. Related studies using rats prelabeled with 45Ca further suggest that the catecholamines, like parathyroid hormone, may act to raise blood calcium by mobilizing calcium from bone. The fact that these catecholamines could induce marked hypercalcemia in acutely TPTX rats but not in intact rats indicated that endogenous TCT protects the thyroid intact rat against hypercalcemia. The present findings support this idea in showing that isoproterenol and salbutamol raised levels of

  11. Cocaine treatment increases expression of a 40 kDa catecholamine-regulated protein in discrete brain regions.

    PubMed

    Sharan, Niki; Chong, Victor Z; Nair, Venugopalan D; Mishra, Ram K; Hayes, Robert J; Gardner, Eliot L

    2003-01-01

    Previous reports from our laboratory have described brain-specific catecholamine-regulated proteins, which bind dopamine and related catecholamines. Evidence from the molecular cloning of a 40 kDa catecholamine-regulated protein (CRP40) revealed that CRP40 is dopamine-inducible and has properties similar to those of the 70 kDa heat shock protein (HSP70) family. The present study investigates the effects of acute and chronic cocaine treatment on CRP40 expression in the striatum, nucleus accumbens, prefrontal cortex, and medulla. Acute treatment with cocaine increased CRP40 expression in the nucleus accumbens and striatum, whereas chronic treatment with cocaine increased CRP40 expression in the nucleus accumbens only. Neither of these treatments affected CRP40 levels in the prefrontal cortex or medulla. In addition, pretreatment with the spin-trapping agent alpha-phenyl-tert-butylnitrone did not attenuate cocaine-induced expression of CRP40, suggesting that the observed increases in CRP40 levels were not caused by free radicals. On the other hand, pretreatment with anisomycin, a protein synthesis inhibitor, blocked the cocaine-induced expression of CRP40. Thus, protein synthesis may be involved in the observed CRP40 level increases. Furthermore, neither acute nor chronic cocaine treatment affected levels of inducible or constitutively expressed HSP70, which indicates a specificity of cocaine's effects on CRP40. Since cocaine has been shown to increase extracellular dopamine levels, these findings suggest that increased expression of CRP40 is associated with high extracellular levels of dopamine (or its metabolites). Elevated levels of CRP40 could play a protective role for dopamine neurons in response to increased oxidative stress that has been shown to be induced by cocaine and that can lead to apoptosis and neurodegeneration.

  12. Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson’s disease and other synucleinopathies

    PubMed Central

    Holmes, Courtney; Sharabi, Yehonatan

    2012-01-01

    Central catecholamine deficiency characterizes α-synucleinopathies such as Parkinson’s disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson’s disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects—108 synucleinopathy patients (34 Parkinson’s disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson’s disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 ± 0.09 (SEM), 1.00 ± 0.09, 1.32 ± 0.12 nmol/l] than controls (2.15 ± 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 ± 0.44, 7.75 ± 0.42, 5.82 ± 0.65 nmol/l) than controls (11.0 ± 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson’s disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson’s disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson’s disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid

  13. Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies.

    PubMed

    Goldstein, David S; Holmes, Courtney; Sharabi, Yehonatan

    2012-06-01

    Central catecholamine deficiency characterizes α-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 ± 0.09 (SEM), 1.00 ± 0.09, 1.32 ± 0.12 nmol/l] than controls (2.15 ± 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 ± 0.44, 7.75 ± 0.42, 5.82 ± 0.65 nmol/l) than controls (11.0 ± 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid

  14. Spectrophotometric determination of some catecholamine drugs using sodium bismuthate.

    PubMed

    Sorouraddin, M H; Manzoori, J L; Kargarzadeh, E; Haji Shabani, A M

    1998-12-01

    A novel spectrophotometric method is described for the determination of epinephrine (EP) and norepinephrine (NE). The method is based on the development of a red colour with sodium bismuthate, as a sensitive chromogenic reagent, in aqueous medium at pH 3. Oxidation of these catecholamines produces aminochrome derivatives which can be measured spectrophotometrically at 486.0 nm. Calibration graphs are linear in the range 4.8-800 (micromol l(-1)) for epinephrine bitartarate and 4.8-600 (micromol l(-1)) for norepinephrine bitartarate with detection limits of 0.26 (micromol l(-1)) and 2.46 (micromol l(-1)) for epinephrine and norepinephrine bitartarate salts, respectively. The method has successfully been applied to determination of these catecholamines in pharmaceutical preparations.

  15. Microfluorometric Detection of Catecholamines with Multiphoton-Excited Fluorescence

    NASA Astrophysics Data System (ADS)

    Balaji, J.; Reddy, Chandra S.; Kaushalya, S. K.; Maiti, Sudipta

    2004-04-01

    We demonstrate sensitive spatially resolved detection of physiological chromophores that emit in the ultraviolet (less than 330 nm). An atypical laser source (a visible wavelength femtosecond optical parametric oscillator), and an unconventional collection geometry (a lensless detector that detects the forward-emitted fluorescence) enable this detection. We report the excitation spectra of the catecholamines dopamine and norepinephrine, together with near-UV emitters serotonin and tryptophan, in the range of 550-595 nm. We estimate the molecular two-photon action cross section of dopamine, norepinephrine, and serotonin to be 1.2 mGM (1 GM, or Goppert Mayor, is equal to 10^-58 m^4 s^-1 photon^-1), 2 mGM, and 43 mGM, respectively, at 560 nm. The sensitivity achieved by this method holds promise for the microscopic imaging of vesicular catecholamines in live cells.

  16. PREDICTORS OF PLASMA AND URINARY CATECHOLAMINE LEVELS IN NORMOTENSIVE AND HYPERTENSIVE MEN AND WOMEN

    PubMed Central

    Saxena, Aditi R.; Chamarthi, Bindu; Williams, Gordon H.; Hopkins, Paul N.; Seely, Ellen W.

    2013-01-01

    Age, sex, hypertension and dietary sodium are proposed to affect plasma and urinary catecholamines. Yet no prior study has examined the simultaneous effects of these factors within the same study population, so results may have been confounded by factors not determined. We investigate, for the first time, the impact of simultaneously determined predictors of plasma and urinary catecholamines, and the relationship of catecholamines with the diagnosis of hypertension. Hypertensive and normotensive subjects (n=308) were studied off antihypertensives in liberal and low sodium balance. Twenty-four hour urinary catecholamines (norepinephrine and epinephrine) were measured. Plasma catecholamines were measured supine after overnight fast. Repeated measures multivariate linear regression models examined effect of sex, race, age, body mass index, dietary salt (liberal salt vs. low salt), hypertension status, and mean arterial pressure on plasma and urinary catecholamines. Logistic regression determined the relationship of catecholamines with diagnosis of hypertension. Dietary sodium restriction and increasing age predicted increased plasma and urinary norepinephrine, with sodium restriction having greatest effect. Female sex predicted lower urinary and plasma epinephrine. Neither plasma nor urinary catecholamines predicted the diagnosis of hypertension. In summary, specific demographic factors variably impact catecholamines and should be considered when assessing catecholamines in research and clinical settings. PMID:24226101

  17. Predictors of plasma and urinary catecholamine levels in normotensive and hypertensive men and women.

    PubMed

    Saxena, A R; Chamarthi, B; Williams, G H; Hopkins, P N; Seely, E W

    2014-05-01

    Age, sex, hypertension and dietary sodium are proposed to affect plasma and urinary catecholamines. Yet no prior study has examined the simultaneous effects of these factors within the same study population. So results may have been confounded by factors not determined. We investigate, for the first time, the impact of simultaneously determined predictors of plasma and urinary catecholamines and the relationship of catecholamines with the diagnosis of hypertension. Hypertensive and normotensive subjects (n=308) were studied off antihypertensives in liberal and low sodium balance. 24 h urinary catecholamines (norepinephrine and epinephrine) were measured. Plasma catecholamines were measured supine after overnight fast. Repeated measures multivariate linear regression models examined the effect of sex, race, age, body mass index (BMI), dietary salt (liberal salt vs low salt), hypertension status and mean arterial pressure (MAP) on plasma and urinary catecholamines. Logistic regression determined the relationship of catecholamines with diagnosis of hypertension. Dietary sodium restriction and increasing age predicted increased plasma and urinary norepinephrine, with sodium restriction having the greatest effect. Female sex predicted lower urinary and plasma epinephrine. Neither plasma nor urinary catecholamines predicted the diagnosis of hypertension. In summary, specific demographic factors variably impact catecholamines and should be considered when assessing catecholamines in research and clinical settings.

  18. Urinary catecholamine levels in children with and without dental caries.

    PubMed

    Vanderas, A P; Manetas, C; Papagiannoulis, L

    1995-10-01

    Urinary catecholamines have been used to measure emotionally stressful states which may affect the development of dental caries. This study investigates the hypothesis that children with and without dental caries do not differ significantly in the mean values of urinary catecholamines such as epinephrine, norepinephrine, and dopamine. As a test of this hypothesis, 314 children, males and females, aged from 6 to 8 years, were included in the study. Dental caries were recorded clinically and radiographically, and oral hygiene was evaluated by the recording of dental plaque. A 24-hour urine sample was collected for each subject, and a representative sample (25 mL) was analyzed by the HPLC technique to assay the catecholamine content. Socioeconomic factors such as parental age, education, and profession were recorded by a questionnaire distributed to the parents. Of the examined children, 38 (14 males and 24 females) were free of dental caries and constituted the case group. Two control groups, A and B, of 38 children each (14 males and 24 females) with dental caries were matched by age and gender. Differences in the quantitative and qualitative data were tested by the paired t test and the X2-test, respectively, while a regression analysis was applied to measure the effects of norepinephrine and dopamine on epinephrine. The logistic multiple-regression analysis was used to test, in the entire population, the impact of catecholamines and other related factors on the probability of subjects' developing dental caries. The 95% probability was used. The results showed statistically significant differences in epinephrine values between the case group and control groups A and B. The data suggest, therefore, that children with emotionally stressful states have higher probability of developing dental caries.

  19. Chronic hyperoxic effects on cat carotid body catecholamines and structure.

    PubMed

    Mokashi, A; Di Guilio, C; Morelli, L; Lahiri, S

    1994-06-01

    To account for the loss of O2 chemoreception in the cat carotid body during chronic hyperoxia, we studied the putative neurotransmitter correlates. Also, we studied the structural aspect of the carotid body tissues. We found that catecholamine concentrations increased and that the densecored vesicles in the glomus cells were not depleted, indicating that a lack of transmitters was not the cause for the loss of O2 chemoreception.

  20. Rutin attenuates ethanol-induced neurotoxicity in hippocampal neuronal cells by increasing aldehyde dehydrogenase 2.

    PubMed

    Song, Kibbeum; Kim, Sokho; Na, Ji-Young; Park, Jong-Heum; Kim, Jae-Kyung; Kim, Jae-Hun; Kwon, Jungkee

    2014-10-01

    Rutin is derived from buckwheat, apples, and black tea. It has been shown to have beneficial anti-inflammatory and antioxidant effects. Ethanol is a central nervous system depressant and neurotoxin. Its metabolite, acetaldehyde, is critically toxic. Aldehyde dehydrogenase 2 (ALDH2) metabolizes acetaldehyde into nontoxic acetate. This study examined rutin's effects on ALDH2 activity in hippocampal neuronal cells (HT22 cells). Rutin's protective effects against acetaldehyde-based ethanol neurotoxicity were confirmed. Daidzin, an ALDH2 inhibitor, was used to clarify the mechanisms of rutin's protective effects. Cell viability was significantly increased after rutin treatment. Rutin significantly reversed ethanol-increased Bax, cytochrome c expression and caspase 3 activity, and decreased Bcl-2 and Bcl-xL protein expression in HT22 cells. Interestingly, rutin increased ALDH2 expression, while daidzin reversed this beneficial effect. Thus, this study demonstrates rutin protects HT22 cells against ethanol-induced neurotoxicity by increasing ALDH2 activity.

  1. Novel free radical spin traps protect against malonate and MPTP neurotoxicity.

    PubMed

    Matthews, R T; Klivenyi, P; Mueller, G; Yang, L; Wermer, M; Thomas, C E; Beal, M F

    1999-05-01

    Both malonate and 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) are neurotoxins which cause energy depletion, secondary excitotoxicity, and free radical generation. Malonate is a reversible inhibitor of succinate dehydrogenase, while MPTP is metabolized to 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I. We examined the effects of pretreatment with the cyclic nitrone free radical spin trap MDL 101,002 on malonate and MPTP neurotoxicity. MDL 101,002 produced dose-dependent neuroprotection against malonate-induced striatal lesions. MDL 101, 002 produced significant protection against MPTP induced depletions of dopamine and its metabolites. MDL 101,002 also significantly attenuated MPTP-induced increases in striatal 3-nitrotyrosine concentrations. The free radical spin trap tempol also produced significant protection against MPTP neurotoxicity. These findings provide further evidence that free radical spin traps produce neuroprotective effects in vivo and suggest that they may be useful in the treatment of neurodegenerative diseases.

  2. Catecholamine differential modulation of PMA and superantigen stimulated lymphocytes

    SciTech Connect

    Downs, M.O.; Johnson, H.M. )

    1991-03-15

    Neurotransmitters have been demonstrated to be important modulators of immune regulation. The authors have previously demonstrated that the catecholamine agonists isoproterenol (Iso), epinephrine (Epi), and norepinephrine (Nor) are potent inhibitors of IFN{gamma} production by phorbol myristate acetate (PMA) stimulated T-cell lymphoma cell line (L12-R4) with the order of potency being Iso > Epi > Nor. Herein, they describe a differential effect of catecholamine influence on staphylococcal enterotoxin A (SEA) stimulated murine splenic cell cultures. Norepinephrine and to a lesser extent Epi can cause a biphasic modulation of IFN{gamma} production. Inhibition of INF{gamma}was seen in the micromolar range while augmentation occurred at the nanomolar range. In light of previous work, these data suggest that {beta}-adrenergic agonist stimulation of antigen presenting cells (APC) may be immunosuppressive while {alpha}-agonist stimulation immunopotentiating. Further, APC may play a central role in determining the net outcome of catecholamine stimulation by being able to mediate signals from both pathways. This response may represent a peripheral neurotransmitter mediated mechanism for fine tuning' immunoreactivity.

  3. Hypotension and reduced catecholamines in neuropeptide Y transgenic rats.

    PubMed

    Michalkiewicz, Mieczyslaw; Knestaut, Kriss M; Bytchkova, Elena Yu; Michalkiewicz, Teresa

    2003-05-01

    The neurons that control blood pressure express neuropeptide Y. Administered centrally, this neuropeptide reduces blood pressure and anxiety, together with lowering sympathetic outflow. The generation of neuropeptide Y transgenic rats overexpressing this peptide, under its natural promoter, has allowed us to examine the role of endogenous neuropeptide Y in the long-term control of blood pressure by the sympathetic nervous system. This study tested a hypothesis that endogenous neuropeptide Y acts to reduce blood pressure and catecholamine release. Blood pressure was measured by radiotelemetry in conscious male transgenic and nontransgenic littermates (control). Novel cage with cold water and forced swimming were used as stressors. Catecholamines were determined in 24-hour urine (baseline) and plasma (cold water stress) by a radioenzymatic assay. Blood pressures in baseline and during the stresses were significantly reduced in the transgenic rats. The lower blood pressure was associated with reduced catecholamines, lower decrease in pressure after autonomic ganglionic blockade, and increased longevity. Data obtained through the use of this transgenic rat model support and extend the evidence for the previously postulated sympatholytic and hypotensive effects of neuropeptide Y and provide novel evidence for an important physiological role of endogenous peptide in blood pressure regulation. As indicated by the increased longevity of these rats, in long-term regulation, these buffering actions of neuropeptide Y may have important cardiovascular protective effects against sympathetic hyperexcitation.

  4. Pendrin localizes to the adrenal medulla and modulates catecholamine release.

    PubMed

    Lazo-Fernandez, Yoskaly; Aguilera, Greti; Pham, Truyen D; Park, Annie Y; Beierwaltes, William H; Sutliff, Roy L; Verlander, Jill W; Pacak, Karel; Osunkoya, Adeboye O; Ellis, Carla L; Kim, Young Hee; Shipley, Gregory L; Wynne, Brandi M; Hoover, Robert S; Sen, Shurjo K; Plotsky, Paul M; Wall, Susan M

    2015-09-15

    Pendrin (Slc26a4) is a Cl(-)/HCO3 (-) exchanger expressed in renal intercalated cells and mediates renal Cl(-) absorption. With pendrin gene ablation, blood pressure and vascular volume fall, which increases plasma renin concentration. However, serum aldosterone does not significantly increase in pendrin-null mice, suggesting that pendrin regulates adrenal zona glomerulosa aldosterone production. Therefore, we examined pendrin expression in the adrenal gland using PCR, immunoblots, and immunohistochemistry. Pendrin protein was detected in adrenal lysates from wild-type but not pendrin-null mice. However, immunohistochemistry and qPCR of microdissected adrenal zones showed that pendrin was expressed in the adrenal medulla, rather than in cortex. Within the adrenal medulla, pendrin localizes to both epinephrine- and norepinephrine-producing chromaffin cells. Therefore, we examined plasma catecholamine concentration and blood pressure in wild-type and pendrin-null mice under basal conditions and then after 5 and 20 min of immobilization stress. Under basal conditions, blood pressure was lower in the mutant than in the wild-type mice, although epinephrine and norepinephrine concentrations were similar. Catecholamine concentration and blood pressure increased markedly in both groups with stress. With 20 min of immobilization stress, epinephrine and norepinephrine concentrations increased more in pendrin-null than in wild-type mice, although stress produced a similar increase in blood pressure in both groups. We conclude that pendrin is expressed in the adrenal medulla, where it blunts stress-induced catecholamine release.

  5. Pendrin localizes to the adrenal medulla and modulates catecholamine release

    PubMed Central

    Lazo-Fernandez, Yoskaly; Aguilera, Greti; Pham, Truyen D.; Park, Annie Y.; Beierwaltes, William H.; Sutliff, Roy L.; Verlander, Jill W.; Pacak, Karel; Osunkoya, Adeboye O.; Ellis, Carla L.; Kim, Young Hee; Shipley, Gregory L.; Wynne, Brandi M.; Hoover, Robert S.; Sen, Shurjo K.; Plotsky, Paul M.

    2015-01-01

    Pendrin (Slc26a4) is a Cl−/HCO3− exchanger expressed in renal intercalated cells and mediates renal Cl− absorption. With pendrin gene ablation, blood pressure and vascular volume fall, which increases plasma renin concentration. However, serum aldosterone does not significantly increase in pendrin-null mice, suggesting that pendrin regulates adrenal zona glomerulosa aldosterone production. Therefore, we examined pendrin expression in the adrenal gland using PCR, immunoblots, and immunohistochemistry. Pendrin protein was detected in adrenal lysates from wild-type but not pendrin-null mice. However, immunohistochemistry and qPCR of microdissected adrenal zones showed that pendrin was expressed in the adrenal medulla, rather than in cortex. Within the adrenal medulla, pendrin localizes to both epinephrine- and norepinephrine-producing chromaffin cells. Therefore, we examined plasma catecholamine concentration and blood pressure in wild-type and pendrin-null mice under basal conditions and then after 5 and 20 min of immobilization stress. Under basal conditions, blood pressure was lower in the mutant than in the wild-type mice, although epinephrine and norepinephrine concentrations were similar. Catecholamine concentration and blood pressure increased markedly in both groups with stress. With 20 min of immobilization stress, epinephrine and norepinephrine concentrations increased more in pendrin-null than in wild-type mice, although stress produced a similar increase in blood pressure in both groups. We conclude that pendrin is expressed in the adrenal medulla, where it blunts stress-induced catecholamine release. PMID:26173457

  6. Copper deficiency in neonatal mice alters brain catecholamine levels

    SciTech Connect

    Bailey, W.R.; Prohaska, J.R. )

    1991-03-15

    Copper (Cu) deficiency was investigated in Swiss albino mice to develop a model that alters brain catecholamine metabolism without serious growth impairment. Cu deficiency was induced by feeding a diet low in Cu to dams beginning either 7 days (d) prior, 4d prior, 4d after, or on the day of parturition. All 4-week-old male Cu-deficient ({minus}Cu) offspring were anemic and exhibited biochemical characteristics of Cu deficiency when compared to their respective +Cu control mice. However, the best model, which resulted in altered catecholamine metabolism characterized by elevation of dopamine (DA) and depression in norepinephrine (NE) in brain, heart, and spleen, was when treatment began 4d prior to birth. Body and brain weight were not altered. However, levels of Cu in brain and liver of {minus}Cu mice were markedly reduced to 21% and 31% of those measured in +Cu controls, respectively. Furthermore, brain NE and DA concentrations of {minus}Cu mice were 72% and 132% of those quantified in +Cu offspring, respectively. A plausible explanation is that dietary Cu deficiency results in lower activity of brain dopamine-{beta}-monooxygenase, the Cu dependent enzyme that catalyzes conversion of DA to NE. It is not yet known if these changes in Ne and DA pool size altered the quantity or characteristics of the neuronal catecholamine receptors, and more importantly, whether or not the observed changes are reversible by nutritional intervention.

  7. Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal.

    PubMed

    Fox, Megan E; Rodeberg, Nathan T; Wightman, R Mark

    2017-02-01

    Dysregulated catecholamine signaling has long been implicated in drug abuse. Although much is known about adaptations following chronic drug administration, little work has investigated how a single drug exposure paired with withdrawal influences catecholamine signaling in vivo. We used fast-scan cyclic voltammetry in freely moving rats to measure real-time catecholamine overflow during acute morphine exposure and naloxone-precipitated withdrawal in two regions associated with the addiction cycle: the dopamine-dense nucleus accumbens (NAc) and norepinephrine-rich ventral bed nucleus of the stria terminalis (vBNST). We compared dopamine transients in the NAc with norepinephrine concentration changes in the vBNST, and correlated release with specific withdrawal-related behaviors. Morphine increased dopamine transients in the NAc, but did not elicit norepinephrine responses in the vBNST. Conversely, dopamine output was decreased during withdrawal, while norepinephrine was released in the vBNST during specific withdrawal symptoms. Both norepinephrine and withdrawal symptoms could be elicited in the absence of morphine by administering naloxone with an α2 antagonist. The data support reciprocal roles for dopamine and norepinephrine signaling during drug exposure and withdrawal. The data also support the allostasis model and show that negative-reinforcement may begin working after a single exposure/withdrawal episode.

  8. Current Challenges in Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    Neurotoxicity risk assessment must continue to evolve in parallel with advances in basic research. Along with this evolution is an expansion in the scope of neurotoxicity assessments of environmental health risks. Examples of this expansion include an increasing emphasis on complex animal models that better replicate human behavior and a wider array of molecular and mechanistic data relevant to interpreting the underlying cause(s) of toxicity. However, modern neurotoxicology studies are often more nuanced and complicated than traditional studies, and they often vary considerably in evaluation methods from one study to the next, impeding comparisons. This can pose particular difficulties for risk assessors, especially given the recent demand for chemical risk assessments to be more systematic and transparent. This presentation will introduce and provide some examples of specific challenges in neurotoxicity assessments of environmental chemicals. Some of these challenges are relatively new to the field, such as the incorporation of data on neuron-supportive glial cells into hazard characterization, while other challenges have persisted for several decades, but only recently are studies being designed to evaluate them, including analyses of latent neurotoxicity. The examples provided illustrate some future research areas of interest for scientists and risk assessors examining human neurotoxicity risk. This abstract will be presented to internal U.S. Food and Drug A

  9. In vitro neurotoxic hazard characterization of different tricresyl phosphate (TCP) isomers and mixtures.

    PubMed

    Duarte, Daniel J; Rutten, Joost M M; van den Berg, Martin; Westerink, Remco H S

    2016-02-03

    Exposure to tricresyl phosphates (TCPs), via for example contaminated cabin air, has been associated with health effects including the so-called aerotoxic syndrome. While TCP neurotoxicity is mainly attributed to ortho-isomers like tri-ortho-cresyl phosphate (ToCP), recent exposure and risk assessments indicate that ToCP levels in cabin air are very low. However, the neurotoxic potential of non-ortho TCP isomers and TCP mixtures is largely unknown. We therefore measured effects of exposure (up to 48h) to different TCP isomers, mixtures and the metabolite of ToCP (CBDP: cresyl saligenin phosphate) on cell viability and mitochondrial activity, spontaneous neuronal electrical activity, and neurite outgrowth in primary rat cortical neurons. The results demonstrate that exposure to TCPs (24-48h, up to 10μM) increases mitochondrial activity, without affecting cell viability. Effects of acute TCP exposure (30min) on neuronal electrical activity are limited. However, electrical activity is markedly decreased for the majority of TCPs (10μM) following 48h exposure. Additional preliminary data indicate that exposure to TCPs (48h, 10μM) did not affect the number of neurites per cell or average neurite length, except for TmCP and the analytical TCP mixture (Sigma) that induced a reduction of average neurite length. The combined neurotoxicity data demonstrate that the different TCPs, including ToCP, are roughly equipotent and a clear structure-activity relation is not apparent for the studied endpoints. The no-observed-effect-concentrations (1μM) are well above current exposure levels indicating limited neurotoxic health risk, although exposures may have been higher in the past. Moreover, prolonged and/or repeated exposure to TCPs may exacerbate the observed neurotoxic effects, which argues for additional research.

  10. Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin.

    PubMed Central

    Screnci, D.; Er, H. M.; Hambley, T. W.; Galettis, P.; Brouwer, W.; McKeage, M. J.

    1997-01-01

    The diaminocyclohexane platinum (Pt(DACH)) derivatives ormaplatin and oxaliplatin have caused severe and dose-limiting peripheral sensory neurotoxicity in a clinical trial. We hypothesized that this toxicity could vary in relation to the biotransformation and stereochemistry of these Pt(DACH) derivatives. We prepared pure R,R and S,S enantiomers of ormaplatin (Pt(DACH)Cl4), oxaliplatin (Pt(DACH)oxalato) and their metabolites (Pt(DACH)Cl2 and Pt(DACH)methionine) and assessed their peripheral sensory neurotoxicity and tissue distribution in the rat and in vitro anti-tumour activity in human ovarian carcinoma cell lines. The R,R enantiomers of Pt(DACH)Cl4, Pt(DACH)oxalato and Pt(DACH)Cl2, induced peripheral sensory neurotoxicity at significantly lower cumulative doses (18 +/- 5.7 vs 32 +/- 2.3 micromol kg(-1); P < 0.01) and at earlier times (4 +/- 1 vs 6.7 +/- 0.6 weeks; P = 0.016) during repeat-dose treatment than the S,S enantiomers. Pt(DACH)methionine enantiomers showed no biological activity. There was no difference between Pt(DACH) enantiomers in the platinum concentration in sciatic nerve, dorsal root ganglia, spinal cord, brain or blood at the end of each experiment. Three human ovarian carcinoma cell lines (41 M, 41 McisR and SKOV-3) showed no (or inconsistent) chiral discrimination in their sensitivity to Pt(DACH) enantiomers, whereas two cell lines (CH-1 and CH-1cisR) showed modest enantiomeric selectivity favouring the R,R isomer (more active). In conclusion, Pt(DACH) derivatives exhibit enantiomeric-selective peripheral sensory neurotoxicity during repeated dosing in rats favouring S,S isomers (less neurotoxic). They exhibited less chiral discrimination in their accumulation within peripheral nerves and in vitro anti-tumour activity. PMID:9275028

  11. Serum Catecholamines and Dysautonomia in Diabetic Gastroparesis and Liver Cirrhosis

    PubMed Central

    Aslam, Naeem; Kedar, Archana; Nagarajarao, Harsha S.; Reddy, Kartika; Rashed, Hani; Cutts, Teresa; Riely, Caroline; Abell, Thomas L.

    2016-01-01

    Background Plasma catecholamine influences autonomic function and control, but there are few reports correlating them. In this study, 47 individuals (mean age, 38 years) were studied: 19 diabetes mellitus (DM) patients with gastroparesis, 16 with liver disease and 12 control subjects. Methods Noninvasive autonomic function was assessed for sympathetic adrenergic functions as peripheral vasoconstriction in response to cold stress test and postural adjustment ratio (PAR) and cholinergic function as Valsalva ratio, represented by change in R-R intervals. Measurements were compared by analysis of variance and Spearman’s correlation, and results were reported as mean ± standard error. Results Plasma norepinephrine (1902.7 ± 263.3; P = 0.001) and epinephrine (224.5 ± 66.5; P = 0.008) levels, as well as plasma dopamine levels (861.3 ± 381.7), and total plasma catecholamine levels were highest for patients with liver disease, who also had significant negative correlation between norepinephrine level and vasoconstriction (P = 0.01; r = −0.5), PAR1 (P = 0.01; r = −0.5), sympathetic adrenergic functions (P = 0.005; r = −0.6), total autonomic index (P = 0.01–0.5) and total autonomic function (P = 0.01; r = −0.2) and also negative correlation between epinephrine plasma level and total autonomic function (P = 0.04; r = 0.4). DM patients were next highest in norepinephrine level (133.26 ± 7.43), but lowest for plasma catecholamine; a positive correlation between dopamine level and PAR1 (P = 0.008; r = 0.6) was also seen in this group. Plasma dopamine levels and spider score correlated negatively (P = 0.04; r = −0.5) and total plasma catecholamine positively with encephalopathy (P = 0.04; r = 0.5) in patients with liver disease. Conclusions Plasma catecholamine levels correlated with adrenergic functions in control subjects and patients with DM and liver disease, with no significant correlation seen for cholinergic function. PMID:26181082

  12. An integrated liquid chromatography-tandem mass spectrometry approach for the ultra-sensitive determination of catecholamines in human peripheral blood mononuclear cells to assess neural-immune communication.

    PubMed

    Li, Xiaoguang Sunny; Li, Shu; Kellermann, Gottfried

    2016-06-03

    Catecholamines play a vital role in the interactions between the nervous and immune systems and their dysfunctions are implicated in various autoimmune and neurological diseases. However, accurate quantitation of catecholamines in the immune system presents a special analytical challenge. We proposed the first LC-MS/MS method for the determination of catecholamines in human peripheral blood mononuclear cells (PBMC) with significantly improved sensitivity, selectivity and throughput without requiring derivatization, evaporation and ion-pairing reagent. PBMC were separated by density gradient centrifugation and lysed with 0.2M acetic acid. The analytical novelty includes the first solid phase extraction on a 96-well hydrophilic-lipophilic-balanced (HLB) μElution plate upon complexation with phenylboronic acid (PBA), enabling specific clean-up and fivefold pre-concentration of catecholamines in a single extraction. LC chromatographic separation was obtained on a PFP column with 0.01% HCOOH as additive with enhanced signal response. Summation of five MRM transitions yielded three-four fold rise in sensitivity. The lower limit of quantification of 1pg/mL for epinephrine (E) and 5pg/mL for norepinephrine (NE) and dopamine (DA) represents a considerable sensitivity improvement over available methods. Less than 8.7% of intraday and interday precision, 91.8-111.3% of accuracy and successful assessment of reference intervals for 40 healthy donors suggested good reproducibility and reliability of the assay. The novel PBA-HLB-PFP-MRM summation approach allows rapid, sensitive and reliable determination of catecholamines in PBMC, which will facilitate better understanding of the new arena of neural-immune network. Additionally, the substantially improved method can be modified to quantify catecholamines and metabolites in other biological matrices.

  13. Volatile Metabolites

    PubMed Central

    Rowan, Daryl D.

    2011-01-01

    Volatile organic compounds (volatiles) comprise a chemically diverse class of low molecular weight organic compounds having an appreciable vapor pressure under ambient conditions. Volatiles produced by plants attract pollinators and seed dispersers, and provide defense against pests and pathogens. For insects, volatiles may act as pheromones directing social behavior or as cues for finding hosts or prey. For humans, volatiles are important as flavorants and as possible disease biomarkers. The marine environment is also a major source of halogenated and sulfur-containing volatiles which participate in the global cycling of these elements. While volatile analysis commonly measures a rather restricted set of analytes, the diverse and extreme physical properties of volatiles provide unique analytical challenges. Volatiles constitute only a small proportion of the total number of metabolites produced by living organisms, however, because of their roles as signaling molecules (semiochemicals) both within and between organisms, accurately measuring and determining the roles of these compounds is crucial to an integrated understanding of living systems. This review summarizes recent developments in volatile research from a metabolomics perspective with a focus on the role of recent technical innovation in developing new areas of volatile research and expanding the range of ecological interactions which may be mediated by volatile organic metabolites. PMID:24957243

  14. Ca/sup 2 +/-stimulated catecholamine release from. cap alpha. -toxin-permeabilized PC12 cells: biochemical evidence for exocytosis and its modulation by protein kinase C and G protein

    SciTech Connect

    Ahnert-Hilger, G.; Braeutigam, M.; Gratzl, M.

    1987-12-01

    Two possible cellular pathways of catecholamines from the chromaffin vesicles of PC12 cells to the surrounding medium are explored in this study. The direct one circumventing the cytoplasm can be activated in ..cap alpha..-toxin-permeabilized cells with micromolar levels of free Ca/sup 2 +/. Catecholamine metabolites formed in the cytoplasm (i.e., 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxyphenylethanol) are neither formed nor released from the cells under these conditions. However, when vesicular catecholamines were discharged into the cytoplasm by addition of the ionophore nigericin, such metabolites are formed and released into the medium independent of Ca/sup 2 +/. Both types of experiments provide direct evidence for the operation of Ca/sup 2 +/-induced exocytosis of dopamine and noradrenaline in permeabilized PC12 cells. The Ca/sup 2 +/ dependence of dopamine or noradrenaline release, as measured by the determination of the endogenous catecholamines using the high-performance liquid chromatography technique, exhibits two different phases. One is already activated below ..mu..M free Ca/sup 2 +/ and plateaus at 1-5 ..mu..M free Ca/sup 2 +/, while a second occurs in the presence of larger amounts of free Ca/sup 2 +/ (10-100 ..mu..M). Ca/sup 2 +/-induced catecholamine release from the permeabilized cells can be modulated in different ways: It is enhanced by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate and the diacylglycerol 1-oleyl-2-acetylglycerol provided Mg/sup 2 +//ATP is present, and it is inhibited by guanosine 5'-O-(3-thiotriphosphate). The latter effect is abolished by pretreatment of the cells with pertussis toxin but not by cholera toxin. Thus, it appears that Ca/sup 2 +/-induced exocytosis can be modulated via the protein kinase C system, as well as via GTP binding proteins.

  15. A 21st Century Update on Neurotoxicity Risk Assessment

    EPA Science Inventory

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing ...

  16. Can Zebrafish be used to Identify Developmentally Neurotoxic Chemicals

    EPA Science Inventory

    Can Zebrafish be Used to Identify Developmentally Neurotoxic Chemicals? The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental neurotoxicity. We are exploring behavioral methods using zebrafish by desig...

  17. Neurotoxicity of heroin-cocaine combinations in rat cortical neurons.

    PubMed

    Cunha-Oliveira, Teresa; Rego, A Cristina; Garrido, Jorge; Borges, Fernanda; Macedo, Tice; Oliveira, Catarina R

    2010-09-30

    Cocaine and heroin are frequently co-abused by humans, in a combination known as speedball. Recently, chemical interactions between heroin (Her) or its metabolite morphine (Mor) and cocaine (Coc) were described, resulting in the formation of strong adducts. In this work, we evaluated whether combinations of Coc and Her affect the neurotoxicity of these drugs, using rat cortical neurons incubated with Coc, Her, Her followed by Coc (Her+Coc) and Her plus Coc (Her:Coc, 1:1). Neurons exposed to Her, Her+Coc and Her:Coc exhibited a decrease in cell viability, which was more pronounced in neurons exposed to Her and Her+Coc, in comparison with neurons exposed to the mixture (Her:Coc). Cells exposed to the mixture showed increased intracellular calcium and mitochondrial dysfunction, as determined by a decrease in intracellular ATP levels and in mitochondrial membrane potential, displaying both apoptotic and necrotic characteristics. Conversely, a major increase in cytochrome c release, caspase 3-dependent apoptosis, and decreased metabolic neuronal viability were observed upon sequential exposure to Her and Coc. The data show that drug combinations potentiate cortical neurotoxicity and that the mode of co-exposure changes cellular death pathways activated by the drugs, strongly suggesting that chemical interactions occurring in Her:Coc, such as adduct formation, shift cell death mechanisms towards necrosis. Since impairment of the prefrontal cortex is involved in the loss of impulse control observed in drug addicts, the data presented here may contribute to explain the increase in treatment failure observed in speedball abusers.

  18. Nucleus accumbens invulnerability to methamphetamine neurotoxicity.

    PubMed

    Kuhn, Donald M; Angoa-Pérez, Mariana; Thomas, David M

    2011-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure.

  19. Plasma and urine catecholamine levels in cosmonauts during long-term stay on Space Station Salyut-7

    NASA Astrophysics Data System (ADS)

    Kvetn̆anský, R.; Davydova, N. A.; Noskov, V. B.; Vigas̆, M.; Popova, I. A.; Us̆akov, A. C.; Macho, L.; Grigoriev, A. I.

    The activity of the sympathetic adrenal system in cosmonauts exposed to a stay in space lasting for about half a year has so far been studied only by measuring catecholamine levels in plasma and urine samples taken before space flight and after landing. The device "Plasma 01", specially designed for collecting and processing venous blood from subjects during space flight on board the station Salyut-7 rendered it possible for the first time to collect and freeze samples of blood from cosmonauts in the course of a long-term 237-day space flight. A physician-cosmonaut collected samples of blood and urine from two cosmonauts over the period of days 217-219 of their stay in space. The samples were transported to Earth frozen. As indicators of the sympathetic adrenal system activity, plasma and urine concentrations of epinephrine and norepinephrine as well as urine levels of the catecholamine metabolites metanephrine, normetanephrine, and vanillylmandelic acid were determined before, during and after space flight. On days 217-219 of space flight plasma epinephrine and norepinephrine levels were slightly increased, yet not substantially different from normal. During stress situations plasma norepinephrine and epinephrine levels usually exhibit a manifold increase. On days 217-219 of space flight norepinephrine and epinephrine levels in urine were comparable with pre-flight values and the levels of their metabolites were even significantly decreased. All the parameters studied, particularly plasma norepinephrine as well as urine norepinephrine, normetanephrine, and vanillylmandelic acid, reached the highest values 8 days after landing. The results obtained suggest that, in the period of days 217-219 of the cosmonauts' stay in space in the state of weightlessness, the sympathetic adrenal system is either not activated at all or there is but a slight activation induced by specific activities of the cosmonauts, whereas in the process of re-adaptation after space flight on

  20. Pb neurotoxicity: neuropsychological effects of lead toxicity.

    PubMed

    Mason, Lisa H; Harp, Jordan P; Han, Dong Y

    2014-01-01

    Neurotoxicity is a term used to describe neurophysiological changes caused by exposure to toxic agents. Such exposure can result in neurocognitive symptoms and/or psychiatric disturbances. Common toxic agents include heavy metals, drugs, organophosphates, bacterial, and animal neurotoxins. Among heavy metal exposures, lead exposure is one of the most common exposures that can lead to significant neuropsychological and functional decline in humans. In this review, neurotoxic lead exposure's pathophysiology, etiology, and epidemiology are explored. In addition, commonly associated neuropsychological difficulties in intelligence, memory, executive functioning, attention, processing speed, language, visuospatial skills, motor skills, and affect/mood are explored.

  1. A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine.

    PubMed

    van Vliet, Erwin; Morath, Siegfried; Eskes, Chantra; Linge, Jens; Rappsilber, Juri; Honegger, Paul; Hartung, Thomas; Coecke, Sandra

    2008-01-01

    There is a need for more efficient methods giving insight into the complex mechanisms of neurotoxicity. Testing strategies including in vitro methods have been proposed to comply with this requirement. With the present study we aimed to develop a novel in vitro approach which mimics in vivo complexity, detects neurotoxicity comprehensively, and provides mechanistic insight. For this purpose we combined rat primary re-aggregating brain cell cultures with a mass spectrometry (MS)-based metabolomics approach. For the proof of principle we treated developing re-aggregating brain cell cultures for 48 h with the neurotoxicant methyl mercury chloride (0.1-100 microM) and the brain stimulant caffeine (1-100 microM) and acquired cellular metabolic profiles. To detect toxicant-induced metabolic alterations the profiles were analysed using commercial software which revealed patterns in the multi-parametric dataset by principal component analyses (PCA), and recognised the most significantly altered metabolites. PCA revealed concentration-dependent cluster formations for methyl mercury chloride (0.1-1 microM), and treatment-dependent cluster formations for caffeine (1-100 microM) at sub-cytotoxic concentrations. Four relevant metabolites responsible for the concentration-dependent alterations following methyl mercury chloride treatment could be identified using MS-MS fragmentation analysis. These were gamma-aminobutyric acid, choline, glutamine, creatine and spermine. Their respective mass ion intensities demonstrated metabolic alterations in line with the literature and suggest that the metabolites could be biomarkers for mechanisms of neurotoxicity or neuroprotection. In addition, we evaluated whether the approach could identify neurotoxic potential by testing eight compounds which have target organ toxicity in the liver, kidney or brain at sub-cytotoxic concentrations. PCA revealed cluster formations largely dependent on target organ toxicity indicating possible potential

  2. The catecholamine response to spaceflight: role of diet and gender

    NASA Technical Reports Server (NTRS)

    Stein, T. P.; Wade, C. E.

    2001-01-01

    Compared with men, women appear to have a decreased sympathetic nervous system (SNS) response to stress. The two manifestations where the sexual dimorphism has been the most pronounced involve the response of the SNS to fluid shifts and fuel metabolism during exercise. The objectives of this study were to investigate whether a similar sexual dimorphism was found in the response to spaceflight. To do so, we compared catecholamine excretion by male and female astronauts from two similar shuttle missions, Spacelab Life Sciences 1 (SLS1, 1991) and 2 (SLS2, 1993) for evidence of sexual dimorphism. To evaluate the variability of the catecholamine response in men, we compared catecholamine excretion from the two SLS missions against the 1996 Life and Microgravity Sciences Mission (LMS) and the 1973 Skylab missions. RESULTS: No gender- or mission-dependent changes were found with epinephrine. Separating out the SLS1/2 data by gender shows that norepinephrine excretion was essentially unchanged with spaceflight in women (98 +/- 10%; n = 3) and substantially decreased with the men (41 +/- 9%; n = 4, P < 0.05). Data are a percentage of mean preflight value +/- SE. Comparisons among males demonstrated significant mission effects on norepinephrine excretion. After flight, there was a transient increase in norepinephrine but no evidence of any gender-specific effects. We conclude that norepinephrine excretion during spaceflight is both mission and gender dependent. Men show the greater response, with at least three factors being involved, a response to microgravity, energy balance, and the ratio of carbohydrate to fat in the diet.

  3. Lorry drivers' work stress evaluated by catecholamines excreted in urine.

    PubMed Central

    van der Beek, A J; Meijman, T F; Frings-Dresen, M H; Kuiper, J I; Kuiper, S

    1995-01-01

    OBJECTIVES--To evaluate lorry drivers' work stress by measurement of adrenaline and noradrenaline excreted in the urine, and to find out which factors in their working situation are related to the excretion rates of these catecholamines. METHODS--The urinary excretion of adrenaline and noradrenaline of 32 lorry drivers, who also had loading and unloading activities to perform, was studied for one working day and one rest day. Each driver was asked to provide six urine samples on both days. RESULTS--For all samples, except the first (overnight) sample, the excretion rates of both catecholamines on the working day were higher than those on the rest day. Hierarchical multiple regression analyses were carried out to find out which factors in the drivers' working situation were related to the excretion rate of the working day. The excretion rate of adrenaline on the rest day, age, and psychosomatic complaints were positively related to the excretion rate on the working day (all P < 0.05). Body mass index and physical workload during loading and unloading were positively related to noradrenaline excretion rate (both P < 0.01). Psychosocial job strain did not significantly contribute to the proportion of variance explained in the excretion rates of both catecholamines. CONCLUSIONS--The excretion rates of adrenaline and, especially, noradrenaline on the working day were higher than those found in earlier studies among professional drivers and insufficient recovery took place after the work was ended. The only association between excretion rate on the working day and work stressors was found for noradrenaline and physical workload. The drivers' sympathoadrenal medullary reactivity to everyday work demands shows the characteristics of sustained activation. PMID:7670621

  4. Interspecies variations in Bordetella catecholamine receptor gene regulation and function.

    PubMed

    Brickman, Timothy J; Suhadolc, Ryan J; Armstrong, Sandra K

    2015-12-01

    Bordetella bronchiseptica can use catecholamines to obtain iron from transferrin and lactoferrin via uptake pathways involving the BfrA, BfrD, and BfrE outer membrane receptor proteins, and although Bordetella pertussis has the bfrD and bfrE genes, the role of these genes in iron uptake has not been demonstrated. In this study, the bfrD and bfrE genes of B. pertussis were shown to be functional in B. bronchiseptica, but neither B. bronchiseptica bfrD nor bfrE imparted catecholamine utilization to B. pertussis. Gene fusion analyses found that expression of B. bronchiseptica bfrA was increased during iron starvation, as is common for iron receptor genes, but that expression of the bfrD and bfrE genes of both species was decreased during iron limitation. As shown previously for B. pertussis, bfrD expression in B. bronchiseptica was also dependent on the BvgAS virulence regulatory system; however, in contrast to the case in B. pertussis, the known modulators nicotinic acid and sulfate, which silence Bvg-activated genes, did not silence expression of bfrD in B. bronchiseptica. Further studies using a B. bronchiseptica bvgAS mutant expressing the B. pertussis bvgAS genes revealed that the interspecies differences in bfrD modulation are partly due to BvgAS differences. Mouse respiratory infection experiments determined that catecholamine utilization contributes to the in vivo fitness of B. bronchiseptica and B. pertussis. Additional evidence of the in vivo importance of the B. pertussis receptors was obtained from serologic studies demonstrating pertussis patient serum reactivity with the B. pertussis BfrD and BfrE proteins.

  5. Interspecies Variations in Bordetella Catecholamine Receptor Gene Regulation and Function

    PubMed Central

    Brickman, Timothy J.; Suhadolc, Ryan J.

    2015-01-01

    Bordetella bronchiseptica can use catecholamines to obtain iron from transferrin and lactoferrin via uptake pathways involving the BfrA, BfrD, and BfrE outer membrane receptor proteins, and although Bordetella pertussis has the bfrD and bfrE genes, the role of these genes in iron uptake has not been demonstrated. In this study, the bfrD and bfrE genes of B. pertussis were shown to be functional in B. bronchiseptica, but neither B. bronchiseptica bfrD nor bfrE imparted catecholamine utilization to B. pertussis. Gene fusion analyses found that expression of B. bronchiseptica bfrA was increased during iron starvation, as is common for iron receptor genes, but that expression of the bfrD and bfrE genes of both species was decreased during iron limitation. As shown previously for B. pertussis, bfrD expression in B. bronchiseptica was also dependent on the BvgAS virulence regulatory system; however, in contrast to the case in B. pertussis, the known modulators nicotinic acid and sulfate, which silence Bvg-activated genes, did not silence expression of bfrD in B. bronchiseptica. Further studies using a B. bronchiseptica bvgAS mutant expressing the B. pertussis bvgAS genes revealed that the interspecies differences in bfrD modulation are partly due to BvgAS differences. Mouse respiratory infection experiments determined that catecholamine utilization contributes to the in vivo fitness of B. bronchiseptica and B. pertussis. Additional evidence of the in vivo importance of the B. pertussis receptors was obtained from serologic studies demonstrating pertussis patient serum reactivity with the B. pertussis BfrD and BfrE proteins. PMID:26371128

  6. DEVELOPMENTAL NEUROTOXICITY OF PYRETHROID INSECTICIDES: CRITICAL REVIEW.

    EPA Science Inventory

    Pyrethroids are widely utilized insecticides whose primary action is the disruption of voltage-sensitive sodium channels (VSSC). Although these compounds have been in use for over 30 years and their acute neurotoxicity has been well characterized, there is considerably less info...

  7. NEUROTOXICITY OF TETRACHLOROETHYLENE (PERCHLOROETHYLENE): DISCUSSION PAPER

    EPA Science Inventory

    This paper is a background document for a meeting of neurotoxicity experts to discuss the central nervous system effects of exposure to perchloroethylene (perc). The document reviews the literature on neurological testing of people exposed to perc occupationally in dry cleanin...

  8. MANAGING EXPOSURES TO NEUROTOXIC AIR POLLUTANTS.

    EPA Science Inventory

    Researchers at EPA's National Health and Environmental Effects Research Laboratory are developing a biologically-based dose-response model to describe the neurotoxic effects of exposure to volatile organic compounds (VOCs). The model is being developed to improve risk assessment...

  9. Manganese neurotoxicity: a focus on the neonate.

    PubMed

    Erikson, Keith M; Thompson, Khristy; Aschner, Judy; Aschner, Michael

    2007-02-01

    Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (>1-5 mg Mn/m(3)) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

  10. Studies of (±)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile.

    PubMed

    Mueller, Melanie; Maldonado-Adrian, Concepcion; Yuan, Jie; McCann, Una D; Ricaurte, George A

    2013-02-01

    The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition.

  11. Clarithromycin-induced neurotoxicity in adults.

    PubMed

    Bandettini di Poggio, M; Anfosso, Sandra; Audenino, Daniela; Primavera, Alberto

    2011-03-01

    Clarithromycin is a relatively new antibiotic of the macrolide family heralded for an improved side effect profile, dosing schedule, and microbiological activity relative to its parent compound, erythromycin. We review the literature on clarithromycin-induced neurotoxicity in adults and present an illustrative case. A total of 38 patients with clarithromycin-induced neurotoxicity have been reported. The average age of patients was 51.3 years (range: 19-87 years) with females comprising 52.6% of patients. Psychiatric illness was the most common comorbidity, while only two patients had renal failure. Clarithromycin had been prescribed for respiratory infections in most patients, and only two patients were receiving more than 1000 mg/day of antibiotic. The symptoms started 1 day to 10 days after starting clarithromycin (mean: 5 days). A total of 71% of patients were under treatment with concomitant medication, and eight patients were undergoing treatment with psychoactive drugs. Patients had a very good outcome after clarithromycin was discontinued, but medication with neuroleptics or benzodiazepine was required for 58% of patients in the acute phase. Only four patients underwent an electroencephalogram (EEG). Our illustrative patient was a 74-year-old woman with clarithromycin-induced delirium due to non-convulsive status epilepticus (NCSE). Her clinical symptoms and electroencephalogram (EEG) readings dramatically improved after discontinuation of clarithromycin. The mechanism underlying the central nervous system side effects remains unclear. We suggest including an EEG in the diagnostic procedures of patients under treatment with clarithromycin who develop features of neurotoxicity because an EEG can help to differentiate patients with psychiatric illness from those with encephalopathy or epilepsy. Because of the widespread use of clarithromycin, clinicians should be aware of its neurotoxicity. Early detection of clarithromycin-induced neurotoxicity and

  12. Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

    PubMed Central

    Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

    2012-01-01

    Purpose. The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro. Methods. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth. Results. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001). Conclusion. Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous

  13. Selective 5-hydroxytryptamine2 receptor antagonists protect against the neurotoxicity of methylenedioxymethamphetamine in rats.

    PubMed

    Schmidt, C J; Abbate, G M; Black, C K; Taylor, V L

    1990-11-01

    The serotonergic deficits resulting from methylenedioxymethamphetamine (MDMA)-induced neurotoxicity were prevented by the simultaneous administration of 5-hydroxytryptamine2 (5-HT2) receptor antagonists such as MDL 11,939 or ritanserin. This effect was not region specific as protection was observed in the cortex, hippocampus and striatum 1 week after the administration of a single dose of MDMA. MDL 11,939 also showed some efficacy at reducing the deficits in 5-HT concentrations and tryptophan hydroxylase activity produced by multiple administrations of MDMA. Protection against the neurotoxicity required the administration of MDL 11,939 within 1 hr of MDMA indicating 5-HT2 receptor activation was an early event in the process leading to terminal damage. Examination of the effect of the 5-HT2 receptor blockade on the early neurochemical alterations induced by MDMA revealed an inhibitory effect on MDMA-stimulated dopamine synthesis. Analysis of these data and the associated changes in dopamine metabolites indicates that 5-HT2 receptor antagonists block MDMA-induced neurotoxicity by interfering with the ability of the dopamine neuron to maintain its cytoplasmic pool of transmitter and thereby sustain carrier-mediated dopamine release.

  14. Is the deficiency of vitamin B12 related to oxidative stress and neurotoxicity in Parkinson's patients?

    PubMed

    Qureshi, G Ali; Qureshi, Aftab A; Devrajani, Bika Ram; Chippa, M A; Syed, S Ali

    2008-02-01

    This review deals with the results showing the relation between vitamin B(12) deficiency and neurotoxicity of homocysteine and nitrite (a metabolite of nitric oxide) in Parkinson's patients treated with levodopa (L-Dopa). We have already reported a linear relationship between the CSF levels of nitrite with glutamic acid and homocysteine suggesting that the production of nitrite is interrelated with the neurotoxic level of homocysteine. The levels of nitrite and homocysteine resulting in the deficiency of vitamin B(12) are some of the factors promoting degeneration in Parkinson's disease. This review emphasizes the importance of these parameters in designing suitable drug therapy for Parkinson disease. Additionally, there is evidence that increased homocysteine levels might accelerate dopaminergic cell death in Parkinson disease (PD), through neurotoxic effects. Furthermore, levodopa (L-Dopa) treatment of PD results in hyperhomocysteinemia as a consequence of L-Dopa methylation by catechol-O-methyltransferase (COMT). Therefore, higher dietary intakes of folate, vitamin B12, and vitamin B6 might decrease the risk of PD through decreasing plasma homocysteine.

  15. DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats.

    PubMed

    Li, Zhen; Cui, Shengzhong; Zhang, Zhuo; Zhou, Rong; Ge, Yingbin; Sokabe, Masahiro; Chen, Ling

    2009-02-01

    Dehydroepiandrosterone (DHEA) has been implicated not only to prevent N-methyl-D-aspartate (NMDA)-induced neurotoxicity but also to enhance Ca(2+) influx through NMDA receptor (NMDAr). However, these DHEA effects, which would produce inconsistent outcomes about neuronal damages, are not well studied in ischemia-induced cerebral damages. Herein, we report that a single administration of DHEA (20 mg/kg) during 3 to 48 h after transient global cerebral ischemia in rats exerted neuroprotective effects such as reduction of ischemia-induced neuronal death in the hippocampal CA1 and improvement of ischemia-induced deficits in spatial learning. By contrast, at 1 h before or after ischemia, the administration of DHEA exacerbated the ischemia-induced neuronal death and learning impairment. This DHEA neurotoxicity appeared to be caused by DHEA itself, but not through its metabolite testosterone, and was inhibited by a pretreatment with the NMDAr blocker MK801 or the sigma-1 (sigma(1)) receptor antagonist NE100. However, the DHEA neuroprotection was blocked by NE100. These results show that DHEA not only provides robust ischemic neuroprotection with a long therapeutic opportunity but also exerts neurotoxicity when administered during ischemia and early reperfusion, which points to the importance of administration timing of DHEA in the clinical treatment of brain damages by the transient brain ischemia including stroke.

  16. Direct effects of recurrent hypoglycaemia on adrenal catecholamine release.

    PubMed

    Orban, Branly O; Routh, Vanessa H; Levin, Barry E; Berlin, Joshua R

    2015-01-01

    In Type 1 and advanced Type 2 diabetes mellitus, elevation of plasma epinephrine plays a key role in normalizing plasma glucose during hypoglycaemia. However, recurrent hypoglycaemia blunts this elevation of plasma epinephrine. To determine whether recurrent hypoglycaemia affects peripheral components of the sympatho-adrenal system responsible for epinephrine release, male rats were administered subcutaneous insulin daily for 3 days. These recurrent hypoglycaemic animals showed a smaller elevation of plasma epinephrine than saline-injected controls when subjected to insulin-induced hypoglycaemia. Electrical stimulation of an adrenal branch of the splanchnic nerve in recurrent hypoglycaemic animals elicited less release of epinephrine and norepinephrine than in controls, without a change in adrenal catecholamine content. Responsiveness of isolated, perfused adrenal glands to acetylcholine and other acetylcholine receptor agonists was also unchanged. These results indicate that recurrent hypoglycaemia compromised the efficacy with which peripheral neuronal activity stimulates adrenal catecholamine release and demonstrate that peripheral components of the sympatho-adrenal system were directly affected by recurrent hypoglycaemia.

  17. Stress, Allostatic Load, Catecholamines, and Other Neurotransmitters in Neurodegenerative Diseases

    PubMed Central

    2017-01-01

    As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators—“homeostats.” Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. “Allostatic load” refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholaminergic neurons leak vesicular contents into the cytoplasm continuously during life and that catecholamines in the neuronal cytoplasm are autotoxic. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time. PMID:21615193

  18. Catecholamine-Based Treatment in AD Patients: Expectations and Delusions

    PubMed Central

    Stefani, Alessandro; Olivola, Enrica; Liguori, Claudio; Hainsworth, Atticus H.; Saviozzi, Valentina; Angileri, Giacoma; D’Angelo, Vincenza; Galati, Salvatore; Pierantozzi, Mariangela

    2015-01-01

    In Alzheimer disease, the gap between excellence of diagnostics and efficacy of therapy is wide. Despite sophisticated imaging and biochemical markers, the efficacy of available therapeutic options is limited. Here we examine the possibility that assessment of endogenous catecholamine levels in cerebrospinal fluid (CSF) may fuel new therapeutic strategies. In reviewing the available literature, we consider the effects of levodopa, monoamine oxidase inhibitors, and noradrenaline (NE) modulators, showing disparate results. We present a preliminary assessment of CSF concentrations of dopamine (DA) and NE, determined by HPLC, in a small dementia cohort of either Alzheimer’s disease (AD) or frontotemporal dementia patients, compared to control subjects. Our data reveal detectable levels of DA, NE in CSF, though we found no significant alterations in the dementia population as a whole. AD patients exhibit a small impairment of the DA axis and a larger increase of NE concentration, likely to represent a compensatory mechanism. While waiting for preventive strategies, a pragmatic approach to AD may re-evaluate catecholamine modulation, possibly stratified to dementia subtypes, as part of the therapeutic armamentarium. PMID:25999852

  19. Stress, Allostatic Load, Catecholamines, and Other Neurotransmitters in Neurodegenerative Diseases

    PubMed Central

    2016-01-01

    As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators—“homeostats.” Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. “Allostatic load” refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholaminergic neurons leak vesicular contents into the cytoplasm continuously during life and that catecholamines in the neuronal cytoplasm are autotoxic. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time. PMID:22297542

  20. A calcium ionophore stimulating the secretion of catecholamines from the cat adrenal.

    PubMed Central

    Garcia, A G; Kirpekar, S M; Prat, J C

    1975-01-01

    1. Experiments were performed on perfused cat adrenal glands to examine the effect of a calcium ionophore A-23187 in the secretion of catecholamines. 2. Ionophore (1-10 muM) caused a dose-dependent release of catecholamines and the output was about 100-fold greater at 10 mum than at 1 mum. 3. Release of catecholamines by the ionophore was dependent on the calcium concentration of the perfusion medium. Omission of calcium blocked the response to the ionophore while excess calcium facilitated it. 4. Magnesium antagonized the secretory response to the ionophore. Excess calcium overcame the inhibitory effect of magnesium. 5. The ionophore did not modify release of catecholamines by induced splanchnic nerve stimulation. 6. The results suggest that the ionophore, like depolarization, introduces calcium into the chromaffin cell to cause release of catecholamines. PMID:1091727

  1. Gap Junction Intercellular Communication Mediates Ammonia-Induced Neurotoxicity.

    PubMed

    Bobermin, Larissa Daniele; Arús, Bernardo Assein; Leite, Marina Concli; Souza, Diogo Onofre; Gonçalves, Carlos-Alberto; Quincozes-Santos, André

    2016-02-01

    Astrocytes are important brain targets of ammonia, a neurotoxin implicated in the development of hepatic encephalopathy. During hyperammonemia, the pivotal role of astrocytes in brain function and homeostasis is impaired. These cells are abundantly interconnected by gap junctions (GJ), which are intercellular channels that allow the exchange of signaling molecules and metabolites. This communication may also increase cellular vulnerability during injuries, while GJ uncoupling could limit the extension of a lesion. Therefore, the current study was performed to investigate whether astrocyte coupling through GJ contributes to ammonia-induced cytotoxicity. We found that carbenoxolone (CBX), an effective GJ blocker, prevented the following effects induced by ammonia in astrocyte primary cultures: (1) decrease in cell viability and membrane integrity; (2) increase in reactive oxygen species production; (3) decrease in GSH intracellular levels; (4) GS activity; (5) pro-inflammatory cytokine release. On the other hand, CBX had no effect on C6 astroglial cells, which are poorly coupled via GJ. To our knowledge, this study provides the first evidence that GJ play a role in ammonia-induced cytotoxicity. Although more studies in vivo are required to confirm our hypothesis, our data suggest that GJ communication between astrocytes may transmit damage signals and excitotoxic components from unhealthy to normal cells, thereby contributing to the propagation of the neurotoxicity of ammonia.

  2. Relationship between Urinary Pesticide Residue Levels and Neurotoxic Symptoms among Women on Farms in the Western Cape, South Africa

    PubMed Central

    Motsoeneng, Portia M.; Dalvie, Mohamed A.

    2015-01-01

    Background: This cross-sectional study aimed to investigate the relationship between urinary pesticide residue levels and neurotoxic symptoms amongst women working on Western Cape farms in South Africa. Method: A total of 211 women were recruited from farms (n = 121) and neighbouring towns (n = 90). Participant assessment was via a Q16 questionnaire, reporting on pesticide exposures and measurement of urinary OP metabolite concentrations of dialkyl phosphates (DAP) and chlorpyriphos, 3,5,6-trichloropyridinol (TCPY) and of pyrethroid (PYR) metabolite concentrations (3- phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), and the cis- and trans isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane-1-carboxylic acid. Results: Median urinary pesticide metabolites were slightly (6%–49%) elevated in the farm group compared to the town group, with 2 metabolites significantly higher and some lower in the farm group. The prevalence of all Q16 symptoms was higher amongst farm women compared to town women. Three Q16 symptoms (problems with buttoning, reading and notes) were significantly positively associated with three pyrethroid metabolites (cis- and trans-DCCA and DBCA), although associations may due to chance as multiple comparisons were made. The strongest association for a pyrethroid metabolite was between problems with buttoning and DBCA (odds ratio (OR) = 8.93, 95% confidence interval (CI):1.71–46.5. There was no association between Q16 symptoms and OP metabolites. Conclusions: Women farm residents and rural women from neighbouring towns in the Western Cape are exposed to OP and PYR pesticides. The study did not provide strong evidence that pesticides are associated with neurotoxic symptoms but associations found could be explored further. PMID:26042367

  3. Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.

    PubMed

    Mathieu, Cécile; Bui, Linh-Chi; Petit, Emile; Haddad, Iman; Agbulut, Onnik; Vinh, Joelle; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

    2017-02-03

    Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.

  4. Accumulation of neurotoxic organochlorines and trace elements in brain of female European eel (Anguilla anguilla).

    PubMed

    Bonnineau, C; Scaion, D; Lemaire, B; Belpaire, C; Thomé, J-P; Thonon, M; Leermaker, M; Gao, Y; Debier, C; Silvestre, F; Kestemont, P; Rees, J-F

    2016-07-01

    Xenobiotics such as organochlorine compounds (OCs) and metals have been suggested to play a significant role in the collapse of European eel stocks in the last decades. Several of these pollutants could affect functioning of the nervous system. Still, no information is so far available on levels of potentially neurotoxic pollutants in eel brain. In present study, carried out on female eels caught in Belgian rivers and canals, we analyzed brain levels of potentially-neurotoxic trace elements (Ag, Al, As, Cd, Co, Cr, Cu, Fe, Hg, MeHg, Mn, Ni, Pb, Sn, Sb, Zn) and OCs (Polychlorinated biphenyls, PCBs; Hexachlorocyclohexanes, HCHs; Dichlorodiphenyltrichloroethane and its metabolites, DDTs). Data were compared to levels in liver and muscle tissues. Eel brain contained very high amounts of OCs, superior to those found in the two other tissues. Interestingly, the relative abundance of PCB congeners markedly differed between tissues. In brain, a predominance of low chlorinated PCBs was noted, whereas highly chlorinated congeners prevailed in muscle and liver. HCHs were particularly abundant in brain, which contains the highest amounts of β-HCH and ϒ-HCH. p,p'-DDTs concentration was similar between brain and muscle (i.e., about twice that of liver). A higher proportion of p,p'-DDT was noticed in brain. Except for Cr and inorganic Hg, all potentially neurotoxic metals accumulated in brain to levels equal to or lower than hepatic levels. Altogether, results indicate that eel brain is an important target for organic and, to a lesser extent, for inorganic neurotoxic pollutants.

  5. Clinical and imaging features of fludarabine neurotoxicity.

    PubMed

    Lee, Michael S; McKinney, Alexander M; Brace, Jeffrey R; Santacruz, Karen

    2010-03-01

    Neurotoxicity from intravenous fludarabine is a rare but recognized clinical entity. Its brain imaging features have not been extensively described. Three patients received 38.5 mg or 40 mg/m per day fludarabine in a 5-day intravenous infusion before bone marrow transplantation in treatment of hematopoietic malignancies. Several weeks later, each patient developed progressive neurologic decline, including retrogeniculate blindness, leading to coma and death. Brain MRI showed progressively enlarging but mild T2/FLAIR hyperintensities in the periventricular white matter. The lesions demonstrated restricted diffusion but did not enhance. Because the neurotoxicity of fludarabine appears long after exposure, neurologic decline in this setting is likely to be attributed to opportunistic disease. However, the imaging features are distinctive in their latency and in being mild relative to the profound clinical features. The safe dose of fludarabine in this context remains controversial.

  6. Mechanisms of methamphetamine-induced dopaminergic neurotoxicity.

    PubMed

    Riddle, Evan L; Fleckenstein, Annette E; Hanson, Glen R

    2006-01-01

    Methamphetamine (METH) is a powerful stimulant of abuse with potent addictive and neurotoxic properties. More than 2.5 decades ago, METH-induced damage to dopaminergic neurons was described. Since then, numerous advancements have been made in the search for the underlying mechanisms whereby METH causes these persistent dopaminergic deficits. Although our understanding of these mechanisms remains incomplete, combinations of various complex processes have been described around a central theme involving reactive species, such as reactive oxygen and/or nitrogen species (ROS and RNS, respectively). For example, METH-induced hyperthermia, aberrant dopamine(DA), or glutamate transmission; or mitochondrial disruption leads to the generation of reactive species with neurotoxic consequences. This review will describe the current understanding of how high-dose METH administration leads to the production of these toxic reactive species and consequent permanent dopaminergic deficits.

  7. Environmental neurotoxicity of chemicals and radiation

    SciTech Connect

    Verity, M.A. )

    1993-06-01

    Epidemiologic and societal concerns continue to stimulate studies in the field of environmental neurotoxicology. Although the role of heavy metals, aluminum, and iron are unclear in the etiology of human neurodegenerative disorders, these toxins have provided fertile ground for in vivo and in vitro experimental studies to elucidate their role in neurotoxic injury. Experimental models of clinical syndromes are discussed with special relevance to developmental neurotoxicology. Cycloleucine, tellurium, and 1,3-dinitrobenzene provide models of subacute combined degeneration, primary peripheral nerve demyelination, and thiamine deficiency-like lesions, respectively. Increasing attention is being given to irradiation neurotoxicity, especially in the developing or young central nervous system. A fuller understanding of the pathogenesis of low-dose irradiation injury allows for a clearer understanding of its neurobiology and also provides a more rational approach to understanding an interventional therapy associated with brain irradiation for childhood neoplasia. 43 refs.

  8. Neurotoxic aspects of porphyinopathies: lead and succinylacetone

    SciTech Connect

    Silbergeld, E.K.; Hruska, R.E.; Bradley, D.; Lamon, J.M.; Frykholm, B.C.

    1982-12-01

    Neurotoxic effects of heavy metals and polyhalogenated hydrocarbons frequently occur at low levels of exposure, in some cases below those levels where direct toxic actions of these compounds have been demonstrated. Rats with acute and chronic lead exposure were compared to rats whose heme synthesis was inhibited by succinylacetone, as a semichronic model of the hereditary heme synthesis disorder, acute intermittent porphyria. Both treatments produce significant inhibition in activity of the enzyme delta-aminolevulinic acid dehydrase and elevations in the heme precursor delta-aminolevulinic acid (ALA) in tissues and urine. Associated with increased ALA is a significant inhibition of neurotransmission utilizing the amino acid ..gamma..-aminobutyric acid (GABA), expressed chemically and behaviorally. The results suggest that in addition to their direct molecular neurotoxicity, porphyrinopathic compounds such as lead may, through altering heme synthesis, adversely affect the brain at low levels of exposure.

  9. [Neurotoxic effects of cobalt: an open question].

    PubMed

    Catalani, S; Apostoli, P

    2011-01-01

    Increased cobalt levels have been associated with neurological diseases (hand tremor, incoordination, cognitive decline, depression, vertigo, hearing loss and visual changes) in addition to "classic" and known cardiac diseases (arrhythmias and cardiomyopathies) and allergic or endocrine symptoms. Cobalt neurotoxicity is reported in isolated cases: old occupational or iatrogenic exposures and more recent releases of metallic ions by prosthesis. The studies of these cases have revealed a typical symptomatology of cobalt probably due to its ability to induce oxidative stress and mitochondrial alterations.

  10. Putative adverse outcome pathways relevant to neurotoxicity

    PubMed Central

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  11. Assessing the Developmental Neurotoxicity of 27 ...

    EPA Pesticide Factsheets

    Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphorus pesticides for developmental neurotoxicity. As such, we are exploring a behavioral testing paradigm that can assess the effects of sublethal and subteratogenic concentrations of developmental neurotoxicants on zebrafish (Danio rerio). This in vivo assay quantifies the locomotor response to light stimuli under tandem light and dark conditions in a 96-well plate using a video tracking system on 6 day post fertilization zebrafish larvae. Each of twenty-seven organophosphorus pesticides was tested for their developmental neurotoxic potential by exposing zebrafish embryos/larvae to the pesticide at several concentrations (≤ 100 μM nominal concentration) during the first five days of development, followed by 24 hours of depuration and then behavioral testing. Approximately 22% of the chemicals (Acephate, Dichlorvos, Diazoxon, Bensulide,Tribufos, Tebupirimfos) did not produce any behavioral changes after developmental exposure, while many (Malaoxon Fosthiazate, Dimethoate, Dicrotophos, Ethoprop, Malathion, Naled, Diazinon, Methamidophos, Terbufos, Trichlorfon, Phorate, Pirimiphos-methyl, Profenofos, Z-Tetrachlorvinphos, Chlorpyrifos, Coumaphos, Phosmet, Omethoate) produced changes in swi

  12. Neurotoxicity of Acrylamide in Exposed Workers

    PubMed Central

    Pennisi, Manuela; Malaguarnera, Giulia; Puglisi, Valentina; Vinciguerra, Luisa; Vacante, Marco; Malaguarnera, Mariano

    2013-01-01

    Acrylamide (ACR) is a water-soluble chemical used in different industrial and laboratory processes. ACR monomer is neurotoxic in humans and laboratory animals. Subchronic exposure to this chemical causes neuropathies, hands and feet numbness, gait abnormalities, muscle weakness, ataxia, skin and in some cases, cerebellar alterations. ACR neurotoxicity involves mostly the peripheral but also the central nervous system, because of damage to the nerve terminal through membrane fusion mechanisms and tubulovescicular alterations. Nevertheless, the exact action mechanism is not completely elucidated. In this paper we have reviewed the current literature on its neurotoxicity connected to work-related ACR exposure. We have analyzed not only the different pathogenetic hypotheses focusing on possible neuropathological targets, but also the critical behavior of ACR poisoning. In addition we have evaluated the ACR-exposed workers case studies. Despite all the amount of work which have being carried out on this topic more studies are necessary to fully understand the pathogenetic mechanisms, in order to propose suitable therapies. PMID:23985770

  13. Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat

    SciTech Connect

    Szabo, S.; Horner, H.C.; Maull, H.; Schnoor, J.; Chiueh, C.C.; Palkovits, M.

    1987-03-01

    Previous structure-activity and pharmacologic studies with duodenal ulcerogens cysteamine and propionitrile implicating catecholamines in the pathogenesis of duodenal ulceration have now been followed up by dose- and time-response biochemical investigations to assess the importance of monoamines in the development of duodenal ulcers. The concentrations of norepinephrine (noradrenaline), dopamine, serotonin and their metabolites were measured in total brain, brain regions, stomach, duodenum, pancreas and adrenals in the rat. Turnover of catecholamines was determined in rats pretreated with the inhibitor of tyrosine hydroxylase alpha-methyl-p-tyrosine. The duodenal ulcerogens caused a dose- and time-dependent depletion of norepinephrine in virtually all the tissues examined. The effect was maximal 4 or 7 hr after cysteamine or propionitrile, and norepinephrine levels returned to normal in 24 hr. Dopamine changes were selective and often biphasic, e.g., elevation in adrenals, biphasic in brain cortex, hippocampus and midbrain, but uniformly decreasing in glandular stomach and duodenum. In the median eminence dopamine levels decreased by 181 and 324% at 15 and 30 min, respectively, after cysteamine, but neither dopamine nor 3,4-dihydroxyphenylacetic acid was modified in the periventricular nucleus. Serotonin levels were relatively stable, revealing slight elevations or no changes in most of the tissues. The turnover of norepinephrine was accelerated by both chemicals in virtually all brain regions, but dopamine turnover was affected only in a few areas, e.g., in the corpus striatum and medulla oblongata cysteamine decreased dopamine turnover, whereas propionitrile first (at 1 hr) accelerated then (at 8 hr) significantly suppressed it.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Changes in rat adrenal catecholamines and proenkephalin metabolism after denervation.

    PubMed

    Fleminger, G; Lahm, H W; Udenfriend, S

    1984-06-01

    Adrenal enkephalin-containing peptides are known to increase 10- to 15-fold in the rat after surgical denervation of the gland. In this report we show that the increase is preceded by a lag of several hours, which is indicative of stimulation of protein synthesis at the transcriptional level. The major species of newly appearing enkephalin-containing peptide appears to be the intact precursor, proenkephalin. Processing of proenkephalin to smaller enkephalin-containing peptides in the denervated glands is slow and limited. The only product that accumulates in the process is a peptide of 3-4 kilodaltons that is derived from the carboxyl terminus of proenkephalin. An interesting observation was the dissociation between the effects of denervation on enkephalin-containing peptides and catecholamines. This is surprising because both are localized in the chromaffin granules of the gland.

  15. Changes in rat adrenal catecholamines and proenkephalin metabolism after denervation.

    PubMed Central

    Fleminger, G; Lahm, H W; Udenfriend, S

    1984-01-01

    Adrenal enkephalin-containing peptides are known to increase 10- to 15-fold in the rat after surgical denervation of the gland. In this report we show that the increase is preceded by a lag of several hours, which is indicative of stimulation of protein synthesis at the transcriptional level. The major species of newly appearing enkephalin-containing peptide appears to be the intact precursor, proenkephalin. Processing of proenkephalin to smaller enkephalin-containing peptides in the denervated glands is slow and limited. The only product that accumulates in the process is a peptide of 3-4 kilodaltons that is derived from the carboxyl terminus of proenkephalin. An interesting observation was the dissociation between the effects of denervation on enkephalin-containing peptides and catecholamines. This is surprising because both are localized in the chromaffin granules of the gland. PMID:6587373

  16. Plasma catecholamines during behavioral treatments for Raynaud's disease.

    PubMed

    Freedman, R R; Keegan, D; Migály, P; Galloway, M P; Mayes, M

    1991-01-01

    We have previously demonstrated that the vasospastic attacks of Raynaud's disease can be induced despite blockade of efferent digital nerves and that feedback-induced vasodilation is mediated through a non-neural, beta-adrenergic mechanism. Here, we sought to determine the role of sympathetic activity, as measured by plasma epinephrine and norepinephrine, during finger temperature feedback and autogenic training. Thirty-one female patients with idiopathic Raynaud's disease were randomly assigned to receive finger temperature feedback or autogenic training over 28 days. Half of each group began and finished training during the follicular phase of the menstrual cycle, the other half during the luteal phase. During training, significant temperature elevations were shown by feedback patients but not by autogenic patients. There were no significant effects for norepinephrine and epinephrine for either group. Cycle phase did not interact with training effects or with catecholamines. These findings do not support the role of decreased sympathetic activation in behavioral treatments for Raynaud's disease.

  17. Effects of water immersion on plasma catecholamines in normal humans

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Johnson, G.; Denunzio, A. G.

    1983-01-01

    An investigation was conducted in order to determine whether water immersion to the neck (NI) alters plasma catecholamines in normal humans. Eight normal subjects were studied during a seated control study (C) and during 4 hr of NI, and the levels of norepinephrine (NE) and epinephrine (E) as determined by radioenzymatic assay were measured hourly. Results show that despite the induction of a marked natriuresis and diuresis indicating significant central hypervolemia, NI failed to alter plasma NE or E levels compared with those of either C or the corresponding prestudy 1.5 hr. In addition, the diuresis and natriuresis was found to vary independently of NE. These results indicate that the response of the sympathetic nervous system to acute volume alteration may differ from the reported response to chronic volume expansion.

  18. The effect of sleep apnea on plasma and urinary catecholamines.

    PubMed

    Dimsdale, J E; Coy, T; Ziegler, M G; Ancoli-Israel, S; Clausen, J

    1995-06-01

    Numerous studies have suggested an alteration of sympathetic nervous system functioning in sleep apnea. However, most of these studies did not control for confounding factors such as diet, obesity, hypertension and anti-hypertensive medications. We examined plasma and urinary catecholamines in 43 patients, including hypertensive and normotensive individuals with and without sleep apnea. Hypertensive patients were studied at least 3 weeks following tapering of anti-hypertensive medication. All patients consumed similar diets and were of similar age and level of obesity. Twenty-four-hour urinary norepinephrine levels were significantly higher in apneics (58.2 ng vs. 40.2 ng in nonapneics, p < 0.002). Urinary norepinephrine in apneics was increased during both day and night. Plasma norepinephrine levels were not significantly elevated in apneic patients but were elevated in hypertensive patients both during sleep and in the morning (p < 0.05).

  19. Effect of heart failure on catecholamine granule morphology and storage in chromaffin cells

    PubMed Central

    Mahata, Sushil K; Zheng, Hong; Mahata, Sumana; Liu, Xuefei

    2016-01-01

    One of the key mechanisms involved in sympathoexcitation in chronic heart failure (HF) is the activation of the adrenal glands. Impact of the elevated catecholamines on the hemodynamic parameters has been previously demonstrated. However, studies linking the structural effects of such overactivation with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not been previously reported. In this study, HF was induced in male Sprague-Dawley rats by ligation of the left coronary artery. Five weeks after surgery, cardiac function was assessed by ventricular hemodynamics. HF rats showed increased adrenal weight and adrenal catecholamine levels (norepinephrine, epinephrine and dopamine) compared with sham-operated rats. Rats with HF demonstrated increased small synaptic and dense core vesicle in splanchnic–adrenal synapses indicating trans-synaptic activation of catecholamine biosynthetic enzymes, increased endoplasmic reticulum and Golgi lumen width to meet the demand of increased catecholamine synthesis and release, and more mitochondria with dilated cristae and glycogen to accommodate for the increased energy demand for the increased biogenesis and exocytosis of catecholamines from the adrenal medulla. These findings suggest that increased trans-synaptic activation of the chromaffin cells within the adrenal medulla may lead to increased catecholamines in the circulation which in turn contributes to the enhanced neurohumoral drive, providing a unique mechanistic insight for enhanced catecholamine levels in plasma commonly observed in chronic HF condition. PMID:27402067

  20. Effect of heart failure on catecholamine granule morphology and storage in chromaffin cells.

    PubMed

    Mahata, Sushil K; Zheng, Hong; Mahata, Sumana; Liu, Xuefei; Patel, Kaushik P

    2016-09-01

    One of the key mechanisms involved in sympathoexcitation in chronic heart failure (HF) is the activation of the adrenal glands. Impact of the elevated catecholamines on the hemodynamic parameters has been previously demonstrated. However, studies linking the structural effects of such overactivation with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not been previously reported. In this study, HF was induced in male Sprague-Dawley rats by ligation of the left coronary artery. Five weeks after surgery, cardiac function was assessed by ventricular hemodynamics. HF rats showed increased adrenal weight and adrenal catecholamine levels (norepinephrine, epinephrine and dopamine) compared with sham-operated rats. Rats with HF demonstrated increased small synaptic and dense core vesicle in splanchnic-adrenal synapses indicating trans-synaptic activation of catecholamine biosynthetic enzymes, increased endoplasmic reticulum and Golgi lumen width to meet the demand of increased catecholamine synthesis and release, and more mitochondria with dilated cristae and glycogen to accommodate for the increased energy demand for the increased biogenesis and exocytosis of catecholamines from the adrenal medulla. These findings suggest that increased trans-synaptic activation of the chromaffin cells within the adrenal medulla may lead to increased catecholamines in the circulation which in turn contributes to the enhanced neurohumoral drive, providing a unique mechanistic insight for enhanced catecholamine levels in plasma commonly observed in chronic HF condition.

  1. Taurine inhibition of metal-stimulated catecholamine oxidation.

    PubMed

    Dawson, R; Baker, D; Eppler, B; Tang, E; Shih, D; Hern, H; Hu, M

    2000-01-01

    Taurine is an abundant amino acid found in mammalian tissues and it has been suggested to have cytoprotective functions. The aim of the present study was to determine if taurine had the potential to reduce oxidative stress associated with metal-stimulated catecholamine oxidation. Taurine and structural analogs of taurine were tested for their ability to inhibit metal-stimulated quinone formation from dopamine or L-dopa. Oxidative damage to proteins and lipids were also assessed in vitro and the effects of taurine were determined. Taurine (20 mM) was found to decrease significantly ferric iron (50-500 microM)- and manganese (10 microM)-stimulated L-dopa or dopamine oxidation. Taurine had no effect on zinc-induced dopamine oxidation and slightly potentiated copper- and NaIO(4)-stimulated quinone formation. Ferric iron-stimulated lipid peroxidation was not affected by taurine (1-20 mM). Protein carbonyl formation induced by ferric iron (500 microM) and L-dopa (500 microM) was significantly reduced by 10 mM taurine. The cytotoxicity of L-dopa (250 microM) and ferric chloride (75 microM) to LLC-PK(1) cells was attenuated by 10 mM taurine or hypotaurine. Homotaurine alone stimulated L-dopa oxidation and potentiated the cytotoxic effects of ferric iron. Homotaurine was found to be cytotoxic when combined with L-dopa or L-dopa/iron. In contrast, hypotaurine inhibited quinone formation and protected LLC-PK(1) cells. These studies suggest that taurine may exhibit cytoprotective effects against the oxidation products of catecholamines by acting as a scavenger for free radicals and cytotoxic quinones.

  2. In Vivo Voltammetric Monitoring of Catecholamine Release in Subterritories of the Nucleus Accumbens Shell

    PubMed Central

    Park, Jinwoo; Aragona, Brandon J.; Kile, Brian M.; Carelli, Regina M.; Wightman, R. Mark

    2010-01-01

    Fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes has been used to demonstrate that sub-second changes in catecholamine concentration occur within the nucleus accumbens (NAc) shell during motivated behaviors, and these fluctuations have been attributed to rapid dopamine signaling. However, FSCV cannot distinguish between dopamine and norepinephrine, and caudal regions of the NAc shell receive noradrenergic projections. Therefore, in the present study, we examined the degree to which norepinephrine contributes to catecholamine release within rostral and caudal portion of NAc shell. Analysis of tissue content revealed that dopamine was the major catecholamine detectable in the rostral NAc shell, whereas both dopamine and norepinephrine were found in the caudal subregion. To examine releasable catecholamines, electrical stimulation was used to evoke release in anesthetized rats with either stimulation of the medial forebrain bundle, a pathway containing both dopaminergic and noradrenergic projections to the NAc, or the ventral tegmental area/substantia nigra, the origin of dopaminergic projections. The catecholamines were distinguished by their responses to different pharmacological agents. The dopamine autoreceptor blocker, raclopride, as well as the monoamine and dopamine transporter blockers, cocaine and GBR 12909, increased evoked catecholamine overflow in both the rostral and caudal NAc shell. The norepinephrine autoreceptor blocker, yohimbine, and the norepinephrine transporter blocker, desipramine, increased catecholamine overflow in the caudal NAc shell without significant alteration of evoked responses in the rostral NAc shell. Thus, the neurochemical and pharmacological results show that norepinephrine signaling is restricted to caudal portions of the NAc shell. Following raclopride and cocaine or raclopride and GBR 12909, robust catecholamine transients were observed within the rostral shell but these were far less apparent in the caudal

  3. Optical fiber biosensor based on enzymatic coating matrix for catecholamines assessment in human urine

    NASA Astrophysics Data System (ADS)

    Silva, Lurdes I. B.; Freitas, Ana C.; Rocha-Santos, Teresa A. P.; Pereira, M. E.; Duarte, Armando C.

    2010-09-01

    An optical fiber (OF) biosensor has been developed and applied for simultaneous determination of catecholamines (dopamine, norepinephrine and epinephrine) in human urine. The developed analytical device shows a high potential for catecholamines quantification with a detection limit of 2.1, 2.6 and 3.4 pg mL-1 for dopamine, norepinephrine and epinephrine, respectively. The analytical performance of the OF biosensor was found to be similar to that of the High Performance Liquid Chromatography - Electrochemical Detector (HPLC-ED) regarding catecholamines determination in samples of human urine.

  4. Catecholamines and in vitro growth of pathogenic bacteria: enhancement of growth varies greatly among bacterial species

    NASA Technical Reports Server (NTRS)

    Belay, Tesfaye; Aviles, Hernan; Vance, Monique; Fountain, Kimberly; Sonnenfeld, Gerald

    2003-01-01

    The purpose of this study was to examine the effects of catecholamines on in vitro growth of a range of bacterial species, including anaerobes. Bacteria tested included: Porphyromonas gingivalis, Bacteriodes fragilis, Shigella boydii, Shigella sonnie, Enterobacter Sp, and Salmonella choleraesuis. The results of the current study indicated that supplementation of bacterial cultures in minimal medium with norepinephrine or epinephrine did not result in increased growth of bacteria. Positive controls involving treatment of Escherichia coli with catecholamines did result in increased growth of that bacterial species. The results of the present study extend previous observations that showed differential capability of catecholamines to enhance bacterial growth in vitro.

  5. Central Neurotoxicity of Immunomodulatory Drugs in Multiple Myeloma

    PubMed Central

    Patel, Urmeel H.; Mir, Muhammad A.; Sivik, Jeffrey K.; Raheja, Divisha; Pandey, Manoj K.; Talamo, Giampaolo

    2015-01-01

    Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy. PMID:25852850

  6. DISTRIBUTION OF ATRAZINE IN PC12 CELLS AND MODULATION OF CATECHOLAMINE SYNTHESIS

    EPA Science Inventory

    Previously, we reported that atrazine disrupts ovarian function by altering hypothalamic catecholamine (CA) concentrations and the consequent regulation of pituitary LH release and prolactin secretion in the young female rat. We also showed that atrazine directly interacts with t...

  7. Effect of dietary copper and sucrose on catecholamine concentrations in the adrenal medulla

    SciTech Connect

    Koo, S.I.; Peterson, D.F.; Mason, P.A. KCOM, Kirksville, MO Air Force/SAM/RZP, Brooks AFB, TX )

    1991-03-11

    The severity of copper (Cu) deficiency in the rat is enhanced by dietary sucrose. Possible interactive effects of Cu status and sucrose on catecholamine concentrations in the adrenal medulla were investigated in Cu deficient rats fed a diet were investigated in Cu deficient rats fed a diet containing either glucose or sucrose, as compared with respective Cu-adequate controls. Catecholamines were analyzed by an HPLC method using 3,4-dihydroxybenxylamine as the internal standard. Cu deficiency caused pronounced decreases in norepinephrine and epinephrine, with no significant effect on dopamine, as expressed in nmoles/mg tissue. Dietary sucrose showed no appreciable effect on catecholamines in the adrenal medulla. The adrenal glands were markedly enlarged in Cu-deficient rats, whether fed glucose or sucrose. Adrenal weights were not affected by dietary sucrose. Data indicate that the increased severity of copper deficiency due to sucrose feeding is not associated with changes in adrenal catecholamine output.

  8. Plasma catecholamines and postoperative gastric emptying and small intestinal propulsion in the rat.

    PubMed

    Dubois, A; Henry, D P; Kopin, I J

    1975-03-01

    The role of adrenal medullary discharge of catecholamines on inhibition of gastric emptying and small intestinal propulsion after laparotomy was examined in rats. The rate of movement of a 51Cr-labeled liquid test meal, which had been introduced by gastric intubation, out of the stomach and through the small intestine, was retarded 12 hr after laparotomy. Adrenal demedullation produced a striking decrease in plasma catecholamines and abolished surgically induced elevation of the catecholamines, but had no significant effect on gastric emptying or intestinal propulsion in rats subjected to laparotomy or in the unoperated control animals. Thus circulating catecholamines play little if any role in controlling normal gastroinestinal motility or in the postoperative decrease in rate of gastric emptying and small intestinal motility.

  9. Valacyclovir and Acyclovir Neurotoxicity With Status Epilepticus.

    PubMed

    Hoskote, Sumedh S; Annapureddy, Narender; Ramesh, Atul K; Rose, Keith; Jones, James P

    2016-01-01

    We present the case of a 52-year-old man with hypertension, diastolic congestive heart failure, end-stage renal disease on hemodialysis 3 times a week and a remote history of a hemorrhagic stroke who presented to the emergency department with a vesicular rash on his left arm. The rash was observed to be in a dermatomal distribution, and a diagnosis of herpes zoster was made. The patient was discharged home on valacyclovir 1 g 3 times a day for a duration of 7 days. The patient took 2 doses of valacyclovir before presenting to the hospital again with irritability and hallucinations. Over the next several days, the patient's neurologic status declined and he became disoriented and increasingly somnolent. Because of a concern for varicella zoster virus (VZV) or herpes simplex virus (HSV) meningoencephalitis, acyclovir was initiated intravenously at 600 mg (10 mg/kg) for every 12 hours. Computed tomography and magnetic resonance imaging of the brain failed to reveal an acute process. Electroencephalogram was interpreted as seizure activity versus metabolic encephalopathy. Lumbar puncture was not suggestive for meningitis, subarachnoid hemorrhage, or HSV/VZV infection. The patient subsequently had a witnessed seizure during dialysis and was felt to have status epilepticus due to acyclovir and valacyclovir neurotoxicity. The patient underwent daily hemodialysis for removal of the drug and eventually made a full neurologic recovery. Our case highlights that acyclovir neurotoxicity can result in status epilepticus, hallucinations, and altered consciousness. Differentiating acyclovir neurotoxicity from HSV or VZV meningoencephalitis is of crucial importance because the symptoms are similar but the management is vastly different.

  10. Does diisocyanate exposure result in neurotoxicity?

    PubMed Central

    2014-01-01

    Context Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest potential neurotoxic effects from exposures to toluene diisocyanate (TDI), 1,6 hexamethylene diisocyanate (HDI), and methylene diisocyanate (MDI). However, a systematic review of the literature evaluating the causal association on humans does not exist to support this alleged association. Objective To perform systematic review examining the body of epidemiologic evidence and provide assessment of causal association based on principles of the Sir Austin Bradford Hill criteria or considerations for causal analysis. Methods A comprehensive search of public databases for published abstracts, case reports, cross-sectional surveys, and cohort studies using key search terms was conducted. Additional searches included regulatory reviews, EU IUCLID and EU Risk Assessment databases, and unpublished reports in the International Isocyanate Institute database. An expert panel consisting of physicians, toxicologists, and an epidemiologist critically reviewed accepted papers, providing examination of epidemiologic evidence of each report. Finally, the Hill criteria for causation were applied to the summative analysis of identified reports to estimate probability of causal association. Results Twelve papers reporting exposed populations with a variety of neurological symptoms or findings suitable for analysis were identified, including eleven case or case series reports, and one cross-sectional study. Three papers reported on the same population. Each of the papers was limited by paucity of diisocyanate exposure estimates, the presence of confounding exposures to known or suspected neurotoxicants, a lack of objective biological measures of exposure or neurotoxic effects, and lack of relative strength of association measures. Additionally, reported health symptoms and syndromes lacked consistency or

  11. Electrochemical sensors and biosensors for determination of catecholamine neurotransmitters: A review.

    PubMed

    Ribeiro, José A; Fernandes, Paula M V; Pereira, Carlos M; Silva, F

    2016-11-01

    This work describes the state of the art of electrochemical devices for the detection of an important class of neurotransmitters: the catecholamines. This class of biogenic amines includes dopamine, noradrenaline (also called norepinephrine) and adrenaline (also called epinephrine). Researchers have focused on the role of catecholamine molecules within the human body because they are involved in many important biological functions and are commonly associated with several diseases, such as Alzheimer's and Parkinson. Furthermore, the release of catecholamines as a consequence of induced stimulus is an important indicator of reward-related behaviors, such as food, drink, sex and drug addiction. Thus, the development of simple, fast and sensitive electroanalytical methodologies for the determination of catecholamines is currently needed in clinical and biomedical fields, as they have the potential to serve as clinically relevant biomarkers for specific disease states or to monitor treatment efficacy. Currently, three main strategies have used by researchers to detect catecholamine molecules, namely: the use electrochemical materials in combination with, for example, HPLC or FIA, the incorporation of new materials/layers on the sensor surfaces (Tables 1-7) and in vivo detection, manly by using FSCV at CFMEs (Section 10). The developed methodologies were able not only to accurately detect catecholamines at relevant concentration levels, but to do so in the presence of co-existing interferences in samples detected (ascorbate, for example). This review examines the progress made in electrochemical sensors for the selective detection of catecholamines in the last 15 years, with special focus on highly innovative features introduced by nanotechnology. As the literature in rather extensive, we try to simplify this work by summarizing and grouping electrochemical sensors according to the manner their substrates were chemically modified. We also discuss the current and future

  12. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines.

    PubMed

    Choi, Sujean; Disilvio, Briana; Fernstrom, Madelyn H; Fernstrom, John D

    2013-11-01

    Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge.

  13. NEUROTOXICITY PRODUCED BY DIBROMOACETIC ACID IN DRINKING WATER OF RATS.

    EPA Science Inventory

    This manuscript examines the neurotoxic potential of a commonly found disinfection by-product (DBP), dibromoacetic acid (DBA). While the Safe Drinking Water Act requires evaluation of DBPs for noncancer health effects, surprisingly few have been tested for neurotoxicity. Rats e...

  14. Mussel-inspired catecholamine polymers as new sizing agents for fiber-reinforced composites

    NASA Astrophysics Data System (ADS)

    Lee, Wonoh; Lee, Jea Uk; Byun, Joon-Hyung

    2015-04-01

    Mussel-inspired catecholamine polymers (polydopamine and polynorepinephrine) were coated on the surface of carbon and glass fibers in order to increase the interfacial shear strength between fibers and polymer matrix, and consequently the interlaminar shear strength of fiber-reinforced composites. By utilizing adhesive characteristic of the catecholamine polymer, fiber-reinforced composites can become mechanically stronger than conventional composites. Since the catecholamine polymer is easily constructed on the surface by the simultaneous polymerization of its monomer under a weak basic circumstance, it can be readily coated on micro-fibers by a simple dipping process without any complex chemical treatments. Also, catecholamines can increase the surface free energy of micro-fibers and therefore, can give better wettability to epoxy resin. Therefore, catecholamine polymers can be used as versatile and effective surface modifiers for both carbon and glass fibers. Here, catecholamine-coated carbon and glass fibers exhibited higher interfacial shear strength (37 and 27% increases, respectively) and their plain woven composites showed improved interlaminar shear strength (13 and 9% increases, respectively) compared to non-coated fibers and composites.

  15. Glial cell response to 3,4-(+/-)-methylenedioxymethamphetamine and its metabolites.

    PubMed

    Herndon, Joseph M; Cholanians, Aram B; Lau, Serrine S; Monks, Terrence J

    2014-03-01

    3,4-(±)-Methylenedioxymethamphetamine (MDMA) and 3,4-(±)-methylenedioxyamphetamine (MDA), a primary metabolite of MDMA, are phenylethylamine derivatives that cause serotonergic neurotoxicity. Although several phenylethylamine derivatives activate microglia, little is known about the effects of MDMA on glial cells, and evidence of MDMA-induced microglial activation remains ambiguous. We initially determined microglial occupancy status of the parietal cortex in rats at various time points following a single neurotoxic dose of MDMA (20mg/kg, SC). A biphasic microglial response to MDMA was observed, with peak microglial occupancy occurring 12- and 72-h post-MDMA administration. Because direct injection of MDMA into the brain does not produce neurotoxicity, the glial response to MDMA metabolites was subsequently examined in vivo and in vitro. Rats were treated with MDA (20mg/kg, SC) followed by ex vivo biopsy culture to determine the activation of quiescent microglia. A reactive microglial response was observed 72 h after MDA administration that subsided by 7 days. In contrast, intracerebroventricular (ICV) administration of MDA failed to produce a microglial response. However, thioether metabolites of MDA derived from α-methyldopamine (α-MeDA) elicited a robust microglial response following icv injection. We subsequently determined the direct effects of various MDMA metabolites on primary cultures of E18 hippocampal mixed glial and neuronal cells. 5-(Glutathion-S-yl)-α-MeDA, 2,5-bis-(glutathion-S-yl)-α-MeDA, and 5-(N-acetylcystein-S-yl)-α-MeDA all stimulated the proliferation of glial fibrillary acidic protein-positive astrocytes at a dose of 10 µM. The findings indicate that glial cells are activated in response to MDMA/MDA and support a role for thioether metabolites of α-MeDA in the neurotoxicity.

  16. Nonhydrolytic sol-gel approach to facile creation of surface-bonded zirconia organic-inorganic hybrid coatings for sample preparation. Ι. Capillary microextraction of catecholamine neurotransmitters.

    PubMed

    Alhendal, Abdullah; Mengis, Stephanie; Matthews, Jacob; Malik, Abdul

    2016-10-14

    Nonhydrolytic sol-gel (NHSG) route was used for the creation of novel zirconia-polypropylene oxide (ZrO2-PPO) sol-gel hybrid sorbents in the form of surface coatings for the extraction and preconcentration of catecholamine neurotransmitters and molecules structurally related to their deaminated metabolites. In comparison to other sorbents made of inorganic transition metal oxides, the presented hybrid organic-inorganic sorbents facilitated reversible sorption properties that allowed for efficient desorption of the extracted analytes by LC-MS compatible mobile phases. The presented sol-gel hybrid sorbents effectively overcame the major drawbacks of traditional silica- or polymer-based sorbents by providing superior pH stability (pH range: 0-14), and a variety of intermolecular interactions. Nonaqueous sol-gel treatment of PPO with ZrCl4 was employed for the derivatization of the terminal hydroxyl groups on PPO, providing zirconium trichloride-containing end groups characterized by enhanced sol-gel reactivity. NHSG ZrO2-PPO sorbent provided excellent microextraction performance for catecholamines, low detection limits (5.6-9.6pM), high run-to-run reproducibility (RSD 0.6-5.1%), high desorption efficiency (95.0-99.5%) and high enrichment factors (∼1480-2650) for dopamine and epinephrine, respectively, extracted from synthetic urine samples. The presented sol-gel sorbents provided effective alternative to conventional extraction media providing unique physicochemical characteristics and excellent extraction capability.

  17. Inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine apparently increases brain serotoninergic activity in the rat: no influence of previous chronic immobilization stress.

    PubMed

    Pol, O; Campmany, L; Armario, A

    1995-09-01

    The functional relationship between brain catecholamines and serotoninergic function was studied in stress-naive and chronically immobilized rats after blockade of catecholamine synthesis with alpha-methyl-p-tyrosine (alpha MpT). The levels of noradrenaline (NA), serotonin, and 5-hydroxyindole acetic acid (5-HIAA) in pons plus medulla, brainstem, hypothalamus, hippocampus, and frontal cortex, and those of 3-methoxy, 4-hydroxyphenile-tileneglicol sulphate (MHPG-SO4) in the hypothalamus were measured by HPLC. Chronic immobilization (IMO) resulted in higher NA levels in pons plus medulla and hypothalamus, the latter area (the only one in which the NA metabolite was determined) also showing slightly elevated MHPG-SO4 levels as compared to stress-naive rats. Chronic IMO did not alter either serotonin or 5-HIAA levels, but acute stress consistently increased 5-HIAA levels in all areas, independently of previous chronic stress. Administration of alpha-MpT drastically reduced NA and increased 5-HIAA levels in all brain regions excepting the frontal cortex. The effect of the drug on serotoninergic function was not altered by previous chronic exposure to IMO. These data suggest that the noradrenergic system appears to exert a tonic inhibitory effect on serotoninergic activity in the brain, with the intensity of the effect depending on the brain area studied. In addition, chronic stress does not appear to alter the functional relationship between noradrenergic and serotoninergic activities, although interactions might exist in more restricted brain areas; this deserves further study.

  18. Neurotoxicity of Dietary Supplements from Annonaceae Species.

    PubMed

    Höllerhage, Matthias; Rösler, Thomas W; Berjas, Magda; Luo, Rensheng; Tran, Kevin; Richards, Kristy M; Sabaa-Srur, Armando U; Maia, José Guilherme S; Moraes, Maria Rosa de; Godoy, Helena T; Höglinger, Günter U; Smith, Robert E

    2015-01-01

    Dietary supplements containing plant materials of Annonaceae species (Annona muricata L., A. squamosa L., A. mucosa JACQ., A. squamosa × cherimola Mabb.) were extracted by hot, pressurized ethyl acetate and analyzed for their effect in vitro on Lund human mesencephalic neurons. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell death was determined by lactate dehydrogenase levels. Three supplements strongly decreased the cell viability at extract concentrations of 1 µg/mL, of which 1 decreased cell viability at 0.1 µg/µL. Also, strong neuronal toxicities of these supplements were found. Cell death was observed at concentrations of 10 µg/mL. The degree of toxicity was comparable to the ones found in Annonaceous fruit extracts. Two fruit pulps of Annonaceae (A. muricata and A. squamosa) showed a reduction in cell viability at lower concentrations. The fruit pulp extract of A. muricata revealed the strongest neurotoxic effect, with 67% cell death at a concentration of 1 µg/mL. A high reduction in cell viability coupled with pronounced cell death was found at 0.1 µg/mL for an Annonaceous seed extract. These results demonstrate that the intake of dietary supplements containing plant material from Annonaceae may be hazardous to health in terms of neurotoxicity.

  19. Meeting report: alternatives for developmental neurotoxicity testing.

    PubMed

    Lein, Pamela; Locke, Paul; Goldberg, Alan

    2007-05-01

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13-15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children's health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders.

  20. Altered catecholamine receptor affinity in rabbit aortic intimal hyperplasia

    SciTech Connect

    O'Malley, M.K.; Cotecchia, S.; Hagen, P.O. )

    1991-08-01

    Intimal thickening is a universal response to endothelial denudation and is also thought to be a precursor of atherosclerosis. The authors have demonstrated selective supersensitivity in arterial intimal hyperplasia to norepinephrine and they now report a possible mechanism for this. Binding studies in rabbit aorta with the selective alpha 1-adrenergic radioligand 125I-HEAT demonstrated that there was no change in receptor density (20 {plus minus} 4 fmole/10(6) cells) in intact vascular smooth muscle cells at either 5 or 14 days after denudation. However, competition studies showed a 2.6-fold increase in alpha 1-adrenergic receptor affinity for norepinephrine in intimal hyperplastic tissue (P less than 0.05). This increased affinity for norepinephrine was associated with a greater increase in 32P-labeled phosphatidylinositol (148% intimal thickening versus 76% control) and phosphatidic acid (151% intimal thickening versus 56% control) following norepinephrine stimulation of free floating rings of intimal hyperplastic aorta. These data suggest that the catecholamine supersensitivity in rabbit aortic intimal hyperplasia is receptor mediated and may be linked to the phosphatidylinositol cycle.

  1. Irrelevant stimulus processing in ADHD: catecholamine dynamics and attentional networks

    PubMed Central

    Aboitiz, Francisco; Ossandón, Tomás; Zamorano, Francisco; Palma, Bárbara; Carrasco, Ximena

    2014-01-01

    A cardinal symptom of attention deficit and hyperactivity disorder (ADHD) is a general distractibility where children and adults shift their attentional focus to stimuli that are irrelevant to the ongoing behavior. This has been attributed to a deficit in dopaminergic signaling in cortico-striatal networks that regulate goal-directed behavior. Furthermore, recent imaging evidence points to an impairment of large scale, antagonistic brain networks that normally contribute to attentional engagement and disengagement, such as the task-positive networks and the default mode network (DMN). Related networks are the ventral attentional network (VAN) involved in attentional shifting, and the salience network (SN) related to task expectancy. Here we discuss the tonic–phasic dynamics of catecholaminergic signaling in the brain, and attempt to provide a link between this and the activities of the large-scale cortical networks that regulate behavior. More specifically, we propose that a disbalance of tonic catecholamine levels during task performance produces an emphasis of phasic signaling and increased excitability of the VAN, yielding distractibility symptoms. Likewise, immaturity of the SN may relate to abnormal tonic signaling and an incapacity to build up a proper executive system during task performance. We discuss different lines of evidence including pharmacology, brain imaging and electrophysiology, that are consistent with our proposal. Finally, restoring the pharmacodynamics of catecholaminergic signaling seems crucial to alleviate ADHD symptoms; however, the possibility is open to explore cognitive rehabilitation strategies to top-down modulate network dynamics compensating the pharmacological deficits. PMID:24723897

  2. Prefrontal/accumbal catecholamine system processes high motivational salience

    PubMed Central

    Puglisi-Allegra, Stefano; Ventura, Rossella

    2012-01-01

    Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested from mild to extreme. Highly motivational experiences promote highly persistent memories. Although this phenomenon is adaptive in normal conditions, experiences with extremely high levels of motivational salience can promote development of memories that can be re-experienced intrusively for long time resulting in maladaptive outcomes. Neural mechanisms mediating motivational salience attribution are, therefore, very important for individual and species survival and for well-being. However, these neural mechanisms could be implicated in attribution of abnormal motivational salience to different stimuli leading to maladaptive compulsive seeking or avoidance. We have offered the first evidence that prefrontal cortical norepinephrine (NE) transmission is a necessary condition for motivational salience attribution to highly salient stimuli, through modulation of dopamine (DA) in the nucleus accumbens (NAc), a brain area involved in all motivated behaviors. Moreover, we have shown that prefrontal-accumbal catecholamine (CA) system determines approach or avoidance responses to both reward- and aversion-related stimuli only when the salience of the unconditioned stimulus (UCS) is high enough to induce sustained CA activation, thus affirming that this system processes motivational salience attribution selectively to highly salient events. PMID:22754514

  3. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis

    PubMed Central

    Nguyen, Khoa D.; Qiu, Yifu; Cui, Xiaojin; Goh, Y.P. Sharon; Mwangi, Julia; David, Tovo; Mukundan, Lata; Brombacher, Frank; Locksley, Richard M.; Chawla, Ajay

    2011-01-01

    All homeotherms utilize thermogenesis to maintain core body temperature, ensuring that cellular functions and physiologic processes can ensue in cold environments1-3. In the prevailing model, when the hypothalamus senses cold temperatures, it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue (BAT) and white adipose tissue (WAT)4,5. Acting via the β3-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes6, whereas it stimulates the expression of thermogenic genes, such as PPARγ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1), and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes7-9. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report an unexpected requirement for the interleukin 4 (IL4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Cold exposure rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in BAT and lipolysis in WAT. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL4 increased thermogenic gene expression, fatty acid mobilization, and energy expenditure, all in a macrophage-dependent manner. We have thus discovered a surprising role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold. PMID:22101429

  4. Secretory patterns of catecholamines in Indo-Pacific bottlenose dolphins.

    PubMed

    Suzuki, Miwa; Nozawa, Aoi; Ueda, Keiichi; Bungo, Takashi; Terao, Hiromi; Asahina, Kiyoshi

    2012-05-15

    Catecholamines (CAs), namely adrenaline (A), noradrenaline (NA), and dopamine (DA), are secreted by the sympathoadrenal system and participate in a diverse array of functions, e.g., heat production, cardiovascular regulation, stress response and so on. However, little is known regarding peripheral CA fluctuations in cetaceans; nevertheless aquatic animals like them have needed to modify their physiological response especially for thermoregulation in water and oxygen economy during diving. To understand CA dynamism in cetaceans, diurnal changes in serum A, NA, and DA concentrations were measured during the winter and summer solstices in four Indo-Pacific bottlenose dolphins (Tursiops aduncus). The average serum NA concentration was much higher than the average A and DA concentrations, and all concentrations were higher than those reported in other cetacean species. No distinct diurnal fluctuations were observed in CA concentrations in either solstice, suggesting inhibition of the decrease in CA concentrations during nocturnal periods by the unique sleep pattern of dolphins. All the serum CA concentrations were negatively correlated with water temperature as body temperatures were, indicating that the sympathoadrenal system might be more active during winter than in summer season, suggesting a role of CA in thermoregulation.

  5. Irrelevant stimulus processing in ADHD: catecholamine dynamics and attentional networks.

    PubMed

    Aboitiz, Francisco; Ossandón, Tomás; Zamorano, Francisco; Palma, Bárbara; Carrasco, Ximena

    2014-01-01

    A cardinal symptom of attention deficit and hyperactivity disorder (ADHD) is a general distractibility where children and adults shift their attentional focus to stimuli that are irrelevant to the ongoing behavior. This has been attributed to a deficit in dopaminergic signaling in cortico-striatal networks that regulate goal-directed behavior. Furthermore, recent imaging evidence points to an impairment of large scale, antagonistic brain networks that normally contribute to attentional engagement and disengagement, such as the task-positive networks and the default mode network (DMN). Related networks are the ventral attentional network (VAN) involved in attentional shifting, and the salience network (SN) related to task expectancy. Here we discuss the tonic-phasic dynamics of catecholaminergic signaling in the brain, and attempt to provide a link between this and the activities of the large-scale cortical networks that regulate behavior. More specifically, we propose that a disbalance of tonic catecholamine levels during task performance produces an emphasis of phasic signaling and increased excitability of the VAN, yielding distractibility symptoms. Likewise, immaturity of the SN may relate to abnormal tonic signaling and an incapacity to build up a proper executive system during task performance. We discuss different lines of evidence including pharmacology, brain imaging and electrophysiology, that are consistent with our proposal. Finally, restoring the pharmacodynamics of catecholaminergic signaling seems crucial to alleviate ADHD symptoms; however, the possibility is open to explore cognitive rehabilitation strategies to top-down modulate network dynamics compensating the pharmacological deficits.

  6. The Portland Neurotoxicity Scale: Validation of a Brief Self-Report Measure of Antiepileptic-Drug-Related Neurotoxicity

    ERIC Educational Resources Information Center

    Salinsky, Martin C.; Storzbach, Daniel

    2005-01-01

    The Portland Neurotoxicity Scale (PNS) is a brief patient-based survey of neurotoxicity complaints commonly encountered with the use of antiepileptic drugs (AEDs). The authors present data on the validity of this scale, particularly when used in longitudinal studies. Participants included 55 healthy controls, 23 epilepsy patient controls, and 86…

  7. Increased gene expression of catecholamine-synthesizing enzymes in adrenal glands contributes to high circulating catecholamines in pigs with tachycardia-induced cardiomyopathy.

    PubMed

    Tomaszek, A; Kiczak, L; Bania, J; Paslawska, U; Zacharski, M; Janiszewski, A; Noszczyk-Nowak, A; Dziegiel, P; Kuropka, P; Ponikowski, P; Jankowska, E A

    2015-04-01

    High levels of circulating catecholamines have been established as fundamental pathophysiological elements of heart failure (HF). However, it is unclear whether the increased gene expression of catecholamine-synthesis enzymes in the adrenal glands contributes to these hormone abnormalities in large animal HF models. We analyzed the mRNA levels of catecholamine-synthesizing enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AAAD), dopamine-β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in adrenal glands of 18 pigs with chronic systolic non-ischaemic HF (tachycardia-induced cardiomyopathy due to right ventricle pacing) and 6 sham-operated controls. Pigs with severe HF demonstrated an increased expression of TH and DBH (but neither AAAD nor PNMT) as compared to animals with milder HF and controls (P<0.05 in all cases). The increased adrenal mRNA expression of TH and DBH was accompanied by a reduced left ventricle ejection fraction (LVEF) (P<0.001) and an elevated plasma B-type natriuretic peptide (BNP) (P<0.01), the other indices reflecting HF severity. There was a positive relationship between the increased adrenal mRNA expression of TH and DBH, and the high levels of circulating adrenaline and noradrenaline (all P<0.05). The association with noradrenaline remained significant also when adjusted for LVEF and plasma BNP, suggesting a significant contribution of adrenals to the circulating pool of catecholamines in subjects with systolic HF.

  8. Evidence for a Critical Role of Catecholamines for Cardiomyocyte Lineage Commitment in Murine Embryonic Stem Cells

    PubMed Central

    Lehmann, Martin; Nguemo, Filomain; Wagh, Vilas; Pfannkuche, Kurt; Hescheler, Jürgen; Reppel, Michael

    2013-01-01

    Catecholamine release is known to modulate cardiac output by increasing heart rate. Although much is known about catecholamine function and regulation in adults, little is known about the presence and role of catecholamines during heart development. The present study aimed therefore to evaluate the effects of different catecholamines on early heart development in an in vitro setting using embryonic stem (ES) cell-derived cardiomyocytes. Effects of catecholamine depletion induced by reserpine were examined in murine ES cells (line D3, αPIG44) during differentiation. Cardiac differentiation was assessed by immunocytochemistry, qRT-PCR, quantification of beating clusters, flow cytometry and pharmacological approaches. Proliferation was analyzed by EB cross-section measurements, while functionality of cardiomyocytes was studied by extracellular field potential (FP) measurements using microelectrode arrays (MEAs). To further differentiate between substance-specific effects of reserpine and catecholamine action via α- and β-receptors we proved the involvement of adrenergic receptors by application of unspecific α- and β-receptor antagonists. Reserpine treatment led to remarkable down-regulation of cardiac-specific genes, proteins and mesodermal marker genes. In more detail, the average ratio of ∼40% spontaneously beating control clusters was significantly reduced by 100%, 91.1% and 20.0% on days 10, 12, and 14, respectively. Flow cytometry revealed a significant reduction (by 71.6%, n = 11) of eGFP positive CMs after reserpine treatment. By contrast, reserpine did not reduce EB growth while number of neuronal cells in reserpine-treated EBs was significantly increased. MEA measurements of reserpine-treated EBs showed lower FP frequencies and weak responsiveness to adrenergic and muscarinic stimulation. Interestingly we found that developmental inhibition after α- and β-adrenergic blocker application mimicked developmental changes with reserpine. Using several

  9. GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation.

    PubMed Central

    Oset-Gasque, M. J.; Parramón, M.; González, M. P.

    1993-01-01

    1. The function of gamma-aminobutyric acidB (GABAB) receptors in modulation of catecholamine secretion by chromaffin cells and the possible mechanism involved in this action have been examined. 2. The GABAB agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) were found to induce a dose-dependent increase of basal catecholamine secretion. The EC50s were 151 +/- 35 microM and 225 +/- 58 microM for baclofen and 3-APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mM of the specific GABAB antagonist CGP-35348. 3. In contrast, preincubation of chromaffin cells with the GABAB agonists was found to inhibit, in a dose-dependent manner, the catecholamine secretion evoked by 10 microM nicotine and 200 microM muscimol. 4. The effects of GABAB agonists on both basal and evoked catecholamine secretion were found to be accompanied by parallel changes in intracellular calcium concentration ([Ca2+]i). GABAB agonists produced a dose-dependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol. 5. The GABAB agonists also produced a dose-dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion and in intracellular cyclic AMP levels. 6. The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and increased by four times the intracellular cyclic AMP levels evoked by GABAB agonists. 7. The possible involvement of adenylate cyclase in the mechanism of GABAA receptor modulation of catecholamine secretion is discussed. PMID:8306105

  10. GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation.

    PubMed

    Oset-Gasque, M J; Parramón, M; González, M P

    1993-12-01

    1. The function of gamma-aminobutyric acidB (GABAB) receptors in modulation of catecholamine secretion by chromaffin cells and the possible mechanism involved in this action have been examined. 2. The GABAB agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) were found to induce a dose-dependent increase of basal catecholamine secretion. The EC50s were 151 +/- 35 microM and 225 +/- 58 microM for baclofen and 3-APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mM of the specific GABAB antagonist CGP-35348. 3. In contrast, preincubation of chromaffin cells with the GABAB agonists was found to inhibit, in a dose-dependent manner, the catecholamine secretion evoked by 10 microM nicotine and 200 microM muscimol. 4. The effects of GABAB agonists on both basal and evoked catecholamine secretion were found to be accompanied by parallel changes in intracellular calcium concentration ([Ca2+]i). GABAB agonists produced a dose-dependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol. 5. The GABAB agonists also produced a dose-dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion and in intracellular cyclic AMP levels. 6. The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and increased by four times the intracellular cyclic AMP levels evoked by GABAB agonists. 7. The possible involvement of adenylate cyclase in the mechanism of GABAA receptor modulation of catecholamine secretion is discussed.

  11. DOPAMINE RECEPTOR ACTIVATION REVEALS A NOVEL, KYNURENATE-SENSITIVE COMPONENT OF STRIATAL NMDA NEUROTOXICITY

    PubMed Central

    Poeggeler, Burkhard; Rassoulpour, Arash; Wu, Hui-Qiu; Guidetti, Paolo; Roberts, Rosalinda C.; Schwarcz, Robert

    2007-01-01

    The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in 2-3-fold increases in excitotoxic lesion size. Pre-treatment with kynurenine 3-hydroxylase inhibitors or dopamine receptor antagonists, two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum. PMID:17629627

  12. Neurotoxicity of anhydroecgonine methyl ester, a crack cocaine pyrolysis product.

    PubMed

    Garcia, Raphael Caio Tamborelli; Dati, Livia Mendonça Munhoz; Fukuda, Suelen; Torres, Larissa Helena Lobo; Moura, Sidnei; de Carvalho, Nathalia Delazeri; Carrettiero, Daniel Carneiro; Camarini, Rosana; Levada-Pires, Adriana Cristina; Yonamine, Mauricio; Negrini-Neto, Osvaldo; Abdalla, Fernando Maurício Francis; Sandoval, Maria Regina Lopes; Afeche, Solange Castro; Marcourakis, Tania

    2012-07-01

    Smoking crack cocaine involves the inhalation of cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). Although there is evidence that cocaine is neurotoxic, the neurotoxicity of AEME has never been evaluated. AEME seems to have cholinergic agonist properties in the cardiovascular system; however, there are no reports on its effects in the central nervous system. The aim of this study was to investigate the neurotoxicity of AEME and its possible cholinergic effects in rat primary hippocampal cell cultures that were exposed to different concentrations of AEME, cocaine, and a cocaine-AEME combination. We also evaluated the involvement of muscarinic cholinergic receptors in the neuronal death induced by these treatments using concomitant incubation of the cells with atropine. Neuronal injury was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The results of the viability assays showed that AEME is a neurotoxic agent that has greater neurotoxic potential than cocaine after 24 and 48 h of exposure. We also showed that incubation for 48 h with a combination of both compounds in equipotent concentrations had an additive neurotoxic effect. Although both substances decreased cell viability in the MTT assay, only cocaine increased LDH release. Caspase-3 activity was increased after 3 and 6 h of incubation with 1mM cocaine and after 6 h of 0.1 and 1.0mM AEME exposure. Atropine prevented the AEME-induced neurotoxicity, which suggests that muscarinic cholinergic receptors are involved in AEME's effects. In addition, binding experiments confirmed that AEME has an affinity for muscarinic cholinergic receptors. Nevertheless, atropine was not able to prevent the neurotoxicity produced by cocaine and the cocaine-AEME combination, suggesting that these treatments activated other neuronal death pathways. Our results suggest a higher risk for neurotoxicity after smoking crack cocaine than after

  13. Neurotoxicity testing during long-term studies.

    PubMed

    Ivens, I

    1990-01-01

    Several tests and methods for the investigation of neurotoxicity were performed with female Wistar rats for up to 187 days. The methods were validated by testing 10 rats treated with beta,beta'-iminodipropionitrile (IDPN) and 10 control rats. Cage side observation of the animals revealed signs of altered behavior and motor dysfunction of the IDPN-treated rats. Results of a neuromuscular screen indicated changes in gait, righting reflex, grip strength and performance of the negative geotropism test. Investigation of the animals in activity monitors and on the accelerating rotarod showed changes of several parameters. The motor nerve conduction velocity, measured 6 months after the first treatment, was reduced by 6.7 meters per second in the IDPN group compared to controls. From the results of the tests it can be concluded that the methods chosen can be used during long-term studies but may be most useful for animals not older than 12 months.

  14. Catecholamine regulation of lactate dehydrogenase in rat brain cell culture

    SciTech Connect

    Kumar, S.; McGinnis, J.F.; de Vellis, J.

    1980-03-25

    The mechanism of catecholamine induction of the soluble cytoplasmic enzyme lactate dehydrogenase (EC 1.1.1.27) was studied in the rat glial tumor cell line, C6. Lactate dehydrogenase was partially purified from extracts of (/sup 3/H)leucine-labeled cells by affinity gel chromatography and quantitatively immunoprecipitated with anti-lactate dehydrogenase-5 IgG and with antilactate dehydrogenase-1 IgG. The immunoprecipitates were dissociated and electrophoresed on sodium dodecyl sulfate polyacrylamide gels. Using this methodology, the increased enzyme activity of lactate dehydrogenase in norepinephrine-treated C6 cells was observed to be concomitant with the increased synthesis of enzyme molecules. Despite the continued presence of norepinephrine, the specific increase in the rate of synthesis of lactate dehydrogenase was transient. It was first detected at 4 h, was maximum at 9 h, and returned to basal levels by 24 h. The half-life of lactate dehydrogenase enzyme activity was 36 h during the induction and 40 h during deinduction. The half-life for decay of /sup 3/H-labeled lactate dehydrogenase was 41 h. These observations suggest that the increase in lactate dehydrogenase activity in norepinephrine-treated cells does not involve any change in the rate of degradation. Norepinephrine increased the specific rate of synthesis of both lactate dehydrogenase-5 (a tetramer of four M subunits) and lactate dehydrogenase-1 (a tetramer of four H subunits), although to different extents. Since these subunits are coded for by two separate genes on separate chromosomes, it suggests that the regulatory mechanism involves at least two separate sites of action.

  15. Plasma catecholamines and renin activity in wrestlers following vigorous swimming.

    PubMed

    Vigas, M; Celko, J; Juránková, E; Jezová, D; Kvetnanský, R

    1998-01-01

    Cardiovascular and neuroendocrine responses to exercise in a physically fit and an untrained group of young healthy subjects were compared to study the significance of physical fitness for performance in a discipline for which the athletes were not trained. Ten wrestlers of national rank prepared for an international competition (age 18 years) and 9 untrained healthy males (age 21 years). Exercise consisted of 27-min swimming, freestyle, in water of 29 degrees C, with last 3 min increased to maximal effort. The blood pressure, heart rate and sublingual temperature were measured and blood samples were withdrawn before exercise, immediately after and after a 30 min period of rest. Catecholamines were analyzed by radioenzymatic method and plasma renin activity (PRA) using commercial kits. Systolic blood pressure and heart rate after swimming were increased comparably in the two groups, diastolic pressure was unchanged in the controls and decreased in the wrestlers. Plasma cortisol remained unchanged. Plasma glucose tended to increase in the controls and so decrease in wrestlers, with a significant difference between them after swimming (p < 0.05). However, plasma adrenaline was concomitantly increased in both groups (p < 0.01). Noradrenaline and PRA were increased after swimming in both the control and trained group. The increments of noradrenaline and PRA in wrestlers were significantly reduced compared to the control group (p < 0.01, p < 0.05, respectively). Higher physical fitness in athletes significantly reduced plasma noradrenaline and angiotensin responses to maximal exercise demanding special skill in work performance which had not been included in their training program. Training of wrestlers did not cause an exaggerated plasma adrenaline response to exercise.

  16. Endoplasmic Reticulum Stress and Ethanol Neurotoxicity.

    PubMed

    Yang, Fanmuyi; Luo, Jia

    2015-10-14

    Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity.

  17. Fumonisin B(1): a neurotoxic mycotoxin.

    PubMed

    Domijan, Ana-Marija

    2012-12-01

    Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium spp. moulds that contaminate crop, predominantly maize, all around the world. More than 15 types of fumonisins have been indentified so far, but FB(1) is the most abundant and toxicologically the most significant one. FB(1) has a wide range of toxic effects, depending on animal species. In horses FB(1) causes equine leukoencephalomalacia (ELEM), in pigs pulmonary oedema and in experimental rodents nephrotoxicity and hepatotoxicity. In humans exposure to FB(1) is linked with higher incidence of primary liver cancer and oesophageal cancer, which are frequent in certain regions of the world (such as Transkei region in South Africa) where maize is staple food. The occurrence of neural tube defect in children in some countries of Central America (such as Mexico and Honduras) is connected with the consumption of FB(1)-contaminated maize-based food. However, possible involvement of FB(1) in the development of human diseases is not clear. Nevertheless, the International Agency for Research on Cancer (IARC) has classified FB(1) as a possible carcinogen to humans (group 2B). FB(1) is a causative agent of ELEM, a brain disorder in equines, indicating that brain is a target organ of FB(1) toxicity. Several studies on experimental animals or on cell cultures of neural origin have established that FB(1) has a neurodegenerative potential, although the mechanism of its neurotoxicity is still vague. The aim of this article is to give an overview of available literature on FB(1) neurotoxicity and involved mechanisms, and to offer a new perspective for future studies.

  18. Prospective, longitudinal assessment of developmental neurotoxicity.

    PubMed Central

    Jacobson, J L; Jacobson, S W

    1996-01-01

    Methodological issues in the design of prospective, longitudinal studies of developmental neurotoxicity in humans are reviewed. A comprehensive assessment of potential confounding influences is important in these studies because inadequate assessment of confounders can threaten the validity of causal inferences drawn from the data. Potential confounders typically include demographic background variables, alcohol and smoking during pregnancy, the quality of parental stimulation, the child's age at test, and the examiner. Exposure to other substances is assessed where significant exposure is expected in the target population. In most studies, control variables even weakly related to outcome are included in all multivariate statistical analyses, and a toxic effect is inferred only if the effect of exposure is significant after controlling for the potential confounders. Once a neurotoxic effect has been identified, suspected mediating variables may be added to the analysis to examine underlying processes or mechanisms through which the exposure may impact on developmental outcome. Individual differences in vulnerability may be examined in terms of either an additive compensatory model or a synergistic "risk and resilience" approach. Failure to detect real effects (Type II error) is of particular concern in these studies because public policy considerations make it likely that negative findings will be interpreted to mean that the exposure is safe. Important sources of Type II error include inadequate representation of highly exposed individuals, overcontrol for confounders, and inappropriate correction for multiple comparisons. Given the high cost and complexity of prospective, longitudinal investigations, cross-sectional pilot studies focusing on highly exposed individuals can be valuable for the initial identification of salient domains of impairment. PMID:9182034

  19. Osmotic pressures of solutions of ATP and catecholamines relating to storage in chromaffin granules.

    PubMed

    Kopell, W N; Westhead, E W

    1982-05-25

    The chromaffin granule, which is the catecholamine storage organelle of the adrenal medulla, contains at least 0.73 M ions, yet it is isotonic with 0.3 osM solutions. One hypothesis which accounts for this disparity is formation of a complex between major constituents of the granule: the catecholamines, the proteins, and the ATP. In this paper we show by vapor pressure osmometry, which affords a direct measure of colligative properties, that ATP-catecholamine mixtures form highly nonideal solutions. At 37 degrees C, solutions containing 0.6 M epinephrine and 0.15 M ATP show an effective osmotic pressure of only 0.25 osM. The existence of polymeric complexes is implied by the fact that the increase of osmotic pressure with increasing concentrations of ATP and catecholamine falls off substantially at concentrations approaching those in the chromaffin granules. Neither inorganic ions nor calcium chelators cause regain of ideal colligative behavior. Osmotic measurements on model compounds suggest that the primary interaction is between the phosphate and amino groups. There is also evidence that the effects are not wholly due to the formation of discrete complexes; factors of nonideal solution behavior also play a role in lowering the osmotic pressure. These observations show that the stability of the chromaffin granule in situ can be accounted for, perhaps entirely, by spontaneous interactions among nucleotides and catecholamines.

  20. Preparation of Sticky Escherichia coli through Surface Display of an Adhesive Catecholamine Moiety

    PubMed Central

    Park, Joseph P.; Choi, Min-Jung; Kim, Se Hun

    2014-01-01

    Mussels attach to virtually all types of inorganic and organic surfaces in aqueous environments, and catecholamines composed of 3,4-dihydroxy-l-phenylalanine (DOPA), lysine, and histidine in mussel adhesive proteins play a key role in the robust adhesion. DOPA is an unusual catecholic amino acid, and its side chain is called catechol. In this study, we displayed the adhesive moiety of DOPA-histidine on Escherichia coli surfaces using outer membrane protein W as an anchoring motif for the first time. Localization of catecholamines on the cell surface was confirmed by Western blot and immunofluorescence microscopy. Furthermore, cell-to-cell cohesion (i.e., cellular aggregation) induced by the displayed catecholamine and synthesis of gold nanoparticles on the cell surface support functional display of adhesive catecholamines. The engineered E. coli exhibited significant adhesion onto various material surfaces, including silica and glass microparticles, gold, titanium, silicon, poly(ethylene terephthalate), poly(urethane), and poly(dimethylsiloxane). The uniqueness of this approach utilizing the engineered sticky E. coli is that no chemistry for cell attachment are necessary, and the ability of spontaneous E. coli attachment allows one to immobilize the cells on challenging material surfaces such as synthetic polymers. Therefore, we envision that mussel-inspired catecholamine yielded sticky E. coli that can be used as a new type of engineered microbe for various emerging fields, such as whole living cell attachment on versatile material surfaces, cell-to-cell communication systems, and many others. PMID:24123747

  1. Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder

    PubMed Central

    Birner, Armin; Platzer, Martina; Bengesser, Susanne Astrid; Dalkner, Nina; Fellendorf, Frederike T.; Queissner, Robert; Pilz, Rene; Rauch, Philipp; Maget, Alexander; Hamm, Carlo; Herzog-Eberhard, Simone; Mangge, Harald; Fuchs, Dietmar; Moll, Natalie; Zelzer, Sieglinde; Schütze, Gregor; Schwarz, Markus; Reininghaus, Bernd; Kapfhammer, Hans-Peter; Reininghaus, Eva Z.

    2017-01-01

    Introduction Bipolar disorder (BD) is a chronic psychiatric disease which can take most different and unpredictable courses. It is accompanied by unspecific brainstructural changes and cognitive decline. The neurobiological underpinnings of these processes are still unclear. Emerging evidence suggests that tryptophan catabolites (TRYCATs), which involve all metabolites of tryptophan towards the kynurenine (KYN) branch, are involved in the etiology as well as in the course of BD. They are proposed to be mediators of immune-inflammation and neurodegeneration. In this study we measured the levels of KYN and its main catabolites consisting of the neurotoxic hydroxykynurenine (3-HK), the more neuroprotective kynurenic acid (KYNA) and anthranilic acid (AA) and evaluated the ratios between end-products and substrates as proxies for the specific enzymatic activity (3-HK/KYN, KYNA/KYN, AA/KYN) as well as 3-HK/KYNA as a proxy for neurotoxic vs. neuroprotective end-product relation in individuals with BD compared to healthy controls (HC). Methods We took peripheral TRYCAT blood levels of 143 euthymic to mild depressive BD patients and 101 HC. For statistical analyses MANCOVA’s controlled for age, sex, body mass index, cardiovascular disease and smoking were performed. Results The levels of KYNA (F = 5,579; p <.05) were reduced in BD compared to HC. The enzymatic activity of the kynurenine-3-monooxygenase (KMO) reflected by the 3-HK/KYN ratio was increased in BD individuals compared to HC (F = 5,394; p <.05). Additionally the ratio of 3-HK/KYNA was increased in individuals with BD compared to healthy controls (F = 11,357; p <.01). Discussion In conclusion our findings subserve the concept of KYN -pathway alterations in the pathophysiology of BD. We present evidence of increased breakdown towards the neurotoxic branch in KYN metabolism even in a euthymic to mild depressive state in BD. From literature we know that depression and mania are accompanied by inflammatory states

  2. INTEGRATING EPIDEMIOLOGY AND TOXICOLOGY IN NEUROTOXICITY RISK ASSESSMENT.

    EPA Science Inventory

    Neurotoxicity risk assessments depend on the best available scientific information, including data from animal toxicity, human experimental studies and human epidemiology studies. There are several factors to consider when evaluating the comparability of data from studies. Reg...

  3. Developmental Neurotoxicology: History and Outline of Developmental Neurotoxicity Study Guidelines.

    EPA Science Inventory

    The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratoge...

  4. TESTING FOR DEVELOPMENTAL NEUROTOXICITY: CURRENT APPROACHES AND FUTURE NEEDS.

    EPA Science Inventory

    There are many adverse effects on the nervous system following exposure to environmental chemicals during development. In a number of cases (e.g., lead, methyl mercury) the developing nervous system is a highly susceptible. Developmental Neurotoxicity Testing (DNT) guidelines...

  5. Recommendations for Developing Alternative Test Methods for Developmental Neurotoxicity

    EPA Science Inventory

    There is great interest in developing alternative methods for developmental neurotoxicity testing (DNT) that are cost-efficient, use fewer animals and are based on current scientific knowledge of the developing nervous system. Alternative methods will require demonstration of the...

  6. Synthesis and Neurotoxicity Profile of 2,4,5-Trihydroxymethamphetamine and its 6-(N-Acetylcystein-S-yl) Conjugate

    PubMed Central

    Neudörffer, Anne; Mueller, Melanie; Martinez, Claire-Marie; Mechan, Annis; McCann, Una; Ricaurte, George A.; Largeron, Martine

    2011-01-01

    The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, “ecstasy”) or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), plays a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in brains of these animals was not related to the unstable nature of the THMA molecule, because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA, or oxidized cyclic forms (e.g. the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo. PMID:21557581

  7. In vitro techniques for the assessment of neurotoxicity.

    PubMed Central

    Harry, G J; Billingsley, M; Bruinink, A; Campbell, I L; Classen, W; Dorman, D C; Galli, C; Ray, D; Smith, R A; Tilson, H A

    1998-01-01

    Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected

  8. Lesson of the month 2: Catecholamine-induced cardiomyopathy - pitfalls in diagnosis and medical management.

    PubMed

    Mamoojee, Yaasir; Arham, Munawar; Elsaify, Wael; Nag, Sath

    2016-04-01

    Cardiomyopathy as the initial presentation of phaeochromocytoma (PCA) is uncommon. Diagnostic work-up and perioperative management may be challenging within this context. We report three cases of PCA presenting with cardiomyopathy to illustrate the pitfalls in diagnosis and management. None of the patients had typical adrenergic symptoms and all three were established on beta-blockers prior to diagnosis. Their fractionated plasma catecholamine levels were elevated and the diagnosis of PCA was confirmed with various imaging modalities and post adrenalectomy. Interpretation of fractionated catecholamine levels in the context of established cardiomyopathy is difficult as cardiac failure of any aetiology generates an adrenergic response. Hence screening all patients with idiopathic cardiomyopathy is likely to generate a high false-positive rate. However, a high index of suspicion should prompt further diagnostic work-up in patients with idiopathic cardiomyopathy for occult PCAs. Peer-reviewed guidelines are required to guide the investigation and management of suspected catecholamine-induced cardiomyopathy.

  9. [Extra-adrenal pheochromocytoma with the manifestation of catecholamines cardiomyopathy: a case report].

    PubMed

    Kuramoto, Tomomi; Nishizawa, Satoshi; Fujii, Reona; Nanpou, Yoshihito; Matsumura, Nagahide; Inagaki, Takeshi; Kohjimoto, Yasuo; Hara, Isao

    2010-11-01

    A 22-year old female had an episode of acute heart and respiratory failure requiring mechanical ventilation ducing a trip overseas. Echocardiography demonstrated akinesis of the apical area (left ventricle ejectionfraction(LVEF) =15%). Since computed tomography (CT) with coronary angiography to rule out acute coronary syndrome showed no abnormalities, she was diagnosed with morphological stress cardiomyopathy due to akinesis of the apical area. After returning to Japan, she was admitted to our hospital for further examination. She had an increased level of catecholamines in 24-hour urine. ¹³¹Imetaiodobenzyguanidine scintigraphy, CT scan and fluorodexyglucose positron emission tomography revealed a retroperitoneal mass. From these results, a diagnosis of extra-adrenal pheochromocytoma with catecholamine-induced cardiomyopathy was made. Histological diagnosis of the laparoscopically resected tumor was pheochromocytoma. After the operation, the level of catecholamines in 24-hour urine was normalized.

  10. Effects of Labor Contractions on Catecholamine Release and Breathing Frequency in Newborn Rats

    PubMed Central

    Ronca, April E.; Abel, Regina A.; Ronan, Patrick J.; Renner, Kenneth J.; Alberts, Jeffrey R.

    2009-01-01

    Plasma catecholamines in newborn rats (0–2 hr old) were analyzed following vaginal birth, cesarean section with simulated labor contractions, or cesarean section without labor contractions. Upon delivery, pups were exposed to key elements of the rat’s natural birth process, that is, umbilical cord occlusion, tactile stimulation, and cooling. Only pups exposed to actual or simulated labor showed an immediate rise in norepinephrine and epinephrine. Initial postpartum respiratory frequencies were higher in vaginal than in cesarean delivered pups and, in all groups, inversely correlated with catecholamine titers, suggesting respiratory distress or transient tachypnea at lower catecholamine levels. These findings establish a rat model for analyzing effects of labor on neonatal adaptive response during the transition from prenatal to postnatal life. PMID:17201476

  11. Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine.

    PubMed

    Cass, Wayne A; Smith, Michael P; Peters, Laura E

    2006-08-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in brain dopamine (DA) and serotonin (5-HT) content. Calcitriol, the active metabolite of vitamin D, has potent effects on brain cells, both in vitro and in vivo, including the ability to upregulate trophic factors and protect against various lesions. The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal and nucleus accumbens levels of DA and 5-HT. Male Fischer-344 rats were administered vehicle or calcitriol (1 microg/kg, s.c.) once a day for eight consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Seven days later the striata and accumbens were harvested from the animals for high-performance liquid chromatography (HPLC) analysis of monoamines and metabolites. In animals treated with vehicle and METH, there were significant reductions in DA, 5-HT, and their metabolites in both the striatum and accumbens. In animals treated with calcitriol and METH, the magnitude of the METH-induced reductions in DA, 5-HT, and metabolites was substantially and significantly attenuated. The calcitriol treatments did not reduce the hyperthermia associated with multiple injections of METH, indicating that the neuroprotective effects of calcitriol are not due to the prevention of increases in body temperature. These results suggest that calcitriol can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of METH.

  12. Gintonin facilitates catecholamine secretion from the perfused adrenal medulla

    PubMed Central

    Na, Seung-Yeol; Kim, Ki-Hwan; Choi, Mi-Sung; Ha, Kang-Su

    2016-01-01

    The present study was designed to investigate the characteristics of gintonin, one of components isolated from Korean Ginseng on secretion of catecholamines (CA) from the isolated perfused model of rat adrenal gland and to clarify its mechanism of action. Gintonin (1 to 30 µg/ml), perfused into an adrenal vein, markedly increased the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. The gintonin-evoked CA secretion was greatly inhibited in the presence of chlorisondamine (1 µM, an autonomic ganglionic bloker), pirenzepine (2 µM, a muscarinic M1 receptor antagonist), Ki14625 (10 µM, an LPA1/3 receptor antagonist), amiloride (1 mM, an inhibitor of Na+/Ca2+ exchanger), a nicardipine (1 µM, a voltage-dependent Ca2+ channel blocker), TMB-8 (1 µM, an intracellular Ca2+ antagonist), and perfusion of Ca2+-free Krebs solution with 5mM EGTA (a Ca2+chelater), while was not affected by sodium nitroprusside (100 µM, a nitrosovasodialtor). Interestingly, LPA (0.3~3 µM, an LPA receptor agonist) also dose-dependently enhanced the CA secretion from the adrenal medulla, but this facilitatory effect of LPA was greatly inhibited in the presence of Ki 14625 (10 µM). Moreover, acetylcholine (AC)-evoked CA secretion was greatly potentiated during the perfusion of gintonin (3 µg/ml). Taken together, these results demonstrate the first evidence that gintonin increases the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. This facilitatory effect of gintonin seems to be associated with activation of LPA- and cholinergic-receptors, which are relevant to the cytoplasmic Ca2+ increase by stimulation of the Ca2+ influx as well as by the inhibition of Ca2+ uptake into the cytoplasmic Ca2+ stores, without the increased nitric oxide (NO). Based on these results, it is thought that gintonin, one of ginseng components, can elevate the CA secretion from adrenal medulla by regulating the Ca2+ mobilization for exocytosis, suggesting

  13. (1)H NMR-Based Metabolomics and Neurotoxicity Study of Cerebrum and Cerebellum in Rats Treated with Cinnabar, a Traditional Chinese Medicine.

    PubMed

    Wei, Lai; Xue, Rong; Zhang, Panpan; Wu, Yijie; Li, Xiaojing; Pei, Fengkui

    2015-08-01

    Cinnabar, an important traditional Chinese mineral medicine, has been widely used as a Chinese patent medicine ingredient for sedative therapy. Nevertheless, the neurotoxic effects of cinnabar have also been noted. In this study, (1)H NMR-based metabolomics, combined with multivariate pattern recognition, were applied to investigate the neurotoxic effects of cinnabar after intragastrical administration (dosed at 2 and 5 g/kg body weight) on male Wistar rats. The metabolite variations induced by cinnabar were characterized by increased levels of glutamate, glutamine, myo-inositol, and choline, as well as decreased levels of GABA, taurine, NAA, and NAAG in tissue extracts of the cerebellum and cerebrum. These findings suggested that cinnabar induced glutamate excitotoxicity, neuronal cell loss, osmotic state changes, membrane fluidity disruption, and oxidative injury in the brain. We also show here that there is a dose- and time-dependent neurotoxicity of cinnabar, and that cerebellum was more sensitive to cinnabar induction than cerebrum. This work illustrates the utility and reliability of (1)H NMR-based metabolomics approach for examining the potential neurotoxic effects of cinnabar and other traditional Chinese medicines.

  14. Potential developmental neurotoxicity of pesticides used in Europe

    PubMed Central

    Bjørling-Poulsen, Marina; Andersen, Helle Raun; Grandjean, Philippe

    2008-01-01

    Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development. PMID:18945337

  15. Estrogenic protection against gp120 neurotoxicity: role of microglia.

    PubMed

    Zemlyak, Ilona; Brooke, Sheila; Sapolsky, Robert

    2005-06-07

    HIV infection of the nervous system can cause neurotoxicity, and the glycoprotein gp120 of HIV seems to play a key role in this. gp120 is neurotoxic through a multi-cellular pathway, stimulating microglia to release excitotoxins, cytokines and reactive oxygen species, which then damage neurons. We have previously shown that estrogen decreases the neurotoxicity of gp120 in mixed neuronal/glial cultures. In this study, we determine whether estrogen a) decreases the collective neurotoxicity of the factors released by gp120-treated microglia, and/or b) enhances the ability of neurons to survive such factors. To do so, we established microglial cultures, mixed neuronal/glial hippocampal cultures, and neuron-enriched cultures, independently manipulating gp120 and estrogen exposure in each type of culture, and inducing neurotoxicity in neuron-containing cultures by introducing conditioned media from gp120-treated microglial cultures. We observe that estrogen can exert some small protective effects at the level of bolstering neuronal resistance, but that the bulk of its protective effects arise at the level of decreasing the neurotoxicity of factors released by microglia.

  16. Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13

    PubMed Central

    Fan, Mengchen; Xu, Haochen; Wang, Lixiang; Luo, Haiyu; Zhu, Ximin; Cai, Ping; Wei, Lixiang; Lu, Lu; Cao, Yongliang; Ye, Rong; Fan, Wenying; Zhao, Bing-Qiao

    2016-01-01

    Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke, but its neurotoxicity is a significant problem. Here we tested the hypothesis that recombinant ADAMTS 13 (rADAMTS 13) would reduce tPA neurotoxicity in a mouse model of stroke. We show that treatment with rADAMTS 13 in combination with tPA significantly reduced infarct volume compared with mice treated with tPA alone 48 hours after stroke. The combination treatment significantly improved neurological deficits compared with mice treated with tPA or vehicle alone. These neuroprotective effects were associated with significant reductions in fibrin deposits in ischemic vessels and less severe cell death in ischemic brain. The effect of rADAMTS13 on tPA neurotoxicity was mimicked by the N-methyl-D-aspartate (NMDA) receptor antagonist M-801, and was abolished by injection of NMDA. Moreover, rADAMTS 13 prevents the neurotoxicity effect of tPA, by blocking its interaction with the NMDA receptor NR2B and the attendant phosphorylation of NR2B and activation of ERK1/2. Finally, the NR2B-specific NMDA receptor antagonist ifenprodil abolished tPA neurotoxicity and rADAMTS 13 treatment had no further beneficial effect. Our data suggest that the combination of rADAMTS 13 and tPA may provide a novel treatment of ischemic stroke by diminishing the neurotoxic effects of exogenous tPA. PMID:27181025

  17. A 21st Century Update on Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing was proposed in “A 21st Century Update on Neurotoxicity Risk Assessment “ (NRC, 2007), stating that traditional toxicity testing was too slow and expensive to develop information on the potential toxicity of the large number of untested chemicals already used in commerce. In addition, new technologies have compounded the problem as new materials, such as engineered nanomaterials, are introduced at a rate exceeding traditional testing capacity. There is currently much effort to develop higher throughput neurotoxicity testing capabilities, especially for developmental neurotoxicity, but there is no general consensus regarding how alternative testing data should be interpreted for neurotoxicity risk assessment. The dependence of critical functions, such as learning, memory or sensory perception, on the operation of integrated neural systems makes the interpretation of data from simple test assays particularly difficult. The concept of Adverse Outcome Pathways (AOP), in which molecular initiating events (MIE) trigger a sequence of steps leading to an adverse outcome, may provide a conceptual framework in which simple alternative testing data indicative of MIEs can be used to predict neur

  18. The neurotoxicity of amphetamines during the adolescent period.

    PubMed

    Teixeira-Gomes, Armanda; Costa, Vera Marisa; Feio-Azevedo, Rita; Bastos, Maria de Lourdes; Carvalho, Félix; Capela, João Paulo

    2015-04-01

    Amphetamine-type psychostimulants (ATS), such as amphetamine (AMPH), 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) are psychoactive substances widely abused, due to their powerful central nervous system (CNS) stimulation ability. Young people particularly use ATS as recreational drugs. Moreover, AMPH is used clinically, particularly for attention deficit hyperactivity disorder, and has the ability to cause structural and functional brain alterations. ATS are known to interact with monoamine transporter sites and easily diffuse across cellular membranes, attaining high levels in several tissues, particularly the brain. Strong evidence suggests that ATS induce neurotoxic effects, raising concerns about the consequences of drug abuse. Considering that many teenagers and young adults commonly use ATS, our main aim was to review the neurotoxic effects of amphetamines, namely AMPH, MDMA, and METH, in the adolescence period of experimental animals. Reports agree that adolescent animals are less susceptible than adult animals to the neurotoxic effects of amphetamines. The susceptibility to the neurotoxic effects of ATS seems roughly located in the early adolescent period of animals. Many authors report that the age of exposure to ATS is crucial for the neurotoxic outcome, showing that the stage of brain maturity has a strong importance. Moreover, recent studies have been undertaken in young adults and/or consumers during adolescence that clearly indicate brain or behavioural damage, arguing for long-term neurotoxic effects in humans. There is an urgent need for more studies during the adolescence period, in order to unveil the mechanisms and the brain dysfunctions promoted by ATS.

  19. Involvement of multiple distinct Bordetella receptor proteins in the utilization of iron liberated from transferrin by host catecholamine stress hormones

    PubMed Central

    Armstrong, Sandra K.; Brickman, Timothy J.; Suhadolc, Ryan J.

    2012-01-01

    Summary Bordetella bronchiseptica is a pathogen that can acquire iron using its native alcaligin siderophore system, but can also use the catechol xenosiderophore enterobactin via the BfeA outer membrane receptor. Transcription of bfeA is positively controlled by a regulator that requires induction by enterobactin. Catecholamine hormones also induce bfeA transcription and B. bronchiseptica can use the catecholamine norepinephrine for growth on transferrin. In this study, B. bronchiseptica was shown to use catecholamines to obtain iron from both transferrin and lactoferrin in the absence of siderophore. In the presence of siderophore, norepinephrine augmented transferrin utilization by B. bronchiseptica, as well as siderophore function in vitro. Genetic analysis identified BfrA, BfrD and BfrE as TonB dependent outer membrane catecholamine receptors. The BfeA enterobactin receptor was found to not be involved directly in catecholamine utilization; however, the BfrA, BfrD and BfrE catecholamine receptors could serve as receptors for enterobactin and its degradation product 2,3-dihydroxybenzoic acid. Thus, there is a functional link between enterobactin-dependent and catecholamine-dependent transferrin utilization. This investigation characterizes a new B. bronchiseptica mechanism for iron uptake from transferrin that uses host stress hormones that not only deliver iron directly to catecholamine receptors, but also potentiate siderophore activity by acting as iron shuttles. PMID:22458330

  20. Catecholamines and myocardial contractile function during hypodynamia and with an altered thyroid hormone balance

    NASA Technical Reports Server (NTRS)

    Pruss, G. M.; Kuznetsov, V. I.; Zhilinskaya, A. A.

    1980-01-01

    The dynamics of catecholamine content and myocardial contractile function during hypodynamia were studied in 109 white rats whose motor activity was severely restricted for up to 30 days. During the first five days myocardial catecholamine content, contractile function, and physical load tolerance decreased. Small doses of thyroidin counteracted this tendency. After 15 days, noradrenalin content and other indices approached normal levels and, after 30 days, were the same as control levels, although cardiac functional reserve was decreased. Thyroidin administration after 15 days had no noticeable effect. A detailed table shows changes in 17 indices of myocardial contractile function during hypodynamia.

  1. Shrinking and development of lipid droplets in adipocytes during catecholamine-induced lipolysis.

    PubMed

    Nagayama, Masafumi; Shimizu, Kyoko; Taira, Toshio; Uchida, Tsutomu; Gohara, Kazutoshi

    2010-01-04

    Time-lapse observation of adipocytes during catecholamine-induced lipolysis clearly shows that shrinking of existing lipid droplets (LDs) occurs in some adipocytes and that small LDs are newly developed in almost all cells. Immunofluorescence imaging reveals that activation and localization of hormone-sensitive lipase (HSL) on the surface of LDs, which are required for conferring maximal lipolysis, are necessary for the shrinking of the LDs. However, not all adipocytes in which phosphorylated HSL is localized on LDs exhibit shrinking of LDs. The simultaneous shrinking and development of LDs yield apparent fragmentation and dispersion of LDs in adipocytes stimulated with catecholamine.

  2. Changes in plasma catecholamines levels as preclinical biomarkers in experimental models of Parkinson's disease.

    PubMed

    Kim, A R; Ugryumov, M V

    2015-01-01

    The goal of this study was to investigate the changes in the concentrations of blood plasma catecholamines as possible biomarkers of Parkinson's disease (PD) in the mouse experimental model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A significant decrease was detected in the levels of dopamine and L-DOPA in the PD preclinical stage model as a result of the catecholamines systemic metabolism disfunction. In the PD early clinical stage models, the level of L-DOPA and dihydroxyphenylacetic acid decreased, which is consistent with the results of blood tests in untreated patients.

  3. Effect of. beta. -endorphin on catecholamine levels in rat hypothalamus and cerebral cortex

    SciTech Connect

    Slavnov, V.N.; Valueva, G.V.; Markov, V.V.; Luchitskii, E.V.

    1986-10-01

    The authors studied the effect of beta-endorphin on catecholamine concentrations in the hypothalmus and cerebral cortex in rats, as a contribution to the explanation of the mechanism of action of this peptide on certain pituitary trophic functions. Concentrations of dopamine, noradrenalin, and adrenalin were determined by a radioenzymatic method. A Mark 3 scintillation system was used for radiometric investigation of the samples. The results of these experiments indicate that beta-endorphin has a marked effect on brain catecholamine levels mainly in the hypothalamus.

  4. Effects of early pregnancy and acute 17 beta-estradiol administration on porcine uterine secretion, cyclic nucleotides, and catecholamines.

    PubMed

    Young, K H; Bazer, F W; Simpkins, J W; Roberts, R M

    1987-01-01

    This study investigated acute effects of 17 beta-estradiol (E) on ions, cyclic nucleotides, and catecholamines and their association with temporal changes in uterine secretory products in pregnant, cyclic, and nonpregnant gilts. Uterine flushings (UTF) and endometrium (ENDOM) from one uterine horn of nonpregnant and pregnant gilts (n = 9) were collected on days 10, 12, and 14 (n = 3). Protein, plasma inhibitor (P less than 0.05), Na+, and K+ (P less than 0.01) increased linearly in UTF of pregnant gilts. Ca2+ changed biphasically, with higher concentrations (P less than 0.01) in pregnant gilts on day 12. Endometrial cAMP and cGMP (P less than 0.05) increased between days 12 and 14 of pregnancy. The UTF norepinephrine (NE) concentrations increased (P less than 0.01) in cyclic gilts between days 12 and 14, while endometrial NE increased between days 10 and 12 and then decreased on day 14. The UTF of pregnant gilts had higher (P less than 0.05) concentrations of dopamine (DA), which peaked on day 12 and then decreased (P less than 0.01) by day 14. DA in UTF of nonpregnant gilts decreased between days 10 and 12 and remained low on day 14. A catecholamine metabolite, 3,4-dihydroxyphenylglycol, in ENDOM (P less than 0.05) and UTF (P less than 0.01) decreased linearly between days 10 and 14. The turnover rate of endometrial catecholamines was 2.4-fold higher (P less than 0.05) during early pregnancy compared with that in cyclic gilts. Effects of acute administration of exogenous E (0.5 mg) were also studied. The UTF and ENDOM were from day 11 nonpregnant gilts 0, 30, 60, and 360 min (n = 3) post-E or post-saline-ethanol (C) injection (n = 9). Potassium, plasma inhibitor (P less than 0.01), and cGMP (P less than 0.05) increased rapidly (30 min) after E injection. The K+ level changed biphasically, with increased concentrations again at 360 min. Plasmin inhibitor returned to levels similar to controls by 60 min, whereas cGMP remained elevated until 360 min postinjection

  5. Neurotoxicity of traffic-related air pollution.

    PubMed

    Costa, Lucio G; Cole, Toby B; Coburn, Jacki; Chang, Yu-Chi; Dao, Khoi; Roqué, Pamela J

    2017-03-01

    The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250-300μg/m(3) for 6h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2.

  6. Cadmium neurotoxicity to a freshwater planarian.

    PubMed

    Wu, Jui-Pin; Lee, Hui-Ling; Li, Mei-Hui

    2014-11-01

    Although freshwater planarians are evolutionarily primitive, they are some of the simplest bilateral animals possessing integrated neural networks similar to those in vertebrates. We attempted to develop planarian Dugesia japonica as a model for investigating the neurotoxicity of environmental pollutants such as cadmium (Cd). This study was therefore designed to study the effects of Cd on the locomotor activity, neurobehavior, and neurological enzymes of D. japonica. After planarians were exposed to Cd at high concentrations, altered neurobehavior was observed that exhibited concentration-dependent patterns. Morphological alterations in Cd-treated planarians included irregular shape, body elongation, screw-like hyperkinesia, and bridge-like position. To study the direct effects of Cd on neurological enzymes, tissue homogenates of planarians were incubated in vitro with Cd before their activity was measured. Results showed that acetylcholinesterase (AChE), adenosine triphosphatase (ATPase), and monoamine oxidase A (MAO-A) activities were inhibited in a concentration-dependent manner. MAO-B activity was significantly induced by Cd at low concentrations and inhibited at high concentrations. Changes in the in vivo activity of AChE and ATPase were also found after planarians were treated with Cd at a sublethal concentration (5.56 μM). These observations indicate that neurotransmission systems in planarians are disturbed after Cd exposure.

  7. Oxidative and nitrosative stress in ammonia neurotoxicity.

    PubMed

    Skowrońska, Marta; Albrecht, Jan

    2013-04-01

    Increased ammonia accumulation in the brain due to liver dysfunction is a major contributor to the pathogenesis of hepatic encephalopathy (HE). Fatal outcome of rapidly progressing (acute) HE is mainly related to cytotoxic brain edema associated with astrocytic swelling. An increase of brain ammonia in experimental animals or treatment of cultured astrocytes with ammonia generates reactive oxygen and nitrogen species in the target tissues, leading to oxidative/nitrosative stress (ONS). In cultured astrocytes, ammonia-induced ONS is invariably associated with the increase of the astrocytic cell volume. Interrelated mechanisms underlying this response include increased nitric oxide (NO) synthesis which is partly coupled to the activation of NMDA receptors and increased generation of reactive oxygen species by NADPH oxidase. ONS and astrocytic swelling are further augmented by excessive synthesis of glutamine (Gln) which impairs mitochondrial function following its accumulation in there and degradation back to ammonia ("the Trojan horse" hypothesis). Ammonia also induces ONS in other cell types of the CNS: neurons, microglia and the brain capillary endothelial cells (BCEC). ONS in microglia contributes to the central inflammatory response, while its metabolic and pathophysiological consequences in the BCEC evolve to the vasogenic brain edema associated with HE. Ammonia-induced ONS results in the oxidation of mRNA and nitration/nitrosylation of proteins which impact intracellular metabolism and potentiate the neurotoxic effects. Simultaneously, ammonia facilitates the antioxidant response of the brain, by activating astrocytic transport and export of glutathione, in this way increasing the availability of precursors of neuronal glutathione synthesis.

  8. Role of Prion Protein Aggregation in Neurotoxicity

    PubMed Central

    Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Nizzari, Mario; Florio, Tullio

    2012-01-01

    In several neurodegenerative diseases, such as Parkinson, Alzheimer’s, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP), the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126) and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death. PMID:22942726

  9. Anatomical and pharmacological characterization of catecholamine transients in the medial prefrontal cortex evoked by ventral tegmental area stimulation

    PubMed Central

    Shnitko, Tatiana A.; Robinson, Donita L.

    2014-01-01

    Voltammetric measurements of catecholamines in the medial prefrontal cortex (mPFC) are infrequent because of lack of chemical selectivity between dopamine and norepinephrine and their overlapping anatomical inputs. Here, we examined the contribution of norepinephrine to the catecholamine release in the mPFC evoked by electrical stimulation of the ventral tegmental area (VTA). Initially, electrical stimulation was delivered in the midbrain at incremental depths of −5 to −9.4mm from bregma while catecholamine release was monitored in the mPFC. Although catecholamine release was observed at dorsal stimulation sites that may correspond to the dorsal noradrenergic bundle (DNB, containing noradrenergic axonal projections to the mPFC), maximal release was evoked by stimulation of the VTA (the source of dopaminergic input to the mPFC). Next, VTA-evoked catecholamine release was monitored in the mPFC before and after knife incision of the DNB, and no significant changes in the evoked catecholamine signals were found These data indicated that DNB fibers did not contribute to the VTA-evoked catecholamine release observed in the mPFC. Finally, while the D2-receptor antagonist raclopride significantly altered VTA-evoked catecholamine release, the α2-adrenergic receptor antagonist idazoxan did not. Specifically, raclopride reduced catecholamine release in the mPFC, opposite to that observed in the striatum, indicating differential autoreceptor regulation of mesocortical and mesostriatal neurons. Together, these findings suggest that the catecholamine release in the mPFC arising from VTA stimulation was predominately dopaminergic rather than noradrenergic. PMID:24285555

  10. Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes

    PubMed Central

    Barbosa, Daniel José; Capela, João Paulo; Oliveira, Jorge MA; Silva, Renata; Ferreira, Luísa Maria; Siopa, Filipa; Branco, Paula Sério; Fernandes, Eduarda; Duarte, José Alberto; de Lourdes Bastos, Maria; Carvalho, Félix

    2012-01-01

    BACKGROUND AND PURPOSE 3,4-Methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro-oxidant reactive metabolites is thought to contribute to its adverse effects. EXPERIMENTAL APPROACH Using mouse brain synaptosomes, we evaluated the pro-oxidant effects of MDMA and its metabolites, α-methyldopamine (α-MeDA), N-methyl-α-methyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA], as well as those of 5-HT, dopamine, l-DOPA and 3,4-dihydroxyphenylacetic acid (DOPAC). KEY RESULTS 5-HT, dopamine, l-DOPA, DOPAC and MDMA metabolites α-MeDA, N-Me-α-MeDA and 5-(GSH)-α-MeDA, concentration- and time-dependently increased H2O2 production, which was significantly reduced by the antioxidants N-acetyl-l-cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H2O2 generation induced by 5-HT was totally dependent on MAO-related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine, l-DOPA and DOPAC concentration-dependently increased quinoproteins formation and, like 5-HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds’ pro-oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial-dependent mechanisms of toxicity in this experimental model. CONCLUSIONS AND IMPLICATIONS MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy. PMID:21506960

  11. The Janus faces of 3-hydroxykynurenine: dual redox modulatory activity and lack of neurotoxicity in the rat striatum.

    PubMed

    Colín-González, Ana Laura; Maya-López, Marisol; Pedraza-Chaverrí, José; Ali, Syed F; Chavarría, Anahí; Santamaría, Abel

    2014-11-17

    3-Hydroxykynurenine (3-HK), an intermediate metabolite of the kynurenine pathway, has been largely hypothesized as a neurotoxic molecule contributing to neurodegeneration in several experimental and clinical conditions. Interestingly, the balance in literature points to a dual role of this molecule in the CNS: in vitro studies describe neurotoxic and/or antioxidant properties, whereas in vivo studies suggest a role of this metabolite as a weak neurotoxin. This work was designed to investigate, under different experimental conditions, whether or not 3-HK is toxic to cells, and if the redox activity exerted by this molecule modulates its actions in the rat striatum. In order to evaluate these effects, 3-HK was administered in vitro to isolated striatal slices, and in vivo to the striatum of rats. In striatal slices, 3-HK exerted a concentration- and time-dependent effect on lipid peroxidation, inducing both pro-oxidant actions at low (5-20) micromolar concentrations, and antioxidant activity at a higher concentration (100µM). Interestingly, while 3-HK was unable to induce mitochondrial dysfunction in slices, at the same range of concentrations it prevented the deleterious effects exerted by the neurotoxin and related metabolite quinolinic acid (QUIN), the mitochondrial toxin 3-nitropropionic acid, and the pro-oxidant compound iron sulfate. These protective actions were related to the stimulation of glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. In addition, 3-HK stimulated the protein content of the transcription factor and antioxidant regulator Nrf2, and some of its related proteins. Accordingly, 3-HK, but not QUIN, exhibited reductive properties at high concentrations. The striatal tissue of animals infused with 3-HK exhibited moderate levels of lipid and protein oxidation at short times post-lesion (h), but these endpoints were substantially decreased at longer times (days). These effects were correlated with an early increase in

  12. MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains

    PubMed Central

    Alam, Gelareh; Miller, Diane B.; O’Callaghan, James P.; Lu, Lu; Williams, Robert W.; Jones, Byron C.

    2016-01-01

    Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5 mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases. PMID:27182044

  13. Fully automated high-performance liquid chromatographic assay for the analysis of free catecholamines in urine.

    PubMed

    Said, R; Robinet, D; Barbier, C; Sartre, J; Huguet, C

    1990-08-24

    A totally automated and reliable high-performance liquid chromatographic method is described for the routine determination of free catecholamines (norepinephrine, epinephrine and dopamine) in urine. The catecholamines were isolated from urine samples using small alumina columns. A standard automated method for pH adjustment of urine before the extraction step has been developed. The extraction was performed on an ASPEC (Automatic Sample Preparation with Extraction Columns, Gilson). The eluate was collected in a separate tube and then automatically injected into the chromatographic column. The catecholamines were separated by reversed-phase ion-pair liquid chromatography and quantified by fluorescence detection. No manual intervention was required during the extraction and separation procedure. One sample may be run every 15 min, ca. 96 samples in 24 h. Analytical recoveries for all three catecholamines are 63-87%, and the detection limits are 0.01, 0.01, and 0.03 microM for norepinephrine, epinephrine and dopamine, respectively, which is highly satisfactory for urine. Day-to-day coefficients of variation were less than 10%.

  14. Concepts of Scientific Integrative Medicine Applied to the Physiology and Pathophysiology of Catecholamine Systems

    PubMed Central

    Goldstein, David S.

    2016-01-01

    This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body’s monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems—especially Parkinson disease—and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era. PMID:24265239

  15. Catecholamine responses to virtual combat: implications for post-traumatic stress and dimensions of functioning

    PubMed Central

    Highland, Krista B.; Costanzo, Michelle E.; Jovanovic, Tanja; Norrholm, Seth D.; Ndiongue, Rochelle B.; Reinhardt, Brian J.; Rothbaum, Barbara; Rizzo, Albert A.; Roy, Michael J.

    2015-01-01

    Posttraumatic stress disorder (PTSD) symptoms can result in functional impairment among service members (SMs), even in those without a clinical diagnosis. The variability in outcomes may be related to underlying catecholamine mechanisms. Individuals with PTSD tend to have elevated basal catecholamine levels, though less is known regarding catecholamine responses to trauma-related stimuli. We assessed whether catecholamine responses to a virtual combat environment impact the relationship between PTSD symptom clusters and elements of functioning. Eighty-seven clinically healthy SMs, within 2 months after deployment to Iraq or Afghanistan, completed self-report measures, viewed virtual-reality (VR) combat sequences, and had sequential blood draws. Norepinephrine responses to VR combat exposure moderated the relationship between avoidance symptoms and scales of functioning including physical functioning, physical-role functioning, and vitality. Among those with high levels of avoidance, norepinephrine change was inversely associated with functional status, whereas a positive correlation was observed for those with low levels of avoidance. Our findings represent a novel use of a virtual environment to display combat-related stimuli to returning SMs to elucidate mind-body connections inherent in their responses. The insight gained improves our understanding of post-deployment symptoms and quality of life in SMs and may facilitate enhancements in treatment. Further research is needed to validate these findings in other populations and to define the implications for treatment effectiveness. PMID:25852586

  16. Fight or flight, forbearance and fortitude: the spectrum of actions of the catecholamines and their cousins.

    PubMed

    Arun, C P

    2004-06-01

    Catecholamines are recognized to play an important part in the fight-or-flight response to impending stress. Catecholamine and other phase-reactant levels are raised in the first 24 h following acute stress, but the bigger picture of their action on the organism is unavailable. In this article, we examine their actions in light of the theory of phase transitions borrowed from the numerate sciences. Phase transitions involve changes in the state of matter or an organism with a common example of what is termed a first-order phase transition (sudden change) being provided by the popular expression "the straw that broke the camel's back." We propose that the response to catecholamines follows a triphasic response: a Phase I response is the fight-or-flight response to impending stress that protects the animal. With mild to intermediate stress, the Phase II or forbearance response allows it to tolerate the physiological upset. With severe stress, however, severe vital organ vasoconstriction leads to a quick death. The present theory has value in understanding the clinical picture in acute stress. Phase II or Forbearance Phase corresponds to Classes I, II, and III of hemorrhagic shock, and Phase III or Fortitude Phase to Class IV. Thus, a Phase III or fortitude response is to the animal what apoptosis is to the individual cell and has social implications. The present framework provides a fresh perspective on the action of the catecholamines and their cousins.

  17. DIFFERENTIAL MODULATION OF CATECHOLAMINES BY CHLOROTRIAZINE HERBICIDES IN PHEOCHROMOCYTOMA (PC12) CELLS IN VITRO

    EPA Science Inventory

    Differential modulation of catecholamines by chlorotriazine herbicides in pheochromocytoma (PC12) cells in vitro.

    Das PC, McElroy WK, Cooper RL.

    Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599, USA.

    Epidemiological, wildlife, and lab...

  18. POTENTIAL MECHANISMS RESPONSIBLE FOR CHLOROTRIAZINE-INDUCED ALTERATIONS IN CATECHOLAMINES IN PHEOCHROMOCYTOMA (PC12) CELLS

    EPA Science Inventory

    ABSTRACT

    Potential Mechanisms Responsible for Chlorotriazine-induced Changes in Catecholamine Metabolism in Pheochromocytoma (PC12) Cells*
    PARIKSHIT C. DAS1, WILLIAM K. McELROY2 , AND RALPH L. COOPER2+
    1Curriculum in Toxicology, University of North Carolina, Chape...

  19. Protective Effects of D-Penicillamine on Catecholamine-Induced Myocardial Injury.

    PubMed

    Říha, Michal; Hašková, Pavlína; Martin, Jan; Filipský, Tomáš; Váňová, Kateřina; Vávrová, Jaroslava; Holečková, Magdalena; Homola, Pavel; Vítek, Libor; Palicka, Vladimír; Šimůnek, Tomáš; Mladěnka, Přemysl

    2016-01-01

    Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury both in vitro and in vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additional in vitro experiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application.

  20. The Control of Responsiveness in ADHD by Catecholamines: Evidence for Dopaminergic, Noradrenergic and Interactive Roles

    ERIC Educational Resources Information Center

    Oades, Robert D.; Sadile, Adolfo G.; Sagvolden, Terje; Viggiano, Davide; Zuddas, Alessandro; Devoto, Paola; Aase, Heidi; Johansen, Espen B.; Ruocco, Lucia A.; Russell, Vivienne A.

    2005-01-01

    We explore the neurobiological bases of attention deficit hyperactivity disorder (ADHD) from the viewpoint of the neurochemistry and psychopharmacology of the catecholamine-based behavioural systems. The contributions of dopamine (DA) and noradrenaline (NA) neurotransmission to the motor and cognitive symptoms of ADHD (e.g. hyperactivity, variable…

  1. Protective Effects of D-Penicillamine on Catecholamine-Induced Myocardial Injury

    PubMed Central

    Říha, Michal; Hašková, Pavlína; Martin, Jan; Filipský, Tomáš; Váňová, Kateřina; Vávrová, Jaroslava; Holečková, Magdalena; Homola, Pavel; Vítek, Libor; Palicka, Vladimír; Šimůnek, Tomáš; Mladěnka, Přemysl

    2016-01-01

    Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury both in vitro and in vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additional in vitro experiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application. PMID:26788248

  2. Potentiometric and NMR complexation studies of phenylboronic acid PBA and its aminophosphonate analog with selected catecholamines

    NASA Astrophysics Data System (ADS)

    Ptak, Tomasz; Młynarz, Piotr; Dobosz, Agnieszka; Rydzewska, Agata; Prokopowicz, Monika

    2013-05-01

    Boronic acids are a class of intensively explored compounds, which according to their specific properties have been intensively explored in last decades. Among them phenylboronic acids and their derivatives are most frequently examined as receptors for diverse carbohydrates. In turn, there is a large gap in basic research concerning complexation of catecholamines by these compounds. Therefore, we decided to undertake studies on interaction of chosen catecholamines, namely: noradrenaline (norephinephrine), dopamine, L-DOPA, DOPA-P (phosphonic analog of L-DOPA) and catechol, with simple phenyl boronic acid PBA by means of potentiometry and NMR spectroscopy. For comparison, the binding properties of recently synthesized phenylboronic receptor 1 bearing aminophosphonate function in meta-position were investigated and showed promising ability to bind catecholamines. The protonation and stability constants of PBA and receptor 1 complexes were examined by potentiometry. The obtained results demonstrated that PBA binds the catecholamines with the following affinity order: noradrenaline ⩾ dopamine ≈ L-DOPA > catechol > DOPA-P, while its modified analog 1 reveals slightly different preferences: dopamine > noradrenaline > catechol > L-DOPA > DOPA-P.

  3. Adrenal Medullary Grafts Restore Olfactory Deficits and Catecholamine Levels of 6-OHDA Amygdala Lesioned Animals

    PubMed Central

    Fernández-Ruiz, Juan; Guzmán, Rubén; Martínez, María Dolores; Miranda, María Isabel; Bermúdez-Rattoni, Federico; Drucker-Colín, René

    1993-01-01

    Aside from motor and cognitive deficits, Parkinson patients also manifest a little-studied olfactory deficit. Since in Parkinson's disease there is a dopamine depletion of the amygdala due to mesocorticolimbic system degeneration, we decided to test olfactory and taste performance of 6-OHDA amygdala lesioned rats, as well as the possible restoration of either function with adrenal medullary transplants. Two 6-OHDA lesioned groups and one control group were tested in the potentiation of odor by taste aversion paradigm. On taste aversion none of the groups showed any impairment. In contrast, the 6-OHDA lesioned rats showed a marked impairment in olfactory aversion. At this point, one of the lesioned groups received a bilateral adrenal medullary graft within the lesioned area. After two months, all groups were submitted again to the behavioral paradigm. Taste remained unaffected, but the lesioned only group did not recover either olfactory aversion or normal catecholamine levels. The grafted group, on the other hand, restored olfactory aversion and catecholamine levels. It can be concluded from this study that catecholamine depletion of the amygdala is sufficient to produce a selective olfactory deficit, not accompanied by taste impairments, and that such a deficit can be reversed by adrenal medullary transplants, which in turn restore catecholamine levels. PMID:7948179

  4. Facial swelling secondary to inhaled bronchodilator abuse: catecholamine-induced sialadenosis.

    PubMed

    Loria, R C; Wedner, H J

    1989-04-01

    A patient with asthma presented with a history of recurrent episodes of facial swelling. The swelling occurred in the preauricular area and extended to the angle of the jaw. The patient attributed these episodes to a "food allergy" as they occurred during or immediately following meals. The only medication the patient was using was inhaled epinephrine (Primatene MistR), two puffs, ten to twenty times a day. Subsequent evaluation revealed that the patient had sarcoidosis. Differential diagnosis of the facial swelling included food-related angioedema, sarcoid parotitis, or catecholamine-induced sialadenosis, which is a rare complication associated with excessive catecholamine administration. A gallium-67 citrate scan demonstrated abnormal pulmonary and hilar uptake of the radiotracer, but not lacrimal or parotid gland uptake, strongly arguing against sarcoidosis as the cause of the facial swelling. Episodes of swelling completely abated when the patient stopped using the epinephrine inhalers. At 5 months of follow-up she has had two recurrent episodes of facial swelling, each time associated with the use of inhaled epinephrine. Thus this patient's facial swelling most likely represents catecholamine-induced sialadenosis. This adverse drug reaction, associated with excessive use of inhaled catecholamines must be kept in mind in patients who abuse inhaled beta-adrenergic agonists and report parotid swelling.

  5. Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.

    PubMed

    Toneff, Thomas; Funkelstein, Lydiane; Mosier, Charles; Abagyan, Armen; Ziegler, Michael; Hook, Vivian

    2013-08-01

    Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.

  6. Hypoxic alligator embryos: chronic hypoxia, catecholamine levels and autonomic responses of in ovo alligators.

    PubMed

    Eme, John; Altimiras, Jordi; Hicks, James W; Crossley, Dane A

    2011-11-01

    Hypoxia is a naturally occurring environmental challenge for embryonic reptiles, and this is the first study to investigate the impact of chronic hypoxia on the in ovo development of autonomic cardiovascular regulation and circulating catecholamine levels in a reptile. We measured heart rate (f(H)) and chorioallantoic arterial blood pressure (MAP) in normoxic ('N21') and hypoxic-incubated ('H10'; 10% O(2)) American alligator embryos (Alligator mississippiensis) at 70, 80 and 90% of development. Embryonic alligator responses to adrenergic blockade with propranolol and phentolamine were very similar to previously reported responses of embryonic chicken, and demonstrated that embryonic alligator has α and β-adrenergic tone over the final third of development. However, adrenergic tone originates entirely from circulating catecholamines and is not altered by chronic hypoxic incubation, as neither cholinergic blockade with atropine nor ganglionic blockade with hexamethonium altered baseline cardiovascular variables in N21 or H10 embryos. In addition, both atropine and hexamethonium injection did not alter the generally depressive effects of acute hypoxia - bradycardia and hypotension. However, H10 embryos showed significantly higher levels of noradrenaline and adrenaline at 70% of development, as well as higher noradrenaline at 80% of development, suggesting that circulating catecholamines reach maximal levels earlier in incubation for H10 embryos, compared to N21 embryos. Chronically elevated levels of catecholamines may alter the normal balance between α and β-adrenoreceptors in H10 alligator embryos, causing chronic bradycardia and hypotension of H10 embryos measured in normoxia.

  7. Development of Sensitive and Direct Methods for Measuring Plasma Aldosterone and Catecholamine Concentrations

    NASA Technical Reports Server (NTRS)

    Haber, E.

    1972-01-01

    Radioimmunoassays for renin activity, angiotensin 1, and angiotensin 2 in the study of vasomotor regulation give new insight into the role of the renin system in maintaining postural homeostatsis. Similar laboratory procedures for specific assays of aldosterone and catecholamines achieve accurate determinations in small human blood samples.

  8. Concepts of scientific integrative medicine applied to the physiology and pathophysiology of catecholamine systems.

    PubMed

    Goldstein, David S

    2013-10-01

    This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body's monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems-especially Parkinson disease-and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era.

  9. A microfluidic platform for chemical stimulation and real time analysis of catecholamine secretion from neuroendocrine cells.

    PubMed

    Ges, Igor A; Brindley, Rebecca L; Currie, Kevin P M; Baudenbacher, Franz J

    2013-12-07

    Release of neurotransmitters and hormones by calcium-regulated exocytosis is a fundamental cellular process that is disrupted in a variety of psychiatric, neurological, and endocrine disorders. As such, there is significant interest in targeting neurosecretion for drug and therapeutic development, efforts that will be aided by novel analytical tools and devices that provide mechanistic insight coupled with increased experimental throughput. Here, we report a simple, inexpensive, reusable, microfluidic device designed to analyze catecholamine secretion from small populations of adrenal chromaffin cells in real time, an important neuroendocrine component of the sympathetic nervous system and versatile neurosecretory model. The device is fabricated by replica molding of polydimethylsiloxane (PDMS) using patterned photoresist on silicon wafer as the master. Microfluidic inlet channels lead to an array of U-shaped "cell traps", each capable of immobilizing single or small groups of chromaffin cells. The bottom of the device is a glass slide with patterned thin film platinum electrodes used for electrochemical detection of catecholamines in real time. We demonstrate reliable loading of the device with small populations of chromaffin cells, and perfusion/repetitive stimulation with physiologically relevant secretagogues (carbachol, PACAP, KCl) using the microfluidic network. Evoked catecholamine secretion was reproducible over multiple rounds of stimulation, and graded as expected to different concentrations of secretagogue or removal of extracellular calcium. Overall, we show this microfluidic device can be used to implement complex stimulation paradigms and analyze the amount and kinetics of catecholamine secretion from small populations of neuroendocrine cells in real time.

  10. Enhanced metabolite generation

    DOEpatents

    Chidambaram, Devicharan [Middle Island, NY

    2012-03-27

    The present invention relates to the enhanced production of metabolites by a process whereby a carbon source is oxidized with a fermentative microbe in a compartment having a portal. An electron acceptor is added to the compartment to assist the microbe in the removal of excess electrons. The electron acceptor accepts electrons from the microbe after oxidation of the carbon source. Other transfers of electrons can take place to enhance the production of the metabolite, such as acids, biofuels or brewed beverages.

  11. Is Neurotoxicity of Metallic Nanoparticles the Cascades of Oxidative Stress?

    NASA Astrophysics Data System (ADS)

    Song, Bin; Zhang, YanLi; Liu, Jia; Feng, XiaoLi; Zhou, Ting; Shao, LongQuan

    2016-06-01

    With the rapid development of nanotechnology, metallic (metal or metal oxide) nanoparticles (NPs) are widely used in many fields such as cosmetics, the food and building industries, and bio-medical instruments. Widespread applications of metallic NP-based products increase the health risk associated with human exposures. Studies revealed that the brain, a critical organ that consumes substantial amounts of oxygen, is a primary target of metallic NPs once they are absorbed into the body. Oxidative stress (OS), apoptosis, and the inflammatory response are believed to be the main mechanisms underlying the neurotoxicity of metallic NPs. Other studies have disclosed that antioxidant pretreatment or co-treatment can reverse the neurotoxicity of metallic NPs by decreasing the level of reactive oxygen species, up-regulating the activities of antioxidant enzymes, decreasing the proportion of apoptotic cells, and suppressing the inflammatory response. These findings suggest that the neurotoxicity of metallic NPs might involve a cascade of events following NP-induced OS. However, additional research is needed to determine whether NP-induced OS plays a central role in the neurotoxicity of metallic NPs, to develop a comprehensive understanding of the correlations among neurotoxic mechanisms and to improve the bio-safety of metallic NP-based products.

  12. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity

    PubMed Central

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin’s ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  13. The sigma receptor ligand (+/-)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors.

    PubMed

    Terleckyj, I; Sonsalla, P K

    1994-04-01

    The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

  14. Distribution of catecholamine and indoleamine neurons in the brain of the common marmoset (Callithrix jacchus).

    PubMed Central

    Schofield, S P; Dixson, A F

    1982-01-01

    The distribution of monoamine neurons in the brains of ten common marmosets (Callithrix jacchus) was examined by means of the Falck-Hillarp formaldehyde histofluorescence technique. Large populations of catecholamine and indoleamine neurons were found throughout the brain stem. Catecholamine cell bodies corresponded essentially to th noradrenaline and dopamine groups defined as A1-A7 and A8-A14, respectively. In contrast to Old World primate species, however, the noradrenaline cell populations (particularly the pontine coeruleal A6 group) were less numerous. Ascending catecholamine fibre pathways were not observed within the medulla or pons, although numerous axons were found near the mesodiencephalic border. These were fine and smooth in appearance in contrast to those of other species and this finding may represent a significant morphological difference. The catecholamine terminal innervation of the diencephalon was modest in the marmoset and was less dense than in other primates. In contrast, limbic areas and the striatum contained very large numbers of terminals. Indoleamine cell bodies, equivalent to the serotonin groups defined as B1-B9, were also observed. The most rostral cell populations (B7-9) were large. In addition, pontine and medullary indoleamine neurons extended laterally through the tegmentum as noted in other primates, such that they often adjacent to catecholamine neurons. A prominent bundle of indoleamine axons was observed in the mesencephalon and corresponded to a fibre pathway seen in rodents and other primates. No terminal varicosities were noted. Images Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:6804424

  15. GABAA and GABAB receptors are functionally active in the regulation of catecholamine secretion by bovine chromaffin cells.

    PubMed

    Castro, E; Oset-Gasque, M J; González, M P

    1989-07-01

    GABA stimulates the basal catecholamine release from adrenal bovine chromaffin cells in a calcium-dependent manner. This release represents about 70% of that obtained by similar doses of nicotine under similar experimental conditions. This effect is mediated by GABAA receptor sites present in chromaffin cells, since it was mimicked by muscimol and reversed by bicuculline. In addition, GABA, through its GABAA receptors, increases the catecholamine release evoked by submaximal doses of nicotine, but it has no effect on nicotine-evoked secretion of catecholamines when nicotine was given at maximal doses. These results seem to indicate that both nicotine and GABA release catecholamines from the same intracellular pool. In contrast, baclofen, a GABAB receptor agonist, depressed both basal and nicotine-evoked catecholamine release; this result indicates that in addition to GABAA control of catecholamine secretion by chromaffin cells, there is a GABAB control of this function. These results support the existence of a dual regulation of catecholamine secretion by both the GABAA and GABAB receptors in a similar way as that proposed for muscarinic and nicotinic cholinergic receptors.

  16. Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

    PubMed

    Itzhak, Y; Martin, J L; Black, M D; Ali, S F

    1998-06-01

    Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH

  17. Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

    SciTech Connect

    Niidome, Tetsuhiro; Goto, Yasuaki; Kato, Masaru; Wang, Pi-Lin; Goh, Saori; Tanaka, Naoki; Akaike, Akinori; Kihara, Takeshi; Sugimoto, Hachiro

    2009-09-04

    Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  18. Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity.

    PubMed

    Manucha, Walter

    Multiple mechanisms underlying glutamate-induced neurotoxicity have recently been discussed. Likewise, a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with neurodegeneration, oxidative stress, and inflammation. This article highlights nitric oxide, an atypical neurotransmitter synthesized and released on demand by the post-synaptic neurons, and has many important implications for nerve cell survival and differentiation. Consequently, synaptogenesis, synapse elimination, and neurotransmitter release, are nitric oxide-modulated. Interesting, an emergent role of nitric oxide pathways has been discussed as regards neurotoxicity from glutamate-induced apoptosis. These findings suggest that nitric oxide pathways modulation could prevent oxidative damage to neurons through apoptosis inhibition. This review aims to highlight the emergent aspects of nitric oxide-mediated signaling in the brain, and how they can be related to neurotoxicity, as well as the development of neurodegenerative diseases development.

  19. Manganese-induced Neurotoxicity: From C. elegans to Humans

    PubMed Central

    Chen, Pan; Chakraborty, Sudipta; Peres, Tanara V.; Bowman, Aaron B.; Aschner, Michael

    2014-01-01

    Manganese (Mn) is one of the most abundant metals on the earth. It is required for normal cellular activities, but overexposure leads to toxicity. Neurons are more susceptible to Mn-induced toxicity than other cells, and accumulation of Mn in the brain results in Manganism that presents with Parkinson's disease (PD)-like symptoms. In the last decade, a number of Mn transporters have been identified, which improves our understanding of Mn transport in and out of cells. However, the mechanism of Mn-induced neurotoxicity is only partially uncovered, with further research needed to explore the whole picture of Mn-induced toxicity. In this review, we will address recent progress in Mn-induced neurotoxicity from C. elegans to humans, and explore future directions that will help understand the mechanisms of its neurotoxicity. PMID:25893090

  20. [Catecholamines and their metabolic enzymes in the rat myocardium after a flight on the Kosmos-936 biosatellite].

    PubMed

    Kwetncanski, R; Tigranian, R A; Torda, T

    1982-01-01

    In the myocardium of the weightless and centrifuged rats flown for 18.5 days onboard the biosatellite Cosmos-936 the catecholamine concentration and activity of enzymes involved in their synthesis and degradation--dopamine-beta-hydroxylase, monoamine oxidase and catechol-O-methyl transferase--were measured. The catecholamine concentration in the myocardium of both flight groups significantly increased, and the enzyme activity did not change. These results suggest that an exposure to space flight increases the catecholamine concentration and exerts no effect on their synthesis and degradation in the rat myocardium.

  1. Tianeptine influence on plasmatic catecholamine levels and anxiety index in rats under variable chronic stress after early maternal separation.

    PubMed

    Trujillo, Verónica; Masseroni, María Lujan; Levin, Gloria; Suárez, Marta Magdalena

    2009-01-01

    The aim of this work was to determine the effect of chronic treatment with 5 mg/kg of tianeptine in male adult Wistar rats separated from the mother as neonates and submitted to variable chronic stress, plasma catecholamines, and anxiety. The plus maze test was performed in order to calculate the anxiety index and catecholamine levels were determined by high-pressure liquid chromatography. Both stress and maternal separation elevated catecholamine levels without affecting anxiety. In the maternally separated stress group, tianeptine decreased epinephrine. Anxiety was reduced in the maternally separated unstressed tianeptine group. Also, all groups showed a tendency to lower anxiety index.

  2. Predicting developmental neurotoxicity in rodents from larval zebrafish - - and vice versa

    EPA Science Inventory

    The complexity of standard mammalian developmental neurotoxicity tests limits evaluation of large numbers of chemicals. Less complex, more rapid assays using larval zebrafish are gaining popularity for evaluating the developmental neurotoxicity of chemicals; there remains, howeve...

  3. A screening approach using zebrafish for the detection and characterization of developmental neurotoxicity.

    EPA Science Inventory

    Thousands of chemicals have little or no data to support developmental neurotoxicity risk assessments. Current developmental neurotoxicity guideline studies mandating mammalian model systems are expensive and time consuming. Therefore a rapid, cost-effective method to assess de...

  4. Vanadium exposure induces olfactory dysfunction in an animal model of metal neurotoxicity.

    PubMed

    Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G

    2014-07-01

    Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson's disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182μg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions.

  5. Vanadium Exposure Induces Olfactory Dysfunction in an Animal Model of Metal Neurotoxicity

    PubMed Central

    Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

    2014-01-01

    Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson’s disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182 µg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3, 4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions. PMID:24362016

  6. Attenuation of Oxidative Damage by Boerhaavia diffusa L. Against Different Neurotoxic Agents in Rat Brain Homogenate.

    PubMed

    Ayyappan, Prathapan; Palayyan, Salin Raj; Kozhiparambil Gopalan, Raghu

    2016-01-01

    Due to a high rate of oxidative metabolic activity in the brain, intense production of reactive oxygen metabolite occurs, and the subsequent generation of free radicals is implicated in the pathogenesis of traumatic brain injury, epilepsy, and ischemia as well as chronic neurodegenerative diseases. In the present study, protective effects of polyphenol rich ethanolic extract of Boerhaavia diffusa (BDE), a neuroprotective edible medicinal plant against oxidative stress induced by different neurotoxic agents, were evaluated. BDE was tested against quinolinic acid (QA), 3-nitropropionic acid (NPA), sodium nitroprusside (SNP), and Fe (II)/EDTA complex induced oxidative stress in rat brain homogenates. QA, NPA, SNP, and Fe (II)/EDTA treatment caused an increased level of thiobarbituric acid reactive substances (TBARS) in brain homogenates along with a decline in the activities of antioxidant enzymes. BDE treatment significantly decreased the production of TBARS (p < .05) and increased the activities of antioxidant enzymes like catalase and superoxide dismutase along with increased concentration of non-enzymatic antioxidant, reduced glutathione (GSH). Similarly, BDE caused a significant decrease in the lipid peroxidation (LPO) in the cerebral cortex. Inhibitory potential of BDE against deoxyribose degradation (IC50 value 38.91 ± 0.12 μg/ml) shows that BDE can protect hydroxyl radical induced DNA damage in the tissues. Therefore, B. diffusa had high antioxidant potential that could inhibit the oxidative stress induced by different neurotoxic agents in brain. Since many of the neurological disorders are associated with free radical injury, these data may imply that B. diffusa, functioning as an antioxidant agent, may be beneficial for reducing various neurodegenerative complications.

  7. Acute neurotoxic effects of mancozeb and maneb in mesencephalic neuronal cultures are associated with mitochondrial dysfunction.

    PubMed

    Domico, Lisa M; Zeevalk, Gail D; Bernard, Laura P; Cooper, Keith R

    2006-09-01

    Recent studies suggest that exposure to agrochemicals may contribute to the development of idiopathic Parkinson's disease. Maneb (MB), a widely used Mn-containing ethylene-bis-dithiocarbamate (EBDC) fungicide, has been implicated in selective dopaminergic neurotoxicity. In this study, we examine the potential neurotoxicity of mancozeb (MZ), a widely used EBDC fungicide that is structurally similar to MB, but contains both Zn and Mn. Primary mesencephalic cells isolated from Sprague-Dawley embryonic day 15 rat embryos were exposed in vitro to either MZ or MB to compare their cytotoxic potential. Exposure to 10-120 microM MZ or MB for 24h resulted in a dose-dependent toxicity in both the dopamine (DA) and GABA mesencephalic populations as assessed by a functional assay for high affinity transporter activity. Consistent with this, cell viability as well as tyrosine hydroxylase-positive neurons decreased with increasing doses of MZ or MB. Toxic potencies for MZ and MB were similar and no difference in sensitivity between the DA and GABA populations was observed with the fungicides. Exposure to ethylene thiourea, the major metabolite of either MZ or MB, was not toxic, implicating the parent compound in toxicity. Both the organic and Mn metal components of the fungicides were found to contribute to toxicity. Non-toxic exposures to the fungicides decreased ATP levels in a dose-dependent manner suggesting impairment of energy metabolism. In whole mitochondrial preparations isolated from adult rat brains, MZ and MB inhibited NADH-linked state 3 respiration. Mild to moderate mitochondrial uncoupling was also observed in response to the fungicides. In conclusion, our findings indicate that acute exposure to high doses of MZ and MB produce equipotent toxic effects in both DA and GABA neurons that may be associated with perturbations in mitochondrial respiration.

  8. The protective effect of Physalis peruviana L. against cadmium-induced neurotoxicity in rats.

    PubMed

    Abdel Moneim, Ahmed E; Bauomy, Amira A; Diab, Marwa M S; Shata, Mohamed Tarek M; Al-Olayan, Ebtesam M; El-Khadragy, Manal F

    2014-09-01

    The present study was carried out to investigate the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced neurotoxicity in rats. Adult male Wistar rats were randomly divided into four groups. Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg bwt of cadmium chloride for 5 days. Group 3 was treated with 200 mg/kg bwt of methanolic extract of Physalis (MEPh). Group 4 was pretreated with MEPh 1 h before cadmium for 5 days. Cadmium treatment induced marked disturbances in neurochemical parameters as indicating by significant (p < 0.05) reduction in dopamine (DA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in cerebellum, hippocampus, and cerebral cortex and enhanced significantly (p < 0.05) the levels of lipid peroxidation and nitric oxide in the brain. Cadmium treatment also decreased the amount of nonenzymatic and enzymatic antioxidants significantly (p < 0.05). Pretreatment with MEPh resulted in significant (p < 0.05) decreases in lipid peroxidation and nitric oxide levels and restored the amount of glutathione successfully. Although, preadministration of MEPh also brought the activities of cellular antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase significantly (p < 0.05) to the control levels, as well as the levels of Ca(2+), Cl(-), DA, 5-HT, and serotonin metabolite, 5-HIAA. These data indicated that Physalis has a beneficial effect in ameliorating the cadmium-induced oxidative neurotoxicity in the brain of rats.

  9. Special Issue: Environmental Chemicals and Neurotoxicity Oxidative stress in MeHg-induced neurotoxicity

    PubMed Central

    Farina, Marcelo; Aschner, Michael; Rocha, João B. T.

    2011-01-01

    Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically

  10. Is ZMP the toxic metabolite in Lesch-Nyhan disease?

    PubMed

    López, José M

    2008-11-01

    The genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), located on the X chromosome, causes a severe neurological disorder in man, known as Lesch-Nyhan disease (LND). The enzyme HPRT is part of the savage pathway of purine biosynthesis and catalyzes the conversion of hypoxanthine and guanine to their respective nucleotides, IMP and GMP. HPRT deficiency is associated with a relatively selective dysfunction of brain dopamine systems. Several metabolites that accumulate in the patients (phosphoribosylpyrophosphate (PRPP), hypoxanthine, guanine, xanthine, and Z-nucleotides) have been proposed as toxic agents in LND. Some authors have pointed that Z-riboside, derived from the accumulation of ZMP, could be the toxic metabolite in LND. However, the available experimental data support a better hypothesis. I suggest that ZMP (and not Z-riboside) is the key toxic metabolite in LND. ZMP is an inhibitor of the bifunctional enzyme adenylosuccinate lyase, and a deficiency of this enzyme causes psychomotor and mental retardation in humans. Moreover, it has been reported that ZMP inhibits mitochondrial oxidative phosphorylation and induces apoptosis in certain cell types. ZMP is also an activator of the AMP-activated protein kinase (AMPK), a homeostatic regulator of energy levels in the cell. The AMPK has been implicated in the regulation of cell viability, catecholamine biosynthesis and cell structure. I propose that accumulation of ZMP will induce a pleiotropic effect in the brain by (1) a direct inhibition of mitochondrial respiration and the bifunctional enzyme adenylosuccinate lyase, and (2) a sustained activation of the AMPK which in turns would reduce cell viability, decrease dopamine synthesis, and alters cell morphology. In addition, a mechanism to explain the accumulation of ZMP in LND is presented. The knowledge of the toxic metabolite, and the way it acts, would help to design a better therapy.

  11. P-Glycoprotein Transport of Neurotoxic Pesticides.

    PubMed

    Lacher, Sarah E; Skagen, Kasse; Veit, Joachim; Dalton, Rachel; Woodahl, Erica L

    2015-10-01

    P-glycoprotein (P-gp) has been associated with a number of neurodegenerative diseases, including Parkinson's disease, although the mechanisms remain unclear. Altered transport of neurotoxic pesticides has been proposed in Parkinson's disease, but it is unknown whether these pesticides are P-gp substrates. We used three in vitro transport models, stimulation of ATPase activity, xenobiotic-induced cytotoxicity, and inhibition of rhodamine-123 efflux, to evaluate P-gp transport of diazinon, dieldrin, endosulfan, ivermectin, maneb, 1-methyl-4-phenyl-4-phenylpyridinium ion (MPP(+)), and rotenone. Diazinon and rotenone stimulated ATPase activity in P-gp-expressing membranes, with Vmax values of 22.4 ± 2.1 and 16.8 ± 1.0 nmol inorganic phosphate/min per mg protein, respectively, and Km values of 9.72 ± 3.91 and 1.62 ± 0.51 µM, respectively, compared with the P-gp substrate verapamil, with a Vmax of 20.8 ± 0.7 nmol inorganic phosphate/min per mg protein and Km of 0.871 ± 0.172 μM. None of the other pesticides stimulated ATPase activity. We observed an increased resistance to MPP(+) and rotenone in LLC-MDR1-WT cells compared with LLC-vector cells, with 15.4- and 2.2-fold increases in EC50 values, respectively. The resistance was reversed in the presence of the P-gp inhibitor verapamil. None of the other pesticides displayed differential cytotoxicity. Ivermectin was the only pesticide to inhibit P-gp transport of rhodamine-123, with an IC50 of 0.249 ± 0.048 μM. Our data demonstrate that dieldrin, endosulfan, and maneb are not P-gp substrates or inhibitors. We identified diazinon, MPP(+), and rotenone as P-gp substrates, although further investigation is needed to understand the role of P-gp transport in their disposition in vivo and associations with Parkinson's disease.

  12. [Neurotoxicity of 1-bromopropane in rats].

    PubMed

    Ohnishi, A; Ishidao, T; Kasai, T; Arashidani, K; Hori, H

    1999-03-01

    Neurotoxicity of 1-bromopropane (1-BP) used as an alternative solvent of fluorocarbons was experimentally studied. Eight rats in the experimental group were exposed to 1-BP at 1500 ppm for six hours a day, five days a week for four weeks in an exposure chamber. Another eight rats in the control group were exposed to room air in a similar exposure chamber as those in the experimental group. During the latter half of the fourth week of exposure, all the rats in the experimental group showed a loss of body weight and ataxic gait compared with control rats. At the end of the fourth week, the rats in both groups were perfused through the ascending aorta and fixed. The cerebellum, medulla oblongata, spinal cord and peripheral nerve were processed for histopathological studies. No statistically significant difference in the frequency of axonal degeneration in both peroneal and sural nerves was found between the experimental and control groups. In the cerebellum, the frequency of degeneration of Purkinje cells in both the vermis and hemisphere was higher in the experimental group than in the control group (P < 0.05). There was no significant difference in the frequency of myelin ovoids in the fifth thoracic and in the third cervical posterior columns of the spinal cord between control and experimental groups. There was also no significant difference in the frequency of axonal swelling in the nucleus gracilis of the medulla oblongata between control and experimental groups. Ataxic gait was considered to be induced by degeneration of Purkinje cells in the cerebellum due to 1-BP exposure. However, degenerative findings of nerve fibers in the peripheral nerve, spinal posterior column and nucleus gracilis of the medulla oblongata due to 1-BP exposure were not evident. At the end of the fourth week of exposure, rats in the experimental group showed loss of body weight and markedly decreased motor activities, and it was considered that they would die if we continued the exposure

  13. Phantom limb pain as a manifestation of paclitaxel neurotoxicity.

    PubMed

    Khattab, J; Terebelo, H R; Dabas, B

    2000-07-01

    Paclitaxel is a chemotherapeutic agent with activity directed against several malignancies. It has multiple adverse effects including neurotoxicity. We describe 2 patients with prior amputation who experienced phantom limb pain (PLP) after receiving paclitaxel therapy. A third patient experienced disabling neurotoxicity in the extremity of a prior ulnar nerve and tendon transposition after receiving paclitaxel. This unique syndrome should be identified as a direct causal effect of paclitaxel. In this report, we review the pathophysiology of PLP and treatment options. Physicians should be aware that PLP can occur after initiation of paclitaxel.

  14. Cancer Treatment-Induced Neurotoxicity: A Focus on Newer Treatments

    PubMed Central

    Stone, Jacqueline B.; DeAngelis, Lisa M.

    2016-01-01

    Neurotoxicity from traditional chemotherapy and radiotherapy is widely recognized. The adverse effects of newer therapeutics such as biological and immunotherapeutic agents are less familiar and they are also associated with significant neurotoxicity in the central and peripheral nervous systems. This review addresses the main toxicities of cancer treatment by symptom with a focus on the newer therapeutics. Recognition of these patterns of toxicity is important as drug discontinuation or dose adjustment may prevent further neurologic injury. Also, knowledge of these toxicities helps to differentiate treatment-related symptoms from progression of cancer or its involvement of the nervous system. PMID:26391778

  15. Urinary catecholamines in essential hypertension: results of 24-hour urine catecholamine analyses from patients in the Medical Research Council trial for mild hypertension and from matched controls.

    PubMed

    Brown, M J; Causon, R C; Barnes, V F; Brennan, P; Barnes, G; Greenberg, G

    1985-10-01

    Four consecutive 24-h urine samples were collected from 134 male and 134 female placebo-treated patients in the Medical Research Council Trial for Mild Hypertension. Similar samples were collected from age and sex-matched normotensive controls. On the fourth day noradrenaline excretion was 22.05 +/- 1.01 nmol/mmol creatinine in the hypertensives compared with 22.22 +/- 1.16 nmol/mmol creatinine in the controls. Adrenaline excretion on the same day was 6.13 +/- 0.33 nmol/mmol creatinine in the hypertensive subjects compared with 6.32 +/- 0.38 nmol/mmol creatinine in the controls. There was no significant difference for either catecholamine between the two groups. However, in the control group there was a highly significant correlation between excretion of adrenaline and systolic blood pressure (r = 0.218, p = 0.0004) and between noradrenaline excretion and systolic blood pressure (r = 0.200, p = 0.001). Catecholamine excretion and blood pressure were not significantly correlated in the hypertensive patients. There were no significant correlations in either group between catecholamine excretion and heart rate, caffeine intake, nicotine consumption or the Bortner self-assessment score of personality type. This study has found no evidence of elevated sympathoadrenal activity in mild hypertensives. The correlations in the control group may reflect the role of sympathoadrenal activity in acute fluctuations in blood pressure or may suggest that the level of blood pressure within the 'normal' range depends in part on the level of sympathoadrenal activity.

  16. Transportable hyperpolarized metabolites

    NASA Astrophysics Data System (ADS)

    Ji, Xiao; Bornet, Aurélien; Vuichoud, Basile; Milani, Jonas; Gajan, David; Rossini, Aaron J.; Emsley, Lyndon; Bodenhausen, Geoffrey; Jannin, Sami

    2017-01-01

    Nuclear spin hyperpolarization of 13C-labelled metabolites by dissolution dynamic nuclear polarization can enhance the NMR signals of metabolites by several orders of magnitude, which has enabled in vivo metabolic imaging by MRI. However, because of the short lifetime of the hyperpolarized magnetization (typically <1 min), the polarization process must be carried out close to the point of use. Here we introduce a concept that markedly extends hyperpolarization lifetimes and enables the transportation of hyperpolarized metabolites. The hyperpolarized sample can thus be removed from the polarizer and stored or transported for use at remote MRI or NMR sites. We show that hyperpolarization in alanine and glycine survives 16 h storage and transport, maintaining overall polarization enhancements of up to three orders of magnitude.

  17. Transportable hyperpolarized metabolites

    PubMed Central

    Ji, Xiao; Bornet, Aurélien; Vuichoud, Basile; Milani, Jonas; Gajan, David; Rossini, Aaron J.; Emsley, Lyndon; Bodenhausen, Geoffrey; Jannin, Sami

    2017-01-01

    Nuclear spin hyperpolarization of 13C-labelled metabolites by dissolution dynamic nuclear polarization can enhance the NMR signals of metabolites by several orders of magnitude, which has enabled in vivo metabolic imaging by MRI. However, because of the short lifetime of the hyperpolarized magnetization (typically <1 min), the polarization process must be carried out close to the point of use. Here we introduce a concept that markedly extends hyperpolarization lifetimes and enables the transportation of hyperpolarized metabolites. The hyperpolarized sample can thus be removed from the polarizer and stored or transported for use at remote MRI or NMR sites. We show that hyperpolarization in alanine and glycine survives 16 h storage and transport, maintaining overall polarization enhancements of up to three orders of magnitude. PMID:28072398

  18. Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on The Way Forward

    EPA Science Inventory

    Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant acr...

  19. The catecholamines up (Catsup) protein of Drosophila melanogaster functions as a negative regulator of tyrosine hydroxylase activity.

    PubMed Central

    Stathakis, D G; Burton, D Y; McIvor, W E; Krishnakumar, S; Wright, T R; O'Donnell, J M

    1999-01-01

    We report the genetic, phenotypic, and biochemical analyses of Catecholamines up (Catsup), a gene that encodes a negative regulator of tyrosine hydroxylase (TH) activity. Mutations within this locus are semidominant lethals of variable penetrance that result in three broad, overlapping effective lethal phases (ELPs), indicating that the Catsup gene product is essential throughout development. Mutants from each ELP exhibit either cuticle defects or catecholamine-related abnormalities, such as melanotic salivary glands or pseudotumors. Additionally, Catsup mutants have significantly elevated TH activity that may arise from a post-translational modification of the enzyme. The hyperactivation of TH in Catsup mutants results in abnormally high levels of catecholamines, which can account for the lethality, visible phenotypes, and female sterility observed in these mutants. We propose that Catsup is a component of a novel system that downregulates TH activity, making Catsup the fourth locus found within the Dopa decarboxylase (Ddc) gene cluster that functions in catecholamine metabolism. PMID:10471719

  20. Physicochemical perspective on "polydopamine" and "poly(catecholamine)" films for their applications in biomaterial coatings.

    PubMed

    Ball, Vincent

    2014-09-01

    Bioinspired poly(catecholamine) based coatings, mostly "polydopamine," were conceived based on the chemistry used by mussels to adhere strongly to the surface of stones and wood in water and to remain attached to their substrates even under conditions of strong shear stresses. These kinds of films can in turn be easily modified with a plethora of molecules and inorganic (nano)materials. This review shows that poly(catecholamine) based coatings are an ideal film forming method for applications in the field of biomaterials. It is written from a physicochemical and a materials science perspective and discusses optical, chemical, electrochemical, and mechanical properties of polydopamine films. It further demonstrates that a better understanding of the polydopamine film deposition mechanism is warranted to improve the properties of these coatings even further.

  1. Colorimetric determination of catecholamines by 2,3,5-triphenyltetrazolium chloride.

    PubMed

    el-Rabbat, N A; Omar, N M

    1978-06-01

    A convenient spectrophotometric method was developed for the determination of epinephrine, levarterenol, isoproterenol, and methyldopa by reduction of 2,3,5-triphenyltetrazolium chloride and subsequent measurement of the formazan at 485 nm. With absolute alcohol as the solvent, maximum color absorption was attained in 30 min at 25 degrees in the presence of 0.1 N KOH. Evidence is provided to account for the reduction of the tetrazolium salt at the expense of the epinephrine catechol moiety. In addition to the considerably high values of the molar absorptivities of the chromogen formed, ideal adherence of the color absorption to the Beer-Lambert law permitted a sensitive microdetermination of these catecholamines in both pure forms and pharmaceutical formulations. The tetrazolium interaction was selective. No interference was encountered from common catecholamine antioxidants, adjuvants, or noncatechol degradation products.

  2. A comparison of overnight and 24 hour collection to measure urinary catecholamines.

    PubMed

    White, I R; Brunner, E J; Barron, J L

    1995-02-01

    The period of urine collection used to measure excretion of catecholamines varies in epidemiological practice. We set out to compare overnight with 24 hour collection. Twenty-four subjects each collected urine for 24 hours, with the overnight urine being separately collected. The correlation of overnight and 24 hour catecholamines was highest when both measures were standardised for creatinine excretion and when creatinine excretion was adjusted for urine flow rate. The observed correlations were 0.74 for dopamine, 0.81 for noradrenaline and 0.54 for adrenaline. The use of overnight collections may therefore require a sample size up to 1.5 times as large (for noradrenaline) or 3.4 times as large (for adrenaline) to achieve the same power as with 24 hour collections. However, the figures given exaggerate the advantage of 24 hour collections if these incorporate measurement errors that are not present in overnight collections.

  3. Adaptation of circadian corticosterone and catecholamine rhythms to light-dark cycle reversal in the rat.

    PubMed

    Miki, K; Sudo, A

    1996-01-01

    Circadian rhythms of urinary excretion of corticosterone and catecholamines were examined in the rat before and after phase reversal of a 12-hour light and 12-hour dark cycle. After the reversal, the acrophase of rhythm was delayed and became constant again on the 6th day for corticosterone and on the 7th or 8th day for adrenaline. The ratios of light-period output to 24-hour output of adrenaline and noradrenaline, however, adjusted to the new light-dark cycle on 10th day, whereas this ratio became constant on 6th day for corticosterone. Thus, circadian corticosterone rhythm seems to adapt to light-dark reversal more quickly than catecholamine rhythm.

  4. Effect of consecutive cooling and immobilization on catecholamine metabolism in rat tissues

    NASA Technical Reports Server (NTRS)

    Matlina, E. S.; Waysman, S. M.; Zaydner, I. G.; Kogan, B. M.; Nozdracheva, L. V.

    1979-01-01

    The combined effect of two stressor stimuli--cooling and immobilization--acting successively on the sympathetic-adrenaline system was studied experimentally in rats that were cooled for 8 hours at 7 C on the first day and immobilized for 6 hours on the next day. The biochemical and histochemical methods used and the experimental technique involved are described in detail. The following conclusions were formulated: (1) the successive action of cooling and immobilization results in a stronger decrease in the adrenaline and noradrenaline content in the adrenal gland than that which could be due to a simple summation of the cooling and immobilization effects; (2) successive cooling and immobilization are followed by activation of catecholamine synthesis in the adrenal gland; and (3) 1-DOPA administration (45 mg/kg 3 times in 2 days) intraabdominally activated catecholamine synthesis in the adrenal glands in both the control and test animals.

  5. Research advances on potential neurotoxicity of quantum dots.

    PubMed

    Wu, Tianshu; Zhang, Ting; Chen, Yilu; Tang, Meng

    2016-03-01

    With rapid development of nanotechnology, quantum dots (QDs) as advanced nanotechnology products have been widely used in biological and biomedical studies, including neuroscience, due to their superior optical properties. In recent years, there has been intense concern regarding the toxicity of QDs with a growing number of studies. However, the knowledge of neurotoxic consequences of QDs applied in living organisms is lagging behind their development, while a potential risk of neurotoxicity arises if mass production of QDs leads to increased exposure and distribution in the nervous system. Owing to the quantum size effect of QDs, they are capable of crossing the blood-brain barrier or moving along neural pathways and entering the brain. Nevertheless, the interactions of QDs with cells and tissues in the central nervous system are not well understood. This review highlighted research advances on the neurotoxicity of QDs in the central nervous system, including oxidative stress injury, elevated cytoplasmic Ca(2+) levels and autophagy to damage in vitro neural cells, and impairments of synaptic transmission and plasticity as well as brain functions in tested animals, with the hope of throwing light on future research directions of QD neurotoxicity, which is a demanding topic that requires further exploration.

  6. Life-threatening motor neurotoxicity in association with bortezomib.

    PubMed

    Gupta, Sunil; Pagliuca, Antonio; Devereux, Steve; Mufti, Ghulam J; Schey, Steve

    2006-07-01

    Bortezomib has been licensed to be used in relapsed and refractory multiple myeloma. It is a promising agent for this incurable condition but our effort is to caution hematologists about the life-threatening neurotoxicity (grade 4) which was seen in two of six patients treated with this agent although the complication cannot definitely be attributed to bortezomib.

  7. Assessment of therapeutic potential of amantadine in methamphetamine induced neurotoxicity.

    PubMed

    Thrash-Williams, Bessy; Ahuja, Manuj; Karuppagounder, Senthilkumar S; Uthayathas, Subramaniam; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

    2013-10-01

    Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity.

  8. Neuroinflammation and Microglia: Considerations and approaches for neurotoxicity assessment

    PubMed Central

    Harry, G. Jean; Kraft, Andrew D.

    2009-01-01

    Background The impact of an inflammatory response, as well as interactions between the immune and nervous systems, are rapidly assuming major roles in neurodegenerative disease and injury. However, it is now appreciated that the exact nature of such responses can differ with each type of insult and interaction. More recently, neuroinflammation and the associated cellular response of microglia are being considered for their contribution to neurotoxicity of environmental agents; yet, to date, the inclusion of inflammatory endpoints into neurotoxicity assessment have relied primarily on relatively limited measures or driven by in vitro models of neurotoxicity. Objective To present background information on relevant biological considerations of neuroinflammation and the microglia response demonstrating the complex integrative nature of these biological processes and raising concern with regards to translation of effects demonstrated in vitro to the in vivo situation. Specific points are addressed that would influence the design and interpretation of neuroinflammation with regards to neurotoxicology assessment. Conclusion There is a complex and dynamic response in the brain to regulate inflammatory processes and maintain a normal homeostatic level. The classification of such responses as beneficial or detrimental is an oversimplification. Neuroinflammation should be considered as a balanced network of processes where subtle modifications can shift the cells toward disparate outcomes. The tendency to over-interpret data obtained in an isolated culture system should be discouraged. Rather, the use of cross-disciplinary approaches to evaluate multiple endpoints should be incorporated into the assessment of inflammatory contributions to the neurotoxicity of environmental exposures. PMID:18798697

  9. Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity

    PubMed Central

    Tarale, Prashant; Chakrabarti, Tapan; Sivanesan, Saravanadevi; Naoghare, Pravin; Bafana, Amit; Krishnamurthi, Kannan

    2016-01-01

    Manganese is a vital nutrient and is maintained at an optimal level (2.5–5 mg/day) in human body. Chronic exposure to manganese is associated with neurotoxicity and correlated with the development of various neurological disorders such as Parkinson's disease. Oxidative stress mediated apoptotic cell death has been well established mechanism in manganese induced toxicity. Oxidative stress has a potential to alter the epigenetic mechanism of gene regulation. Epigenetic insight of manganese neurotoxicity in context of its correlation with the development of parkinsonism is poorly understood. Parkinson's disease is characterized by the α-synuclein aggregation in the form of Lewy bodies in neuronal cells. Recent findings illustrate that manganese can cause overexpression of α-synuclein. α-Synuclein acts epigenetically via interaction with histone proteins in regulating apoptosis. α-Synuclein also causes global DNA hypomethylation through sequestration of DNA methyltransferase in cytoplasm. An individual genetic difference may also have an influence on epigenetic susceptibility to manganese neurotoxicity and the development of Parkinson's disease. This review presents the current state of findings in relation to role of epigenetic mechanism in manganese induced neurotoxicity, with a special emphasis on the development of Parkinson's disease. PMID:27314012

  10. DEVELOPMENTAL NEUROTOXICITY TESTING GUIDELINES: VARIABILITY IN MORPHOMETRIC ASSESSMENTS OF NEUROPATHOLOGY.

    EPA Science Inventory

    The USEPA Developmental Neurotoxicity (DNT) Study Test Guideline (OPPTS 870.6300) calls for neuropathological and morphometric assessments of rat pups on postnatal day (PND) 11 and at study termination (after PND 60). In recent discussions about conducting these studies on pesti...

  11. INTEGRATING EPIDEMIOLOGY AND TOXICOLOGY IN NEUROTOXICITY RISK ASSESSMENT.

    EPA Science Inventory

    This manuscript provides an overview of the use of data from toxicology and epidemiology studies for neurotoxicity risk assessment. Parameters such as the use of subjects, study designs, exposures, and measured outcomes are compared and contrasted. The main concern for use of d...

  12. Neurotoxicity in Aquatic Systems: Evaluation of Anthropogenic Trace Substances

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity, as well as acute and developmental neurotoxicity. In this endeavor, one of our focuses is on contaminants found in drinking water. To exp...

  13. Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity.

    PubMed

    Ambrosius, Björn; Faissner, Simon; Guse, Kirsten; von Lehe, Marec; Grunwald, Thomas; Gold, Ralf; Grewe, Bastian; Chan, Andrew

    2017-03-11

    HIV-associated neurocognitive disorders (HAND) affect about 50% of infected patients despite combined antiretroviral therapy (cART). Ongoing compartmentalized inflammation mediated by microglia which are activated by HIV-infected monocytes has been postulated to contribute to neurotoxicity independent from viral replication. Here, we investigated effects of teriflunomide and monomethylfumarate on monocyte/microglial activation and neurotoxicity. Human monocytoid cells (U937) transduced with a minimal HIV-Vector were co-cultured with human microglial cells (HMC3). Secretion of pro-inflammatory/neurotoxic cytokines (CXCL10, CCL5, and CCL2: p < 0.001; IL-6: p < 0.01) by co-cultures was strongly increased compared to microglia in contact with HIV-particles alone. Upon treatment with teriflunomide, cytokine secretion was decreased (CXCL10, 3-fold; CCL2, 2.5-fold; IL-6, 2.2-fold; p < 0.001) and monomethylfumarate treatment led to 2.9-fold lower CXCL10 secretion (p < 0.001). Reduced toxicity of co-culture conditioned media on human fetal neurons by teriflunomide (29%, p < 0.01) and monomethylfumarate (27%, p < 0.05) indicated functional relevance. Modulation of innate immune functions by teriflunomide and monomethylfumarate may target neurotoxic inflammation in the context of HAND.

  14. The catecholamine stress hormones norepinephrine and dopamine increase the virulence of pathogenic Vibrio anguillarum and Vibrio campbellii.

    PubMed

    Pande, Gde Sasmita J; Suong, Nguyen Thao; Bossier, Peter; Defoirdt, Tom

    2014-12-01

    Obtaining a better understanding of mechanisms involved in bacterial infections is of paramount importance for the development of novel agents to control disease caused by (antibiotic resistant) pathogens in aquaculture. In this study, we investigated the impact of catecholamine stress hormones on growth and virulence factor production of pathogenic vibrios (i.e. two Vibrio campbellii strains and two Vibrio anguillarum strains). Both norepinephrine and dopamine (at 100 μM) significantly induced growth in media containing serum. The compounds also increased swimming motility of the tested strains, whereas they had no effect on caseinase, chitinase, and hemolysin activities. Further, antagonists for eukaryotic catecholamine receptors were able to neutralize some of the effects of the catecholamines. Indeed, the dopaminergic receptor antagonist chlorpromazine neutralized the effect of dopamine, and the α-adrenergic receptor antagonists phentolamine and phenoxybenzamine neutralized the effect of norepinephrine, whereas the β-adrenergic receptor antagonist propranolol had limited to no effect. Finally, pretreatment of pathogenic V. campbellii with catecholamines significantly increased its virulence toward giant freshwater prawn larvae. However, the impact of catecholamine receptor antagonists on in vivo virulence was less clear-cut when compared to the in vitro experiments. In summary, our results show that—similar to enteric pathogens—catecholamines also increase the virulence of vibrios that are pathogenic to aquatic organisms by increasing motility and growth in media containing serum.

  15. Fish in hot water: hypoxaemia does not trigger catecholamine mobilization during heat shock in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Currie, S; Ahmady, E; Watters, M A; Perry, S F; Gilmour, K M

    2013-06-01

    Rainbow trout (Oncorhynchus mykiss) exposed to an acute heat shock (1 h at 25 °C after raising water temperature from 13 °C to 25 °C over 4 h) mount a significant catecholamine response. The present study investigated the proximate mechanisms underlying catecholamine mobilization. Trout exposed to heat shock in vivo exhibited a significant reduction in arterial O(2) tension, but arterial O(2) concentration was not affected by heat shock, nor was catecholamine release during heat shock prevented by prior and concomitant exposure to hyperoxia (to prevent the fall in arterial O(2) tension). Thus, catecholamine mobilization probably was not triggered by impaired blood O(2) transport. Heat-shocked trout also exhibited an elevation of arterial CO(2) tension coupled with a fall in arterial pH, but these factors are not expected to trigger catecholamine release. The changes in blood O(2) and CO(2) tension occurred despite a significant hyperventilatory response to heat shock. Future studies should investigate whether catecholamine mobilization during heat shock in rainbow trout is triggered by a specific effect of high temperature activating the sympathetic nervous system via a thermosensitive transient receptor potential channel.

  16. Growth Stimulation by Catecholamines in Plant Tissue/Organ Cultures 1

    PubMed Central

    Protacio, Calixto M.; Dai, Yao-ren; Lewis, Eldrin F.; Flores, Hector E.

    1992-01-01

    Addition of catecholamines at micromolar concentrations caused a dramatic stimulation of growth of tobacco (Nicotiana tabacum) thin cell layers (TCLs) and Acmella oppositifolia “hairy” root cultures. A threefold increase in the rate of ethylene evolution was observed in the catecholamine-treated explants. Aminooxyacetic acid and silver thiosulfate, inhibitors of ethylene biosynthesis and action, respectively, reduced the growth-promoting effect of dopamine. However, these compounds alone could also inhibit the growth of the TCL explants. When ethylene in the culture vessel was depleted by trapping with mercuric perchlorate, dopamine-stimulated growth was still obtained, suggesting that ethylene does not mediate the dopamine effect. Dopamine potentiated the growth of TCLs grown in Murashige and Skoog medium supplemented with indoleacetic acid (IAA) and kinetin. When IAA was replaced by 2,4-dichlorophenoxyacetic acid, dopamine addition showed no growth-promoting effect. Instead, 2,4-dichlorophenoxyacetic acid stimulated the growth of TCL explants to the same extent as that obtained with IAA plus dopamine. Because synthetic auxins do not appear to be substrates for IAA oxidizing enzymes, we hypothesized that catecholamines exert their effect by preventing IAA oxidation. Consistent with this explanation, dopamine (25 micromolar) inhibited IAA oxidase activity by 60 to 100% in crude enzyme extracts from tobacco roots and etiolated corn coleoptiles, but had no effect on peroxidase activity in the same extracts. Furthermore, addition of dopamine to TCL cultures resulted in a fourfold reduction in the oxidative degradation of [1-14C]IAA fed to the explants. Because the growth enhancement by catecholamines is observed in both IAA-requiring and IAA-independent cultures, we suggest that these aromatic amines may have a role in the regulation of IAA levels in vivo. ImagesFigure 2 PMID:16668653

  17. The effects of sleep on circulating catecholamines and aqueous flow in human subjects.

    PubMed

    Maus, T L; McLaren, J W; Shepard, J W; Brubaker, R F

    1996-04-01

    We measured the rate of aqueous flow and analysed its relation to the time of day, the state of wakefulness and the urinary excretion of catecholamines. Two groups of subjects were studied. One group comprised 20 normal subjects who were studied over two 22-hr periods. During one period, the subjects were permitted to sleep during their customary hours of sleep; during the other, they were not permitted to sleep, but remained active for all 22 hr. The other group comprised ten subjects with obstructive sleep apnea who were studied over a 22-hr period and slept during their customary hours of sleep but without the aid of any respiratory device. Aqueous flow was measured with fluorophotometry. Motion of the wrist was monitored by a seismograph (wrist Actigraph) and served as a surrogate of activity and wakefulness. Urinary catecholamine excretion was measured during different periods of the wake/sleep cycle. Both groups exhibited the normal nocturnal suppression of flow (59% lower compared to morning in the normal group; 56% lower compared to morning in the apneic group). During sleep deprivation, the rate of flow at night in normal subjects was 30% lower than during the morning (P < 0.001) and 60% higher than during sleep (P < 0.001). Lid closure during sleep deprivation had no effect on the results. Aqueous flow correlated with a 'catecholamine index', derived from the combined excretion of epinephrine and norepinephrine. Flow also correlated with an 'activity index', and 'sleep efficiency', indices derived from motion of the wrist. We conclude that the day-night difference of aqueous humor flow as measured by clearance of fluorescein from the human eye is driven partly by a factor that has a circadian rhythm and partly by a factor that depends on the activity of the subject. We hypothesize that these factors are the catecholamines, epinephrine and norepinephrine.

  18. Utilization of iron-catecholamine complexes involving ferric reductase activity in Listeria monocytogenes.

    PubMed Central

    Coulanges, V; Andre, P; Ziegler, O; Buchheit, L; Vidon, D J

    1997-01-01

    Listeria monocytogenes is a ubiquitous potentially pathogenic organism requiring iron for growth and virulence. Although it does not produce siderophores, L. monocytogenes is able to obtain iron by using either exogenous siderophores produced by various microorganisms or natural catechol compounds widespread in the environment. In the presence of tropolone, an iron-chelating agent, growth of L. monocytogenes is completely inhibited. However, the growth inhibition can be relieved by the addition of dopamine or norepinephrine under their different isomeric forms, while the catecholamine derivatives 4-hydroxy-3-methoxyphenylglycol and normetanephrine did not relieve the inhibitory effect of tropolone. Preincubation of L. monocytogenes with chlorpromazine and yohimbine did not antagonize the growth-promoting effect of catecholamines in iron-complexed medium. In addition, norepinephrine stimulated the growth-promoting effect induced by human transferrin in iron-limited medium. Furthermore, dopamine and norepinephrine allowed 55Fe uptake by iron-deprived bacterial cells. The uptake of iron was energy dependent, as indicated by inhibition of 55Fe uptake at 0 degrees C as well as by preincubating the bacteria with KCN. Inhibition of 55Fe uptake by L. monocytogenes was also observed in the presence of Pt(II). Moreover, when assessed by a whole-cell ferric reductase assay, reductase activity of L. monocytogenes was inhibited by Pt(II). These data demonstrate that dopamine and norepinephrine can function as siderophore-like compounds in L. monocytogenes owing to their ortho-diphenol function and that catecholamine-mediated iron acquisition does not involve specific catecholamine receptors but acts through a cell-bound ferrireductase activity. PMID:9199450

  19. Reserpine-induced reduction in norepinephrine transporter function requires catecholamine storage vesicles.

    PubMed

    Mandela, Prashant; Chandley, Michelle; Xu, Yao-Yu; Zhu, Meng-Yang; Ordway, Gregory A

    2010-01-01

    Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5min decreased [(3)H]NE uptake capacity, an effect characterized by a robust decrease in the V(max) of the transport of [(3)H]NE. As expected, reserpine did not displace the binding of [(3)H]nisoxetine from the NET in membrane homogenates. The potency of reserpine for reducing [(3)H]NE uptake was dramatically lower in SK-N-SH cells that have reduced storage capacity for catecholamines. Reserpine had no effect on [(3)H]NE uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack catecholamine storage vesicles. NET regulation by reserpine was independent of trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors of several intracellular signaling cascades known to regulate the NET, including Ca(2+)/Ca(2+)-calmodulin dependent kinase and protein kinases A, C and G, did not affect the ability of reserpine to reduce [(3)H]NE uptake. Treatment of PC12 cells with the catecholamine depleting agent, alpha-methyl-p-tyrosine, increased [(3)H]NE uptake and eliminated the inhibitory effects of reserpine on [(3)H]NE uptake. Reserpine non-competitively inhibits NET activity through a Ca(2+)-independent process that requires catecholamine storage vesicles, revealing a novel pharmacological method to modify NET function. Further characterization of the molecular nature of reserpine's action could lead to the development of alternative therapeutic strategies for treating disorders known to be benefitted by treatment with traditional competitive NET inhibitors.

  20. Insignificant effects of plasma catecholamines on dynamic heart rate regulation by the cardiac sympathetic nerve.

    PubMed

    Kawada, T; Inagaki, M; Zheng, C; Li, M; Sunagawa, K; Sugimachi, M

    2005-01-01

    Although plasma catecholamines such as norepinephrine (NE) and epinephrine (Epi) increase during severe exercise, the effects of high levels of plasma catecholamines on dynamic heart rate (HR) regulation by the cardiac sympathetic nerve remains unknown. The aim of the present study was to examine the effects of plasma catecholamines on the transfer function from sympathetic nerve stimulation to HR. In anesthetized rabbits, we randomly stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring HR. The effects of intravenous NE administration at 1 and 10 mugmiddotkg-1middoth-1 were examined in 6 rabbits. The effects of intravenous Epi administration at 1 and 10 mugmiddotkg-1middoth-1 were examined in different 6 rabbits. Although plasma NE increased 10 times as high as the baseline level during the NE administration at mugmiddotkg-1middoth-1 , dynamic gain of the transfer function was not changed significantly (7.1plusmn1.2, 6.9plusmn1.1, and 7.7plusmn1.1 beatsmiddotmin-1middotHz-1). Similarly, although plasma Epi increased 10 times as high as the baseline level during the Epi administration at 10 mugmiddotkg-1middoth-1, dynamic gain of the transfer function was not changed significantly (7.5plusmn0.8, 7.9plusmn0.8, and 7.6plusmn1.2 beatsmiddotmin-1middotHz-1). In conclusion, plasma catecholamines of physiologically-relevant high concentrations did not interfere with the dynamic HR regulation by the cardiac sympathetic nerve.

  1. Vasopressin use in critically ill cirrhosis patients with catecholamine-resistant septic shock: The CVICU cohort

    PubMed Central

    Myc, Lukasz A; Stine, Jonathan G; Chakrapani, Rinita; Kadl, Alexandra; Argo, Curtis K

    2017-01-01

    AIM To examine patient-centered outcomes with vasopressin (AVP) use in patients with cirrhosis with catecholamine-refractory septic shock. METHODS We conducted a single center, retrospective cohort study enrolling adult patients with cirrhosis treated for catecholamine-resistant septic shock in the intensive care unit (ICU) from March 2011 through December 2013. Other etiologies of shock were excluded. Multivariable regression models were constructed for seven and 28-d mortality comparing AVP as a second-line therapy to a group of all other vasoactive agents. RESULTS Forty-five consecutive patients with cirrhosis were treated for catecholamine-resistant septic shock; 21 received AVP while the remaining 24 received another agent [phenylephrine (10), dopamine (6), norepinephrine (4), dobutamine (2), milrinone (2)]. In general, no significant differences in baseline demographics, etiology of cirrhosis, laboratory values, vital signs or ICU mortality/severity of illness scores were observed with the exception of higher MELD scores in the AVP group (32.4, 95%CI: 28.6-36.2 vs 27.1, 95%CI: 23.6-30.6, P = 0.041). No statistically significant difference was observed in unadjusted 7-d (52.4% AVP vs 58.3% and P = 0.408) or 28-d mortality (81.0% AVP vs 87.5% non-AVP, P = 0.371). Corticosteroid administration was associated with lower 28-d mortality (HR = 0.37, 95%CI: 0.16-0.86, P = 0.021) independent of AVP use. CONCLUSION AVP is similar in terms of patient centered outcomes of seven and 28-d mortality, in comparison to all other vasopressors when used as a second line vasoactive agent in catecholamine resistant septic shock. Large-scale prospective study would help to refine current consensus standards and provide further support to our findings. PMID:28144392

  2. Occupational EMF exposure from radar at X and Ku frequency band and plasma catecholamine levels.

    PubMed

    Singh, Sarika; Kapoor, Neeru

    2015-09-01

    Workers in certain occupations such as the military may be exposed to technical radiofrequency radiation exposure above current limits, which may pose a health risk. The present investigation intended to find the effect of chronic electromagnetic field (EMF) exposure from radar on plasma catecholamines in the military workforce. In the study, 166 male personnel selected randomly were categorized into three groups: control (n = 68), exposure group-I (X-band, 8-12 GHz, n = 40), and exposure group-II (Ku-band, 12.5-18 GHz, n = 58). The three clusters were further divided into two groups according to their years of service (YOS) (up to 9 years and ≥10 years) to study the effect of years of radar exposure. Enzyme immunoassay was employed to assess catecholamine concentrations. EMF levels were recorded at different occupational distances from radar. Significant adrenaline diminution was registered in exposure group-II with no significant difference in exposure group-I when both groups were weighed against control. Nor-adrenaline and dopamine levels did not vary significantly in both exposure groups when compared to controls. Exposure in terms of YOS also did not yield any significant alteration in any of the catecholamines and in any of the exposure groups when compared with their respective control groups. The shift from baseline catecholamine values due to stress has immense significance for health and well-being. Their continual alteration may prove harmful in due course. Suitable follow-up studies are needed to further strengthen these preliminary observations and for now, exposures should be limited as much as possible with essential safeguards.

  3. Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons.

    PubMed

    Li, Ai-Jun; Wang, Qing; Dinh, Thu T; Powers, Bethany R; Ritter, Sue

    2014-02-15

    Previous work has shown that hindbrain catecholamine neurons are required components of the brain's glucoregulatory circuitry. However, the mechanisms and circuitry underlying their glucoregulatory functions are poorly understood. Here we examined three drugs, glucosamine (GcA), phloridzin (Phl) and 5-thio-d-glucose (5TG), that stimulate food intake but interfere in different ways with cellular glucose utilization or transport. We examined feeding and blood glucose responses to each drug in male rats previously injected into the hypothalamic paraventricular nucleus with anti-dopamine-β-hydroxylase conjugated to saporin (DSAP), a retrogradely transported immunotoxin that selectively lesions noradrenergic and adrenergic neurons, or with unconjugated saporin (SAP) control. Our major findings were 1) that GcA, Phl, and 5TG all stimulated feeding in SAP controls whether injected into the lateral or fourth ventricle (LV or 4V), 2) that each drug's potency was similar for both LV and 4V injections, 3) that neither LV or 4V injection of these drugs evoked feeding in DSAP-lesioned rats, and 4) that only 5TG, which blocks glycolysis, stimulated a blood glucose response. The antagonist of the MEK/ERK signaling cascade, U0126, attenuated GcA-induced feeding, but not Phl- or 5TG-induced feeding. Thus GcA, Phl, and 5TG, although differing in mechanism and possibly activating different neural populations, stimulate feeding in a catecholamine-dependent manner. Although results do not exclude the possibility that catecholamine neurons possess glucose-sensing mechanisms responsive to all of these agents, currently available evidence favors the possibility that the feeding effects result from convergent neural circuits in which catecholamine neurons are a required component.

  4. Psychostimulants as Cognitive Enhancers: The Prefrontal Cortex, Catecholamines and Attention Deficit Hyperactivity Disorder

    PubMed Central

    Berridge, Craig W.; Devilbiss, David M.

    2010-01-01

    Psychostimulants exert behavioral-calming and cognition-enhancing actions in the treatment of attention deficit hyperactivity disorder (ADHD). Contrary to early views, extensive research demonstrates that these actions are not unique to ADHD. Specifically, when administered at low and clinically-relevant doses, psychostimulants improve a variety of behavioral and cognitive processes dependent on the prefrontal cortex (PFC) in subjects with and without ADHD. Despite the longstanding clinical use of these drugs, the neural mechanisms underlying their cognition-enhancing/therapeutic actions have only recently begun to be examined. At behaviorally-activating doses, psychostimulants produce large and widespread increases in extracellular levels of brain catecholamines. In contrast, cognition-enhancing doses of psychostimulants exert regionally-restricted actions, elevating extracellular catecholamine levels and enhancing neuronal signal processing preferentially within the PFC. Additional evidence suggests a prominent role of PFC α2- and D1 receptors in the behavioral and electrophysiological actions of low-dose psychostimulants. These and other observations indicate a pivotal role of PFC catecholamines in the cognition-enhancing and therapeutic actions of psychostimulants as well as other drugs used in the treatment of ADHD. This information may be particularly relevant for the development of novel pharmacological treatments for ADHD and other conditions associated with PFC dysregulation. PMID:20875636

  5. Brief Report: Prevention Moderates Associations Between Family Risks and Youth Catecholamine Levels

    PubMed Central

    Brody, Gene H.; Yu, Tianyi; Chen, Edith; Miller, Gregory E.

    2014-01-01

    Objective The purpose of this study was to establish, using a quasi-experimental design, whether two family risk factors, parental psychological dysfunction and nonsupportive parenting, during preadolescence could longitudinally predict elevated sympathetic nervous system (SNS) activity 9 years later, and to determine whether participation in an efficacious family-centered prevention program could moderate these associations if they emerged. Methods Rural African American preadolescents (N = 476) were assigned randomly to the Strong African American Families (SAAF) program or to a control condition. When youths were 11 years of age (M = 11.2 years), primary caregivers provided data on their own depressive symptoms and self-esteem, and youths provided data on their receipt of nonsupportive parenting. When the youths were 20 years of age, indicators of SNS activity, the catecholamines epinephrine and norepinephrine, were assayed from their overnight urine voids. Results Parental psychological dysfunction and nonsupportive parenting forecast elevated catecholamine levels for youths in the control condition, but not for those in the SAAF condition. Conclusions The demonstration that a prevention program can induce reduction of catecholamine levels is important from both theoretical and public health perspectives, because it shows that the developmental progression from family risk factors to heightened sympathetic nervous system activity is not immutable. PMID:24588631

  6. Prenatal excess glucocorticoid exposure and adult affective disorders: a role for serotonergic and catecholamine pathways.

    PubMed

    Wyrwoll, Caitlin S; Holmes, Megan C

    2012-01-01

    Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal 'programming' of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety- and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways.

  7. Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression

    PubMed Central

    Homan, P; Neumeister, A; Nugent, A C; Charney, D S; Drevets, W C; Hasler, G

    2015-01-01

    Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catecholaminergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber's selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Using identical neuroimaging procedures with [18F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared with healthy controls in a double-blind, randomized, crossover design. Although TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex. Although we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. In conclusion, this study showed that serotonin and catecholamines have common and differential roles in the pathophysiology of depression. PMID:25781231

  8. beta-Sonogel-carbon electrodes: a new alternative for the electrochemical determination of catecholamines.

    PubMed

    Izaoumen, Nissrin; Cubillana-Aguilera, Laura M; Naranjo-Rodríguez, Ignacio; de Cisneros, José L Hidalgo-Hidalgo; Bouchta, Dounia; Temsamani, Khalid R; Palacios-Santander, José M

    2009-04-30

    In this work, a new alternative for the electrochemical determination of catecholamines based on beta-cyclodextrin-Sonogel-Carbon electrodes is reported. The incorporation of beta-CD and graphite in the preparation of the Sonogel-Carbon material leads to a modification of the electrode surface properties which causes a significant increase in the oxidation peak current of biomolecules such as dopamine, L-epinephrine, D,L-norepinephrine and catechol. This phenomenon might be attributed to the formation of an inclusion complex between beta-CD and the catecholamines. The amount of beta-CD necessary to form the Sonogel electrode was studied and optimization of electrochemical parameters, perm selectivity and mechanical stability of the sensor are discussed. Scanning electron microscopy and electrochemical impedance spectroscopy measurements were employed to characterize the electrical parameters and the structural properties of the new electrode surface, respectively. Cyclic voltammetry (CV) and Adsorptive differential pulse voltammetry (AdDPV) measurements were also used to explore the electrochemical behaviour of the electrode versus the quoted catecholamines. The beta-CD-Sonogel-Carbon electrode offers fast and linear responses towards dopamine, norepinephrine, epinephrine and catechol, with good and low detection limits: 0.164, 0.294, 0.699 and 0.059 micromol L(-1), respectively.

  9. Inhibition of adrenomedullary catecholamine release by propranolol isomers and clonidine involving mechanisms unrelated to adrenoceptors.

    PubMed Central

    Orts, A.; Orellana, C.; Cantó, T.; Ceña, V.; González-García, C.; García, A. G.

    1987-01-01

    1 Transmural electrical stimulation (10 Hz, 40 V, 1 ms for 60s) increased total catecholamine secretion from perfused cat adrenal glands; this response was enhanced by neostigmine and inhibited by mecamylamine, suggesting that release of acetylcholine from splanchnic nerve terminals was stimulating nicotinic receptors and enhancing catecholamine secretion. 2 Isoprenaline, (-)-propranolol and (+)-propranolol (10(-7)-10(-5)M) inhibited the electrically-evoked secretory response by 40-70%; similar reductions were obtained with clonidine and yohimbine. Neither, (+)-propranolol nor (-)-propranolol inhibited K-evoked secretion from cat adrenals; in contrast, nimodipine potently inhibited it (IC50 = 24 nM). 3 Either, racemic propranolol or the (+)- or (-)-isomers (1-10 microM) equally inhibited [3H]-noradrenaline release evoked by nicotine or acetylcholine from cultured bovine adrenal chromaffin cells; clonidine (10 microM) inhibited secretion by 50% and yohimbine or isoprenaline did not affect it. 4 The results indicate that adrenomedullary catecholamine release evoked by splanchnic nerve stimulation is not modulated by alpha- or beta-adrenoceptors and suggest that propranolol may inhibit secretion by blocking ion fluxes through the acetylcholine receptor ionophore. Clonidine may inhibit secretion by this same mechanism, and/or by interfering with some intracellular event in the secretory mechanism. PMID:2827826

  10. Catecholamines are required for androgen-induced ODC expression but not for hypertrophy of mouse kidney.

    PubMed

    Manteuffel-Cymborowska, M; Peska, M; Chmurzyńska, W; Grzelakowska-Sztabert, B

    1997-05-27

    Catecholamine depletion, evoked by reserpine, dramatically impaired (5-fold) the testosterone-induced increase of ornithine decarboxylase (ODC) activity in female mouse kidney. However, reserpine did not prevent kidney hypertrophy evoked by testosterone. This is evidenced by the activity of sensitive, biochemical markers of renal hypertrophy, namely arginase and ornithine aminotransferase (OAT), that responded with the increase and decrease of activities to testosterone treatment, respectively. Arginine and ornithine, substrates and/or products of marker enzymes, showed a striking homeostasis as their level was not affected by testosterone and reserpine, and only slightly by DFMO. Northern blot analysis revealed that the ODC mRNA level, that was increased 10-fold by testosterone, was decreased 2-fold in catecholamine-depleted hypertrophic kidney. Thus, ODC transcript level, lowered by reserpine, correlated partially with an attenuated response of ODC activity to testosterone. This was in contrast to DFMO, which inhibited ODC activity, but significantly increased its mRNA content. It is concluded that catecholamines could be involved together with testosterone in regulation of the ODC gene expression in mouse kidney.

  11. Decreased catecholamine secretion from the adrenal medullae of chronically diabetic BB-Wistar rats

    NASA Technical Reports Server (NTRS)

    Wilke, R. A.; Riley, D. A.; Lelkes, P. I.; Hillard, C. J.

    1993-01-01

    Many humans with IDDM eventually lose the capacity to secrete epinephrine from their adrenal medullae. The mechanism for this pathological change is unknown. We hypothesized that this abnormality is attributable to neuropathic changes in the greater splanchnic nerves or in the chromaffin cells that they innervate. To study this hypothesis, we isolated rat adrenal glands, perfused them ex vivo, and measured the epinephrine content of the perfusate under various conditions of stimulation. We used transmural electrical stimulation (20-80 V, at 10 Hz) to induce epinephrine secretion indirectly by selectively activating residual splanchnic nerve terminals within the isolated glands. Under these conditions, epinephrine secretion was severely attenuated in glands from female BB-Wistar rats with diabetes of 4 mo duration compared with their age-matched, nondiabetic controls. These perfused diabetic adrenal medullae also demonstrated decreased catecholamine release in response to direct chromaffin cell depolarization with 20 mM K+, evidence that a functional alteration exists within the chromaffin cells themselves. Nonetheless, total catecholamine content of adrenal medullae from these diabetic rats was not significantly different from controls, indicating that the secretory defect was not simply attributable to a difference in the amount of catecholamines stored and available for release. Herein, we also provide histological evidence of degenerative changes within the cholinergic nerve terminals that innervate these glands.

  12. Multifunctional Polyphenols- and Catecholamines-Based Self-Defensive Films for Health Care Applications.

    PubMed

    Dhand, Chetna; Harini, Sriram; Venkatesh, Mayandi; Dwivedi, Neeraj; Ng, Alice; Liu, Shouping; Verma, Navin Kumar; Ramakrishna, Seeram; Beuerman, Roger W; Loh, Xian Jun; Lakshminarayanan, Rajamani

    2016-01-20

    In an era of relentless evolution of antimicrobial resistance, there is an increasing demand for the development of efficient antimicrobial coatings or surfaces for food, biomedical, and industrial applications. This study reports the laccase-catalyzed room-temperature synthesis of mechanically robust, thermally stable, broad spectrum antimicrobial films employing interfacial interactions between poly(vinyl alcohol), PVA, and 14 naturally occurring catecholamines and polyphenols. The oxidative products of catecholamines and polyphenols reinforce the PVA films and also alter their surface and bulk properties. Among the catecholamines-reinforced films, optimum surface and bulk properties can be achieved by the oxidative products of epinephrine. For polyphenols, structure-property correlation reveals an increase in surface roughness and elasticity of PVA films with increasing number of phenolic groups in the precursors. Interestingly, PVA films reinforced with oxidized/polymerized products of pyrogallol (PG) and epinephrine (EP) display potent antimicrobial activity against pathogenic Gram-positive and Gram-negative strains, whereas hydroquinone (HQ)-reinforced PVA films display excellent antimicrobial properties against Gram-positive bacteria only. We further demonstrate that HQ and PG films retain their antimicrobial efficacy after steam sterilization. With an increasing trend of giving value to natural and renewable resources, our results have the potential as durable self-defensive antimicrobial surfaces/films for advanced healthcare and industrial applications.

  13. Modulation of a 40-kDa catecholamine regulated protein by dopamine receptor antagonists.

    PubMed

    Sharan, N; Nair, V D; Mishra, R K

    2001-02-09

    Previous reports have shown that catecholamine regulated proteins (CRP) are central nervous system specific and covalently bind to catecholamines. In the present study, we report the subcellular localization and differential modulation of a 40-kDa catecholamine regulated protein (CRP40) by dopamine D1 and D2 receptor antagonists. CRP40 was found to be localized with nuclear and synaptosomal/mitochondrial and fractions. Chronic treatment with dopamine D2 receptor antagonist haloperidol in rats significantly increased the levels of CRP40 in the striatum, whereas, chronic R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) dopamine D1 receptor antagonist administration significantly decreased striatal CRP40 levels. Moreover, acute haloperidol treatment did not alter the levels of CRP40 in any of the brain regions. Despite a sequence homology with the heat shock protein 70 (HSP70), levels of HSP70 remained unchanged after either drug treatment, suggesting a distinct function of CRP40 than HSP70. These results further suggest that CRP40 play an important role in dopaminergic neuronal function and the dopamine D1 receptor-mediated signaling pathway may be involved in the regulation of CRP40.

  14. Insulin, catecholamines, glucose and antioxidant enzymes in oxidative damage during different loads in healthy humans.

    PubMed

    Koska, J; Blazícek, P; Marko, M; Grna, J D; Kvetnanský, R; Vigas, M

    2000-01-01

    Exercise, insulin-induced hypoglycemia and oral glucose loads (50 g and 100 g) were used to compare the production of malondialdehyde and the activity of antioxidant enzymes in healthy subjects. Twenty male volunteers participated in the study. Exercise consisted of three consecutive work loads on a bicycle ergometer of graded intensity (1.5, 2.0, and 2.5 W/kg, 6 min each). Hypoglycemia was induced by insulin (Actrapid MC Novo, 0.1 IU/kg, i.v.). Oral administration of 50 g and 100 g of glucose was given to elevate plasma glucose. The activity of superoxide dismutase (SOD) was determined in red blood cells, whereas glutathione peroxidase (GSH-Px) activity was measured in whole blood. The concentration of malondialdehyde (MDA) was determined by HPLC, catecholamines were assessed radioenzymatically and glucose was measured by the glucose-oxidase method. Exercise increased MDA concentrations, GSH-Px and SOD activities as well as plasma noradrenaline and adrenaline levels. Insulin hypoglycemia increased plasma adrenaline levels, but the concentrations of MDA and the activities of GSH-Px and SOD were decreased. Hyperglycemia increased plasma MDA concentrations, but the activities of GSH-Px and SOD were significantly higher after a larger dose of glucose only. Plasma catecholamines were unchanged. These results indicate that the transient increase of plasma catecholamine and insulin concentrations did not induce oxidative damage, while glucose already in the low dose was an important triggering factor for oxidative stress.

  15. Corticotropin releasing factor and catecholamines enhance glutamatergic neurotransmission in the lateral subdivision of the central amygdala.

    PubMed

    Silberman, Yuval; Winder, Danny G

    2013-07-01

    Glutamatergic neurotransmission in the central nucleus of the amygdala (CeA) plays an important role in many behaviors including anxiety, memory consolidation and cardiovascular responses. While these behaviors can be modulated by corticotropin releasing factor (CRF) and catecholamine signaling, the mechanism(s) by which these signals modify CeA glutamatergic neurotransmission remains unclear. Utilizing whole-cell patch-clamp electrophysiology recordings from neurons in the lateral subdivision of the CeA (CeAL), we show that CRF, dopamine (DA) and the β-adrenergic receptor agonist isoproterenol (ISO) all enhance the frequency of spontaneous excitatory postsynaptic currents (sEPSC) without altering sEPSC kinetics, suggesting they increase presynaptic glutamate release. The effect of CRF on sEPSCs was mediated by a combination of CRFR1 and CRFR2 receptors. While previous work from our lab suggests that CRFRs mediate the effect of catecholamines on excitatory transmission in other subregions of the extended amygdala, blockade of CRFRs in the CeAL failed to significantly alter effects of DA and ISO on glutamatergic transmission. These findings suggest that catecholamine and CRF enhancement of glutamatergic transmission onto CeAL neurons occurs via distinct mechanisms. While CRF increased spontaneous glutamate release in the CeAL, CRF caused no significant changes to optogenetically evoked glutamate release in this region. The dissociable effects of CRF on different types of glutamatergic neurotransmission suggest that CRF may specifically regulate spontaneous excitatory transmission.

  16. Effects of body mass on nicotine-induced thermogenesis and catecholamine release in male smokers.

    PubMed

    Walker, J F; Kane, C J

    2002-10-25

    The aims of this study were to examine the effects of nicotine on resting energy expenditure (REE) and plasma catecholamine release following ad libitum smoking in fasted, middle-aged males; and, to determine if the acute responses in REE and catecholamine release to smoking differ between normal weight (< or = 25 kg/m(2)) and overweight (> 25 kg/m(2)) smoker groups. REE was measured by indirect calorimetry in 32 fasted male smokers prior to, and 30 minutes after, consuming either two 0.16 mg nicotine (low yield) or two 1.74 mg nicotine (high yield) cigarettes. Plasma nicotine and norepinephrine levels were simultaneously measured. There was no thermic effect of nicotine or catecholamine response after smoking low yield cigarettes in both groups, nor after smoking high yield cigarettes in the overweight group. In contrast, REE increased 7.2%, which was accompanied by an increase in plasma norepinephrine release, after smoking high yield cigarettes in the normal weight group. Controlling plasma nicotine level ablated these increases. In conclusion, body mass interacts with the thermic effect of nicotine and neuroendocrine function in male smokers. Smoking-induced increase in the plasma nicotine level accounts for the observed responses, which are blunted in overweight smokers. This finding may have implications for potential weight gain following smoking cessation by normal weight individuals, related to lost smoking-induced thermogenesis.

  17. Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies

    PubMed Central

    Farina, Marcelo; Rocha, João B. T.; Aschner, Michael

    2011-01-01

    Neurological disorders are common, costly, and can cause enduring disability. Although mostly unknown, a few environmental toxicants are recognized causes of neurological disorders and subclinical brain dysfunction. One of the best known neurotoxins is methylmercury (MeHg), a ubiquitous environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. In the aquatic environment, MeHg is accumulated in fish, which represent a major source of human exposure. Although several episodes of MeHg poisoning have contributed to the understanding of the clinical symptoms and histological changes elicited by this neurotoxicant in humans, experimental studies have been pivotal in elucidating the molecular mechanisms that mediate MeHg-induced neurotoxicity. The objective of this mini-review is to summarize data from experimental studies on molecular mechanisms of MeHg-induced neurotoxicity. While the full picture has yet to be unmasked, in vitro approaches based on cultured cells, isolated mitochondria and tissue slices, as well as in vivo studies based mainly on the use of rodents, point to impairment in intracellular calcium homeostasis, alteration of glutamate homeostasis and oxidative stress as important events in MeHg-induced neurotoxicity. The potential relationship among these events is discussed, with particular emphasis on the neurotoxic cycle triggered by MeHg-induced excitotoxicity and oxidative stress. The particular sensitivity of the developing brain to MeHg toxicity, the critical role of selenoproteins and the potential protective role of selenocompounds are also discussed. These concepts provide the biochemical bases to the understanding of MeHg neurotoxicity, contributing to the discovery of endogenous and exogenous molecules that counteract such toxicity and provide efficacious means for ablating this vicious cycle. PMID:21683713

  18. Neurotoxic Non-proteinogenic Amino Acid β-N-Methylamino-L-alanine and Its Role in Biological Systems.

    PubMed

    Popova, A A; Koksharova, O A

    2016-08-01

    Secondary metabolites of photoautotrophic organisms have attracted considerable interest in recent years. In particular, molecules of non-proteinogenic amino acids participating in various physiological processes and capable of producing adverse ecological effects have been actively investigated. For example, the non-proteinogenic amino acid β-N-methylamino-L-alanine (BMAA) is neurotoxic to animals including humans. It is known that BMAA accumulation via the food chain can lead to development of neurodegenerative diseases in humans such as Alzheimer's and Parkinson's diseases as well as amyotrophic lateral sclerosis. Moreover, BMAA can be mistakenly incorporated into a protein molecule instead of serine. Natural sources of BMAA and methods for its detection are discussed in this review, as well as the role of BMAA in metabolism of its producers and possible mechanisms of toxicity of this amino acid in different living organisms.

  19. Microalgal metabolites: a new perspective.

    PubMed

    Shimizu, Y

    1996-01-01

    Occurrence of secondary metabolites in microalgae (protoctista) is discussed with respect to the phylogenic or taxonomic relationships of organisms. Biosynthetic mechanisms of certain metabolites such as paralytic shellfish poisoning toxins and polyether toxins are also discussed, and genetic aspects of the secondary metabolite production as well.

  20. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water.

    PubMed

    Krishna, Saritha; Dodd, Celia A; Hekmatyar, Shahryar K; Filipov, Nikolay M

    2014-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e., mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post-Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure.

  1. Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine.

    PubMed

    Nash, J F; Yamamoto, B K

    1992-05-29

    The effect of repeated administration of either methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA) or vehicle on the extracellular concentrations of glutamate (GLU), aspartate, taurine, dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was studied in awake, freely moving rats using in vivo microdialysis. MA (7.5 mg/kg, i.p.) administered every 2 h for a total of 3 injections, increased the extracellular concentration of GLU in the anteromedial striatum. By contrast, neither vehicle nor MDMA (9.2 and 13.8 mg/kg) increased GLU efflux following repeated administration. Both MA and MDMA increased the extracellular concentration of DA in the striatum. However, the cumulative increase in DA was significantly greater in the MDMA treated animals as compared to the MA group. The concentrations of DA, serotonin (5-HT) and their metabolites were determined in the striatum 7 days following the repeated administration of MA, MDMA and vehicle. MA, but not MDMA or vehicle, decreased the concentration of DA in the striatum. Conversely, MDMA (13.8 mg/kg) decreased the concentration of 5-HT, whereas MA, MDMA (9.2 mg/kg) and vehicle had no effect on striatal 5-HT content. These data are suggestive that the long-term (7 day) DA neurotoxicity produced by the repeated administration of MA is mediated, in part, by a delayed increase in extracellular concentrations of GLU. In contrast, repeated administration of MDMA, at a dose which produced a long-term (7 day) depletion of striatal 5-HT content, had no effect on GLU efflux in the striatum.

  2. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water

    PubMed Central

    Saritha, Krishna; Celia, Dodd A.; Shahryar, Hekmatyar K.; Nikolay, Filipov M.

    2013-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e. mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) level, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure. PMID:23832297

  3. Interactions of chronic lead exposure and intermittent stress: consequences for brain catecholamine systems and associated behaviors and HPA axis function.

    PubMed

    Virgolini, Miriam B; Chen, Kevin; Weston, Doug D; Bauter, Mark R; Cory-Slechta, Deborah A

    2005-10-01

    Elevated lead (Pb) burden and high stress levels are co-occurring risk factors in low socioeconomic status (SES) children. Our previous work demonstrated that maternal Pb exposure can permanently alter hypothalamic-pituitary-adrenal (HPA) axis function and responsivity to stress challenges in offspring. The current study sought to determine the consequences of chronic Pb exposures initiated later in development combined with variable intermittent stress challenges. Male rats were exposed chronically from weaning to 0, 50, or 150 ppm Pb acetate drinking solutions (producing blood Pb levels of <5, 9-15, and 23-27 mug/dl, respectively). Pb itself decreased basal plasma corticosterone, with greater effects at 50 than 150 ppm; 150 ppm reduced both cytosolic and nuclear glucocorticoid receptor binding. Responsivity to stress challenges including novelty, cold, and restraint, was measured as changes in Fixed Interval (FI) schedule-controlled behavior in a subset of rats within each group. FI performance was modified by novelty stress only in Pb-treated rats, whereas cold and restraint stress effects were comparable across groups. Novelty elevated corticosterone equivalently across groups, but cold stress markedly increased corticosterone only in Pb-treated groups. The pattern of Pb-induced changes in serotonin (5-HT) or its metabolite 5-HIAA in frontal cortex, nucleus accumbens, striatum, and hypothalamus resembled that observed for basal corticosterone levels indicating a relationship between these variables. In addition to suggesting the potential for HPA axis-mediated effects of Pb on the central nervous system, these findings also raise questions about whether single chemicals studied in isolation from other relevant risk factors can adequately identify neurotoxic hazards.

  4. Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.

    PubMed

    Yang, Lichuan; Zhao, Kesheng; Calingasan, Noel Y; Luo, Guoxiong; Szeto, Hazel H; Beal, M Flint

    2009-09-01

    A large body of evidence suggests that mitochondrial dysfunction and oxidative damage play a role in the pathogenesis of Parkinson's disease (PD). A number of antioxidants have been effective in animal models of PD. We have developed a family of mitochondria-targeted peptides that can protect against mitochondrial swelling and apoptosis (SS peptides). In this study, we examined the ability of two peptides, SS-31 and SS-20, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. SS-31 produced dose-dependent complete protection against loss of dopamine and its metabolites in striatum, as well as loss of tyrosine hydroxylase immunoreactive neurons in substantia nigra pars compacta. SS-20, which does not possess intrinsic ability in scavenging reactive oxygen species, also demonstrated significant neuroprotective effects on dopaminergic neurons of MPTP-treated mice. Both SS-31 and SS-20 were very potent (nM) in preventing MPP+ (1-methyl-4-phenylpyridinium)-induced cell death in cultured dopamine cells (SN4741). Studies with isolated mitochondria showed that both SS-31 and SS-20 prevented MPP+-induced inhibition of oxygen consumption and ATP production, and mitochondrial swelling. These findings provide strong evidence that these neuroprotective peptides, which target both mitochondrial dysfunction and oxidative damage, are a promising approach for the treatment of PD.

  5. Mitochondria Targeted Peptides Protect Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Neurotoxicity

    PubMed Central

    Yang, Lichuan; Zhao, Kesheng; Calingasan, Noel Y.; Luo, Guoxiong; Szeto, Hazel H.

    2009-01-01

    Abstract A large body of evidence suggests that mitochondrial dysfunction and oxidative damage play a role in the pathogenesis of Parkinson's disease (PD). A number of antioxidants have been effective in animal models of PD. We have developed a family of mitochondria-targeted peptides that can protect against mitochondrial swelling and apoptosis (SS peptides). In this study, we examined the ability of two peptides, SS-31 and SS-20, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. SS-31 produced dose-dependent complete protection against loss of dopamine and its metabolites in striatum, as well as loss of tyrosine hydroxylase immunoreactive neurons in substantia nigra pars compacta. SS-20, which does not possess intrinsic ability in scavenging reactive oxygen species, also demonstrated significant neuroprotective effects on dopaminergic neurons of MPTP-treated mice. Both SS-31 and SS-20 were very potent (nM) in preventing MPP+ (1-methyl-4-phenylpyridinium)-induced cell death in cultured dopamine cells (SN4741). Studies with isolated mitochondria showed that both SS-31 and SS-20 prevented MPP+-induced inhibition of oxygen consumption and ATP production, and mitochondrial swelling. These findings provide strong evidence that these neuroprotective peptides, which target both mitochondrial dysfunction and oxidative damage, are a promising approach for the treatment of PD. Antioxid. Redox Signal. 11, 2095–2104. PMID:19203217

  6. Early and Late Pathomechanisms in Alzheimer's Disease: From Zinc to Amyloid-β Neurotoxicity.

    PubMed

    Szutowicz, Andrzej; Bielarczyk, Hanna; Zyśk, Marlena; Dyś, Aleksandra; Ronowska, Anna; Gul-Hinc, Sylwia; Klimaszewska-Łata, Joanna

    2016-12-30

    There are several systemic and intracerebral pathologic conditions, which limit provision and utilization of energy precursor metabolites in neuronal cells. Energy deficits cause excessive depolarization of neuronal cells triggering glutamate-zinc evoked excitotoxic cascade. The intracellular zinc excess hits several intraneuronal targets yielding collapse of energy balance and impairment functional and structural impairments cholinergic neurons. Disturbances in metabolism of acetyl-CoA, which is a direct precursor for energy, acetylcholine, N-acetyl-L-aspartate and acetylated proteins synthesis, play an important role in these pathomechanisms. Disruption of brain homeostasis activates slow accumulation of amyloid-β 1-42 , which extra and intracellular oligomeric deposits disrupt diverse transporting and signaling processes in all membrane structures of the cell. Both neurotoxic signals may combine aggravating detrimental effects on neuronal cell. Different neuroglial and neuronal cell types may display differential susceptibility to similar pathogenic insults depending on specific features of their energy and functional parameters. This review, basing on findings gained from cellular and animal models of Alzheimer's disease, discusses putative energy/acetyl-CoA dependent mechanism in early and late stages of neurodegeneration.

  7. The content of catecholamines in the adrenal glands and sections of the brain under hypokinesia and injection of some neurotropic agents

    NASA Technical Reports Server (NTRS)

    Melnik, B. E.; Paladiy, E. S.

    1980-01-01

    The dynamics of catecholamine content were studied in the adrenal glands and in various region of the brain of white rats under hypokinesia and injections of neurotropic agents. Profound changes in body catecholamine balance occured as a result of prolonged acute restriction of motor activity. Adrenalin retention increased and noradrenanalin retention decreased in the adrenal glands, hypothalamus, cerebral hemispheres, cerebellum and medulla oblongata. Observed alterations in catecholamine retention varied depending upon the type of neurotropic substance utilized. Mellipramine increased catecholamine retention in the tissues under observation while spasmolytin brought about an increase in adrenalin concentration in the adrenals and a decrease in the brain.

  8. High-performance liquid chromatographic assay for catecholamines and metanephrines using fluorimetric detection with pre-column 9-fluorenylmethyloxycarbonyl chloride derivatization.

    PubMed

    Chan, E C; Wee, P Y; Ho, P Y; Ho, P C

    2000-12-01

    A convenient HPLC-fluorescent assay of norepinephrine (NE), epinephrine (E), dopamine (DA) and their 3-O-methylated metabolites, normetanephrine (NM) and metanephrine (MN) was developed. These analytes were coupled to 9-fluorenylmethyloxycarbonyl chloride (FMOC-Cl) before assays. Results showed that using a linear gradient elution, peaks of FMOC-NE, FMOC-E, FMOC-DA, FMOC-NM, FMOC-MN and FMOC-DHBA (3,4-dihydroxybenzylamine, internal standard) were simultaneously resolved within 40 min. Optimization of the chromatographic and derivatization conditions, and validation of the assay were further discussed in the paper. The structures of these derivatives were confirmed by atmospheric pressure chemical ionization mass spectrometry (APCI-MS). The molecular ions [M+H]- of FMOC-NE, FMOC-E, FMOC-DA, FMOC-NM and FMOC-MN were m/z 836, 850, 820, 628 and 642, respectively. Based on these findings, the FMOC-derivatives of metanephrines and catecholamines were confirmed to be bi-substituted and tri-substituted respectively at the amino and catechol functional groups. Finally, the assay was successfully applied to the measurement of urinary E, DA, NM and MN after direct derivatization and simple cleaning.

  9. Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice.

    PubMed

    Achat-Mendes, Cindy; Ali, Syed F; Itzhak, Yossef

    2005-06-01

    The abuse of substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) can result in neurotoxicity, manifested as the depletion of dopamine (DA) and 5-hydroxytriptamine (5-HT; serotonin) axon terminal markers in humans and animal models. Human METH and MDMA users exhibit impairments in memory and executive functions, which may be a direct consequence of the neurotoxic potential of amphetamines. The objective of this study was to investigate the influence of amphetamines-induced neurotoxicity on Pavlovian learning. Using mouse models of selective DA neurotoxicity (METH; 5 mg/kg x 3), selective 5-HT neurotoxicity (fenfluramine /FEN; 25 mg/kg x 4) and dual DA and 5-HT neurotoxicity (MDMA; 15 mg/kg x 4), appetitive and aversive conditioning were investigated. Dopaminergic neurotoxicity significantly impaired METH and cocaine conditioned place preference (CPP), but had no effect on LiCl-induced conditioned place aversion (CPA). In contrast, serotonergic neurotoxicity significantly enhanced CPP, and had no effect on CPA. Dual dopaminergic/serotonergic neurotoxicity had no apparent effect on CPP; however, CPA was significantly attenuated. Postmortem analysis revealed that significantly diminished levels of DA and 5-HT markers persisted in the striatum, frontal cortex, hippocampus, and amygdala. These findings suggest that amphetamines-induced dopaminergic and serotonergic neurotoxicity exert opposing influences on the affective state produced by subsequent drug reward, while dual dopaminergic/serotonergic neurotoxicity impairs associative learning of aversive conditioning. Furthermore, results revealed that amphetamines-induced DA and 5-HT neurotoxicity modulates appetitive Pavlovian conditioning similar to other DA and 5-HT neurotoxins. Modulation of Pavlovian conditioning by amphetamines-induced neurotoxicity may be relevant to compulsive drug-seeking behavior in METH and MDMA abusers.

  10. The double-edged sword: Neurotoxicity of chemotherapy.

    PubMed

    Magge, Rajiv S; DeAngelis, Lisa M

    2015-03-01

    The number of available therapies for hematologic malignancies continues to grow at a rapid pace. Unfortunately, many of these treatments carry both central and peripheral nervous system toxicities, potentially limiting a patient's ability to tolerate a full course of treatment. Neurotoxicity with chemotherapy is common and second only to myelosuppression as a reason to limit dosing. This review addresses the neurotoxicity of newly available therapeutic agents including brentuximab vedotin and blinatumomab as well as classic ones such as methotrexate, vinca alkaloids and platinums. Although peripheral neuropathy is common with many drugs, other complications such as seizures and encephalopathy may require more immediate attention. Rapid recognition of adverse neurologic effects may lead to earlier treatment and appropriate adjustment of dosing regimens. In addition, knowledge of common toxicities may help differentiate chemotherapy-related symptoms from actual progression of cancer into the CNS.

  11. Persistent neurotoxicity from a battery fire: is cadmium the culprit?

    PubMed

    Kilburn, K H; McKinley, K L

    1996-07-01

    Two train conductors had chest tightness, painful breathing, muscle cramps, and nausea after fighting a fire in a battery box under a passenger coach. Shortly thereafter, they became anosmic and had excessive fatigue, persistent headaches, sleep disturbances, irritability, unstable moods, and hypertension. Urinary cadmium and nickel levels were elevated. Neurobehavioral testing showed, in comparison to referents, prolonged reaction times, abnormal balance, prolonged blink reflex latency, severely constricted visual fields, and decreased vibration sense. Test scores showed that immediate verbal and visual recall were normal but delayed recall was reduced. Scores on overlearned information were normal. Tests measuring dexterity, coordination, decision making, and peripheral sensation and discrimination revealed abnormalities. Repeat testing 6 and 12 months after exposure showed persistent abnormalities. Cadmium and vinyl chloride are the most plausible causes of the neurotoxicity, but fumes from the fire may have contained other neurotoxic chemicals.

  12. Functional, Structural, and Neurotoxicity Biomarkers in Integrative Assessment of Concussions

    PubMed Central

    Dambinova, Svetlana A.; Maroon, Joseph C.; Sufrinko, Alicia M.; Mullins, John David; Alexandrova, Eugenia V.; Potapov, Alexander A.

    2016-01-01

    Concussion is a complex, heterogeneous process affecting the brain. Accurate assessment and diagnosis and appropriate management of concussion are essential to ensure that athletes do not prematurely return to play or others to work or active military duty, risking re-injury. To date, clinical diagnosis relies primarily on evaluating subjects for functional impairment using instruments that include neurocognitive testing, subjective symptom report, and neurobehavioral assessments, such as balance and vestibular-ocular reflex testing. Structural biomarkers, defined as advanced neuroimaging techniques and biomarkers assessing neurotoxicity and immunoexcitotoxicity, may complement the use of functional biomarkers. We hypothesize that neurotoxicity AMPA, NMDA, and kainite receptor biomarkers might be utilized as a part of comprehensive approach to concussion evaluations, with the goal of increasing diagnostic accuracy and facilitating treatment planning and prognostic assessment. PMID:27761129

  13. Highly neurotoxic monomeric α-helical prion protein

    PubMed Central

    Zhou, Minghai; Ottenberg, Gregory; Sferrazza, Gian Franco; Lasmézas, Corinne Ida

    2012-01-01

    Prion diseases are infectious and belong to the group of protein misfolding neurodegenerative diseases. In these diseases, neuronal dysfunction and death are caused by the neuronal toxicity of a particular misfolded form of their cognate protein. The ability to specifically target the toxic protein conformer or the neuronal death pathway would provide powerful therapeutic approaches to these diseases. The neurotoxic forms of the prion protein (PrP) have yet to be defined but there is evidence suggesting that at least some of them differ from infectious PrP (PrPSc). Herein, without making an assumption about size or conformation, we searched for toxic forms of recombinant PrP after dilution refolding, size fractionation, and systematic biological testing of all fractions. We found that the PrP species most neurotoxic in vitro and in vivo (toxic PrP, TPrP) is a monomeric, highly α-helical form of PrP. TPrP caused autophagy, apoptosis, and a molecular signature remarkably similar to that observed in the brains of prion-infected animals. Interestingly, highly α-helical intermediates have been described for other amyloidogenic proteins but their biological significance remains to be established. We provide unique experimental evidence that a monomeric α-helical form of an amyloidogenic protein represents a cytotoxic species. Although toxic PrP has yet to be purified from prion-infected brains, TPrP might be the equivalent of one highly neurotoxic PrP species generated during prion replication. Because TPrP is a misfolded, highly neurotoxic form of PrP reproducing several features of prion-induced neuronal death, it constitutes a useful model to study PrP-induced neurodegenerative mechanisms. PMID:22323583

  14. A review of the neurotoxicity risk of selected hydrocarbon fuels.

    PubMed

    Ritchie, G D; Still, K R; Alexander, W K; Nordholm, A F; Wilson, C L; Rossi, J; Mattie, D R

    2001-01-01

    Over 1.3 million civilian and military personnel are occupationally exposed to hydrocarbon fuels, emphasizing gasoline, jet fuel, diesel fuel, or kerosene. These exposures may occur acutely or chronically to raw fuel, vapor, aerosol, or fuel combustion exhaust by dermal, respiratory inhalation, or oral ingestion routes, and commonly occur concurrently with exposure to other chemicals and stressors. Hydrocarbon fuels are complex mixtures of 150-260+ aliphatic and aromatic hydrocarbon compounds containing varying concentrations of potential neurotoxicants including benzene, n-hexane, toluene, xylenes, naphthalene, and certain n-C9-C12 fractions (n-propylbenzene, trimethylbenzene isomers). Due to their natural petroleum base, the chemical composition of different hydrocarbon fuels is not defined, and the fuels are classified according to broad performance criteria such as flash and boiling points, complicating toxicological comparisons. While hydrocarbon fuel exposures occur typically at concentrations below permissible exposure limits for their constituent chemicals, it is unknown whether additive or synergistic interactions may result in unpredicted neurotoxicity. The inclusion of up to six performance additives in existing fuel formulations presents additional neurotoxicity challenge. Additionally, exposures to hydrocarbon fuels, typically with minimal respiratory or dermal protection, range from weekly fueling of personal automobiles to waist-deep immersion of personnel in raw fuel during maintenance of aircraft fuel tanks. Occupational exposures may occur on a near daily basis for from several months to over 20 yr. A number of published studies have reported acute or persisting neurotoxic effects from acute, subchronic, or chronic exposure of humans or animals to hydrocarbon fuels, or to certain constituent chemicals of these fuels. This review summarizes human and animal studies of hydrocarbon fuel-induced neurotoxicity and neurobehavioral consequences. It is

  15. Neurotoxicity produced by dibromoacetic acid in drinking water of rats.

    PubMed

    Moser, V C; Phillips, P M; Levine, A B; McDaniel, K L; Sills, R C; Jortner, B S; Butt, M T

    2004-05-01

    An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.

  16. The dopamine transporter: role in neurotoxicity and human disease

    SciTech Connect

    Bannon, Michael J. . E-mail: mbannon@med.wayne.edu

    2005-05-01

    The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD)

  17. Study of neurotoxic intracellular calcium signalling triggered by amyloids.

    PubMed

    Villalobos, Carlos; Caballero, Erica; Sanz-Blasco, Sara; Núñez, Lucía

    2012-01-01

    Neurotoxicity in Alzheimer's disease (AD) is associated to dishomeostasis of intracellular Ca(2+) induced by amyloid β peptide (Aβ) species. Understanding of the effects of Aβ on intracellular Ca(2+) homeostasis requires preparation of the different Aβ assemblies including oligomers and fibrils and the testing of their effects on cytosolic and mitochondrial Ca(2+) in neurons. Procedures for cerebellar granule cell culture, preparation of Aβ species as well as fluorescence and bioluminescence imaging of cytosolic and mitochondrial Ca(2+) in neurons are described.

  18. Manganese: Recent advances in understanding its transport and neurotoxicity

    SciTech Connect

    Aschner, Michael . E-mail: Michael.Aschner@vanderbilt.edu; Guilarte, Tomas R.; Schneider, Jay S.; Zheng Wei

    2007-06-01

    The present review is based on presentations from the meeting of the Society of Toxicology in San Diego, CA (March 2006). It addresses recent developments in the understanding of the transport of manganese (Mn) into the central nervous system (CNS), as well as brain imaging and neurocognitive studies in non-human primates aimed at improving our understanding of the mechanisms of Mn neurotoxicity. Finally, we discuss potential therapeutic modalities for treating Mn intoxication in humans.

  19. Exploration of Prostate Cancer Treatment Induced Neurotoxicity with Neuroimaging

    DTIC Science & Technology

    2008-05-01

    AD_________________ Award Number: W81XWH-06-1-0033 TITLE: Exploration of Prostate Cancer Treatment Induced...Prostate Cancer Treatment Induced Neurotoxicity with Neuroimaging 5b. GRANT NUMBER W81XWH-06-1-0033 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jeri...consequences on brain health of prostate cancer treatments in men despite data suggesting that ADT may cause memory or other cognitive impairments. Our study

  20. Toxicity testing of neurotoxic pesticides in Caenorhabditis elegans.

    PubMed

    Meyer, Dean; Williams, Phillip L

    2014-01-01

    The use of pesticides is ubiquitous worldwide, and these chemicals exert adverse effects on both target and nontarget species. Understanding the modes of action of pesticides, as well as quantifying exposure concentration and duration, is an important goal of clinicians and environmental health scientists. Some chemical exposures result in adverse effects on the nervous system. The nematode Caenorhabditis elegans (C. elegans) is a model lab organism well established for studying neurotoxicity, since the components of its nervous system are mapped and known, and most of its neurotransmitters correspond to human homologs. This review encompasses published studies in which C. elegans nematodes were exposed to pesticides with known neurotoxic actions. Endpoints measured include changes in locomotion, feeding behavior, brood size, growth, life span, and cell death. From data presented, evidence indicates that C. elegans can serve a role in assessing the effects of neurotoxic pesticides at the sublethal cellular level, thereby advancing our understanding of the mechanisms underlying toxicity induced by these chemicals. A proposed toxicity testing scheme for water-soluble chemicals is also included.

  1. In vitro neurotoxic hazard characterisation of dinitrophenolic herbicides.

    PubMed

    Heusinkveld, Harm J; van Vliet, Arie C; Nijssen, Peter C G; Westerink, Remco H S

    2016-06-11

    Dinitrophenolic compounds are powerful toxicants with a long history of use in agriculture and industry. While (high) human exposure levels are not uncommon, in particular for agricultural workers during the spraying season, the neurotoxic mechanism(s) that underlie the human health effects are largely unknown. We therefore investigated the in vitro effects of two dinitrophenolic herbicides (DNOC and dinoseb) on a battery of neurotoxicity endpoints in (dopaminergic) rat PC12 cells. Cell viability, mitochondrial activity, oxidative stress and caspase activation were assessed using fluorescence-based bioassays (CFDA, alamar Blue, H2DCFDA and Ac-DEVD-AMC, respectively), whereas changes in intracellular [Ca(2+)]i were assessed using single-cell fluorescence microscopy with Fura-2AM. The combined results demonstrate that exposure to both DNOC and dinoseb is linked to calcium release from the endoplasmic reticulum and activation of caspase-mediated apoptotic pathways. In subsequent experiments, immunofluorescent labelling with specific antibodies was used to determine changes in intracellular α-synuclein levels, demonstrating that both DNOC and dinoseb increase levels of intracellular α-synuclein. The combined results indicate that in vitro exposure to DNOC and dinoseb activates pathways that are not only involved in acute neurotoxicity but also in long-term effects as seen in neurodegeneration.

  2. Peripheral ammonia as a mediator of methamphetamine neurotoxicity.

    PubMed

    Halpin, Laura E; Yamamoto, Bryan K

    2012-09-19

    Ammonia is metabolized by the liver and has established neurological effects. The current study examined the possibility that ammonia contributes to the neurotoxic effects of methamphetamine (METH). The results show that a binge dosing regimen of METH to the rat increased plasma and brain ammonia concentrations that were paralleled by evidence of hepatotoxicity. The role of peripheral ammonia in the neurotoxic effects of METH was further substantiated by the demonstration that the enhancement of peripheral ammonia excretion blocked the increases in brain and plasma ammonia and attenuated the long-term depletions of dopamine and serotonin typically produced by METH. Conversely, the localized perfusion of ammonia in combination with METH, but not METH alone or ammonia alone, into the striatum recapitulated the neuronal damage produced by the systemic administration of METH. Furthermore, this damage produced by the local administration of ammonia and METH was blocked by the GYKI 52466 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzamine hydrochloride], an AMPA receptor antagonist. These findings highlight the importance of ammonia derived from the periphery as a small-molecule mediator of METH neurotoxicity and more broadly emphasize the importance of peripheral organ damage as a possible mechanism that mediates the neuropathology produced by drugs of abuse and other neuroactive molecules.

  3. Phytochemicals Mediated Remediation of Neurotoxicity Induced by Heavy Metals.

    PubMed

    Gupta, Vivek Kumar; Singh, Shweta; Agrawal, Anju; Siddiqi, Nikhat Jamal; Sharma, Bechan

    2015-01-01

    Almost all the environmental components including both the abiotic and biotic factors have been consistently threatened by excessive contamination of heavy metals continuously released from various sources. Different heavy metals have been reported to generate adverse effects in many ways. Heavy metals induced neurotoxicity and impairment in signalling cascade leading to cell death (apoptosis) has been indicated by several workers. On one hand, these metals are required by the cellular systems to regulate various biological functions of normal cells, while on the other their biomagnification in the cellular systems produces adverse effects. The mechanism by which the heavy metals induce neurotoxicity follows free radicals production pathway(s) specially the generation of reactive oxygen species and reactive nitrogen species. These free radicals produced in excess have been shown to create an imbalance between the oxidative and antioxidative systems leading to emergence of oxidative stress, which may cause necrosis, DNA damage, and many neurodegenerative disorders. This mini review summarizes the current knowledge available on the protective role of varied natural products isolated from different herbs/plants in imparting protection against heavy metals (cadmium, lead, arsenic, and mercury) mediated neurotoxicity.

  4. Glial Reactivity in Resistance to Methamphetamine-Induced Neurotoxicity

    PubMed Central

    Friend, Danielle M.; Keefe, Kristen A.

    2013-01-01

    Neurotoxic regimens of methamphetamine (METH) result in reactive microglia and astrocytes in striatum. Prior data indicate that rats with partial dopamine (DA) loss resulting from prior exposure to METH are resistant to further decreases in striatal DA when re-exposed to METH 30 days later. Such resistant animals also do not show an activated microglia phenotype, suggesting a relation between microglial activation and METH-induced neurotoxicity. To date, the astrocyte response in such resistance has not been examined. Thus, this study examined glial-fibrillary acidic protein (GFAP) and CD11b protein expression in striata of animals administered saline or a neurotoxic regimen of METH on postnatal days 60 and/or 90 (Saline:Saline, Saline:METH, METH:Saline, METH:METH). Consistent with previous work, animals experiencing acute toxicity (Saline:METH) showed both activated microglia and astocytes, whereas those resistant to the acute toxicity (METH:METH) did not show activated microglia. Interestingly, GFAP expression remained elevated in rats exposed to METH at PND60 (METH:Saline), and was not elevated further in resistant rats treated for the second time with METH (METH:METH). These data suggest that astrocytes remain reactive up to 30 days post-METH exposure. Additionally, these data indicate that astrocyte reactivity does not reflect acute, METH-induced DA terminal toxicity, whereas microglial reactivity does. PMID:23414433

  5. Developmental neurotoxic effects of Malathion on 3D neurosphere system

    PubMed Central

    Salama, Mohamed; Lotfy, Ahmed; Fathy, Khaled; Makar, Maria; El-emam, Mona; El-gamal, Aya; El-gamal, Mohamed; Badawy, Ahmad; Mohamed, Wael M.Y.; Sobh, Mohamed

    2015-01-01

    Developmental neurotoxicity (DNT) refers to the toxic effects induced by various chemicals on brain during the early childhood period. As human brains are vulnerable during this period, various chemicals would have significant effects on brains during early childhood. Some toxicants have been confirmed to induce developmental toxic effects on CNS; however, most of agents cannot be identified with certainty. This is because available animal models do not cover the whole spectrum of CNS developmental periods. A novel alternative method that can overcome most of the limitations of the conventional techniques is the use of 3D neurosphere system. This in-vitro system can recapitulate many of the changes during the period of brain development making it an ideal model for predicting developmental neurotoxic effects. In the present study we verified the possible DNT of Malathion, which is one of organophosphate pesticides with suggested possible neurotoxic effects on nursing children. Three doses of Malathion (0.25 μM, 1 μM and 10 μM) were used in cultured neurospheres for a period of 14 days. Malathion was found to affect proliferation, differentiation and viability of neurospheres, these effects were positively correlated to doses and time progress. This study confirms the DNT effects of Malathion on 3D neurosphere model. Further epidemiological studies will be needed to link these results to human exposure and effects data. PMID:27054080

  6. Phytochemicals Mediated Remediation of Neurotoxicity Induced by Heavy Metals

    PubMed Central

    Gupta, Vivek Kumar; Singh, Shweta; Agrawal, Anju; Siddiqi, Nikhat Jamal; Sharma, Bechan

    2015-01-01

    Almost all the environmental components including both the abiotic and biotic factors have been consistently threatened by excessive contamination of heavy metals continuously released from various sources. Different heavy metals have been reported to generate adverse effects in many ways. Heavy metals induced neurotoxicity and impairment in signalling cascade leading to cell death (apoptosis) has been indicated by several workers. On one hand, these metals are required by the cellular systems to regulate various biological functions of normal cells, while on the other their biomagnification in the cellular systems produces adverse effects. The mechanism by which the heavy metals induce neurotoxicity follows free radicals production pathway(s) specially the generation of reactive oxygen species and reactive nitrogen species. These free radicals produced in excess have been shown to create an imbalance between the oxidative and antioxidative systems leading to emergence of oxidative stress, which may cause necrosis, DNA damage, and many neurodegenerative disorders. This mini review summarizes the current knowledge available on the protective role of varied natural products isolated from different herbs/plants in imparting protection against heavy metals (cadmium, lead, arsenic, and mercury) mediated neurotoxicity. PMID:26618004

  7. Serotonin activates catecholamine neurons in the solitary tract nucleus by increasing spontaneous glutamate inputs.

    PubMed

    Cui, Ran Ji; Roberts, Brandon L; Zhao, Huan; Zhu, Mingyan; Appleyard, Suzanne M

    2012-11-14

    Serotonin (5-HT) is a critical neurotransmitter in the control of autonomic functions. 5-HT(3) receptors participate in vagal afferent feedback to decrease food intake and regulate cardiovascular reflexes; however, the phenotype of the solitary tract nucleus (NTS) neurons involved is not known. A(2)/C(2) catecholamine (CA) neurons in the NTS are directly activated by visceral afferents and are important for the control of food intake and cardiovascular function, making them good candidates to respond to and mediate the effects of serotonin at the level of the NTS. This study examines serotonin's effects on NTS-CA neurons using patch-clamp techniques and transgenic mice expressing an enhanced green fluorescent protein driven by the tyrosine hydroxylase (TH) promoter (TH-EGFP) to identify catecholamine neurons. Serotonin increased the frequency of spontaneous glutamate excitatory postsynaptic currents (sEPSCs) in >90% of NTS-TH-EGFP neurons, an effect blocked by the 5-HT(3) receptor antagonist ondansetron and mimicked by the 5-HT(3) receptor agonists SR5227 and mCPBG. In contrast, 5-HT(3) receptor agonists increased sEPSCs on a minority (<30%) of non-TH neurons. 5-HT(3) receptor agonists increased the frequency, but not the amplitude, of mini-EPSCs, suggesting that their actions are presynaptic. 5-HT(3) receptor agonists increased the firing rate of TH-EGFP neurons, an effect dependent on the increased spontaneous glutamate inputs as it was blocked by the ionotropic glutamate antagonist NBQX, but independent of visceral afferent activation. These results demonstrate a cellular mechanism by which serotonin activates NTS-TH neurons and suggest a pathway by which it can increase catecholamine release in target regions to modulate food intake, motivation, stress, and cardiovascular function.

  8. Pituitary adenylate cyclase-activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis.

    PubMed

    Hamelink, Carol; Tjurmina, Olga; Damadzic, Ruslan; Young, W Scott; Weihe, Eberhard; Lee, Hyeon-Woo; Eiden, Lee E

    2002-01-08

    The adrenal gland is important for homeostatic responses to metabolic stress: hypoglycemia stimulates the splanchnic nerve, epinephrine is released from adrenomedullary chromaffin cells, and compensatory glucogenesis ensues. Acetylcholine is the primary neurotransmitter mediating catecholamine secretion from the adrenal medulla. Accumulating evidence suggests that a secretin-related neuropeptide also may function as a transmitter at the adrenomedullary synapse. Costaining with highly specific antibodies against the secretin-related neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) and the vesicular acetylcholine transporter (VAChT) revealed that PACAP is found in nerve terminals at all mouse adrenomedullary cholinergic synapses. Mice with a targeted deletion of the PACAP gene had otherwise normal cholinergic innervation and morphology of the adrenal medulla, normal adrenal catecholamine and blood glucose levels, and an intact initial catecholamine secretory response to insulin-induced hypoglycemia. However, insulin-induced hypoglycemia was more profound and longer-lasting in PACAP knock-outs, and was associated with a dose-related lethality absent in wild-type mice. Failure of PACAP-deficient mice to adequately counterregulate plasma glucose levels could be accounted for by impaired long-term secretion of epinephrine, secondary to a lack of induction of tyrosine hydroxylase, normally occurring after insulin hypoglycemia in wild-type mice, and a consequent depletion of adrenomedullary epinephrine stores. Thus, PACAP is needed to couple epinephrine biosynthesis to secretion during metabolic stress. PACAP appears to function as an "emergency response" cotransmitter in the sympathoadrenal axis, where the primary secretory response is controlled by a classical neurotransmitter but sustained under paraphysiological conditions by a neuropeptide.

  9. Caries increment in children and urinary catecholamines: findings at one-year.

    PubMed

    Vanderas, A P; Manetas, K; Papagiannoulis, L

    2000-01-01

    This one-year follow-up study investigates the relationship between urinary catecholamine levels and dental caries increment in 314 children, boys and girls, ages six to eight years. Dental caries was recorded clinically and radiographically and oral hygiene was evaluated by recording the dental plaque. A 24-hour urine sample was collected for each subject, in a year interval, and a representative sample was analyzed by the HPLC technique to assay the catecholamine content. Socioeconomic factors such as parental age, education, and profession were recorded by a questionnaire distributed to the parents. Of the examined children, forty-four (16 boys and 28 girls) did not develop new dental caries and constituted the Caries-Free group. Two New Caries groups, A and B, of forty-four children each (16 boys and 28 girls) were matched by age and sex. Differences were tested in the quantitative and qualitative data by the paired t-test and the chi 2 test, respectively, while a regression analysis was applied to measure the effects of norepinephrine and dopamine on epinephrine. The logistic multiple-regression analysis was used to test, in the entire population, the impact of catecholamines and other related factors on the probability of a subject's developing new dental caries. The 95 percent probability was used. The results showed statistically significant differences in epinephrine and norepinephrine values between Caries-Free and New Caries group A in both examinations. Also, significant differences were found between Caries-Free and New Caries group B in epinephrine and norepinephrine at the first examination, while at the second examination the difference was significant only in epinephrine. The data provide evidence, therefore, that an emotionally stressful state can be an etiologic factor of dental caries.

  10. Plasma glucose, insulin and catecholamine responses to a Wingate test in physically active women and men.

    PubMed

    Vincent, Sophie; Berthon, Phanélie; Zouhal, Hassane; Moussa, Elie; Catheline, Michel; Bentué-Ferrer, Danièle; Gratas-Delamarche, Arlette

    2004-01-01

    The influence of gender on the glucose response to exercise remains contradictory. Moreover, to our knowledge, the glucoregulatory responses to anaerobic sprint exercise have only been studied in male subjects. Hence, the aim of the present study was to compare glucoregulatory metabolic (glucose and lactate) and hormonal (insulin, catecholamines and estradiol only in women) responses to a 30-s Wingate test, in physically active students. Eight women [19.8 (0.7) years] and eight men [22.0 (0.6) years] participated in a 30-s Wingate test on a bicycle ergometer. Plasma glucose, insulin, and catecholamine concentrations were determined at rest, at the end of both the warm-up and the exercise period and during the recovery (5, 10, 20, and 30 min). Results showed that the plasma glucose increase in response to a 30-s Wingate test was significantly higher in women than in men [0.99 (0.15) versus 0.33 (0.20) mmol l(-1) respectively, P<0.05]. Plasma insulin concentrations peaked at 10 min post-exercise and the increase between this time of recovery and the end of the warm-up was also significantly higher in women than in men [14.7 (2.9) versus 2.3 (1.9) pmol l(-1) respectively, P<0.05]. However, there was no gender difference concerning the catecholamine response. The study indicates a gender-related difference in post-exercise plasma glucose and insulin responses after a supramaximal exercise.

  11. Catecholamine-induced cardiac mitochondrial dysfunction and mPTP opening: protective effect of curcumin.

    PubMed

    Izem-Meziane, Malika; Djerdjouri, Bahia; Rimbaud, Stephanie; Caffin, Fanny; Fortin, Dominique; Garnier, Anne; Veksler, Vladimir; Joubert, Frederic; Ventura-Clapier, Renee

    2012-02-01

    The present study was designed to characterize the mitochondrial dysfunction induced by catecholamines and to investigate whether curcumin, a natural antioxidant, induces cardioprotective effects against catecholamine-induced cardiotoxicity by preserving mitochondrial function. Because mitochondria play a central role in ischemia and oxidative stress, we hypothesized that mitochondrial dysfunction is involved in catecholamine toxicity and in the potential protective effects of curcumin. Male Wistar rats received subcutaneous injection of 150 mg·kg(-1)·day(-1) isoprenaline (ISO) for two consecutive days with or without pretreatment with 60 mg·kg(-1)·day(-1) curcumin. Twenty four hours after, cardiac tissues were examined for apoptosis and oxidative stress. Expression of proteins involved in mitochondrial biogenesis and function were measured by real-time RT-PCR. Isolated mitochondria and permeabilized cardiac fibers were used for swelling and mitochondrial function experiments, respectively. Mitochondrial morphology and permeability transition pore (mPTP) opening were assessed by fluorescence in isolated cardiomyocytes. ISO treatment induced cell damage, oxidative stress, and apoptosis that were prevented by curcumin. Moreover, mitochondria seem to play an important role in these effects as respiration and mitochondrial swelling were increased following ISO treatment, these effects being again prevented by curcumin. Importantly, curcumin completely prevented the ISO-induced increase in mPTP calcium susceptibility in isolated cardiomyocytes without affecting mitochondrial biogenesis and mitochondrial network dynamic. The results unravel the importance of mitochondrial dysfunction in isoprenaline-induced cardiotoxicity as well as a new cardioprotective effect of curcumin through prevention of mitochondrial damage and mPTP opening.

  12. Effects of lactic acid and catecholamines on contractility in fast-twitch muscles exposed to hyperkalemia.

    PubMed

    Hansen, Anders Krogh; Clausen, Torben; Nielsen, Ole Baekgaard

    2005-07-01

    Intensive exercise is associated with a pronounced increase in extracellular K+ ([K+]o). Because of the ensuing depolarization and loss of excitability, this contributes to muscle fatigue. Intensive exercise also increases the level of circulating catecholamines and lactic acid, which both have been shown to alleviate the depressing effect of hyperkalemia in slow-twitch muscles. Because of their larger exercise-induced loss of K+, fast-twitch muscles are more prone to fatigue caused by increased [K+]o than slow-twitch muscles. Fast-twitch muscles also produce more lactic acid. We therefore compared the effects of catecholamines and lactic acid on the maintenance of contractility in rat fast-twitch [extensor digitorum longus (EDL)] and slow-twitch (soleus) muscles. Intact muscles were mounted on force transducers and stimulated electrically to evoke short isometric tetani. Elevated [K+]o (11 and 13 mM) was used to reduce force to approximately 20% of control force at 4 mM K+. In EDL, the beta2-agonist salbutamol (10(-5) M) restored tetanic force to 83 +/- 2% of control force, whereas in soleus salbutamol restored tetanic force to 93 +/- 1%. In both muscles, salbutamol induced hyperpolarization (5-8 mV), reduced intracellular Na+ content and increased Na+-K+ pump activity, leading to an increased K+ tolerance. Lactic acid (24 mM) restored force from 22 +/- 4% to 58 +/- 2% of control force in EDL, an effect that was significantly lower than in soleus muscle. These results amplify and generalize the concept that the exercise-induced acidification and increase in plasma catecholamines counterbalance fatigue arising from rundown of Na+ and K+ gradients.

  13. Circadian variations of catecholamines and blood pressure in patients with pseudohypoparathyroidism and hypertension.

    PubMed

    Brickman, A S; Stern, N; Sowers, J R

    1990-01-01

    The relationship between 24-h recumbent blood pressure levels and secretory patterns of catecholamines was investigated in 4 patients with pseudohypoparathyroidism (PsHP) and hypertension and in 9 patients with essential hypertension. A clear circadian rhythm of blood pressure and catecholamines was documented in both groups with lowest levels of blood pressures and catecholamines occurring during sleep. During the 24-h period of recumbency mean arterial blood pressure (MAP) was correlated (r = 0.63, p less than or equal to 0.01) with plasma norepinephrine (N) in the patients with essential hypertension, but this correlation was weaker in patients with PsHP (r = 0.38, p less than or equal to 0.05). MAP was more closely related to plasma epinephrine (E) (r = 0.62, p less than or equal to 0.01) than to plasma NE in patients with PsHP. Plasma NE and E levels were considerably lower in patients with PsHP than in patients with essential hypertension throughout the 24-h recumbent period. The sleep-related decline in blood pressure and NE was less than in patients with essential hypertension. These results suggest that while the sympathetic nervous system may have a role in hour-to-hour maintenance of blood pressure in patients with PsHP and hypertension, it does not appear to be responsible for the elevated arterial pressure in these patients. Factors other than those investigated, such as obesity, alterations in sodium homeostasis of refractoriness of the vascular smooth muscle to the vasodilatory effect of PTH may be involved in the pathogenesis of hypertension in PsHP.

  14. Serotonin Activates Catecholamine Neurons in the Solitary Tract Nucleus by Increasing Spontaneous Glutamate Inputs

    PubMed Central

    Cui, Ran Ji; Roberts, Brandon L.; Zhao, Huan; Zhu, Mingyan

    2012-01-01

    Serotonin (5-HT) is a critical neurotransmitter in the control of autonomic functions. 5-HT3 receptors participate in vagal afferent feedback to decrease food intake and regulate cardiovascular reflexes; however, the phenotype of the solitary tract nucleus (NTS) neurons involved is not known. A2/C2 catecholamine (CA) neurons in the NTS are directly activated by visceral afferents and are important for the control of food intake and cardiovascular function, making them good candidates to respond to and mediate the effects of serotonin at the level of the NTS. This study examines serotonin's effects on NTS-CA neurons using patch-clamp techniques and transgenic mice expressing an enhanced green fluorescent protein driven by the tyrosine hydroxylase (TH) promoter (TH-EGFP) to identify catecholamine neurons. Serotonin increased the frequency of spontaneous glutamate excitatory postsynaptic currents (sEPSCs) in >90% of NTS-TH-EGFP neurons, an effect blocked by the 5-HT3 receptor antagonist ondansetron and mimicked by the 5-HT3 receptor agonists SR5227 and mCPBG. In contrast, 5-HT3 receptor agonists increased sEPSCs on a minority (<30%) of non-TH neurons. 5-HT3 receptor agonists increased the frequency, but not the amplitude, of mini-EPSCs, suggesting that their actions are presynaptic. 5-HT3 receptor agonists increased the firing rate of TH-EGFP neurons, an effect dependent on the increased spontaneous glutamate inputs as it was blocked by the ionotropic glutamate antagonist NBQX, but independent of visceral afferent activation. These results demonstrate a cellular mechanism by which serotonin activates NTS-TH neurons and suggest a pathway by which it can increase catecholamine release in target regions to modulate food intake, motivation, stress, and cardiovascular function. PMID:23152635

  15. Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis.

    PubMed

    Schneider, Johanna; Lother, Achim; Hein, Lutz; Gilsbach, Ralf

    2011-06-01

    Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.

  16. Catecholamine response during 12 days of high-altitude exposure (4, 300 m) in women.

    PubMed

    Mazzeo, R S; Child, A; Butterfield, G E; Mawson, J T; Zamudio, S; Moore, L G

    1998-04-01

    We have previously demonstrated that acclimatization to high altitude elicits increased sympathetic nerve activity in men. The purpose of this investigation was to determine 1) whether women respond in a similar manner as found previously in men and 2) the extent to which menstrual cycle phase influences this response. Sixteen eumenorrheic women (age, 23.6 +/- 1.2 yr; weight, 56.2 +/- 4. 3 kg) were studied at sea level and during 12 days of high-altitude exposure (4,300 m) in either their follicular (F; n = 11) or luteal (L; n = 5) phase. Twenty-four-hour urine samples were collected at sea level and during each day at altitude. Catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Compared with sea-level values, urinary norepinephrine excretion increased significantly during altitude exposure, peaking on days 4-6. Thereafter, levels remained constant throughout the duration of altitude exposure. The magnitude of this increase was similar between the F (138%) and L (93%) phase. Urinary epinephrine levels were elevated on day 2 of altitude exposure compared with sea-level values for both F and L subjects (93%). Thereafter, urinary epinephrine excretion returned to sea-level values, and no differences were found between F and L subjects. Plasma catecholamine content was consistent with urinary values and supports the concept of an elevation in sympathetic activity over time at altitude. Mean and diastolic blood pressure as well as heart rate adjustments to high altitude correlated significantly with urinary norepinephrine excretion rates. It was concluded that 1) urinary and plasma catecholamine responses to 12 days of high-altitude exposure in women are similar to those previously documented to occur for men; 2) whereas no differences in catecholamine levels were observed between F- and L-phase assignments, for a given urinary norepinephrine excretion rate, blood pressure and heart rates were lower for F vs. L

  17. Training status (endurance or sprint) and catecholamine response to the Wingate-test in women.

    PubMed

    Jacob, C; Zouhal, H; Vincent, S; Gratas-Delamarche, A; Berthon, P M; Bentué-Ferrer, D; Delamarche, P

    2002-07-01

    The aim of this study was to verify if, as for men, training status induces different catecholamine responses to exercise. To do this, we investigated the effect of training status (sprint or endurance) on plasma catecholamine response to a supramaximal exercise in women. Nineteen subjects took part in our study: six untrained subjects (UT), seven endurance trained subjects (ET) and six sprint trained ones (ST). The trained subjects (ET and ST) were all competing at a high national level. The maximal power (W max ) and the mean power (W) were determined from the Wingate-test. Blood lactate, adrenaline (A) and noradrenaline (NA) were analysed at rest (La 0, A 0 and NA 0 ), immediately at the end of the exercise (A max and NA max ) and after 5 min recovery (La max [3 min in arterialized blood], A 5 and NA 5 ). The disappearance of A and NA was judged by the ratio (A max -A 5 )/A max and (NA max -NA 5 )/NA 5. The ratio A max /NA max was considered as an index of the adrenal medulla responsiveness to the sympathetic nervous activity. As expected, during the Wingate-test ST exhibited significantly higher performances compared to UT and ET. But in contrast to the men's data no difference was observed between the three groups both for La max (13.1 +/- 0.8 mmol x L (-1); 14.8 +/- 1.0 mmol x L (-1) and 11.2 +/- 0.5 mmol x L (-1) respectively for ET, ST and UT), NA max (22.1 +/- 1.2 nmol x L (-1); 13.1 +/- 2.4 nmol x L (-1) and 20.2 +/- 7 nmol x L (-1)respectively for ET, ST and UT) and A max (4.1 +/- 0.8 nmol x L (-1); 2.6 +/- 0.6 nmol x L (-1); 13.1 +/- 0.6 nmol x L (-1) respectively for ET, ST and UT). Consequently the ratio A max /NA max was similar in UT, ET and ST (respectively 0.2 +/- 0.03; 0.2 +/- 0.04; 0.17 +/- 0.04), These results indicated, in contrast to the men's data, that the catecholamine response to the Wingate-test did not differ between female subjects of different status of training. In conclusion this study did not find any significant effect of training

  18. Catecholamines of the adrenal medula and their morphological changes during adaptation to repeated immobilization stress

    NASA Technical Reports Server (NTRS)

    Kvetnansky, R.; Mitro, A.; Mikulaj, L.; Hocman, G.

    1980-01-01

    Changes of the adrenal medulla of rats were studied in the course of adaptation to repeated immobilization stress. An increase in the number of cells in the adrenal medulla was found in the adapted animals; this increase was confirmed by weight indices of the medulla and by cell counts per surface unit. Simultaneous karyometric measurements of the nuclei of adrenal medulla cells and an analysis of the catecholamine contents in the adrenals explain the increased activity of the adrenal medulla in the course of adaptation.

  19. Anti-syntaxin antibodies inhibit calcium-dependent catecholamine secretion from permeabilized chromaffin cells.

    PubMed

    Gutierrez, L M; Quintanar, J L; Viniegra, S; Salinas, E; Moya, F; Reig, J A

    1995-01-05

    Adrenomedullary chromaffin cells release catecholamines in response to the intracellular calcium rise upon stimulation by different secretagogues. The presence of syntaxin 1, a protein presumably involved in docking of synaptic vesicles to presynaptic membranes, has been investigated in chromaffin cells. The study using two different monoclonal antibodies shows that syntaxin 1 is present in the chromaffin cell membrane fraction. Functional experiments demonstrate that anti-syntaxin antibodies inhibit calcium-dependent secretion in permeabilized cells. These results suggest that syntaxin 1 is an important component of the secretory machinery in chromaffin cells.

  20. Mutagenic azide metabolite is azidoalanine

    SciTech Connect

    Owais, W.M.; Rosichan, J.L.; Ronald, R.C.; Kleinhofs, A.; Nilan, R.A.

    1981-01-01

    Sodium axide produces high mutation rates in a number of species. Azide mutagenicity is mediated through a metabolite in barley and bacteria. Many studies showed that azide affects the L-cysteine biosynthesis pathway. Cell-free extracts of Salmonella typhimurium convert azide and O-acetylserine to the mutagenic metabolite. O-acetylserine sulfhydrylase was identified as the enzyme responsible for the metabolite biosynthesis. To confirm the conclusion that the azide metabolite is formed through the ..beta..-substitution pathway of L-cysteine, we radioactively labeled the azide metabolite using /sup 14/C-labeled precursors. Moreover, the mutagenic azide metabolite was purified and identified as azidoalanine based on mass spectroscopy and elemental analysis. 26 refs., 3 figs., 1 tab.

  1. Rapamycin regulates biochemical metabolites

    PubMed Central

    Tucci, Paola; Porta, Giovanni; Agostini, Massimiliano; Antonov, Alexey; Garabadgiu, Alexander Vasilievich; Melino, Gerry; Willis, Anne E

    2013-01-01

    The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth, and deregulation of this pathway is associated with tumorigenesis. p53, and its less investigated family member p73, have been shown to interact closely with mTOR pathways through the transcriptional regulation of different target genes. To investigate the metabolic changes that occur upon inhibition of the mTOR pathway and the role of p73 in this response primary mouse embryonic fibroblast from control and TAp73−/− were treated with the macrocyclic lactone rapamycin. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analysis were used to obtain a rapamycin-dependent global metabolome profile from control or TAp73−/− cells. In total 289 metabolites involved in selective pathways were identified; 39 biochemical metabolites were found to be significantly altered, many of which are known to be associated with the cellular stress response. PMID:23839040

  2. Striking observations during emergency catecholamine treatment of cardiac syncope in a patient with initially unrecognized takotsubo cardiomyopathy.

    PubMed

    Dandel, Michael; Lehmkuhl, Hans B; Schmidt, Gunther; Knosalla, Christoph; Hetzer, Roland

    2009-08-01

    A case is presented of initially unrecognized takotsubo cardiomyopathy with a dramatic clinical course after emergency catecholamine treatment for circulatory support during stress-induced cardiac syncope followed by complete recovery of cardiac function after catecholamine withdrawal and starting beta-blocker therapy. Echocardiography including 2D-strain imaging suggested that the left ventricle (LV) wall motion abnormality was mainly the consequence of geometry-induced regional differences in wall stress (progressively amplified by catecholamines), which might be another possible pathophysiological mechanism involved in the development of LV dysfunction in takotsubo cardiomyopathy. This case also suggests that in emergency, before coronary angiography is possible, echocardiography can be helpful for initial therapeutic decisions, especially to avoid emergency inotropic therapy in such patients.

  3. Acyclovir-Induced Neurotoxicity: A Case Report and Review of Literature.

    PubMed

    Chowdhury, Mohammed Andaleeb; Derar, Nada; Hasan, Syed; Hinch, Bryan; Ratnam, Shoba; Assaly, Ragheb

    2016-01-01

    Neurotoxicity can develop as a side effect of intravenous acyclovir use in patients with renal impairment. It is underreported in clinical practice and often confused with worsening herpes encephalitis. We present a 69-year-old woman with end-stage renal disease on hemodialysis with acyclovir neurotoxicity treated with daily extended hemodialysis sessions. Daily hemodialysis for extended period may shorten the neurotoxicity period and can help with faster return to normal mentation. A high index of suspicion is warranted to diagnose acyclovir-induced neurotoxicity.

  4. Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (``Ecstasy'')

    NASA Astrophysics Data System (ADS)

    Ricaurte, George A.; Yuan, Jie; Hatzidimitriou, George; Cord, Branden J.; McCann, Una D.

    2002-09-01

    The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or ``ecstasy'') is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

  5. Effects of Altered Catecholamine Metabolism on Pigmentation and Physical Properties of Sclerotized Regions in the Silkworm Melanism Mutant

    PubMed Central

    Liu, Xiaofan; He, Songzhen; Tong, Xiaoling; Wu, Songyuan; Hu, Hai; Wang, Rixin; Hu, Hongwei; Chen, Lushi; Zhang, Li; Wu, Jie; Dai, Fangyin; Lu, Cheng; Xiang, Zhonghuai

    2012-01-01

    Catecholamine metabolism plays an important role in the determination of insect body color and cuticle sclerotization. To date, limited research has focused on these processes in silkworm. In the current study, we analyzed the interactions between catecholamines and melanin genes and their effects on the pigmentation patterns and physical properties of sclerotized regions in silkworm, using the melanic mutant melanism (mln) silkworm strain as a model. Injection of β-alanine into mln mutant silkworm induced a change in catecholamine metabolism and turned its body color yellow. Further investigation of the catecholamine content and expression levels of the corresponding melanin genes from different developmental stages of Dazao-mln (mutant) and Dazao (wild-type) silkworm revealed that at the larval and adult stages, the expression patterns of melanin genes precipitated dopamine accumulation corresponding to functional loss of Bm-iAANAT, a repressive effect of excess NBAD on ebony, and upregulation of tan in the Dazao-mln strain. During the early pupal stage, dopamine did not accumulate in Dazao-mln, since upregulation of ebony and black genes led to conversion of high amounts of dopamine into NBAD, resulting in deep yellow cuticles. Scanning electron microscope analysis of a cross-section of adult dorsal plates from both wild-type and mutant silkworm disclosed the formation of different layers in Dazao-mln owing to lack of NADA, compared to even and dense layers in Dazao. Analysis of the mechanical properties of the anterior wings revealed higher storage modulus and lower loss tangent in Dazao-mln, which was closely associated with the altered catecholamine metabolism in the mutant strain. Based on these findings, we conclude that catecholamine metabolism is crucial for the color pattern and physical properties of cuticles in silkworm. Our results should provide a significant contribution to Lepidoptera cuticle tanning research. PMID:22937004

  6. [Catecholamines and their metabolic enzymes in the hypothalamus of rats after a flight on the Kosmos-782 biosatellite].

    PubMed

    Kvetnanský, R; Tigranian, R A; Torda, T; Babusiková, D; Jahnová, E

    1979-01-01

    The concentration of catecholamines, and activity of enzymes involved in their synthesis (tyrosine hydroxylase and dopamine-beta-hydroxylase) and degradation (monoamine oxidase) were measured in the hypothalamus of rats flown for 19.5 days aboard the biosatellite Cosmos-782, synchronous and vivarium controls sacrificed on R+O and R+25 days. No significant changes in the above parameters of the flight rats were found. The findings give evidence that a prolonged space flight induces no changes in the content, synthesis or degradation of catecholamines in the rat hypothalamus. This seems to indicate that weightlessness does not act as an acute stressor.

  7. Types of aggressiveness and catecholamine response in essential hypertensives and healthy controls.

    PubMed

    Netter, P; Neuhäuser-Metternich, S

    1991-01-01

    Relationships between plasma catecholamine responses, and levels and types of aggression in hyper- and normotensives were investigated by analyses of data obtained in a large psychophysiological experiment on 97 hypertensives (EH) and 98 normotensives (CO) each. Subjects were divided according to levels (high vs low) and types (repressed vs manifest) of aggressiveness according to self rating questionnaire scores. Their plasma catecholamine responses to defined stressors indicating sympathetic arousability were compared by four factor analyses of covariance adjusting for age. Repressed aggression was significantly more frequent among male EH, whereas manifest aggression was significantly more frequent among the male COs. High as compared to low hostility was associated with significantly elevated values of plasma epinephrine in EH but not in CO. The immediate norepinephrine stress response was blunted but showed a delayed increase during the subsequent period of rest in high aggressives of both the EH and CO group, a pattern particularly pronounced in repressed aggressive hypertensives. Neither cardiovascular reactions nor speed of performance were observed to be substantially different in subjects of repressed and of manifest hostility. It was concluded that aggression in general is characterized by a delayed norepinephrine stress response and that an association with high epinephrine is typical for aggressiveness in hypertensives. Repressed hostility, however, does not produce a sympathomedullary pattern substantially different from that of manifest aggression thus casting doubt on the physiological significance of repression claimed by Alexander.

  8. Latent Oxidative Polymerization of Catecholamines as Potential Cross-linkers for Biocompatible and Multifunctional Biopolymer Scaffolds.

    PubMed

    Dhand, Chetna; Barathi, Veluchamy Amutha; Ong, Seow Theng; Venkatesh, Mayandi; Harini, Sriram; Dwivedi, Neeraj; Goh, Eunice Tze Leng; Nandhakumar, Muruganantham; Venugopal, Jayarama Reddy; Diaz, Silvia Marrero; Fazil, Mobashar Hussain Urf Turabe; Loh, Xian Jun; Ping, Liu Shou; Beuerman, Roger W; Verma, Navin Kumar; Ramakrishna, Seeram; Lakshminarayanan, Rajamani

    2016-11-30

    Electrospinning of naturally occurring biopolymers for biological applications requires postspinning cross-linking for endurance in protease-rich microenvironments and prevention of rapid dissolution. The most commonly used cross-linkers often generate cytotoxic byproducts, which necessitate high concentrations or time-consuming procedures. Herein, we report the addition of "safe" catecholamine cross-linkers to collagen or gelatin dope solutions followed by electrospinning yielded junction-containing nanofibrous mats. Subsequent in situ oxidative polymerization of the catecholamines increased the density of soldered junctions and maintained the porous nanofiber architecture. This protocol imparted photoluminescence to the biopolymers, a smooth noncytotoxic coating, and good mechanical/structural stability in aqueous solutions. The utility of our approach was demonstrated by the preparation of durable antimicrobial wound dressings and mineralized osteoconductive scaffolds via peptide antibiotics and calcium chloride (CaCl2) incorporation into the dope solutions. The mineralized composite mats consist of amorphous calcium carbonate that enhanced the osteoblasts cell proliferation, differentiation, and expression of important osteogenic marker proteins. In proof-of-concept experiments, antibiotic-loaded mats displayed superior antimicrobial properties relative to silver (Ag)-based dressings, and accelerated wound healing in a porcine deep dermal burn injury model.

  9. Circadian rhythm of catecholamine excretion in rats after phase shift of light-dark cycle.

    PubMed

    Sudo, A; Miki, K

    1995-01-01

    To clarify the time course of circadian rhythm adaptation to a phase shift of the light-dark (LD) cycle, urinary excretion of catecholamines was measured in rats before and after a 12-hour or 6-hour phase delay of a 12-hour light and 12-hour dark schedule. In rats under a basal condition, distinct circadian rhythms in catecholamine excretion were observed, especially in adrenaline excretion. During the 1st and 2nd days after a 12-hour phase delay, the acrophase and amplitude of adrenaline rhythm remained almost unchanged, but thereafter the acrophase was retarded and the amplitude was reduced. The acrophase once again became constant after 5 or 6 days, but the ratio of amplitude to mesor in the circadian rhythm of adrenaline excretion and the ratio of light-period to 24-hour noradrenaline excretion were readjusted to the new LD schedule on 11th or 12th day. IN the 6-hour phase delay of the LD cycle, similar findings were observed, and the results suggested adaptation on the 5-6th day. It is considered that the circadian rhythms of the sympathetic adrenomedullary function are restored, at the latest, 12 days after a 12-hour delay of the LD cycle, and 6 days after a 6-hour delay, suggesting that rats need approximately 1 day to adapt to a 1-hour phase shift.

  10. Differential effects of catecholamines on in vitro growth of pathogenic bacteria

    NASA Technical Reports Server (NTRS)

    Belay, Tesfaye; Sonnenfeld, Gerald

    2002-01-01

    Supplementation of minimal medium inoculated with bacterial cultures with norepinephrine, epinephrine, dopamine, or isoproterenol resulted in marked increases in growth compared to controls. Norepinephrine and dopamine had the greatest enhancing effects on growth of cultures of Pseudomonas aeruginosa and Klebsiella pneumoniae, while epinephrine and isoproterenol also enhanced growth to a lesser extent. The growth of Escherichia coli in the presence of norepinephrine was greater than growth in the presence of the three other neurochemicals used in the study. Growth of Staphylococcus aureus was also enhanced in the presence of norepinephrine, but not to the same degree as was the growth of gram negative bacteria. Addition of culture supernatants from E. coli cultures that had been grown in the presence of norepinephrine was able to enhance the growth of K. pneumoniae. Addition of the culture supernatant fluid culture from E. coli cultures that had been grown in the presence of norepinephrine did not enhance growth of P. aeruginosa or S. aureus. Culture supernatant fluids from bacteria other than E. coli grown in the presence of norepinephrine were not able to enhance the growth of any bacteria tested. The results suggest that catecholamines can enhance growth of pathogenic bacteria, which may contribute to development of pathogenesis; however, there is no uniform effect of catecholamines on bacterial growth.

  11. Resting-State Peripheral Catecholamine and Anxiety Levels in Korean Male Adolescents with Internet Game Addiction.

    PubMed

    Kim, Nahyun; Hughes, Tonda L; Park, Chang G; Quinn, Laurie; Kong, In Deok

    2016-03-01

    The purpose of this study was to compare the resting-state plasma catecholamine and anxiety levels of Korean male adolescents with Internet game addiction (IGA) and those without IGA. This cross-sectional comparative study was conducted with 230 male high school students in a South Korean city. Convenience and snowball sampling methods were employed, and data were collected using (1) participant blood samples analyzed for dopamine (DA), epinephrine (Epi), and norepinephrine (NE) and (2) two questionnaires to assess IGA and anxiety levels. Using SPSS 15.0, data were analyzed by descriptive analysis, χ(2)-tests, t-tests, and Pearson's correlation tests. The plasma Epi (t = 1.962, p < 0.050) and NE (t = 2.003, p = 0.046) levels were significantly lower in the IGA group than in the non-IGA group; DA levels did not significantly differ between the groups. The mean anxiety level of the IGA group was significantly higher compared with the non-IGA group (t = -6.193, p < 0.001). No significant correlations were found between catecholamine and anxiety levels. These results showed that excessive Internet gaming over time induced decreased peripheral Epi and NE levels, thus altering autonomic regulation, and increasing anxiety levels in male high school students. Based on these physiological and psychological effects, interventions intended to prevent and treat IGA should include stabilizing Epi, NE, and anxiety levels in adolescents.

  12. Changes of immunoregulatory cells induced by psychological and physical stress: relationship to plasma catecholamines.

    PubMed Central

    Landmann, R M; Müller, F B; Perini, C; Wesp, M; Erne, P; Bühler, F R

    1984-01-01

    Lymphocyte subpopulations were measured before and after physical and psychological stress in 15 healthy subjects and correlated with plasma catecholamine and cortisol levels. During psychological stress monocytes (P less than 0.05), NK (P less than 0.01), B cells (P less than 0.05) and heart rate (P less than 0.001) increased, while catecholamines remained unchanged. With physical stress granulocytes, monocytes and all lymphocyte subsets increased significantly, although B cells rose more than T cells and T (suppressor) cells more than T (helper) cells. Thus the ratio of T/B cells and of Th/Ts cells decreased (P less than 0.001 and P less than 0.01). Adrenaline and noradrenaline concentrations increased (P less than 0.001), while cortisol remained unchanged. There was a negative relationship between adrenaline and the Th/Ts cell ratio before and after stress (P less than 0.05). Lymphocyte subpopulations from a different group of 4 healthy subjects were analysed before and after isoproterenol infusion. There was a small increase in Ts and B cells only (P less than 0.1) and a decrease of the T/B cell ratio (P less than 0.05). The predominant enrichment of circulating B, Ts and NK cells during short lasting adrenergic activation, as well as the relationship of the T cell changes to plasma adrenaline, suggest an immunoregulatory effect of the sympathetic nervous system in stress. PMID:6478647

  13. Catecholamines are required for testosterone induction of ornithine decarboxylase in the mouse kidney.

    PubMed

    Cremades, A; Tovar, A; Peñafiel, R

    1992-08-01

    This report presents a study on the influence of the adrenergic system on androgen-regulated ornithine decarboxylase activity (ODC) in the mouse kidney. We have found that the existing levels of renal ODC in male mice and the increase induced by testosterone in male, female, castrated male and hypophysectomized mice were dramatically impaired by catecholamine depletion produced by treatment with either alpha-methyl-p-tyrosine or reserpine. Blockade of beta-receptors by treatment of the animals with the antagonists propranolol or bisoprolol was unable to prevent the effect of testosterone on the renal enzyme. However, alpha i-blockade obtained by treatment with prazosin or phenoxybenzamine was partially effective to produce the decrease of basal ODC in control male or to diminish ODC induction produced by androgens. All these findings demonstrate that catecholamines and alpha 1-adrenergic receptors are implicated in androgen-regulated ODC activity in the mouse kidney and suggest a plausible role of sympathetic renal innervation in enzyme induction by steroid hormones in this organ.

  14. Circulating renin-angiotensin system and catecholamines in childhood: is there a role for birthweight?

    PubMed

    Franco, Maria C P; Casarini, Dulce E; Carneiro-Ramos, Marcela S; Sawaya, Ana L; Barreto-Chaves, Maria L M; Sesso, Ricardo

    2008-03-01

    There have been only a few reports on the sympathoadrenal and renin-angiotensin systems in children of small gestational age. The purpose of the present study was to investigate plasma levels of ACE (angiotensin-converting enzyme) activity, angiotensin and catecholamines in 8- to 13-year-old children and to determine whether there are correlations between the components of these systems with both birthweight and BP (blood pressure) levels. This clinical study included 66 children (35 boys and 31 girls) in two groups: those born at term with an appropriate birthweight [AGA (appropriate-for-gestational age) group, n=31] and those born at term but with a small birthweight for gestational age [SGA (small-for-gestational age) group, n=35]. Concentrations of angiotensin, catecholamines and ACE activity were determined in plasma. Circulating noradrenaline levels were significantly elevated in SGA girls compared with AGA girls (P=0.036). In addition, angiotensin II and ACE activity were higher in SGA boys (P=0.024 and P=0.050 respectively). There was a significant association of the circulating levels of both angiotensin II and ACE activity with BP levels in our study population. Although the underlying mechanisms that link restricted fetal growth with later cardiovascular events are not fully understood, the findings in the present study support the link between low birthweight and overactivity of both sympathoadrenal and renin-angiotensin systems into later childhood.

  15. Resting-State Peripheral Catecholamine and Anxiety Levels in Korean Male Adolescents with Internet Game Addiction

    PubMed Central

    Kim, Nahyun; Hughes, Tonda L.; Park, Chang G.; Quinn, Laurie

    2016-01-01

    Abstract The purpose of this study was to compare the resting-state plasma catecholamine and anxiety levels of Korean male adolescents with Internet game addiction (IGA) and those without IGA. This cross-sectional comparative study was conducted with 230 male high school students in a South Korean city. Convenience and snowball sampling methods were employed, and data were collected using (1) participant blood samples analyzed for dopamine (DA), epinephrine (Epi), and norepinephrine (NE) and (2) two questionnaires to assess IGA and anxiety levels. Using SPSS 15.0, data were analyzed by descriptive analysis, χ2-tests, t-tests, and Pearson's correlation tests. The plasma Epi (t = 1.962, p < 0.050) and NE (t = 2.003, p = 0.046) levels were significantly lower in the IGA group than in the non-IGA group; DA levels did not significantly differ between the groups. The mean anxiety level of the IGA group was significantly higher compared with the non-IGA group (t =−6.193, p < 0.001). No significant correlations were found between catecholamine and anxiety levels. These results showed that excessive Internet gaming over time induced decreased peripheral Epi and NE levels, thus altering autonomic regulation, and increasing anxiety levels in male high school students. Based on these physiological and psychological effects, interventions intended to prevent and treat IGA should include stabilizing Epi, NE, and anxiety levels in adolescents. PMID:26849530

  16. The effects of mind-body training on stress reduction, positive affect, and plasma catecholamines.

    PubMed

    Jung, Ye-Ha; Kang, Do-Hyung; Jang, Joon Hwan; Park, Hye Yoon; Byun, Min Soo; Kwon, Soo Jin; Jang, Go-Eun; Lee, Ul Soon; An, Seung Chan; Kwon, Jun Soo

    2010-07-26

    This study was designed to assess the association between stress, positive affect and catecholamine levels in meditation and control groups. The meditation group consisted of 67 subjects who regularly engaged in mind-body training of "Brain-Wave Vibration" and the control group consisted of 57 healthy subjects. Plasma catecholamine (norepinephrine (NE), epinephrine (E), and dopamine (DA)) levels were measured, and a modified form of the Stress Response Inventory (SRI-MF) and the Positive Affect and Negative Affect Scale (PANAS) were administered. The meditation group showed higher scores on positive affect (p=.019) and lower scores on stress (p<.001) compared with the control group. Plasma DA levels were also higher in the meditation (p=.031) than in the control group. The control group demonstrated a negative correlation between stress and positive affects (r=-.408, p=.002), whereas this correlation was not observed in the meditation group. The control group showed positive correlations between somatization and NE/E (r=.267, p=.045) and DA/E (r=.271, p=.042) ratios, whereas these correlations did not emerge in the meditation group. In conclusion, these results suggest that meditation as mind-body training is associated with lower stress, higher positive affect and higher plasma DA levels when comparing the meditation group with the control group. Thus, mind-body training may influence stress, positive affect and the sympathetic nervous system including DA activity.

  17. Secondary metabolite components of kiwifruit.

    PubMed

    McGhie, Tony K

    2013-01-01

    Both green and gold kiwifruit contain high concentrations of vitamin C, and much of the "health story" of kiwifruit involves this vitamin. Kiwifruit also contain other compounds that are bioactive and beneficial to health. In this chapter, the secondary metabolite composition of kiwifruit is presented. Although there are limited compositional data for kiwifruit published in the scientific literature, the concentrations of 42 compounds have been documented. Included are compounds that are often associated with "healthfulness," such as the vitamins (A, C, E, and K), carotenoids (lutein and β-carotene), folate, and antioxidant phenolic compounds. Metabolite discovery is advancing rapidly with the introduction of "metabolomic" studies where the goal is to identify and measure the complete metabolite composition of a sample. In a metabolomic experiment using liquid chromatography and high-resolution mass spectrometry, it was possible to measure more than 500 metabolites in kiwifruit extracts. The large number of detectable metabolites present suggests that there is an abundance of kiwifruit metabolites still to be discovered. Such studies will provide a more complete understanding of the metabolite composition of kiwifruit that will lead to new and improved hypotheses as to the function and effects of kiwifruit metabolites, including their relevance to human health.

  18. DEVELOPMENTAL NEUROTOXICITY OF POLYBROMINATED DIPHENYL ETHER (PBDE) FLAME RETARDANTS

    PubMed Central

    Costa, Lucio G.; Giordano, Gennaro

    2007-01-01

    Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in a variety of consumer products. In the past 25 years, PBDEs have become ubiquitous environmental contaminants. They have been detected in soil, air, sediments, birds, marine species, fish, house dust, and human tissues, blood and breast milk. Diet and house dust appear to be the major sources of PBDE exposure in the general population, though occupational exposure can also occur. Levels of PBDEs in human tissues are particularly high in North America, compared to Asian and European countries, and have been increasing in the past 30 years. Concentrations of PBDEs are particularly high in breast milk, resulting in high exposure of infants. In addition, for toddlers, dust has been estimated to account for a large percentage of exposure. PBDEs can also cross the placenta, as they have been detected in fetal blood and liver. Tetra-, penta- and hexa BDEs are most commonly present in human tissues. The current greatest concern for potential adverse effects of PBDEs relates to their developmental neurotoxicity. Pre- or postnatal exposure of mice or rats to various PBDEs has been shown to cause long-lasting changes in spontaneous motor activity, mostly characterized as hyperactivity or decreased habituation, and to disrupt performance in learning and memory tests. While a reduction in circulating thyroid hormone (T4) may contribute to the developmental neurotoxicity of PBDEs, direct effects on the developing brain have also been reported. Among these, PBDEs have been shown to affect signal transduction pathways and to cause oxidative stress. Levels of PBDEs causing developmental neurotoxicity in animals are not much dissimilar from levels found in highly exposed infants and toddlers. PMID:17904639

  19. Reversible neurotoxicity of kanamycin on dorsal cochlear nucleus.

    PubMed

    Fan, Guo-Run; Yin, Ze-Deng; Sun, Yu; Chen, Sen; Zhang, Wen-Juan; Huang, Xiang; Kong, Wei-Jia; Zhang, Hong-Lian

    2013-03-28

    The time course of aminoglycoside neurotoxic effect on cochlear nucleus is still obscure. We examined dynamic pathological changes of dorsal cochlear nucleus (DCN) and investigated whether apoptosis or autophagy was upregulated in the neurotoxic course of kanamycin on DCN after kanamycin treatment. Rats were treated with kanamycin sulfate/kg/day at a dose of 500mg by subcutaneous injection for 10 days. Dynamic pathological changes, neuron density and neuron apoptosis of the DCN were examined at 1, 7, 14, 28, 56, 70 and 140 days after kanamycin treatment. The expressions of JNK1, DAPK2, Bcl-2, p-Bcl-2, Caspase-3, LC3B and Beclin-1 were also detected. Under transmission electron microscopy, the mitochondrial swelling and focal vacuoles as well as endoplasmic reticulum dilation were progressively aggravated from 1 day to 14 days, and gradually recovered from 28 days to 140 days. Meanwhile, both autophagosomes and autolysosomes were increased from 1 day to 56 days. Only few neurons were positive to the TUNEL staining. Moreover, neither the expressions of caspase-3 and DAPK2 nor neurons density of DCN changed significantly. LC3-II was drastically increased at 7 days. Beclin-1 was upgraded at 1 and 7 days. P-Bcl-2 increased at 1, 7, 14 and 28 days. JNK1 increased at 7 days, and Bcl-2 was downgraded at 140 days. LC3-B positive neurons were increased at 1, 7 and 14 days. These data demonstrated that the neurons damage of the DCN caused by kanamycin was reversible and autophagy was upregulated in the neurotoxic course of kanamycin on DCN through JNK1-mediated phosphorylation of Bcl-2 pathway.

  20. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    SciTech Connect

    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  1. Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

    SciTech Connect

    Milatovic, Dejan; Yu, Yingchun

    2009-10-15

    Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F{sub 2}-isoprostanes (F{sub 2}-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 {mu}M Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E{sub 2} (PGE{sub 2}). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F{sub 2}-IsoPs and PGE{sub 2} in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.

  2. Neurotoxicity induced by mephedrone: An up-to-date review.

    PubMed

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Pacifici, Roberta; di Luca, Alessandro; Busardò, Francesco Paolo; Marinelli, Enrico

    2016-11-30

    Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: "Mephedrone", "4-MMC," "neurotoxicity," "neuropharmacology", "patents", "monoamine transporters" and "neurochemical effects". Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-HT and DA systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health.

  3. Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase.

    PubMed

    Milatovic, Dejan; Jenkins, Jerry W; Hood, Jonathan E; Yu, Yingchun; Rongzhu, Lu; Aschner, Michael

    2011-10-01

    Among several available antimalarial drugs, mefloquine has proven to be effective against drug-resistant Plasmodium falciparum and remains the drug of choice for both therapy and chemoprophylaxis. However, mefloquine is known to cause adverse neurological and/or psychiatric symptoms, which offset its therapeutic advantage. The exact mechanisms leading to the adverse neurological effects of mefloquine are poorly defined. Alterations in neurotransmitter release and calcium homeostasis, the inhibition of cholinesterases and the interaction with adenosine A(2A) receptors have been hypothesized to play prominent roles in mediating the deleterious effects of this drug. Our recent data have established that mefloquine can also trigger oxidative damage and subsequent neurodegeneration in rat cortical primary neurons. Furthermore, we have utilized a system biology-centered approach and have constructed a pathway model of cellular responses to mefloquine, identifying non-receptor tyrosine kinase 2 (Pyk2) as a critical target in mediating mefloquine neurotoxicity. In this study, we sought to establish an experimental validation of Pyk2 using gene-silencing techniques (siRNA). We have examined whether the downregulation of Pyk2 in primary rat cortical neurons alters mefloquine neurotoxicity by evaluating cell viability, apoptosis and oxidative stress. Results from our study have confirmed that mefloquine neurotoxicity is associated with apoptotic response and oxidative injury, and we have demonstrated that mefloquine affects primary rat cortical neurons, at least in part, via Pyk2. The implication of these findings may prove beneficial in suppressing the neurological side effects of mefloquine and developing effective therapeutic modalities to offset its adverse effects.

  4. Mechanisms and Modifiers of Methylmercury-Induced Neurotoxicity

    PubMed Central

    Fretham, Stephanie JB; Caito, Samuel; Martinez-Finley, Ebany J; Aschner, Michael

    2016-01-01

    The neurotoxic consequences of methylmercury (MeHg) exposure have long been known, however a complete understanding of the mechanisms underlying this toxicity is elusive. Recent epidemiological and experimental studies have provided many mechanistic insights, particularly into the contribution of genetic and environmental factors that interact with MeHg to modify toxicity. This review will outline cellular processes directly and indirectly affected by MeHg, including oxidative stress, cellular signaling and gene expression, and discuss genetic, environmental and nutritional factors capable of modifying MeHg toxicity. PMID:27795823

  5. Herpes zoster encephalopathy or acyclovir neurotoxicity: a management dilemma.

    PubMed

    Sacchetti, Daniel; Alawadhi, Aydah; Albakour, Mustafa; Rapose, Alwyn

    2014-04-28

    This is a case report of a 69-year-old morbidly obese woman who presented with mental status changes after she was treated with acyclovir for shingles. The predominant symptoms were word-finding difficulties and visual hallucinations. Complicating her presentation was acyclovir-induced acute renal injury causing her creatinine level to rise up to 7.4 mg/dL. Acyclovir was discontinued on the suspicion of acyclovir neurotoxicity. Even though PCR for varicella zoster virus in the cerebrospinal fluid was positive, acyclovir was not restarted and the patient continued to improve and returned to her baseline.

  6. Pramipexole prevents neurotoxicity induced by oligomers of beta-amyloid.

    PubMed

    Uberti, Daniela; Bianchi, Irene; Olivari, Luca; Ferrari-Toninelli, Giulia; Canonico, PierLuigi; Memo, Maurizio

    2007-08-27

    Here we demonstrate that pramipexole, an antiparkinsonian dopamine receptor agonist drug, exerts neuroprotective effects against beta-amyloid neurotoxicity. Using a specific protocol to test individually oligomers, fibrils, or unaggregated amyloid beta-peptide, we found pramipexole able to protect cells against oligomers and fibrils. Unaggregated amyloid beta-peptide was found unable to cause cell death. Fibrils and oligomers were also found to produce elevated amount of free radicals, and this effect was prevented by pramipexole. We propose pramipexole may become in the future a coadjuvant in the treatment of neuropathologies, besides Parkinson's disease, where amyloid beta-peptide-mediated oxidative injury exerts a relevant role.

  7. Successful treatment of hydromorphone-induced neurotoxicity and hyperalgesia.

    PubMed

    Chung, Keun Sam; Carson, Shawn; Glassman, David; Vadivelu, Nalini

    2004-10-01

    There has been an increase in opioid consumption world wide in the last decade. There has also been a disturbing increase in the number of reports of neuroexcitatory opioid-related side effects observed in patients receiving large doses of systemically administered morphine and its structural analogue, hydromorphone. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected pain. We describe an interesting case of successful management of hydromorphone-induced neurotoxicity and hyperalgesia produced by short-term therapy with rapidly escalating doses of systemic hydromorphone.

  8. Enantioselectivity in the methylation of the catecholic phase I metabolites of methylenedioxy designer drugs and their capability to inhibit catechol-O-methyltransferase-catalyzed dopamine 3-methylation.

    PubMed

    Meyer, Markus R; Maurer, Hans H

    2009-06-01

    The designer drugs R,S-3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy), R,S-3,4-methylenedioxy-ethylamphetamine (MDEA, Eve), and R,S-N-methyl-benzodioxolyl-butanamine (MBDB, Eden) are chiral compounds, and their in vitro and in vivo metabolism is enantioselective with a preference for the S-enantiomer caused in part by P450-mediated demethylenation. As the elimination of the catecholamine metabolites could also be enantioselective, the aim of the present study was to investigate the O-methylation to the corresponding methoxy derivatives catalyzed by the soluble or membrane-bound form of the catechol-O-methyltransferase (COMT). As all three compounds showed substrate inhibition effects during the incubation, their inhibition potential was quantified using the methylation of dopamine as a marker reaction. For investigation of the catechol-O-methylation catalyzed by the soluble form of the COMT (sCOMT), incubations with human liver cytosol (HLC) were performed. Human liver microsomes (HLM) were used for investigation of the membrane-bound form. For inhibition studies, 3-hydroxytyramine (dopamine) was incubated in HLC. The respective catechols were added at various concentrations to check whether they influence the methylation of 3-hydroxytyramine. Our data showed that the S-enantiomers of all studied catecholamines were preferably O-methylated by both types of COMT. Comparing the resulting kinetics of the HLC and HLM assays, the affinity for all substrates was 10-fold higher for the membrane-bound COMT, whereas the turnover rate was 10-fold higher for the soluble COMT. Uncompetitive inhibition of dopamine methylation could be observed for all tested catechols. In conclusion, elimination of the catecholamine metabolites of MDMA, MDEA, and MBDB was shown to be enantioselective and might therefore contribute to the different pharmacokinetic properties observed for both enantiomers. Furthermore, the catecholic metabolites were identified to be uncompetitive inhibitors

  9. Novel Methods at Molecular Level for Developmental Neurotoxicity Testing in 21st Century-Utility of Structure-Activity Relationship

    EPA Science Inventory

    Current neurotoxicity and developmental neurotoxicity testing methods for hazard identification rely on in vivo neurobehavior, neurophysiological, and gross pathology of the nervous system. These measures may not be sensitive enough to detect small changes caused by realistic ex...

  10. In Vitro Assessment of Developmental Neurotoxicity: Use of Microelectrode Arrays to Measure Functional Changes in Neuronal Network Ontogeny*

    EPA Science Inventory

    Because the Developmental Neurotoxicity Testing Guidelines require large numbers of animals and is expensive, development of in vitro approaches to screen chemicals for potential developmental neurotoxicity is a high priority. Many proposed approaches for screening are biochemica...

  11. IN VITRO ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: USE OF MICROELECTRODE ARRAYS TO MEASURE FUNCTIONAL CHANGES IN NEURONAL NETWORK ONTOGENY

    EPA Science Inventory

    Because the Developmental Neurotoxicity Testing Battery requires large numbers of animals and is expensive, development of in vitro approaches to screen chemicals for potential developmental neurotoxicity is a high priority. Many proposed approaches for screening are biochemical,...

  12. Magnetron sputtered diamond-like carbon microelectrodes for on-chip measurement of quantal catecholamine release from cells.

    PubMed

    Gao, Yuanfang; Chen, Xiaohui; Gupta, Sanju; Gillis, Kevin D; Gangopadhyay, Shubhra

    2008-10-01

    Carbon electrodes are widely used in electrochemistry due to their low cost, wide potential window, and low and stable background noise. Carbon-fiber electrodes (CFE) are commonly used to electrochemically measure "quantal" catecholamine release via exocytosis from individual cells, but it is difficult to integrate CFEs into lab-on-a-chip devices. Here we report the development of nitrogen doped diamond-like carbon (DLC:N) microelectrodes on a chip to monitor quantal release of catecholamines from cells. Advantages of DLC:N microelectrodes are that they are batch producible at low cost, and are harder and more durable than graphite films. The DLC:N microelectrodes were prepared by a magnetron sputtering process with nitrogen doping. The 30 microm by 40 microm DLC:N microelectrodes were patterned onto microscope glass slides by photolithography and lift-off technology. The properties of the DLC:N microelectrodes were characterized by AFM, Raman spectroscopy and cyclic voltammetry. Quantal catecholamine release was recorded amperometrically from bovine adrenal chromaffin cells on the DLC:N microelectrodes. Amperometric spikes due to quantal release of catecholamines were similar in amplitude and area as those recorded using CFEs and the background current and noise levels of microchip DLC:N electrodes were also comparable to CFEs. Therefore, DLC:N microelectrodes are suitable for microchip-based high-throughput measurement of quantal exocytosis with applications in basic research, drug discovery and cell-based biosensors.

  13. Molecular profiling: Catecholamine modulation of gene expression in Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Investigations of Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium have demonstrated that these bacterial pathogens can respond to the presence of catecholamines including norepinephrine and/or epinephrine in their environment by modulating gene expression and exhibiting various ...

  14. Modulation of catecholamine-synthesizing enzymes in adrenal medulla and stellate ganglia by treadmill exercise of stressed rats.

    PubMed

    Gavrilovic, Ljubica; Spasojevic, Natasa; Dronjak, Sladjana

    2012-03-01

    The sympatho-adrenal system represents one of the main systems involved in the response to stressful events because its stress-induced activation results in an increased release of catecholamines. Exercise training acts as an important modulator of sympatho-adrenal system, adrenal medulla and stellate ganglia being two components of this system. This study aimed at investigating physical exercise-related changes in gene expression of catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase in the adrenal medulla and stellate ganglia of chronically psychosocially stressed adult rats exposed daily to 20-min treadmill exercise for 12 weeks, using TaqMan RT-PCR assay. Chronic psychosocial stress decreased gene expression of the examined enzymes in the adrenal medulla and treadmill exercise did not lead to further modulation of the corresponding gene expression. On the other hand, chronic psychosocial stress produced a significant increase of TH (about 51%) and DBH (about 103%) gene expression in stellate ganglia, while treadmill exercise decreased gene expression of these enzymes to control levels in psychosocially stressed rats. Our data indicate that treadmill exercise leads to a decreased gene transcription of catecholamine biosynthetic enzymes in stellate ganglia and attenuation of cardiac noradrenaline production in stressful situations. Reduction of catecholamine synthesis in stellate ganglia may be linked to the beneficial effects of treadmill exercise on cardiovascular system in stressed animals.

  15. Catecholamine secretion and adrenal nerve activity in response to movements of normal and inflamed knee joints in cats.

    PubMed Central

    Sato, A; Sato, Y; Schmidt, R F

    1986-01-01

    The effects of articular stimulation on adrenal catecholamine secretion and adrenal sympathetic nerve activity were studied using halothane anaesthetized cats. Various natural passive movements were applied to the normal and inflamed knee joints. Rhythmic flexions and extensions as well as rhythmic inward and outward rotation of normal knee joints within their physiological range of motion did not change nerve activity or the secretion of adrenal catecholamines. Static outward rotation in the normal working range was also ineffective. However, as soon as this static rotation was extended into the noxious range, significant increases in both of these variables were elicited. In the acutely inflamed knee joint, various passive movements produced increases in both adrenal sympathetic and catecholamine secretion. Especially noteworthy was the finding that movements of the inflamed knee joint that were within the normal range of motion produced increases in all variables. Articularly induced increases in adrenal sympathetic nerve activity were diminished by severing various hind-limb somatic afferent nerves and abolished by complete denervation of the knee joint. Additionally, section of the adrenal sympathetic nerves eliminated the catecholamine secretion response. From these data it was concluded that the responses observed in these experiments were reflexes having an afferent limb in hind-limb nerves and an efferent limb in the adrenal sympathetic nerves. A contribution of supraspinal structures was suggested for the reflex responses of sympatho-adrenal medullary function evoked by knee joint stimulations, since spinal transection at the C2 level completely abolished the responses. PMID:3795070

  16. Catecholamine excretion and circadian blood pressure profile in patients with pheochromocytoma.

    PubMed

    Dabrowska, Elzbieta; Lewandowski, Jacek; Jedrusik, Piotr; Symonides, Bartosz; Wocial, Bozena; Lapinski, Mariusz; Gaciong, Zbigniew

    2006-08-01

    Circadian blood pressure (BP) rhythm is often disturbed in patients with secondary forms of hypertension. The aim of the present article was to investigate changes in circadian BP profile parameters using two-step statistical approach by Fourier analysis in relation to day and night urinary catecholamine excretion in 35 patients with pheochromocytoma (mean age 42+/-19 years). Twenty-four-hour ambulatory BP measurements (ABPM) were obtained using the SpaceLabs 90,207 monitor. Daytime and night-time urine collection was obtained in all patients to determine circadian catecholamine excretion. Fourier analysis was applied to estimate measures of BP circadian rhythm in ABPM, including the highest (Max) and lowest (Min) systolic (SBP) and diastolic (DBP) BP values, norad (ampSBP, ampDBP), and early acrophase (APSBP, APDBP). The Fourier indices of circadian BP rhythm were: MaxSBP 153+/-28 mm Hg, MaxDBP 99+/-16 mm Hg, MinSBP 117+/-17 mm Hg, MinDBP 69+/-11 mm Hg, ampSBP 18+/-8 mm Hg, ampDBP 14+/-5 mm Hg, APSBP 10+/-5 (h), and APDBP 11+/-3 (h). Urine noradrenaline (NA), adrenaline (A), and dopamine (DA) excretion during the day (d) and night (n) were: dNA 103.5+/-89.8 microg/14 h, nNA 52+/-70.8 microg/10 h, dA 13.2+/-17.9 microg/14 h; nA 6.13+/-9.6 microg/10 h, dD 181.8+/-87.3 microg/14 h, and nD 89.3+/-59.8 microg/10 h. A positive correlation was observed between urine dNa excretion and MaxDBP (r=0.37, P<0.05), and urine nNA and urine dA excretion were correlated with APDBP (r=0.47, r=0.35, respectively, both P<0.05). Thus, in addition to the effect on mean 24-h BP values, catecholamines released by tumor may also disturb circadian BP rhythm in patients with pheochromocytoma.

  17. Bidirectional regulation of bakuchiol, an estrogenic-like compound, on catecholamine secretion

    SciTech Connect

    Mao, Haoping; Wang, Hong; Ma, Shangwei; Xu, Yantong; Zhang, Han; Wang, Yuefei; Niu, Zichang; Fan, Guanwei; Zhu, Yan; Gao, Xiu Mei

    2014-01-01

    Excess or deficiency of catecholamine (CA) secretion was related with several diseases. Recently, estrogen and phytoestrogens were reported to regulate the activity of CA system. Bakuchiol is a phytoestrogen isolated from the seeds of Psoralea corylifolia L. (Leguminosae) which has been used in Traditional Chinese medicine as a tonic or aphrodisiac. In the present study, bovine adrenal medullary cells were employed to investigate the effects and mechanisms of bakuchiol on the regulation of CA secretion. Further, its anti-depressant like and anti-stress effects were evaluated by using behavioral despair and chronic immobilization stress models. Our results indicated that bakuchiol showed bidirectional regulation on CA secretion. It stimulated basal CA secretion in a concentration dependent manner (p < 0.01), while it reduced 300 μM acetylcholine (ACh) (p < 0.01), 100 μM veratridine (Ver) (p < 0.01) and 56 mM K{sup +} (p < 0.05) induced CA secretion, respectively. We also found that the stimulation of basal CA secretion by bakuchiol may act through estrogen-like effect and the JNK pathway in an extra-cellular calcium independent manner. Further, bakuchiol elevated tyrosine hydroxylase Ser40 and Ser31 phosphorylation (p < 0.01) through the PKA and ERK1/2 pathways, respectively. Bakuchiol inhibited ACh, Ver and 56 mM K{sup +} induced CA secretion was related with reduction of intracellular calcium rise. In vivo experiments, we found that bakuchiol significantly reduced immobilization time in behavioral despair mouse (p < 0.05 or 0.01), and plasma epinephrine (E) and norepinephrine (NE) levels in chronic immobilization stress (p < 0.05). Overall, these results present a bidirectional regulation of bakuchiol on CA secretion which indicated that bakuchiol may exert anti-stress and the potential anti-depressant-like effects. - Highlights: • Bakuchiol stimulated basal catecholamine secretion. • Bakuchiol inhibited various secretagogues induced catecholamine secretion

  18. Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus.

    PubMed

    Cui, R J; Roberts, B L; Zhao, H; Andresen, M C; Appleyard, S M

    2012-10-11

    Brainstem A2/C2 catecholamine (CA) neurons within the solitary tract nucleus (NTS) influence many homeostatic functions, including food intake, stress, respiratory and cardiovascular reflexes. They also play a role in both opioid reward and withdrawal. Injections of opioids into the NTS modulate many autonomic functions influenced by catecholamine neurons including food intake and cardiac function. We recently showed that NTS-CA neurons are directly activated by incoming visceral afferent inputs. Here we determined whether opioid agonists modulate afferent activation of NTS-CA neurons using transgenic mice with EGFP expressed under the control of the tyrosine hydroxylase promoter (TH-EGFP) to identify catecholamine neurons. The opioid agonist Met-enkephalin (Met-Enk) significantly attenuated solitary tract-evoked excitatory postsynaptic currents (ST-EPSCs) in NTS TH-EGFP neurons by 80%, an effect reversed by wash or the mu opioid receptor-specific antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP). Met-Enk had a significantly greater effect to inhibit afferent inputs onto TH-EGFP-positive neurons than EGFP-negative neurons, which were only inhibited by 50%. The mu agonist, DAMGO, also inhibited the ST-EPSC in TH-EGFP neurons in a dose-dependent manner. In contrast, neither the delta agonist DPDPE, nor the kappa agonist, U69,593, consistently inhibited the ST-EPSC amplitude. Met-Enk and DAMGO increased the paired pulse ratio, decreased the frequency, but not amplitude, of mini-EPSCs and had no effect on holding current, input resistance or current-voltage relationships in TH-EGFP neurons, suggesting a presynaptic mechanism of action on afferent terminals. Met-Enk significantly reduced both the basal firing rate of NTS TH-EGFP neurons and the ability of afferent stimulation to evoke an action potential. These results suggest that opioids inhibit NTS-CA neurons by reducing an excitatory afferent drive onto these neurons through presynaptic inhibition of

  19. Recovery of presynaptic dopaminergic functioning in rats treated with neurotoxic doses of methamphetamine.

    PubMed

    Cass, W A; Manning, M W

    1999-09-01

    Repeated administration of methamphetamine (METH) to animals can result in long-lasting decreases in striatal dopamine (DA) content. In addition, the evoked overflow of striatal DA is reduced in rats 1 week after neurotoxic doses of METH. However, whether these functional changes in DA release are permanent or tend to recover over time has not been established. In the present study we used in vivo electrochemistry and microdialysis to examine evoked overflow of DA in the striatum of METH-treated rats at several time points after treatment to determine if DA overflow would spontaneously recover. Male Fischer-344 rats were administered METH (5 mg/kg, s.c. ) or saline four times in one day at 2 hr intervals. In vivo electrochemistry experiments in anesthetized rats, and in vivo microdialysis studies in awake rats, were carried out 1 week, 1 month, 6 months, and 12 months after treatment. At 1 week after treatment there were significant decreases in potassium- and amphetamine-evoked overflow of DA, and in clearance of DA, in the striatum of the METH-treated animals. Basal extracellular levels of DA and its metabolites were also decreased. Evoked overflow had partially recovered by 1 month. By 6 months evoked overflow of DA appeared to be normal in the METH-treated rats. However, whole tissue levels of striatal DA were still significantly decreased. All parameters were back to control values by 12 months. These results suggest that presynaptic dopaminergic functioning can recover to normal levels in the striatum of METH-treated rats by 12 months after treatment.

  20. Restorative effects of GDNF on striatal dopamine release in rats treated with neurotoxic doses of methamphetamine.

    PubMed

    Cass, W A; Manning, M W; Bailey, S L

    2000-09-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) release and content. Glial cell line-derived neurotrophic factor (GDNF) has pronounced effects on dopaminergic systems in vivo, including neuroprotective effects against METH. The present experiments were designed to examine the ability of GDNF to reverse, or accelerate recovery from, METH-induced alterations in striatal DA release. Male Fischer-344 rats were administered METH (5 mg/kg, s.c.) or saline 4 times in one day at 2-hour intervals. Seven days later the animals were anesthetized and given a single injection of 10 microg GDNF, or vehicle, into the right striatum. Three weeks later microdialysis experiments were carried out in both the right and left striata to examine basal and evoked levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In animals treated with METH followed by vehicle 7 days later, there were significant reductions in potassium- and amphetamine-evoked overflow of DA, and in basal levels of DOPAC and HVA, compared to control animals. In rats treated with METH followed 7 days later with GDNF, there were significant increases in potassium- and amphetamine-evoked overflow of DA on the right, GDNF-treated, side of the brain compared to the left side. Basal levels of DOPAC and HVA were also elevated on the GDNF-treated side of the brain. These results suggest that GDNF can accelerate recovery of dopaminergic release processes in the striatum of rats treated with neurotoxic doses of METH.

  1. A terbium-sensitized spectrofluorimetric method for determination of catecholamines in a serum sample with micelle medium.

    PubMed

    Kamruzzaman, Mohammad; Alam, Al-Mahmnur; Lee, Sang Hak; Kim, Young Ho; Kim, Sung Hong

    2012-01-01

    A terbium-sensitized spectrofluorimetric method has been developed for determination of catecholamines such as norepinephrine (NE), epinephrine (EP) and dopamine (DA), using sodium dodecyl benzene sulphonate (SDBS). Fluorescence sensitization of terbium ions (Tb(3+) ) by complexation with catecholamines in the presence of SDBS was observed. The fluorescence intensities of the Tb(3+) -catecholamine complexes were highly enhanced by introducing SDBS with an emission maximum at 545 nm after excitation at 290 nm. The conditions for the complex formation of Tb(3+) -catecholamine were investigated systematically and optimized to determine catecholamines in a serum sample. Under the optimum conditions, the fluorescence intensities of the Tb(3+) -catecholamine complexes were increased linearly with the concentration of NE, EP and DA over the ranges 2.5 × 10(-10) -1.0 × 10(-8) , 2.5 × 10(-10) -1.0 × 10(-8) and 2.5 × 10(-9) -1.0 × 10(-7)  g/mL with correlation coefficients of 0.999, 0.999 and 0.9996, respectively. The limits of detection (3δ) of NE, EP and DA were found to be 4.6 × 10(-11) , 7.8 × 10(-11) and 8.38 × 10(-10)  g/mL, respectively. Precision of the method was tested at the concentration level of 1.2 × 10(-7)  g/mL for five replicate measurements of NE, EP and DA, giving relative standard deviations (RSDs) of 1.41%, 1.23% and 1.89%, respectively. The interaction mechanism of the Tb(3+) -catecholamine complexes system was investigated and presented with ultraviolet absorption spectra. The proposed method has been applied for the quantitative determination of NE, EP and DA in a spiked serum sample and a pharmaceutical preparation sample.

  2. A neurotoxicity assessment of high flash aromatic naphtha.

    PubMed

    Douglas, J F; McKee, R H; Cagen, S Z; Schmitt, S L; Beatty, P W; Swanson, M S; Schreiner, C A; Ulrich, C E; Cockrell, B Y

    1993-01-01

    Catalytic reforming is a refining process that converts naphthenes to aromatics by dehydrogenation to make higher octane gasoline blending components. A portion of this wide-boiling range hydrocarbon stream can be separated by distillation and used for other purposes. One such application is a mixture of predominantly 9-carbon aromatic molecules (C9 Aromatics, primarily isomers of ethyltoluene and trimethylbenzene), which is removed and used as a solvent also known as High Flash Aromatic Naphtha (HFAN). A program was initiated to assess the toxicological properties of HFAN since there may be human exposure, especially in the workplace. The current study was conducted to assess the potential for neurotoxicity in the rat. Adult male Sprague-Dawley rats of approximately 300 grams body weight, in groups of twenty, were exposed by inhalation to HFAN for 90 days at concentrations of 0, 100, 500, and 1500 ppm. During this period the animals were tested monthly for motor activity and in a functional observation battery. After three months of exposure, for 6 hours/day, 5 days/week, 10 animals/group/sex were sacrificed and selected nervous system tissue was examined histopathologically. No signs of neurotoxicity were seen in any of the evaluated parameters, nor was there evidence of pathologic changes in any of the examined tissues.

  3. Involvement of Sphingolipids in Ethanol Neurotoxicity in the Developing Brain

    PubMed Central

    Saito, Mariko; Saito, Mitsuo

    2013-01-01

    Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation. Such apoptotic pathways are often mediated by sphingolipids, a class of bioactive lipids ubiquitously present in eukaryotic cellular membranes. While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that ethanol-induced neuronal apoptosis in animal models of FASD is mediated or regulated by cellular sphingolipids, including via the pro-apoptotic action of ceramide and through the neuroprotective action of GM1 ganglioside. Such sphingolipid involvement in ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against FASD. Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate. PMID:24961420

  4. Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

    PubMed Central

    Yin, Zhaoobao; Aschner, Judy L.; Santos, Ana Paula dos; Aschner, Michael

    2008-01-01

    Chronic exposure to excessive levels of Mn results in a movement disorder termed manganism, which resembles Parkinson’s disease (PD). The pathogenic mechanisms underlying this disorder are not fully understood. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity. In the present study, we investigated the effects of Mn on mitochondrial function. Primary astrocyte cultures were prepared from cerebral cortices of one-day-old Sprague–Dawley rats. We have examined the cellular toxicity of Mn and its effects on the phosphorylation of extracellular signal-regulated kinase (ERK) and activation of the precursor protein of caspase-3. The potentiometric dye, tetramethylrhodamine ethyl ester (TMRE), was used to assess the effect of Mn on astrocytic mitochondrial inner membrane potential (ΔΨm). Our studies show that, in a concentration-dependent manner, Mn induces significant (p<0.05) activation of astrocyte caspase-3 and phosphorylated extracellular signal-regulated kinase (p-ERK). Mn treatment (1 and 6 hrs) also significantly (p<0.01) dissipates the ΔΨm in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. These results suggest that activations of astrocytic caspase-3 and ERK are involved in Mn-induced neurotoxicity via mitochondrial-dependent pathways. PMID:18313649

  5. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    PubMed Central

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

  6. Neurotoxicity of trimethyltin in rat cochlear organotypic cultures

    PubMed Central

    Yu, Jintao; Ding, Dalian; Sun, Hong; Salvi, Richard; Roth, Jerome A.

    2015-01-01

    Trimethyltin (TMT), which has a variety of applications in industry and agricultural is a neurotoxin that is known to affect the auditory system as well as central nervous system (CNS) of humans and experimental animals. However, the mechanisms underlying TMT-induced auditory dysfunction are poorly understood. To gain insights into the neurotoxic effect of TMT on the peripheral auditory system, we treated cochlear organotypic cultures with concentrations of TMT ranging from 5 to 100 μM for 24 h. Interestingly, TMT preferentially damaged auditory nerve fibers and spiral ganglion neurons in a dose-dependent manner, but had no noticeable effects on the sensory hair cells at the doses employed. TMT-induced damage to auditory neurons was associated with significant soma shrinkage, nuclear condensation and activation of caspase-3, biomarkers indicative of apoptotic cell death. Our findings show that TMT is exclusively neurotoxicity in rat cochlear organotypic culture and that TMT-induced auditory neuron death occurs through a caspase-mediated apoptotic pathway. PMID:25957118

  7. Subchronic organophosphorus ester-induced delayed neurotoxicity in mallards

    USGS Publications Warehouse

    Hoffman, D.J.; Sileo, L.; Murray, H.C.

    1984-01-01

    Eighteen-week-old mallard hens received 0, 10, 30, 90, or 270 ppm technical grade EPN (phenylphosphonothioic acid O-ethyl-O-4-nitrophenyl ester) in the diet for 90 days. Ataxia was first observed in the 270-ppm group after 16 days, in the 90-ppm group after 20 days, in the 30-ppm group after 38 days; 10 ppm failed to produce ataxia. By the end of 90 days all 6 birds in the 270-ppm group exhibited ataxia or paralysis whereas 5 of 6 birds in the 90-ppm group and 2 of 6 birds in the 30-ppm group were visibly affected. Treatment with 30 ppm or more resulted in a significant reduction in body weight. Brain neurotoxic esterase activity was inhibited by averages of 16, 69, 73, and 74% in the 10-, 30-, 90-, and 270-ppm groups, respectively. Brain acetylcholinesterase, plasma cholinesterase, and plasma alkaline phosphatase were significantly inhibited as well. Distinct histopathological effects were seen in the 30-, 90-, and 270-ppm groups which included demyelination and degeneration of axons of the spinal cord. Additional ducks were exposed in a similar manner to 60-, 270-, or 540-ppm leptophos (phosphonothioic acid O-4-bromo-2,5-dichlorophenyl-O-methylphenyl ester) which resulted in similar behavioral, biochemical, and histopathological alterations. These findings indicate that adult mallards are probably somewhat less sensitive than chickens to subchronic dietary exposure to organophosphorus insecticides that induce delayed neurotoxicity.

  8. Involvement of sphingolipids in ethanol neurotoxicity in the developing brain.

    PubMed

    Saito, Mariko; Saito, Mitsuo

    2013-04-26

    Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation. Such apoptotic pathways are often mediated by sphingolipids, a class of bioactive lipids ubiquitously present in eukaryotic cellular membranes. While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that ethanol-induced neuronal apoptosis in animal models of FASD is mediated or regulated by cellular sphingolipids, including via the pro-apoptotic action of ceramide and through the neuroprotective action of GM1 ganglioside. Such sphingolipid involvement in ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against FASD. Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate.

  9. Evidence for neurotoxicity associated with amoxicillin in juvenile rats.

    PubMed

    Atli, O; Demir-Ozkay, U; Ilgin, S; Aydin, T H; Akbulut, E N; Sener, E

    2016-08-01

    Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity.

  10. Neurotoxic Effects and Biomarkers of Lead Exposure: A Review

    PubMed Central

    Sanders, Talia; Liu, Yiming; Buchner, Virginia; Tchounwou, Paul B.

    2010-01-01

    Biological monitoring techniques are useful for risk assessment of toxic agents in the field of environmental health. Lead, a systemic toxicant affecting virtually every organ system, primarily affects the central nervous system, particularly the developing brain. Consequently, children are at a greater risk than adults of suffering from the neurotoxic effects of lead. The ability of lead to pass through the blood-brain barrier is due in large part to its ability to substitute for calcium ions. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer’s disease, Parkinson’s disease, and schizophrenia. At the molecular level, lead interferes with the regulatory action of calcium on cell functions and disrupts many intracellular biological activities. Experimental studies have also shown that lead exposure may have genotoxic effects, especially in the brain, bone marrow, liver, and lung cells. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children, adults, and experimental animals, updated to January 2009. PMID:19476290

  11. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

    PubMed

    Voorhees, Jaymie R; Rohlman, Diane S; Lein, Pamela J; Pieper, Andrew A

    2016-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.

  12. Lithium Protects Against Anaesthesia Neurotoxicity In The Infant Primate Brain

    PubMed Central

    Noguchi, Kevin K.; Johnson, Stephen A.; Kristich, Lauren E.; Martin, Lauren D.; Dissen, Gregory A.; Olsen, Emily A.; Olney, John W.; Brambrink, Ansgar M.

    2016-01-01

    Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li’s potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants. PMID:26951756

  13. Lithium Protects Against Anaesthesia Neurotoxicity In The Infant Primate Brain.

    PubMed

    Noguchi, Kevin K; Johnson, Stephen A; Kristich, Lauren E; Martin, Lauren D; Dissen, Gregory A; Olsen, Emily A; Olney, John W; Brambrink, Ansgar M

    2016-03-08

    Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li's potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants.

  14. The neurotoxic effects of intrathecal midazolam and neostigmine in rabbits.

    PubMed

    Demirel, E; Ugur, H C; Dolgun, H; Kahilogullari, G; Sargon, M E; Egemen, N; Kecik, Y

    2006-04-01

    In parallel with improvements in understanding pain neurophysiology, many chemicals have recently been investigated for spinal anaesthesia and analgesia. However, studies discussing the effects of these drugs on neural tissue indicate that knowledge about some aspects of neurotoxicity is limited. Forty-nine New Zealand albino rabbits, weighing 2.2 +/- 0.2 kg, were randomly assigned to seven groups of seven animals each. Single dose groups received intrathecally through the atlantooccipital membrane 0.9% saline 1.5 ml; midazolam 100 microg/kg (low dose midazolam group) or 500 microg/kg (high dose midazolam group); neostigmine 10 microg/kg (low dose neostigmine group) or 50 microg/kg (high dose neostigmine group). Two groups had seven days of repeated dosing with either midazolam 100 microg/kg/day (repeat midazolam group) or 10 microg/kg/day neostigmine (repeat neostigmine group). The animals were sacrificed on day 8, and two spinal cord sections from the fourth cervical level and fourth lumbar level were removed and prepared for histopathological study. Transmission electron microscopic evaluations were performed on transverse spinal cord sections by a neuropathologist blinded to the group allocation. Twenty myelinated axons and neurones in the cervical and lumbar sections were investigated for the histopathological study. This study indicates that midazolam and neostigmine have different neurotoxic effects that depend on the dose and the repetition of dosing when these drugs are administered intrathecally.

  15. Considerations for the Use of Anesthetics in Neurotoxicity Studies

    PubMed Central

    Karmarkar, Sumedha W; Bottum, Kathleen M; Tischkau, Shelley A

    2010-01-01

    Anesthetics are widely used in experiments investigating neurotoxicity and neuroprotection; however, these agents are known to interfere with the outcome of these experiments. The purpose of this overview is to review these effects and suggest methods for minimizing unintended consequences on experimental outcomes. Information on the neuroprotective and neurotoxic effects of isoflurane, dexmedetomidine, propofol, ketamine, barbiturates, halothane, xenon, carbon dioxide, and nitrous oxide is summarized. The pertinent cell signaling pathways of these agents are discussed. Methods of humane animal euthanasia without anesthetics are considered. Most anesthetics alter the processes of neuronal survival and death. When designing survival surgeries, sham controls subjected to anesthesia but not the surgical intervention should be compared with controls subjected to neither anesthesia nor surgery. Additional controls could include using an anesthetic with a different mechanism of action from the primary anesthetic used. Because the effects of anesthetics lessen with time after surgery, survival surgeries should include later time points until at least 7 d after the procedure. Humane methods of animal euthanasia that do not require anesthetics exist and should be used whenever appropriate. PMID:20819374

  16. Mitochondria: key players in the neurotoxic effects of amphetamines.

    PubMed

    Barbosa, Daniel José; Capela, João Paulo; Feio-Azevedo, Rita; Teixeira-Gomes, Armanda; Bastos, Maria de Lourdes; Carvalho, Félix

    2015-10-01

    Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.

  17. Signaling Mechanisms and Disrupted Cytoskeleton in the Diphenyl Ditelluride Neurotoxicity

    PubMed Central

    Pessoa-Pureur, Regina; Heimfarth, Luana; Rocha, João B.

    2014-01-01

    Evidence from our group supports that diphenyl ditelluride (PhTe)2 neurotoxicity depends on modulation of signaling pathways initiated at the plasma membrane. The (PhTe)2-evoked signal is transduced downstream of voltage-dependent Ca2+ channels (VDCC), N-methyl-D-aspartate receptors (NMDA), or metabotropic glutamate receptors activation via different kinase pathways (protein kinase A, phospholipase C/protein kinase C, mitogen-activated protein kinases (MAPKs), and Akt signaling pathway). Among the most relevant cues of misregulated signaling mechanisms evoked by (PhTe)2 is the cytoskeleton of neural cells. The in vivo and in vitro exposure to (PhTe)2 induce hyperphosphorylation/hypophosphorylation of neuronal and glial intermediate filament (IF) proteins (neurofilaments and glial fibrillary acidic protein, resp.) in different brain structures of young rats. Phosphorylation of IFs at specific sites modulates their association/disassociation and interferes with important physiological roles, such as axonal transport. Disrupted cytoskeleton is a crucial marker of neurodegeneration and is associated with reactive astrogliosis and apoptotic cell death. This review focuses the current knowledge and important results on the mechanisms of (PhTe)2 neurotoxicity with special emphasis on the cytoskeletal proteins and their differential regulation by kinases/phosphatases and Ca2+-mediated mechanisms in developmental rat brain. We propose that the disrupted cytoskeletal homeostasis could support brain damage provoked by this neurotoxicant. PMID:25050142

  18. A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

    PubMed Central

    Costa, Lucio G.; de Laat, Rian; Tagliaferri, Sara; Pellacani, Claudia

    2013-01-01

    Polybrominated diphenyl ethers (PBDEs), extensively used in the past few decades as flame retardants in a variety of consumer products, have become world-wide persistent environmental pollutants. Levels in North America are usually higher than those in Europe and Asia, and body burden is 3 to 9-fold higher in infants and toddlers than in adults. The latter has raised concern for potential developmental toxicity and neurotoxicity of PBDEs. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or post-natal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. The mechanisms underlying the developmental neurotoxic effects of PBDEs are not known, though several hypotheses have been put forward. One general mode of action relates to the ability of PBDEs to impair thyroid hormone homeostasis, thus indirectly affecting the developing brain. An alternative or additional mode of action involves a direct effect of PBDEs on nervous system cells; PBDEs can cause oxidative stress-related damage (DNA damage, mitochondrial dysfunction, apoptosis), and interfere with signal transduction (particularly calcium signaling), and with neurotransmitter systems. Important issues such as bioavailability and metabolism of PBDEs, extrapolation of results to low level of exposures, and the potential effects of interactions among PBDE congeners and between PBDEs and other contaminants also need to be taken into account. PMID:24270005

  19. Hydrogen sulfide, endoplasmic reticulum stress and alcohol mediated neurotoxicity.

    PubMed

    George, Akash K; Behera, Jyotirmaya; Kelly, Kimberly E; Zhai, Yuankun; Tyagi, Neetu

    2017-02-14

    Alcohol is one of the most socially accepted addictive drugs in modern society. Its abuse affects virtually all organ systems with the central nervous system (CNS) being particularly vulnerable to excessive alcohol exposure. Alcohol exposure also causes profound damage to both the adult and developing brain. Excessive alcohol consumption induces numerous pathophysiological stress responses, one of which is the endoplasmic reticulum (ER) stress response. Potential mechanisms that trigger the alcohol induced ER stress response are either directly or indirectly related to alcohol metabolism, which include toxic levels of acetaldehyde and homocysteine, oxidative stress and abnormal epigenetic modifications. Growing evidence suggests that H2S is the most recently recognized gasotransmitter with tremendous physiological protective functions against oxidative stress induced neurotoxicity. In this review we address the alcohol induced oxidative stress mediated ER stress and the role of H2S in its mitigation in the context of alcohol neurotoxicity. Interruption of ER stress triggers is anticipated to have therapeutic benefits for alcohol mediated diseases and disorders.

  20. Amyloid Oligomer Neurotoxicity, Calcium Dysregulation, and Lipid Rafts

    PubMed Central

    Malchiodi-Albedi, Fiorella; Paradisi, Silvia; Matteucci, Andrea; Frank, Claudio; Diociaiuti, Marco

    2011-01-01

    Amyloid proteins constitute a chemically heterogeneous group of proteins, which share some biophysical and biological characteristics, the principal of which are the high propensity to acquire an incorrect folding and the tendency to aggregate. A number of diseases are associated with misfolding and aggregation of proteins, although only in some of them—most notably Alzheimer's disease (AD) and transmissible spongiform encephalopathies (TSEs)—a pathogenetic link with misfolded proteins is now widely recognized. Lipid rafts (LRs) have been involved in the pathophysiology of diseases associated with protein misfolding at several levels, including aggregation of misfolded proteins, amyloidogenic processing, and neurotoxicity. Among the pathogenic misfolded proteins, the AD-related protein amyloid β (Aβ) is by far the most studied protein, and a large body of evidence has been gathered on the role played by LRs in Aβ pathogenicity. However, significant amount of data has also been collected for several other amyloid proteins, so that their ability to interact with LRs can be considered an additional, shared feature characterizing the amyloid protein family. In this paper, we will review the evidence on the role of LRs in the neurotoxicity of huntingtin, α-synuclein, prion protein, and calcitonin. PMID:21331330

  1. Rethinking cycad metabolite research.

    PubMed

    Snyder, Laura R; Marler, Thomas E

    2011-01-01

    Cycads are among the most ancient of extant Spermatophytes, and are known for their numerous pharmacologically active compounds. One compound in particular, β-methylamino-L-alanine (BMAA), has been implicated as the cause of amyotrophic lateral sclerosis/Parkinson dementia complex (ALS/PDC) on Guam. Previous studies allege that BMAA is produced exclusively by cyanobacteria, and is transferred to cycads through the symbiotic relationship between these cyanobacteria and the roots of cycads. We recently published data showing that Cycas micronesica seedlings grown without endophytic cyanobacteria do in fact increase in BMAA, invalidating the foundation of the BMAA hypothesis. We use this example to suggest that the frenzy centered on BMAA and other single putative toxins has hindered progress. The long list of cycad-specific compounds may have important roles in signaling or communication, but these possibilities have been neglected during decades of attempts to force single metabolites into a supposed anti-herbivory function. We propose that an unbiased, comprehensive approach may be a more appropriate means of proceeding with cycad biochemistry research.

  2. Synthesis Of Labeled Metabolites

    DOEpatents

    Martinez, Rodolfo A.; Silks, III, Louis A.; Unkefer, Clifford J.; Atcher, Robert

    2004-03-23

    The present invention is directed to labeled compounds, for example, isotopically enriched mustard gas metabolites including: [1,1',2,2'-.sup.13 C.sub.4 ]ethane, 1,1'-sulfonylbis[2-(methylthio); [1,1',2,2'-.sup.13 C.sub.4 ]ethane, 1-[[2-(methylsulfinyl)ethyl]sulfonyl]-2-(methylthio); [1,1',2,2'-.sup.13 C.sub.4 ]ethane, 1,1'-sulfonylbis[2-(methylsulfinyl)]; and, 2,2'-sulfinylbis([1,2-.sup.13 C.sub.2 ]ethanol of the general formula ##STR1## where Q.sup.1 is selected from the group consisting of sulfide (--S--), sulfone (--S(O)--), sulfoxide (--S(O.sub.2)--) and oxide (--O--), at least one C* is .sup.13 C, X is selected from the group consisting of hydrogen and deuterium, and Z is selected from the group consisting of hydroxide (--OH), and --Q.sup.2 --R where Q.sup.2 is selected from the group consisting of sulfide (--S--), sulfone(--S(O)--), sulfoxide (--S(O.sub.2)--) and oxide (--O--), and R is selected from the group consisting of hydrogen, a C.sub.1 to C.sub.4 lower alkyl, and amino acid moieties, with the proviso that when Z is a hydroxide and Q.sup.1 is a sulfide, then at least one X is deuterium.

  3. The autonomic nervous system and chromaffin tissue: neuroendocrine regulation of catecholamine secretion in non-mammalian vertebrates.

    PubMed

    Perry, Steve F; Capaldo, Anna

    2011-11-16

    If severe enough, periods of acute stress in animals may be associated with the release of catecholamine hormones (noradrenaline and adrenaline) into the circulation; a response termed the acute humoral adrenergic stress response. The release of catecholamines from the sites of storage, the chromaffin cells, is under neuroendocrine control, the complexity of which appears to increase through phylogeny. In the agnathans, the earliest branching vertebrates, the chromaffin cells which are localized predominantly within the heart, lack neuronal innervation and thus catecholamine secretion in these animals is initiated solely by humoral mechanisms. In the more advanced teleost fish, the chromaffin cells are largely confined to the walls of the posterior cardinal vein at the level of the head kidney where they are intermingled with the steroidogenic interrenal cells. Catecholamine secretion from teleost chromaffin cells is regulated by a host of cholinergic and non-cholinergic pathways that ensure sufficient redundancy and flexibility in the secretion process to permit synchronized responses to a myriad of stressors. The complexity of catecholamine secretion control mechanisms continues through the amphibians, reptiles and birds although neural (cholinergic) regulation may become increasingly important in birds. Discrete adrenal glands are present in the non-mammalian tetrapods but unlike in mammals, there is no clear division of a steroidogenic cortex and a chromaffin cell enriched medulla. However, in all groups, there is an obvious intermingling of chromaffin and steroiodogenic cells. The association of the two cell types may be particularly important in the amphibians and birds because like in mammals, the enzyme catalysing the methylation of noradrenaline to adrenaline, PNMT, is under the control of the steroid cortisol.

  4. Cyclic nucleotides of canine antral smooth muscle. Effects of acetylcholine, catecholamines and gastrin.

    PubMed

    Baur, S; Grant, B; Wooton, J

    1981-01-07

    1. The effects of acetylcholine, catecholamines and gastrin on the intracellular content of cyclic AMP and cyclic GMP in antral circular muscle have been determined. 2. Acetylcholine results in a significant but transient increase in intracellular cyclic GMP. 3. Isoproterenol and norepinephrine increase intracellular cyclic AMP. Based on half-maximal effective doses, isoproterenol is 2.7-times more effective than norepinephrine. The increase in intracellular cyclic AMP by both agents is inhibited by propranolol but not phentolamine, indicating that both agents act on the muscle cell by a beta-receptor-coupled mechanism. 4. Gastrin has no demonstrable effect on either cyclic AMP or cyclic GMP. This suggests that while gastrin and acetylcholine can produce a like myoelectric response in the muscle cell, the action of gastrin is mediated by a separate receptor, presumably on the muscle cell, and not by a release of acetylcholine.

  5. Effects of exercise on plasma renin, aldosterone and catecholamines before and after surgery for aortic coarctation.

    PubMed

    Sehested, J; Kornerup, H J; Pedersen, E B; Christensen, N J

    1983-01-01

    The pre- and postoperative values of blood pressure, pulse rate, plasma renin activity, plasma aldosterone concentration and circulating catecholamines were studied in a group of 12 patients with uncomplicated aortic coarctation before and after exercise. Mean age of patients studied was 21.5 years. Postoperative studies were carried out on average 204 days after surgery. Following operation, both resting and exercising upper extremity pressures decreased. Six out of the 11 patients still had an abnormally high exercising blood pressure when compared with a normal control group of six persons. Postoperative pulse rates during exercise were significantly higher than pre-operatively (P less than 0.01). No statistically significant differences between pre- and postoperative values, and between patients and normal controls were found in the hormonal studies. This study suggests that the renin-aldosterone-system does not have a major role in the maintenance of the hypertension associated with coarctation of the aorta.

  6. Enhanced BDNF signalling following chronic hypoxia potentiates catecholamine release from cultured rat adrenal chromaffin cells

    PubMed Central

    Scott, Angela L; Zhang, Min; Nurse, Colin A

    2015-01-01

    Environmental stressors, including chronic hypoxia, enhance the ability of adrenomedullary chromaffin cells (AMCs) to secrete catecholamines; however, the underlying molecular mechanisms remain unclear. Here, we investigated the role of brain-derived neurotrophic factor (BDNF) signalling in rat AMCs exposed to chronic hypoxia. In rat adrenal glands, BDNF and its tropomyosin-related kinase B (TrkB) receptor are highly expressed in the cortex and medulla, respectively. Exposure of AMCs to chronic hypoxia (2% O2; 48 h) in vitro caused a significant increase to TrkB mRNA expression. A similar increase was observed in an immortalized chromaffin cell line (MAH cells); however, it was absent in MAH cells deficient in the transcription factor HIF-2α. A specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), stimulated quantal catecholamine secretion from chronically hypoxic (CHox; 2% O2) AMCs to a greater extent than normoxic (Nox; 21% O2) controls. Activation of TrkB by BDNF or 7,8-DHF increased intracellular Ca2+ ([Ca2+]i), an effect that was significantly larger in CHox cells. The 7,8-DHF-induced [Ca2+]i rise was sensitive to the tyrosine kinase inhibitor K252a and nickel (2 mm), but not the Ca2+ store-depleting agent cyclopiazonic acid. Blockade of T-type calcium channels with TTA-P2 (1 μm) or voltage-gated Na+ channels with TTX inhibited BDNF-induced [Ca2+]i increases. BDNF also induced a dose-dependent enhancement of action potential firing in CHox cells. These data demonstrate that during chronic hypoxia, enhancement of BDNF-TrkB signalling increases voltage-dependent Ca2+ influx and catecholamine secretion in chromaffin cells, and that T-type Ca2+ channels play a key role in the signalling pathway. Key points We investigated the role of the neurotrophin BDNF signalling via the TrkB receptor in rat adrenomedullary chromaffin cells (AMCs) exposed to normoxia (Nox; 21% O2) and chronic hypoxia (CHox; 2% O2) in vitro for ∼48 h. TrkB receptor expression was

  7. Determination of catecholamines in plasma by HPLC and amperometric detection. Comparison with a radioenzymatic method.

    PubMed

    Bauersfeld, W; Ratge, D; Knoll, E; Wisser, H

    1986-03-01

    The determination of norepinephrine and epinephrine in plasma by HPLC with amperometric detection was modified, giving detection limits of 25 ng/l for norepinephrine and epinephrine, respectively, using 1 ml plasma. In order to achieve this sensitivity, it was necessary to minimize the background noise by modification of instrumentation and specimen handling. Particularly important was the extra purification of the reagents, the application of micro-bore HPLC, the enzymatic cleavage of uric acid and temperature control of the amperometric cell and the amplifier. Comparison of the present method with the radioenzymatic determination of catecholamines resulted in coefficients of correlation of r = 0.924 and 0.919 for norepinephrine and epinephrine, resp. (n = 38). The concentrations of the 38 different samples used for the comparison were in the physiological range.

  8. Mechanisms of radio-protection by catecholamines in the hamster /Mesocricetus auratus/

    NASA Technical Reports Server (NTRS)

    Prewitt, R. L.; Musacchia, X. J.

    1975-01-01

    Experiments were conducted on normal and splenectomized male and female hamsters between 2 and 3 months old subjected to a whole-body exposure of 1000 or 2000 rads in a Co-60 source with a view toward evaluating their radio-protection by norepinephrine, isoproterenol, and phenylephrine. Vasoconstriction hypoxia mechanism of radio-protection is examined along with the hypothesis that isoproterenol protects by hypercalcemia-induced cell proliferation. Radiation experiment results are found to be consistent with the hypothesis that stimulation of alpha receptors results in radio-protection through a tissue hypoxia mechanism. Beta agonists seem to protect by a hypotensive-hypoxia mechanism. The catecholamines protect against the hematopoietic syndrome, but show no evidence of protection against the gastrointestinal syndrome.

  9. Response of plasma endorphins, prolactin and catecholamines in women to intense heat in a sauna.

    PubMed

    Laatikainen, T; Salminen, K; Kohvakka, A; Pettersson, J

    1988-01-01

    Concentrations of immunoreactive beta-endorphin (ir beta-E), corticotropin, cortisol, prolactin and catecholamines in plasma were followed in 11 healthy women during and after exposure to intense heat in a Finnish sauna bath, and compared to those in a similar control situation without exposure to heat. Heat stress significantly increased prolactin and norepinephrine secretion; the percentage increases from the initial plasma concentrations varied from 113 to 1280% (mean 510%) and from 18 to 150% (mean 86%), respectively. The response of the plasma levels of epinephrine, ir beta-E, corticotropin and cortisol to heat exposure was variable. Compared to the control situation, no statistically significant effect of heat exposure on the plasma levels of these hormones was found.

  10. A cyclodextrin-based approach for selective detection of catecholamine hormone mixtures

    NASA Astrophysics Data System (ADS)

    Yang, Jung-Hoon; Kim, Hyun Tae; Kim, Hanseup

    2014-12-01

    This paper presents an electrochemical sensing approach that enables quantitative detection of three major catecholamine hormones from a mixture by specifically employing a chemically-modified microelectrode array with α-, β- and γ-cyclodextrin (CD) `catchers' holding unique physical matching (size and shape) as well as chemical enticing (stereochemistry and surface charge) properties. The developed neurotransmitter sensor has selectively identified L-tyrosine, dihydroxyphenylalanine (L-DOPA) and dopamine in the absence of ascorbic acid. It exhibited the relatively linear sensitivities to each neurotransmitter with logarithmically increasing concentrations range of 5μM-10mM, while demonstrating stability up to 6 hours from the fabrication and the average accuracy of 91.2%.

  11. Adrenocortical hemorrhagic necrosis: the role of catecholamines and retrograde medullary-cell embolism

    SciTech Connect

    Szabo, S.; McComb, D.J.; Kovacs, K.; Huettner, I.

    1981-10-01

    We investigated the pathogenesis of adrenal necrosis using animal models of the disease (induced by administration of acrylonitrile, cysteamine, or pyrazole) and human cases. Results of electron-microscopic and histochemical time-response studies with rat models revealed an early, retrograde embolization of medullary cells and cell fragments in the cortical capillaries that showed prominent endothelial injury. The experimental adrenal lesions were prevented by surgical removal of the medulla one month before administration of adrenocorticolytic chemicals, or by the administration of the alpha-adrenergic antagonist phenoxybenzamine hydrochloride. Histochemical staining for medullary (argyrophil) granules in human cases of adrenal necrosis demonstrated tissue fragments that stained positively for silver in vascular cortical spaces in nine of ten autopsy specimens and in all four surgical cases we reviewed. Thus, catecholamines released from the adrenal medulla and from the retrograde medullary emboli in the cortex may have a role in the pathogenesis of adrenocortical necrosis.

  12. The sympathetic nervous system and catecholamines metabolism in obstructive sleep apnoea

    PubMed Central

    Bisogni, Valeria; Pengo, Martino F.; Maiolino, Giuseppe

    2016-01-01

    Obstructive sleep apnoea (OSA) is the most common sleep disorder of breathing in middle-aged and overweight subjects. It features recurrent episodes of upper airway total (apnoea) o partial (hypopnea) collapse during sleep, which are associated with a reduction in blood oxygen saturation and with arousal from sleep to re-establish airway patency. An association of OSA with dysregulation of the autonomous nervous system (ANS) and altered catecholamines (CAs) metabolism has been contended for years. However, the pathophysiology mechanisms underlying these alterations remain to be fully clarified. Nonetheless, these alterations are deemed to play a key pathogenic role in the established association of OSA with several conditions besides arterial hypertension (HT), including coronary artery disease, stroke, and, more in general, with increased risk of cardiovascular (CV) events. Hence, in this review we will analyse the relationship between the sleep disturbances associated with OSA and the altered function of the ANS, including CAs metabolism. PMID:26904265

  13. F-actin and myosin II accelerate catecholamine release from chromaffin granules

    PubMed Central

    Berberian, Khajak; Torres, Alexis J; Fang, Qinghua; Kisler, Kassandra

    2009-01-01

    The roles of non-muscle myosin II and cortical actin filaments in chromaffin granule exocytosis were studied by confocal fluorescence microscopy, amperometry, and cell-attached capacitance measurements. Fluorescence imaging indicated decreased mobility of granules near the plasma membrane following inhibition of myosin II function with Blebbistatin. Slower fusion pore expansion rates and longer fusion pore lifetimes were observed after inhibition of actin polymerization using Cytochalasin-D. Amperometric recordings revealed increased amperometric spike half-widths without change in quantal size after either myosin II inhibition or actin disruption. These results suggest that actin and myosin II facilitate release from individual chromaffin granules by accelerating dissociation of catecholamines from the intragranular matrix possibly through generation of mechanical forces. PMID:19158310

  14. Acute ethanol-induced changes in edema and metabolite concentrations in rat brain.

    PubMed

    Liu, Huimin; Zheng, Wenbin; Yan, Gen; Liu, Baoguo; Kong, Lingmei; Ding, Yan; Shen, Zhiwei; Tan, Hui; Zhang, Guishan

    2014-01-01

    The aim of this study is to describe the acute effects of EtOH on brain edema and cerebral metabolites, using diffusion weight imaging (DWI) and proton magnetic resonance spectroscopy ((1)H-MRS) at a 7.0T MR and to define changes in apparent diffusion coefficient (ADC) values and the concentration of metabolites in the rat brain after acute EtOH intoxication. ADC values in each ROI decreased significantly at 1 h and 3 h after ethanol administration. ADC values in frontal lobe were decreased significantly compared with other regions at 3 h. For EtOH/Cr+PCr and cerebral metabolites (Cho, Tau, and Glu) differing over time, no significant differences for Ins, NAA, and Cr were observed in frontal lobes. Regression analysis revealed a significant association between TSEtOH/Cr+PCr and TSCho, TSTau, TSGlu, and TSADC. The changes of ADC values in different brain regions reflect the process of the cytotoxic edema in vivo. The characterization of frontal lobes metabolites changes and the correlations between TSEtOH/Cr+PCr and TSCho, TSTau, and TSGlu provide a better understanding for the biological mechanisms in neurotoxic effects of EtOH on the brain. In addition, the correlations between TSEtOH/Cr+PCr and TSADC will help us to understand development of the ethanol-induced brain cytotoxic edema.

  15. Influence of cholesterol on catecholamine release from the fusion pore of large dense core chromaffin granules.

    PubMed

    Wang, Nan; Kwan, Christina; Gong, Xiandi; de Chaves, Elena Posse; Tse, Amy; Tse, Frederick W

    2010-03-17

    Changes in cellular cholesterol can affect exocytosis, but the influence of cholesterol in fusion pore kinetics is unclear. Using carbon fiber amperometry, we monitored quantal catecholamine release from rat chromaffin cells. To bypass any possible effect of cholesterol perturbation on ion channels or the colocalization of voltage-gated Ca(2+) channels with sites of exocytosis, exocytosis was stimulated via uniform elevation of cytosolic [Ca(2+)] (with whole-cell dialysis of a Ca(2+)-buffered solution). Under this condition, alterations of cellular cholesterol affected neither the mean number of amperometric events triggered per cell nor their quantal size and the kinetics of their main spike (which reflects the rapid release during and after rapid fusion pore dilation). In contrast, the reduction of cellular cholesterol shortened the "prespike foot" signals (which reflect the leakage of catecholamine via a semi-stable fusion pore) and reduced the proportion of "stand-alone foot" signals (which reflect the release via a flickering fusion pore that may close before it dilates significantly), whereas an oversupply of cholesterol had opposite effects. Acute extraction of cholesterol from the cytosol (via whole-cell dialysis of a cholesterol extractor) also shortened the prespike foot signals and reduced the proportion of stand-alone foot signals, but acute extracellular application of cholesterol extractor or "soluble" cholesterol had no effect. Our data raise the possibility that cholesterol molecules, particularly those in the cytoplasmic leaflet, helps to constrain the narrow waistline of a semi-stable fusion pore while it is flickering or before it starts to dilate rapidly.

  16. Structural and biochemical remodelling in catecholamine-induced cardiomyopathy: comparative and ontogenetic aspects.

    PubMed

    Ostádal, B; Pelouch, V; Ostádalová, I; Nováková, O

    Excessive release or administration of beta-mimetic catecholamines may induce cardiomegaly, necrotic lesions and accumulation of connective tissue in the heart of adult homoiotherms. It was examined here whether similar changes can also be observed at different stages of evolution of the cardiovascular system, i.e. in poikilotherms and in homoiotherms during embryonic life. Sensitivity of the poikilothermic hearts (carp, frog, turtle) to isoproterenol (IPRO) was significantly lower than in the homoiotherms. Necrotic lesions, if present, were localized in the inner spongious musculature which has no vascular supply but which exhibits higher activities of enzymes connected with aerobic oxidation. Moreover, the IPRO-induced decrease of the phospholipid content was also significantly more expressed in the spongious layer. IPRO treatment did not influence the total weight of the fish heart but the proportion of the outer compact layer was significantly higher. These changes were accompanied by an increase of collagen, higher water content and an increase of isomyosin with a lower ATPase activity. The response of the poikilothermic heart to IPRO-induced overload thus differs significantly from that in the homoiotherms. The administration of IPRO during embryonic life of homoiotherms (chick) induces serious cardiovascular disturbances, including cardiomegaly and cellular oedema. Necroses of myofibrils, characteristic of IPRO-induced lesions of adults, were, however, rather exceptional. IPRO did not elevate the concentration of 85Sr (as a calcium homologue) in the immature myocardium; it seems, therefore, that IPRO-induced changes of the embryonic heart are not necessarily due to an intracellular calcium overload. It may be concluded that the character of catecholamine-induced cardiomyopathy is not uniform and depends strictly on the stage of cardiac development.

  17. Catecholamines and their enzymes in discrete brain areas of rats after space flight on biosatellites Cosmos

    NASA Astrophysics Data System (ADS)

    Kvetǹanskỳ, R.; Čulman, J.; Serova, L. V.; Tigranjan, R. A.; Torda, T.; Macho, L.

    The activity of the catecholaminergic system was measured in the hypothalamus of rats which had experienced an 18.5-19.5-day-long stay in the state of weightlessness during space flights on board Soviet biosatellites of the type Cosmos. In the first two experiments, Cosmos 782 and 936, the concentration of norepinephrine and the activities of synthesizing enzymes tyrosine hydroxylase and dopamine-β-hydroxylase and of the degrading enzyme monoamine oxidase were measured in the total hypothalamus. None of the given parameters was changed after space flight. In the light of the changes of these parameters recorded after exposure to acute stress on Earth, this finding indicates that long-term state of weightlessness does not represent an intensive stressogenic stimulus for the system studied. In the space experiment Cosmos 1129, the concentration of norepinephrine, epinephrine, and dopamine was studied in isolated nuclei of the hypothalamus of rats within 6-10 hr following return from space. Norepinephrine was found to be significantly reduced in the arcuate nucleus, median eminence and periventricular nucleus, epinephrine in the median eminence, periventricular and suprachiasmatic nuclei, whereas dopamine was not significantly changed after space flight. The decreased catecholamine levels found in some hypothalamic nuclei of rats which had undergone space flight indicate that no chronic intensive stressor could have acted during the flight, otherwise the catecholamine concentration would have been increased in the nuclei. The decreased levels must have been induced by the effect of a stressogenic factor acting for a short time only, and that either during the landing maneuver or immediately after landing. Thus long-term exposure of the organism to the state of weightlessness does not represent a stressogenic stimulus for the catecholaminergic system in the hypothalamus, which is one of the regulators of the activation of neuroendocrine reactions under stress.

  18. Participation of endogenous catecholamines in the regulation of left ventricular mass in progeny of hypertensive parents.

    PubMed

    Trimarco, B; Ricciardelli, B; De Luca, N; De Simone, A; Cuocolo, A; Galva, M D; Picotti, G B; Condorelli, M

    1985-07-01

    To investigate whether adrenergic activity is a determinant of left ventricular hypertrophy in human hypertension, in each of 10 normotensive subjects with two hypertensive parents we have examined the relationship between changes in echocardiographic parameters of left ventricular anatomy and those in circulating catecholamine levels induced by three, 3 week periods of different sodium and potassium intakes. A high sodium-normal potassium regimen induced a significant reduction in upright plasma norepinephrine (from 599 +/- 89 to 379 +/- 45 pg/ml, p less than .01) and in posterior wall (PWT) and interventricular septal (IVST) thickness, as well as in the left ventricular mass index (LVMi). Changes in upright plasma norepinephrine concentrations correlated with those in IVST (r = .822, p less than .01) and in LVMi (r = .833, p less than .01). A low sodium-normal potassium diet resulted in increases in supine and upright plasma norepinephrine levels (from 356 +/- 44 to 488 +/- 89 pg/ml, p less than .001; and from 565 +/- 42 to 744 +/- 33 pg/ml, p less than .01) as well as increases in IVST and LVMi (from 97 +/- 7 to 107 +/- 7 g/m2, p less than .001). The changes in norepinephrine levels in supine and upright subjects correlated with changes in IVST (r = .836, p less than .01 and r = .796, p less than .01) and in LVMi (r = .931, p less than .001 and r = .947, p less than .001). No significant change in plasma catecholamine concentrations or in PWT, IVST, or LVMi was detected after a low sodium-high potassium regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy

    PubMed Central

    Thoonen, Robrecht; Ernande, Laura; Cheng, Juan; Nagasaka, Yasuko; Yao, Vincent; Miranda-Bezerra, Alexandre; Chen, Chan; Chao, Wei; Panagia, Marcello; Sosnovik, David E.; Puppala, Dheeraj; Armoundas, Antonis A.; Hindle, Allyson; Bloch, Kenneth D.; Buys, Emmanuel S.; Scherrer-Crosbie, Marielle

    2015-01-01

    Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1−/−) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1−/− mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1−/− mice. UCP1−/− mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1−/− mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1−/− BAT transplanted to either UCP1−/− or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1−/− mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1−/− mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy. PMID:25968336

  20. Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat.

    PubMed

    Liles, John T; Ida, Kevin K; Joly, Kristin M; Chapo, Joseph; Plato, Craig F

    2011-08-01

    Contractile reserve decreases with advancing age and chronic isoproterenol (ISO) administration is a well-characterized model of cardiac hypertrophy known to impair cardiovascular function. This study evaluated whether nonsenescent, mature adult rats are more susceptible to detrimental effects of chronic ISO administration than younger adult rats. Rats received daily injections of ISO (0.1 mg/kg sc) or vehicle for 3 wk. ISO induced a greater impairment in contractile reserve [maximum of left ventricular pressure development (Δ+dP/dt(max))] in mature adult ISO-treated (MA-ISO) than in young adult ISO-treated rats (YA-ISO) in response to infusions of mechanistically distinct inotropes (digoxin, milrinone; 20-200 μl·kg(-1)·min(-1)), while basal and agonist-induced changes in heart rate and systolic arterial pressure (SAP) were not different across groups. ISO decreased expression of the calcium handling protein, sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a, in MA-ISO compared with YA, YA-ISO, and MA rats. Chronic ISO also induced greater increases in cardiac hypertrophy [left ventricular (LV) index: 33 ± 3 vs. 22 ± 5%] and caspase-3 activity (34 vs. 5%) in MA-ISO relative to YA-ISO rats. Moreover, β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased β-MHC and ANF expression. Although several studies report age-related declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life.

  1. Repeated stress-induced stimulation of catecholamine response is not followed by altered immune cell redistribution.

    PubMed

    Imrich, Richard; Tibenska, Elena; Koska, Juraj; Ksinantova, Lucia; Kvetnansky, Richard; Bergendiova-Sedlackova, Katarina; Blazicek, Pavol; Vigas, Milan

    2004-06-01

    Stress response is considered an important factor in the modulation of immune function. Neuroendocrine hormones, including catecholamines, affect the process of immune cell redistribution, important for cell-mediated immunity. This longitudinal investigation was aimed at evaluating the effect of repeated stress-induced elevation of catecholamines on immune cell redistribution and expression of adhesive molecules. We assessed the responses of epinephrine (EPI), norepinephrine (NE), cortisol, changes in lymphocytes subpopulations, and percentages of CD11a+, CD11b+, and CD62L+ lymphocytes to a 20-min treadmill exercise of an intensity equal to 80% of the individual's Vo(2)max. The exercise was performed before and after 6 weeks of endurance training consisting of a 1-h run 4 times a week (ET) and after 5 days of bed rest (HDBR) in 10 healthy males. We did not observe any significant changes in the basal levels of EPI, NE, and cortisol in the plasma, nor in the immune parameters after ET and HDBR. The exercise test led to a significant (P <.001) elevation of EPI and NE levels after both ET and HDBR, a significant elevation (P <.01) of cortisol after HDBR, an increase in the absolute numbers of leukocytes, granulocytes, monocytes, CD3+, CD4+, CD8+, CD16+, CD19+ lymphocytes, percentage of CD11a+ and CD11b+ lymphocytes, and to a decrease of CD62L1 before, after ET, and after HDBR. We found comparable changes in all measured immune parameters after ET and HDBR. In conclusion, repeated stress-induced elevation of EPI and NE was not associated with an alteration in immune cell redistribution found in response to the single bout of exercise.

  2. Intraperitoneal administration of CDP-choline and its cholinergic and pyrimidinergic metabolites induce hyperglycemia in rats: involvement of the sympathoadrenal system.

    PubMed

    Ilcol, Y O; Cansev, M; Yilmaz, M S; Hamurtekin, E; Ulus, I H

    2007-01-01

    CDP-choline is an endogenous metabolite in phosphatidylcholine biosynthesis. Exogenous administration of CDP-choline has been shown to affect brain metabolism and to exhibit neuroprotective actions. On the other hand, little is known regarding its peripheral actions. Intraperitoneal administration of CDP-choline (200-600 micromol/kg) induced a dose- and time-dependent hyperglycemia in rats. Hyperglycemic response to CDP-choline was associated with several-fold elevations in serum concentrations of CDP-choline and its metabolites. Intraperitoneal administration of phosphocholine, choline, cytidine, cytidine monophosphate, cytidine diphosphate, cytidine triphosphate, uridine, uridine monophosphate, uridine diphosphate and uridine triphosphate also produced significant hyperglycemia. Pretreatment with atropine methyl nitrate failed to alter the hyperglycemic responses to CDP-choline and its metabolites whereas hexamethonium, the ganglionic nicotinic receptor antagonist which blocks nicotinic cholinergic neurotransmission at the autonomic ganglionic level, blocked completely the hyperglycemia induced by CDP-choline, phosphocholine and choline, and attenuated the hyperglycemic response to cytidine monophosphate and cytidine. Increased blood glucose following CDP-choline, phosphocholine and choline was accompanied by elevated plasma catecholamine concentrations. Hyperglycemia elicited by CDP-choline and its metabolites was entirely blocked either by pretreatment with a nonselective -adrenoceptor antagonist phentolamine or by the 2-adrenoceptor antagonist, yohimbine. Hyperglycemic responses to CDP-choline, choline, cytidine monophosphate and cytidine were not affected by chemical sympathectomy, but were prevented by bilateral adrenalectomy. Phosphocholine-induced hyperglycemia was attenuated by bilateral adrenalectomy or by chemical sympathectomy. These data show that CDP-choline and its metabolites induce hyperglycemia which is mediated by activation of ganglionic

  3. Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P–diphtheria toxoid conjugate

    SciTech Connect

    Schellenberger, Mario T.; Grova, Nathalie; Farinelle, Sophie; Willième, Stéphanie; Muller, Claude P.

    2013-09-01

    Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P–diphtheria toxoid (B[a]P–DT) conjugate vaccine were sub-acutely exposed to 2 mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P–DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P. - Highlights: • B[a]P-antibodies attenuated B[a]P induced NMDA expression in several brain regions. • B[a]P had measurable consequences on anxiety, short term learning and memory. • B[a]P immunization attenuated the pharmacological and neurotoxic effects of B[a]P. • Vaccination may also provide some protection against chemical carcinogenesis.

  4. TNT metabolites in animal tissues

    SciTech Connect

    Shugart, L.R.

    1990-01-01

    The overall objectives of this project are: to provide quantitative analytical procedures for the analysis of TNT and at least eight of its metabolites in animal tissues; and to obtain representative samples of tissues from animals from designated Army sites, and to determine the presence or absence of TNT and its metabolites in these samples. The study is divided into two Phases corresponding to the stated overall objectives of the project. 5 figs., 4 tabs.

  5. Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

    PubMed

    Castelli, M Paola; Madeddu, Camilla; Casti, Alberto; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M Grazia

    2014-01-01

    Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our

  6. Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

    PubMed Central

    Castelli, M. Paola; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M. Grazia

    2014-01-01

    Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4×10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (−19% and −28% for 1 mg/kg pre- and post-treated animals; −25% and −21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (−50%) and by pre-treatment with 3 mg/kg Δ9-THC (−53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (−34% and −47% for 1 mg/kg pre- and post-treated animals; −37% and −29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the

  7. Serum metabolites from walnut-fed aged rats attenuate stress-induced neurotoxicity in brain cells in vitro

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The shift in equilibrium towards excess reactive oxygen or nitrogen species production from innate antioxidant defense in brain is a critical factor in the declining neural functions and cognitive deficits accompanying age. In aging, there are noticeable alterations in the membrane microenvironment,...

  8. Serum metabolites from walnut-fed aged rats attenuate stress-induced neurotoxicity in BV-2 microglial cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The shift in equilibrium towards excess reactive oxygen or nitrogen species production from innate antioxidant defenses in brain is a critical factor in the declining neural function and cognitive deficit accompanying age. Previous studies from our laboratory have reported that walnuts, rich in poly...

  9. Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P-diphtheria toxoid conjugate.

    PubMed

    Schellenberger, Mario T; Grova, Nathalie; Farinelle, Sophie; Willième, Stéphanie; Schroeder, Henri; Muller, Claude P

    2013-09-01

    Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P-diphtheria toxoid (B[a]P-DT) conjugate vaccine were sub-acutely exposed to 2mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P-DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P.

  10. Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

    PubMed

    Thomas, David M; Kuhn, Donald M

    2005-02-01

    Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

  11. HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.

    PubMed

    Fan, Yan; He, Johnny J

    2016-10-21

    Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membrane-associated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tat-induced lysosomal exocytosis was tightly coupled to astrocyte-mediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases.

  12. Predicting the acute neurotoxicity of diverse organic solvents using probabilistic neural networks based QSTR modeling approaches.

    PubMed

    Basant, Nikita; Gupta, Shikha; Singh, Kunwar P

    2016-03-01

    Organic solvents are widely used chemicals and the neurotoxic properties of some are well established. In this study, we established nonlinear qualitative and quantitative structure-toxicity relationship (STR) models for predicting neurotoxic classes and neurotoxicity of structurally diverse solvents in rodent test species following OECD guideline principles for model development. Probabilistic neural network (PNN) based qualitative and generalized regression neural network (GRNN) based quantitative STR models were constructed using neurotoxicity data from rat and mouse studies. Further, interspecies correlation based quantitative activity-activity relationship (QAAR) and global QSTR models were also developed using the combined data set of both rodent species for predicting the neurotoxicity of solvents. The constructed models were validated through deriving several statistical coefficients for the test data and the prediction and generalization abilities of these models were evaluated. The qualitative STR models (rat and mouse) yielded classification accuracies of 92.86% in the test data sets, whereas, the quantitative STRs yielded correlation (R(2)) of >0.93 between the measured and model predicted toxicity values in both the test data (rat and mouse). The prediction accuracies of the QAAR (R(2) 0.859) and global STR (R(2) 0.945) models were comparable to those of the independent local STR models. The results suggest the ability of the developed QSTR models to reliably predict binary neurotoxicity classes and the endpoint neurotoxicities of the structurally diverse organic solvents.

  13. The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity

    PubMed Central

    Thomas, David M.; Francescutti-Verbeem, Dina M.; Kuhn, Donald M.

    2009-01-01

    The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor α-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. L-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, L-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH. PMID:18088364

  14. The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity.

    PubMed

    Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

    2008-05-01

    The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. l-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, l-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.

  15. Neurotoxic behavioral effects of Lake Ontario salmon diets in rats

    SciTech Connect

    Hertzler, D.R. )

    1990-03-01

    Six experiments were conducted to examine possible neurotoxic effects of the exposure to contaminants in Lake Ontario salmon administered through the diets of rats. Rats were fed different concentrations of fish (8%, 15% or 30%) in one of three diet conditions: Lake Ontario salmon, Pacific Ocean salmon, or laboratory rat chow only. Following 20 days on the diets, rats were tested for five minutes per day in a modified open field for one or three days. Lake Ontario salmon diets consistently produced significantly lower activity, rearing, and nosepoke behaviors in comparison with ocean salmon or rat chow diet conditions. A dose-response effect for concentration of lake salmon was obtained, and the attenuation effect occurred in males, females, adult or young animals, and postweaning females, with fish sampled over a five-year period. While only two of several potential contaminants were tested, both fish and brain analyses of mirex and PCBs relate to the behavioral effects.

  16. Effects of potential neurotoxic pesticides on hearing loss: a review.

    PubMed

    Gatto, M P; Fioretti, M; Fabrizi, G; Gherardi, M; Strafella, E; Santarelli, L

    2014-05-01

    Several pesticides are supposed to be neurotoxic for humans, consequently, they may also affect the auditory system. This review analyzes human and experimental animal studies testing the hypothesis that exposure to pesticides is associated with hearing loss. The literature on this topic is still sparse and methodological limitations of some papers evaluated are identified. As a whole, available data indicate a possible ototoxic action of pesticides, but alternative hypotheses could not be ruled out, also considering some confounders, such as the co-exposure to noise. Therefore, further studies are necessary in order to clarify the association between pesticides exposure and hearing loss. While awaiting more evidence, for precautionary action we recommend considering pesticides as possible ototoxic agents, in particular for vulnerable targets, such as pregnant women and children during early development.

  17. A plastic stabilizer dibutyltin dilaurate induces subchronic neurotoxicity in rats.

    PubMed

    Jin, Minghua; Song, Peilin; Li, Na; Li, Xuejun; Chen, Jiajun

    2012-10-05

    Dibutyltin dilaurate functions as a stabilizer for polyvinyl chloride. In this study, experimental rats were intragastrically administered 5, 10, or 20 mg/kg dibutyltin dilaurate to model sub-chronic poisoning. After exposure, our results showed the activities of superoxide dismutase and glutathione peroxidase decreased in rat brain tissue, while the malondialdehyde and nitric oxide content, as well as nitric oxide synthase activity in rat brain tissue increased. The cell cycle in the right parietal cortex was disordered and the rate of apoptosis increased. DNA damage was aggravated in the cerebral cortex, and the ultrastructure of the right parietal cortex tissues was altered. The above changes became more apparent with exposure to increasing doses of dibutyltin dilaurate. Our experimental findings confirmed the neurotoxicity of dibutyltin dilaurate in rat brain tissues, and demonstrated that the poisoning was dose-dependent.

  18. Reversible neurotoxicity following hyperfractionated radiation therapy of brain stem glioma

    SciTech Connect

    Griebel, M.; Friedman, H.S.; Halperin, E.C.; Wiener, M.D.; Marks, L.; Oakes, W.J.; Hoffman, J.M.; DeLong, G.R.; Schold, S.C.; Hockenberger, B. )

    1991-01-01

    Two patients with brain stem gliomas were treated with hyperfractionated radiation therapy (HFR) (7,020 and 7,560 cGy, respectively). Despite initial clinical improvement during irradiation, both patients demonstrated clinical deterioration approximately 3 weeks after completion of radiotherapy. Cranial magnetic resonance imaging (MRI) revealed a progressive increase in distribution of abnormal brain stem signal consistent with either tumor or edema. {sup 18}FDG positron emission tomography (PET) was obtained in one patient and demonstrated a hypermetabolic lesion at diagnosis and a hypometabolic lesion at the time of clinical deterioration postirradiation. Management with a tapering dose of dexamethasone alone resulted in marked clinical (both patients) and radiographic (one patient) improvement, allowing reduction or discontinuation of this medication. These results suggest that patients with brain stem tumors demonstrating clinical and radiographic evidence of progressive tumor shortly after completion of HFR should be initially managed conservatively with dexamethasone, since these findings may be manifestations of reversible radiation-related neurotoxicity.

  19. Rodent neurotoxicity bioassays for screening contaminated Great Lakes fish

    SciTech Connect

    Beattie, M.K.; Hoffman, R.; Gerstenberger, S.; Dellinger, J.A.

    1996-03-01

    Standard laboratory rat neurotoxicity protocols were used to study the consequences resulting from the consumption of walleye (Stizostedion vitreum), whitefish (Coregonus clupeaformis), and lake trout (Salvelinus namaycush) from Lake Superior (LS) and the consumption of carp (Cyprinus carpio) from Little Lake Butte des Morte (LLBM) near Oshkosh, Wisconsin, USA. Two 90-d subchronic studies are described, including a 45-d exposure to fish diets using male Sprague-Dawley hooded rats, and a 90-d exposure to fish diets using female rats of the same species. Behavioral alterations were tested using a battery of behavioral tests. In addition, pharmacologic challenges using apomorphine and D-amphetamine were administered to the rats to reveal latent neurotoxic effects. Cumulative fish consumption data were recorded daily, weight gain recorded weekly, and behavior data collected prior to exposure, and on days 7, 14, 55 {+-} 2, 85 {+-} 2. Motor activity data were collected on days 30 {+-} 2, 60 {+-} 2, and 90 {+-} 2 of the feeding protocols. Brain tissue from rodents fed these fish were subsequently analyzed for either mercury (Hg) or polychlorinated biphenyls (PCB). Mercury concentrations were increased in the brains of the walleye-fed rats, and PCB concentrations ranged from 0.5 nl/L to 10 nl/L in the brains of rats fed carp from LLBM, a Lake Michigan tributary. Adult male rats fed LLBM carp for 45 d exhibited the greatest behavior responses to the dopaminergic agonist apomorphine on the accelerating rotarod, although these differences were not significant. The 90-d exposure of LS walleye or Hg-spiked LS walleye resulted in behavior alterations on tactile startle response and second footsplay. D-Amphetamine challenge caused changes in tactile startle response, second footsplay, and accelerating rotarod performance after consuming walleye diets. Rats fed LLBM carp had altered behavioral responses to apomorphine on the accelerating rotarod.

  20. Selenium as a potential protective factor against mercury developmental neurotoxicity.

    PubMed

    Choi, Anna L; Budtz-Jørgensen, Esben; Jørgensen, Poul J; Steuerwald, Ulrike; Debes, Frodi; Weihe, Pál; Grandjean, Philippe

    2008-05-01

    Experimental studies suggest that selenium (Se) may decrease methylmercury (MeHg) toxicity under certain exposure regimens. In epidemiological studies, the exposure to MeHg occurs from fish and seafood, which are also a source of beneficial nutrients such as selenium. However, little is known about the potential protective effects of dietary Se against MeHg neurotoxicity in humans. The possible interaction was assessed in two birth cohorts in the Faroe Islands, consisting of singleton term births from 1986 to 1987 (N=1,022), and 1994 to 1995 (N=182), respectively. Dietary habits in this fishing population included frequent consumption of seafood, including whale meat high in mercury. Both Hg and Se were measured in cord whole blood. Neurodevelopmental outcomes were evaluated at age 7 years in both cohorts, and the smaller cohort also included neurological assessment on several prior occasions. Each outcome was modeled as a function of Hg and Se interactions (with adjustments for potential risk factors) by expressing the effects of log10(Hg) within the lowest 25%, the middle 50%, and the highest 25% of the Se distribution. Surplus Se was present in cord blood, the average being a 10-fold molar excess above MeHg. Regression analyses failed to show consistent effects of Se, or statistically significant interaction terms between Se and MeHg. Overall, no evidence was found that Se was an important protective factor against MeHg neurotoxicity. Prevention, therefore, needs to address MeHg exposures rather than Se intakes. Because of the benefits associated with fish intake during pregnancy, consumers should be advised to maintain a high fish and seafood intake that is low in Hg contamination. Additional research is needed to determine the identity of the nutrients responsible for the beneficial effects.

  1. Oxidative stress in MeHg-induced neurotoxicity

    SciTech Connect

    Farina, Marcelo; Aschner, Michael; Rocha, Joao B.T.

    2011-11-15

    Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically

  2. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity.

    PubMed

    Vilela, Luciano R; Gobira, Pedro H; Viana, Thercia G; Medeiros, Daniel C; Ferreira-Vieira, Talita H; Doria, Juliana G; Rodrigues, Flávia; Aguiar, Daniele C; Pereira, Grace S; Massessini, André R; Ribeiro, Fabíola M; de Oliveira, Antonio Carlos P; Moraes, Marcio F D; Moreira, Fabricio A

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In c