The effect of aniracetam on cerebral glucose metabolism in rats after lesioning of the basal forebrain measured by PET.

PubMed

Ouchi, Y; Kakiuchi, T; Okada, H; Nishiyama, S; Tsukada, H

1999-03-15

To evaluate the effect of aniracetam, a potent modulator of the glutamatergic and cholinergic systems, on the altered cerebral glucose metabolism after lesioning of the basal forebrain, we measured the cerebral metabolic rate of glucose (CMRGlc) with positron emission tomography and the choline acetyltransferase (ChAT) activity in the frontal cortex of the lesioned rats after treating them with aniracetam. Continuous administration of aniracetam for 7 days after the surgery prevented CMRGlc reduction in the frontal cortex ipsilateral to the lesion while the lesioned rats without aniracetam showed significant CMRGlc reduction in the frontal cortex. The level of CMRGlc in the lesion-side basal forebrain was lower in all rats regardless of the aniracetam treatment. Biochemical studies showed that aniracetam did not alter the reduction in the frontal ChAT activity. These results showed that aniracetam prevents glucose metabolic reduction in the cholinergically denervated frontal cortex with little effect on the cortical cholinergic system. The present study suggested that a neurotransmitter system other than the cholinergic system, e.g. the glutamatergic system, plays a central role in the cortical metabolic recovery after lesioning of the basal forebrain.

Review: Cerebral microvascular pathology in aging and neurodegeneration

PubMed Central

Brown, William R.; Thore, Clara R.

2010-01-01

This review of age-related brain microvascular pathologies focuses on topics studied by this laboratory, including anatomy of the blood supply, tortuous vessels, venous collagenosis, capillary remnants, vascular density, and microembolic brain injury. Our studies feature thick sections, large blocks embedded in celloidin, and vascular staining by alkaline phosphatase (AP). This permits study of the vascular network in three dimensions, and the differentiation of afferent from efferent vessels. Current evidence suggests that there is decreased vascular density in aging, Alzheimer’s disease (AD), and leukoaraiosis (LA), and cerebrovascular dysfunction precedes and accompanies cognitive dysfunction and neurodegeneration. A decline in cerebrovascular angiogenesis may inhibit recovery from hypoxia-induced capillary loss. Cerebral blood flow (CBF) is inhibited by tortuous arterioles and deposition of excessive collagen in veins and venules. Misery perfusion due to capillary loss appears to occur before cell loss in LA, and CBF is also reduced in the normal-appearing white matter. Hypoperfusion occurs early in AD, inducing white matter lesions and correlating with dementia. In vascular dementia, cholinergic reductions are correlated with cognitive impairment, and cholinesterase inhibitors have some benefit. Most lipid microemboli from cardiac surgery pass through the brain in a few days, but some remain for weeks. They can cause what appears to be a type of vascular dementia years after surgery. Donepezil has shown some benefit. Emboli, such as clots, cholesterol crystals, and microspheres can be extruded through the walls of cerebral vessels, but there is no evidence yet that lipid emboli undergo such extravasation. PMID:20946471

Noradrenergic Dysfunction in Alzheimer's and Parkinson's Diseases-An Overview of Imaging Studies.

PubMed

Peterson, Andrew C; Li, Chiang-Shan R

2018-01-01

Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined noradrenergic dysfunction as a target for medication development. We review the literature of noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging have facilitated greater understanding of how structural and functional alteration of the LC may contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies, structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity with the default mode network (DMN). LC degeneration may accompany deficient capacity in suppressing DMN activity and increasing saliency and task control network activities to meet behavioral challenges. We finish by proposing potential and new directions of research to address noradrenergic dysfunction in AD and PD.

Is Vasomotion in Cerebral Arteries Impaired in Alzheimer’s Disease?

PubMed Central

Di Marco, Luigi Yuri; Farkas, Eszter; Martin, Chris; Venneri, Annalena; Frangi, Alejandro F.

2015-01-01

Abstract A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer’s disease (AD). Cerebral hypoperfusion and blood-brain barrier dysfunction have been indicated as key elements of this pathway. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-β (Aβ) peptide in cerebral blood vessel walls. CAA is associated with loss of vascular integrity, resulting in impaired regulation of cerebral circulation, and increased susceptibility to cerebral ischemia, microhemorrhages, and white matter damage. Vasomotion— the spontaneous rhythmic modulation of arterial diameter, typically observed in arteries/arterioles in various vascular beds including the brain— is thought to participate in tissue perfusion and oxygen delivery regulation. Vasomotion is impaired in adverse conditions such as hypoperfusion and hypoxia. The perivascular and glymphatic pathways of Aβ clearance are thought to be driven by the systolic pulse. Vasomotion produces diameter changes of comparable amplitude, however at lower rates, and could contribute to these mechanisms of Aβ clearance. In spite of potential clinical interest, studies addressing cerebral vasomotion in the context of AD/CAA are limited. This study reviews the current literature on vasomotion, and hypothesizes potential paths implicating impaired cerebral vasomotion in AD/CAA. Aβ and oxidative stress cause vascular tone dysregulation through direct effects on vascular cells, and indirect effects mediated by impaired neurovascular coupling. Vascular tone dysregulation is further aggravated by cholinergic deficit and results in depressed cerebrovascular reactivity and (possibly) impaired vasomotion, aggravating regional hypoperfusion and promoting further Aβ and oxidative stress accumulation. PMID:25720414

Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain

USDA-ARS?s Scientific Manuscript database

The cholinergic theory of aging states that dysfunction of cholinergic neurons arising from the basal forebrain and terminating in the cortex and hippocampus may be involved in the cognitive decline that occurs during aging and Alzheimer’s disease. Despite years of research, pharmacological interven...

Houttuynia cordata Improves Cognitive Deficits in Cholinergic Dysfunction Alzheimer's Disease-Like Models.

PubMed

Huh, Eugene; Kim, Hyo Geun; Park, Hanbyeol; Kang, Min Seo; Lee, Bongyong; Oh, Myung Sook

2014-05-01

Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer's disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD.

Houttuynia cordata Improves Cognitive Deficits in Cholinergic Dysfunction Alzheimer’s Disease-Like Models

PubMed Central

Huh, Eugene; Kim, Hyo Geun; Park, Hanbyeol; Kang, Min Seo; Lee, Bongyong; Oh, Myung Sook

2014-01-01

Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer’s disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD. PMID:25009697

Cholinergic dysfunction and amnesia in patients with Wernicke-Korsakoff syndrome: a transcranial magnetic stimulation study.

PubMed

Nardone, Raffaele; Bergmann, Jürgen; De Blasi, Pierpaolo; Kronbichler, Martin; Kraus, Jörg; Caleri, Francesca; Tezzon, Frediano; Ladurner, Gunther; Golaszewski, Stefan

2010-03-01

The specific neurochemical substrate underlying the amnesia in patients with Wernicke-Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Corsi's Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

Intrinsic Cholinergic Mechanisms Regulating Cerebral Blood Flow as a Target for Organophosphate Action

DTIC Science & Technology

1988-10-01

autoregulation, render the cerebral circulation dependent upon systemic circulation exposing brain to ischernic damage or edema in shock or stress...Thus, sharp reductions of arterial pressure, as might occur in hemorrhagic or traumatic shock, will render the cerebral circulation vulnerable to...autoregulated range, rendering local areas of the brain vulnerable to cerebral edema and breakdown of the blood brain barrier. -2- 8. Cerebral blood

Central cholinergic dysfunction could be associated with oropharyngeal dysphagia in early Parkinson's disease.

PubMed

Lee, Kyung Duck; Koo, Jung Hoi; Song, Sun Hong; Jo, Kwang Deog; Lee, Moon Kyu; Jang, Wooyoung

2015-11-01

Dysphagia is an important issue in the prognosis of Parkinson's disease (PD). Although several studies have reported that oropharyngeal dysphagia may be associated with cognitive dysfunction, the exact relationship between cortical function and swallowing function in PD patients is unclear. Therefore, we investigated the association between an electrophysiological marker of central cholinergic function, which reflected cognitive function, and swallowing function, as measured by videofluoroscopic studies (VFSS). We enrolled 29 early PD patients. Using the Swallowing Disturbance Questionnaire (SDQ), we divided the enrolled patients into two groups: PD with dysphagia and PD without dysphagia. The videofluoroscopic dysphagia scale (VDS) was applied to explore the nature of the dysphagia. To assess central cholinergic dysfunction, short latency afferent inhibition (SAI) was evaluated. We analyzed the relationship between central cholinergic dysfunction and oropharyngeal dysphagia and investigated the characteristics of the dysphagia. The SAI values were significantly different between the two groups. The comparison of each VFSS component between the PD with dysphagia group and the PD without dysphagia group showed statistical significance for most of the oral phase components and for a single pharyngeal phase component. The total score on the VDS was higher in the PD with dysphagia group than in the PD without dysphagia group. The Mini-Mental State Examination and SAI values showed significant correlations with the total score of the oral phase components. According to binary logistic regression analysis, SAI value independently contributed to the presence of dysphagia in PD patients. Our findings suggest that cholinergic dysfunction is associated with dysphagia in early PD and that an abnormal SAI value is a good biomarker for predicting the risk of dysphagia in PD patients.

Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction

PubMed Central

Gavioli, Mariana; Lara, Aline; Almeida, Pedro W. M.; Lima, Augusto Martins; Damasceno, Denis D.; Rocha-Resende, Cibele; Ladeira, Marina; Resende, Rodrigo R.; Martinelli, Patricia M.; Melo, Marcos Barrouin; Brum, Patricia C.; Fontes, Marco Antonio Peliky; Souza Santos, Robson A.; Prado, Marco A. M.; Guatimosim, Silvia

2014-01-01

Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease. PMID:24992197

Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid-β peptide oligomers.

PubMed

Nunes-Tavares, Nilson; Santos, Luís Eduardo; Stutz, Bernardo; Brito-Moreira, Jordano; Klein, William L; Ferreira, Sérgio T; de Mello, Fernando G

2012-06-01

Dysregulated cholinergic signaling is an early hallmark of Alzheimer disease (AD), usually ascribed to degeneration of cholinergic neurons induced by the amyloid-β peptide (Aβ). It is now generally accepted that neuronal dysfunction and memory deficits in the early stages of AD are caused by the neuronal impact of soluble Aβ oligomers (AβOs). AβOs build up in AD brain and specifically attach to excitatory synapses, leading to synapse dysfunction. Here, we have investigated the possibility that AβOs could impact cholinergic signaling. The activity of choline acetyltransferase (ChAT, the enzyme that carries out ACh production) was inhibited by ~50% in cultured cholinergic neurons exposed to low nanomolar concentrations of AβOs. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, lactate dehydrogenase release, and [(3)H]choline uptake assays showed no evidence of neuronal damage or loss of viability that could account for reduced ChAT activity under these conditions. Glutamate receptor antagonists fully blocked ChAT inhibition and oxidative stress induced by AβOs. Antioxidant polyunsaturated fatty acids had similar effects, indicating that oxidative damage may be involved in ChAT inhibition. Treatment with insulin, previously shown to down-regulate neuronal AβO binding sites, fully prevented AβO-induced inhibition of ChAT. Interestingly, we found that AβOs selectively bind to ~50% of cultured cholinergic neurons, suggesting that ChAT is fully inhibited in AβO-targeted neurons. Reduction in ChAT activity instigated by AβOs may thus be a relevant event in early stage AD pathology, preceding the loss of cholinergic neurons commonly observed in AD brains.

Neuroprotective effect of curcumin on okadaic acid induced memory impairment in mice.

PubMed

Rajasekar, N; Dwivedi, Subhash; Tota, Santosh Kumar; Kamat, Pradeep Kumar; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

2013-09-05

Okadaic acid (OKA) has been observed to cause memory impairment in human subjects having seafood contaminated with dinoflagellate (Helicondria okadai). OKA induces tau hyperphosphorylation and oxidative stress leading to memory impairment as our previous study has shown. Curcumin a natural antioxidant has demonstrated neuroprotection in various models of neurodegeneration. However, the effect of curcumin has not been explored in OKA induced memory impairment. Therefore, present study evaluated the effect of curcumin on OKA (100ng, intracerebrally) induced memory impairment in male Swiss albino mice as evaluated in Morris water maze (MWM) and passive avoidance tests (PAT). OKA administration resulted in memory impairment with a decreased cerebral blood flow (CBF) (measured by laser doppler flowmetry), ATP level and increased mitochondrial (Ca(2+))i, neuroinflammation (increased TNF-α, IL-1β, COX-2 and GFAP), oxidative-nitrosative stress, increased Caspase-9 and cholinergic dysfunction (decreased AChE activity/expression and α7 nicotinic acetylcholine receptor expression) in cerebral cortex and hippocampus of mice brain. Oral administration of curcumin (50mg/kg) for 13 days significantly improved memory function in both MWM and PAT along with brain energy metabolism, CBF and cholinergic function. It decreased mitochondrial (Ca(2+))i, and ameliorated neuroinflammation and oxidative-nitrostative stress in different brain regions of OKA treated mice. Curcumin also inhibited astrocyte activation as evidenced by decreased GFAP expression. This neuroprotective effect of curcumin is due to its potent anti-oxidant action thus confirming previous studies. Therefore, use of curcumin should be encouraged in people consuming sea food (contaminated with dinoflagellates) to prevent cognitive impairment. © 2013 Elsevier B.V. All rights reserved.

Cardiopulmonary Arrest and Resuscitation Disrupts Cholinergic Anti-Inflammatory Processes: A Role for Cholinergic α7 Nicotinic Receptors

PubMed Central

Morris, John S.; Karelina, Kate; Weil, Zachary M.; Zhang, Ning; Al-Abed, Yousef; Brothers, Holly M.; Wenk, Gary L.; Pavlov, Valentin A.; Tracey, Kevin J.; DeVries, A. Courtney

2011-01-01

Cardiac arrest is a leading cause of death worldwide. While survival rates following sudden cardiac arrest remain relatively low, recent advancements in patient care have begun to increase the proportion of individuals who survive cardiac arrest. However, many of these individuals subsequently develop physiological and psychiatric conditions that likely result from ongoing neuroinflammation and neuronal death. The present study was conducted to better understand the pathophysiological effects of cardiac arrest on neuronal cell death and inflammation, and their modulation by the cholinergic system. Using a well validated model of cardiac arrest, here we show that global cerebral ischemia increases microglial activation, proinflammatory cytokine mRNA expression (interleukin-1β, interleukin-6, tumor necrosis factor-α), and neuronal damage. Cardiac arrest also induces alterations in numerous cellular components of central cholinergic signaling, including a reduction in choline acetyltransferase enzymatic activity and the number of choline acetyltransferase-positive neurons, as well as, reduced acetylcholinesterase and vesicular acetylcholine transporter mRNA. However, treatment with a selective agonist of the α7 nicotinic acetylcholine receptor, the primary receptor mediating the cholinergic anti-inflammatory pathway, significantly decreases the neuroinflammation and neuronal damage resulting from cardiac arrest. These data suggest that global cerebral ischemia results in significant declines in central cholinergic signaling, which may in turn diminish the capacity of the cholinergic anti-inflammatory pathway to control inflammation. Furthermore, we provide evidence that pharmacological activation of α7 nicotinic acetylcholine receptors provide significant protection against ischemia-related cell death and inflammation within a clinically relevant time frame. PMID:21368056

Glycogen synthase kinase-3 reduces acetylcholine level in striatum via disturbing cellular distribution of choline acetyltransferase in cholinergic interneurons in rats.

PubMed

Zhao, L; Chu, C-B; Li, J-F; Yang, Y-T; Niu, S-Q; Qin, W; Hao, Y-G; Dong, Q; Guan, R; Hu, W-L; Wang, Y

2013-01-01

Cholinergic interneurons, which provide the main source of acetylcholine (ACh) in the striatum, control the striatal local circuits and deeply involve in the pathogenesis of neurodegenerative diseases. Glycogen synthase kinase-3 (GSK-3) is a crucial kinase with diverse fundamental functions and accepted that deregulation of GSK-3 activity also plays important roles in diverse neurodegenerative diseases. However, up to now, there is no direct proof indicating whether GSK-3 activation is responsible for cholinergic dysfunction. In the present study, with combined intracerebroventricular injection of Wortmannin and GF-109203X, we activated GSK-3 and demonstrated the increased phosphorylation level of microtubule-associated protein tau and neurofilaments (NFs) in the rat striatum. The activated GSK-3 consequently decreased ACh level in the striatum as a result of the reduction of choline acetyltransferase (ChAT) activity. The alteration of ChAT activity was due to impaired ChAT distribution rather than its expression. Furthermore, we proved that cellular ChAT distribution was dependent on low phosphorylation level of NFs. Nevertheless, the cholinergic dysfunction in the striatum failed to induce significant neuronal number reduction. In summary, our data demonstrates the link between GSK-3 activation and cholinergic dysfunction in the striatum and provided beneficial evidence for the pathogenesis study of relevant neurodegenerative diseases. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Chotosan, a kampo formula, ameliorates chronic cerebral hypoperfusion-induced deficits in object recognition behaviors and central cholinergic systems in mice.

PubMed

Zhao, Qi; Murakami, Yukihisa; Tohda, Michihisa; Obi, Ryosuke; Shimada, Yutaka; Matsumoto, Kinzo

2007-04-01

We previously demonstrated that the Kampo formula chotosan (CTS) ameliorated spatial cognitive impairment via central cholinergic systems in a chronic cerebral hypoperfusion (P2VO) mouse model. In this study, the object discrimination tasks were used to determine if the ameliorative effects of CTS on P2VO-induced cognitive deficits are a characteristic pharmacological profile of this formula, with the aim of clarifying the mechanisms by which CTS enhances central cholinergic function in P2VO mice. The cholinesterase inhibitor tacrine (THA) and Kampo formula saikokeishito (SKT) were used as controls. P2VO impaired object discrimination performance in the object recognition, location, and context tests. Daily administration of CTS (750 mg/kg, p.o.) and THA (2.5 mg/kg, i.p.) improved the object discrimination deficits, whereas SKT (750 mg/kg, p.o.) did not. In ex vivo assays, tacrine but not CTS or SKT inhibited cortical cholinesterase activity. P2VO reduced the mRNA expression of m(3) and m(5) muscarinic receptors and choline acetyltransferase but not that of other muscarinic receptor subtypes in the cerebral cortex. Daily administration of CTS and THA but not SKT reversed these expression changes. These results suggest that CTS and THA improve P2VO-induced cognitive impairment by normalizing the deficit of central cholinergic systems and that the beneficial effect on P2VO-induced cognitive deficits is a distinctive pharmacological characteristic of CTS.

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

PubMed

Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

2017-06-01

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia.

PubMed

Román, Gustavo C; Kalaria, Raj N

2006-12-01

Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.

Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.

PubMed

Amenta, F; Tayebati, S K

2008-01-01

Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.

Stress, Chemical Defense Agents and Cholinergic Receptors

DTIC Science & Technology

1989-11-30

reasons: I) Bused on the observations of Dam et al. (1982), i.e., low-dose oxotremorine activation of cerebral glucose utilization in cortical layers IVNb...QNB Lower: Localization of the binding of 2.0 nM ( H]- Oxotremorine -M The highest levels of binding for both radioligands are observed in the cerebral

Hypertension-Induced Cerebral Small Vessel Disease Leading to Cognitive Impairment.

PubMed

Liu, Yang; Dong, Yan-Hong; Lyu, Pei-Yuan; Chen, Wei-Hong; Li, Rui

2018-03-05

Alzheimer's disease and vascular dementia are responsible for more than 80% of dementia cases. These two conditions share common risk factors including hypertension. Cerebral small vessel disease (CSVD) is strongly associated with both hypertension and cognitive impairment. In this review, we identify the pathophysiological changes in CSVD that are caused by hypertension and further explore the relationship between CSVD and cognitive impairment. We searched and scanned the PubMed database for recently published literatures up to December 2017. We used the keywords of "hypertension", "cerebral small vessel disease", "white matter lesions", "enlarged perivascular spaces", "lacunar infarcts", "cerebral microbleeds", and "cognitive impairment" in the database of PubMed. Articles were obtained and reviewed to analyze the hypertension-induced pathophysiological changes that occur in CSVD and the correlation between CSVD and cognitive impairment. In recent years, studies have demonstrated that hypertension-related changes (e.g., small vascular lesions, inflammatory reactions, hypoperfusion, oxidative stress, damage to autoregulatory processes and the blood-brain barrier, and cerebral amyloid angiopathy) can occur over time in cerebral small vessels, potentially leading to lower cognitive function when blood pressure (BP) control is poor or lacking. Both isolated and co-occurrent CSVD can lead to cognitive deterioration, and this effect may be attributable to a dysfunction in either the cholinergic system or the functionality of cortical and subcortical tracts. We explore the currently available evidence about the hypertensive vasculopathy and inflammatory changes that occur in CSVD. Both are vital prognostic indicators of the development of cognitive impairment. Future studies should be performed to validate the relationship between BP levels and CSVD progression and between the numbers, volumes, and anatomical locations of CSVD and cognitive impairment.

Nicotinic α4β2 acetylcholine receptors and cognitive function in Parkinson's disease.

PubMed

Lorenz, R; Samnick, S; Dillmann, U; Schiller, M; Ong, M F; Faßbender, K; Buck, A; Spiegel, J

2014-09-01

Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD. Twenty-five non-demented patients with IPD underwent a 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4β2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction. In the CERAD, the IPD patients exhibited deficits in non-verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of α4β2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region). These significant correlations between the results of the CERAD subtests and the cerebral α4β2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis

PubMed Central

Casas, Caty; Herrando-Grabulosa, Mireia; Manzano, Raquel; Mancuso, Renzo; Osta, Rosario; Navarro, Xavier

2013-01-01

Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1G93A ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1G93A mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic-related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis. PMID:23531559

Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb.

PubMed

Uchida, Sae; Kagitani, Fusako

2017-05-12

The olfactory bulb receives cholinergic basal forebrain input, as does the neocortex; however, the in vivo physiological functions regarding the release of extracellular acetylcholine and regulation of regional blood flow in the olfactory bulb are unclear. We used in vivo microdialysis to measure the extracellular acetylcholine levels in the olfactory bulb of urethane-anesthetized rats. Focal chemical stimulation by microinjection of L-glutamate into the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, which is the main source of cholinergic input to the olfactory bulb, increased extracellular acetylcholine release in the ipsilateral olfactory bulb. When the regional cerebral blood flow was measured using laser speckle contrast imaging, the focal chemical stimulation of the HDB did not significantly alter the blood flow in the olfactory bulb, while increases were observed in the neocortex. Our results suggest a functional difference between the olfactory bulb and neocortex regarding cerebral blood flow regulation through the release of acetylcholine by cholinergic basal forebrain input.

Imaging: what can it tell us about parkinsonian gait?

PubMed Central

Bohnen, Nicolaas I.; Jahn, Klaus

2013-01-01

Functional neuroimaging has provided new tools to study cerebral gait control in Parkinson disease (PD). First, imaging of blood flow functions has identified a supraspinal locomotor network that includes the (frontal) cortex, basal ganglia, brainstem tegmentum and the cerebellum. These studies emphasize also the cognitive and attentional dependency of gait in PD. Furthermore, gait in PD and related syndromes like progressive supranuclear palsy may be associated with dysfunction of the indirect, modulatory prefrontal–subthalamic–pedunculopontine loop of locomotor control. The direct, stereotyped locomotor loop from the primary motor cortex to the spinal cord with rhythmic cerebellar input appears preserved and may contribute to the unflexible gait pattern in parkinsonian gait. Second, neurotransmitter and proteinopathy imaging studies are beginning to unravel novel mechanisms of parkinsonian gait and postural disturbances. Dopamine displacement imaging studies have shown evidence for a mesofrontal dopaminergic shift from a depleted striatum in parkinsonian gait. This may place additional burden on other brain systems mediating attention functions to perform previously automatic motor tasks. For example, our preliminary cholinergic imaging studies suggest significant slowing of gait speed when additional forebrain cholinergic denervation occurs in PD. Cholinergic denervation of the pedunculopontine nucleus and its thalamic projections have been associated with falls and impaired postural control. Deposition of β-amyloid may represent another non-dopaminergic correlate of gait disturbance in PD. These findings illustrate the emergence of dopamine non-responsive gait problems to reflect the transition from a predominantly hypodopaminergic disorder to a multisystem neurodegenerative disorder involving non-dopaminergic locomotor network structures and pathologies. PMID:24132837

A Review of the Pedunculopontine Nucleus in Parkinson's Disease.

PubMed

French, Isobel T; Muthusamy, Kalai A

2018-01-01

The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.

A Review of the Pedunculopontine Nucleus in Parkinson's Disease

PubMed Central

French, Isobel T.; Muthusamy, Kalai A.

2018-01-01

The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients. PMID:29755338

Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation.

PubMed

Mattsson, Anna; Lindqvist, Eva; Ogren, Sven Ove; Olson, Lars

2005-11-07

Altered cholinergic function is considered as a potential contributing factor in the pathogenesis of schizophrenia. We hypothesize that cortical cholinergic denervation may result in changes in glutamatergic activity. Therefore, we lesioned the cholinergic corticopetal projections by local infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of rats. Possible effects of this lesion on glutamatergic systems were examined by phencyclidine-induced locomotor activity, and also by N-methyl-D-aspartate receptor binding. We find that cholinergic lesioning of neocortex leads to enhanced sensitivity to phencyclidine in the form of a dramatic increase in horizontal activity. Further, N-methyl-D-aspartate receptor binding is unaffected in denervated rats. These results suggest that aberrations in cholinergic function might lead to glutamatergic dysfunctions, which might be of relevance for the pathophysiology for schizophrenia.

Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge

PubMed Central

Li, Xiufeng; Spence, Jeffrey S.; Buhner, David M.; Hart, John; Cullum, C. Munro; Biggs, Melanie M.; Hester, Andrea L.; Odegard, Timothy N.; Carmack, Patrick S.; Haley, Robert W.

2011-01-01

Purpose: To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. Materials and Methods: The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups—syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)—and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. Results: Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. Conclusion: Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101715/-/DC1 PMID:21914840

Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: evidence from fMRI in healthy subjects.

PubMed

Voss, Bianca; Thienel, Renate; Reske, Martina; Kellermann, Thilo; Sheldrick, Abigail J; Halfter, Sarah; Radenbach, Katrin; Shah, Nadim J; Habel, Ute; Kircher, Tilo T J

2012-06-01

The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning.

Effects of lateral fluid percussion injury on cholinergic markers in the newborn piglet brain.

PubMed

Donat, Cornelius K; Walter, Bernd; Kayser, Tanja; Deuther-Conrad, Winnie; Schliebs, Reinhard; Nieber, Karen; Bauer, Reinhard; Härtig, Wolfgang; Brust, Peter

2010-02-01

Traumatic brain injury is a leading cause of death and disability in children. Studies using adult animal models showed alterations of the central cholinergic neurotransmission as a result of trauma. However, there is a lack of knowledge about consequences of brain trauma on cholinergic function in the immature brain. It is hypothesized that trauma affects the relative acetylcholine esterase activity and causes a loss of cholinergic neurons in the immature brain. Severe fluid percussion trauma (FP-TBI, 3.8+/-0.3atm) was induced in 15 female newborn piglets, monitored for 6h and compared with 12 control animals. The hemispheres ipsilateral to FP-TBI obtained from seven piglets were used for acetylcholine esterase histochemistry on frozen sagittal slices, while regional cerebral blood flow and oxygen availability was determined in the remaining eight FP-TBI animals. Post-fixed slices were immunohistochemically labelled for choline acetyltransferase as well as for low-affinity neurotrophin receptor in order to characterize cholinergic neurons in the basal forebrain. Regional cerebral blood flow and brain oxygen availability were reduced during the first 2h after FP-TBI (P<0.05). In addition, acetylcholine esterase activity was significantly increased in the neocortex, basal forebrain, hypothalamus and medulla after trauma (P<0.05), whereas the number of choline acetyltransferase and low-affinity neurotrophin receptor positive cells in the basal forebrain were unaffected by the injury. Thus, traumatic brain injury evoked an increased relative activity of the acetylcholine esterase in the immature brain early after injury, without loss of cholinergic neurons in the basal forebrain. These changes may contribute to developmental impairments after immature traumatic brain injury. Copyright 2009 ISDN. Published by Elsevier Ltd. All rights reserved.

Red Dermographism in Autism Spectrum Disorders: A Clinical Sign of Cholinergic Dysfunction?

ERIC Educational Resources Information Center

Lemonnier, E.; Grandgeorge, M.; Jacobzone-Leveque, C.; Bessaguet, C.; Peudenier, S.; Misery, L.

2013-01-01

The authors hypothesised that red dermographism--a skin reaction involving the cholinergic system--is more frequent in children with autism spectrum disorders (ASDs) than in children exhibiting typical development. We used a dermatological examination to study red dermographism in this transverse study, which compared forty six children with ASDs…

Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia.

PubMed

Stryjer, Rafael; Strous, Rael D; Bar, Faina; Werber, Edith; Shaked, Ginette; Buhiri, Yosef; Kotler, Moshe; Weizman, Abraham; Rabey, Jose M

2003-01-01

Comorbid schizophrenia and dementia is a common clinical phenomenon; however, management of the coexisting illnesses remains incomplete. Donepezil, a cholinesterase inhibitor, may be beneficial for the management of symptoms of Alzheimer's disease, a disease in which cholinergic pathways in the cerebral cortex and basal forebrain are well known to be compromised. Furthermore, impaired cognition in elderly schizophrenic patients has been observed to be more than two thirds; however, there are no published controlled studies reporting the use of cholinesterase inhibitors in the management of schizophrenia in patients with associated dementia. In this study, six patients with chronic schizophrenia and comorbid dementia were administered donepezil, 5 mg, in single-blind fashion as augmentation to their standard antipsychotic medication for a 4-week period. Patients were evaluated with the Mini Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale, Cognitive subscale; Positive and Negative Symptom Scale (PANSS); and the Clinical Global Impression (CGI) scales. A significant improvement was noted in MMSE scores (P < 0.01) and for CGI scores (P < 0.01). In addition, three patients demonstrated improvement on the PANSS. Donepezil appears to be an effective treatment for the management of symptoms of dementia accompanying patients with comorbid schizophrenia and dementia. Since cholinergic dysfunction may be present in some patients with schizophrenia, the authors' findings further demonstrate the possibility that this disorder may be managed with cholinergic medications as augmenting agents, at least in this specific subpopulation of patients with comorbid dementia. To confirm the findings of this preliminary trial, further investigation is mandated with a larger sample of subjects in the context of a double-blind medication trial.

Lactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway.

PubMed

Venkatesan, Ramu; Subedi, Lalita; Yeo, Eui-Ju; Kim, Sun Yeou

2016-10-01

Cholinergic activity plays a vital role in cognitive function, and is reduced in individuals with neurodegenerative diseases. Scopolamine, a muscarinic cholinergic antagonist, has been employed in many studies to understand, identify, and characterize therapeutic targets for Alzheimer's disease (AD). Scopolamine-induced dementia is associated with impairments in memory and cognitive function, as seen in patients with AD. The current study aimed to investigate the molecular mechanisms underlying scopolamine-induced cholinergic neuronal dysfunction and the neuroprotective effect of lactucopicrin, an inhibitor of acetylcholine esterase (AChE). We investigated apoptotic cell death, caspase activation, generation of reactive oxygen species (ROS), mitochondrial dysfunction, and the expression levels of anti- and pro-apoptotic proteins in scopolamine-treated C6 cells. We also analyzed the expression levels of antioxidant enzymes and nuclear factor (erythroid-derived 2)-like 2 (NRF2) in C6 cells and neurite outgrowth in N2a neuroblastoma cells. Our results revealed that 1 h scopolamine pre-treatment induced cytotoxicity by increasing apoptotic cell death via oxidative stress-mediated caspase 3 activation and mitochondrial dysfunction. Scopolamine also downregulated the expression the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase, and the transcription factor NRF2. Lactucopicrin treatment protected C6 cells from scopolamine-induced toxicity by reversing the effects of scopolamine on those markers of toxicity. In addition, scopolamine attenuated the secretion of neurotrophic nerve growth factor (NGF) in C6 cells and neurite outgrowth in N2a cells. As expected, lactucopicrin treatment enhanced NGF secretion and neurite outgrowth. Our study is the first to show that lactucopicrin, a potential neuroprotective agent, ameliorates scopolamine-induced cholinergic dysfunction via NRF2 activation and subsequent expression of antioxidant enzymes. Copyright © 2016. Published by Elsevier Ltd.

Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice

PubMed Central

Hemmati, Ali Asghar; Ahangarpour, Akram

2018-01-01

The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ)-induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30–35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ-induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice. PMID:29719448

Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice.

PubMed

Hemmati, Ali Asghar; Alboghobeish, Soheila; Ahangarpour, Akram

2018-05-01

The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ)-induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30-35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ-induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice.

A Cell Line Producing Recombinant Nerve Growth Factor Evokes Growth Responses in Intrinsic and Grafted Central Cholinergic Neurons

NASA Astrophysics Data System (ADS)

Ernfors, Patrik; Ebendal, Ted; Olson, Lars; Mouton, Peter; Stromberg, Ingrid; Persson, Hakan

1989-06-01

The rat β nerve growth factor (NGF) gene was inserted into a mammalian expression vector and cotransfected with a plasmid conferring resistance to neomycin into mouse 3T3 fibroblasts. From this transfection a stable cell line was selected that contains several hundred copies of the rat NGF gene and produces excess levels of recombinant NGF. Such genetically modified cells were implanted into the rat brain as a probe for in vivo effects of NGF on central nervous system neurons. In a model of the cortical cholinergic deficits in Alzheimer disease, we demonstrate a marked increase in the survival of, and fiber outgrowth from, grafts of fetal basal forebrain cholinergic neurons, as well as stimulation of fiber formation by intact adult intrinsic cholinergic circuits in the cerebral cortex. Adult cholinergic interneurons in intact striatum also sprout vigorously toward implanted fibroblasts. Our results suggest that this model has implications for future treatment of neurodegenerative diseases.

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

PubMed Central

Shekhar, Shashank; Liu, Ruen; Travis, Olivia K; Roman, Richard J; Fan, Fan

2017-01-01

Aging and chronic hypertension are associated with dysfunction in vascular smooth muscle, endothelial cells, and neurovascular coupling. These dysfunctions induce impaired myogenic response and cerebral autoregulation, which diminish the protection of cerebral arterioles to the cerebral microcirculation from elevated pressure in hypertension. Chronic hypertension promotes cerebral focal ischemia in response to reductions in blood pressure that are often seen in sedentary elderly patients on antihypertensive therapy. Cerebral autoregulatory dysfunction evokes Blood-Brain Barrier (BBB) leakage, allowing the circulating inflammatory factors to infiltrate the brain to activate glia. The impaired cerebral autoregulation-induced inflammatory and ischemic injury could cause neuronal cell death and synaptic dysfunction which promote cognitive deficits. In this brief review, we summarize the pathogenesis and signaling mechanisms of cerebral autoregulation in hypertension and ischemic stroke-induced cognitive deficits, and discuss our new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the altered cerebral vascular function. PMID:29333537

Mangifera indica Fruit Extract Improves Memory Impairment, Cholinergic Dysfunction, and Oxidative Stress Damage in Animal Model of Mild Cognitive Impairment

PubMed Central

Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-Mee, Wipawee; Ingkaninan, Kornkanok; Wittaya-Areekul, Sakchai

2014-01-01

To date, the effective preventive paradigm against mild cognitive impairment (MCI) is required. Therefore, we aimed to determine whether Mangifera indica fruit extract, a substance possessing antioxidant and cognitive enhancing effects, could improve memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment. Male Wistar rats, weighing 180–200 g, were orally given the extract at doses of 12.5, 50, and 200 mg·kg−1 BW for 2 weeks before and 1 week after the bilateral injection of AF64A (icv). At the end of study, spatial memory, cholinergic neurons density, MDA level, and the activities of SOD, CAT, and GSH-Px enzymes in hippocampus were determined. The results showed that all doses of extract could improve memory together with the decreased MDA level and the increased SOD and GSH-Px enzymes activities. The increased cholinergic neurons density in CA1 and CA3 of hippocampus was also observed in rats treated with the extract at doses of 50 and 200 mg·kg−1 BW. Therefore, our results suggested that M. indica, the potential protective agent against MCI, increased cholinergic function and the decreased oxidative stress which in turn enhanced memory. However, further researches are essential to elucidate the possible active ingredients and detail mechanism. PMID:24672632

Mangifera indica fruit extract improves memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment.

PubMed

Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-Mee, Wipawee; Ingkaninan, Kornkanok; Wittaya-Areekul, Sakchai

2014-01-01

To date, the effective preventive paradigm against mild cognitive impairment (MCI) is required. Therefore, we aimed to determine whether Mangifera indica fruit extract, a substance possessing antioxidant and cognitive enhancing effects, could improve memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment. Male Wistar rats, weighing 180-200 g, were orally given the extract at doses of 12.5, 50, and 200 mg · kg(-1) BW for 2 weeks before and 1 week after the bilateral injection of AF64A (icv). At the end of study, spatial memory, cholinergic neurons density, MDA level, and the activities of SOD, CAT, and GSH-Px enzymes in hippocampus were determined. The results showed that all doses of extract could improve memory together with the decreased MDA level and the increased SOD and GSH-Px enzymes activities. The increased cholinergic neurons density in CA1 and CA3 of hippocampus was also observed in rats treated with the extract at doses of 50 and 200 mg · kg(-1) BW. Therefore, our results suggested that M. indica, the potential protective agent against MCI, increased cholinergic function and the decreased oxidative stress which in turn enhanced memory. However, further researches are essential to elucidate the possible active ingredients and detail mechanism.

Dysfunctional penile cholinergic nerves in diabetic impotent men

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

Blanco, R.; Saenz de Tejada, I.; Goldstein, I.

1990-08-01

Impotence in the diabetic man may be secondary to a neuropathic condition of the autonomic penile nerves. The relationship between autonomic neuropathy and impotence in diabetes was studied in human corporeal tissue obtained during implantation of a penile prosthesis in 19 impotent diabetic and 15 nondiabetic patients. The functional status of penile cholinergic nerves was assessed by determining their ability to accumulate tritiated choline (34), and synthesize (34) and release (19) tritiated-acetylcholine after incubation of corporeal tissue with tritiated-choline (34). Tritiated-choline accumulation, and tritiated-acetylcholine synthesis and release were significantly reduced in the corporeal tissue from diabetic patients compared to thatmore » from nondiabetic patients (p less than 0.05). The impairment in acetylcholine synthesis worsened with the duration of diabetes (p less than 0.025). No differences in the parameters measured were found between insulin-dependent (11) and noninsulin-dependent (8) diabetic patients. The ability of the cholinergic nerves to synthesize acetylcholine could not be predicted clinically with sensory vibration perception threshold testing. It is concluded that there is a functional penile neuropathic condition of the cholinergic nerves in the corpus cavernosum of diabetic impotent patients that may be responsible for the erectile dysfunction.« less

Relation between cognition and neural connection from injured cingulum to brainstem cholinergic nuclei in chronic patients with traumatic brain injury.

PubMed

Yoo, Jin-Sun; Kim, Oh Lyong; Kim, Seong Ho; Kim, Min Su; Jang, Sung Ho

2014-01-01

This study investigated the relation between cognition and the neural connection from injured cingulum to brainstem cholinergic nuclei in patients with traumatic brain injury (TBI), using diffusion tensor tractography (DTT). Among 353 patients with TBI, 20 chronic patients who showed discontinuation of both anterior cingulums from the basal forebrain on DTT were recruited for this study. The Wechsler Intelligence Scale and the Memory Assessment Scale (MAS; short-term, verbal, visual and total memory) were used for assessment of cognition. Patients were divided into two groups according to the presence of a neural connection between injured cingulum and brainstem cholinergic nuclei. Eight patients who had a neural connection between injured cingulum and brainstem cholinergic nuclei showed better short-term memory on MAS than 12 patients who did not (p < 0.05). However, other results of neuropsychological testing showed no significant difference (p > 0.05). Better short-term memory in patients who had the neural connection between injured cingulum and brainstem cholinergic nuclei appears to have been attributed to the presence of cholinergic innervation to the cerebral cortex through the neural connection instead of the injured anterior cingulum. The neural connection appears to compensate for the injured anterior cingulum in obtaining cholinergic innervation.

Conversion of elderly to Alzheimer's dementia: role of confluence of hypothermia and senescent stigmata--the plausible pathway.

PubMed

Daulatzai, Mak Adam

2010-01-01

Aging is a consequence of progressive decline in special and somatosensory functions and specific brain stem nuclei. Many senescent stigmata, including hypoxia, hypoxemia, depressed cerebral blood flow and glucose metabolism, diseases of senescence, and their medications all enhance hypothermia as do alcohol, cold environment, and malnutrition. Hypothermia is a critical factor having deleterious impact on brain stem and neocortical functions. Additionally, anesthesia in elderly also promotes hypothermia; anesthetics not only cause consciousness (sensory and motor) changes, but memory impairment as well. Anesthesia inhibits cholinergic pathways, reticular and thalamocortical systems, cortico-cortical connectivity, and causes post-operative delirium and cognitive dysfunction. Increasing evidence indicates that anesthetic exposures may contribute to dementia onset and Alzheimer's disease (AD) in hypothermic elderly. Inhaled anesthetics potentiate caspases, BACE, tau hyperphosphorylation, and apoptosis. This paper addresses the important question: "Why do only some elderly fall victim to AD"? Based on information on the pathogenesis of early stages of cognitive dysfunction in elderly (i.e., due to senescent stigmata), and the effects of anesthesia superimposed, a detailed plausible neuropathological substrate (mechanism/pathway) is delineated here that reveals the possible cause(s) of AD. Basically, it encompasses several risk factors for cognitive dysfunction during senescence plus several hypothermia-enhancing routes; they all converge and tip the balance towards dementia onset. This knowledge of the confluence of heterogeneous risk factors in perpetuating dementia relentlessly is of importance in order to: (a) avoid their convergence; (b) take measures to stop/reverse cognitive dysfunction; and (c) to develop therapeutic strategies to enhance cognitive function and attenuate AD.

Cerebral Dysfunctions Related to Perinatal Organic Damage: Clinical-Neuropathologic Correlations.

ERIC Educational Resources Information Center

Towbin, Abraham

1978-01-01

Recent neuropathology studies identify hypoxia as the main cause of perinatal cerebral damage. Cerebral lesions present at birth, with transition to chronic scar lesions, are correlated to mental retardation, cerebral palsy, epilepsy, and minimal brain dysfunction. Gestation age and severity of hypoxic exposure essentially determine the cerebral…

Bedside diagnosis of mitochondrial dysfunction after malignant middle cerebral artery infarction.

PubMed

Nielsen, T H; Schalén, W; Ståhl, N; Toft, P; Reinstrup, P; Nordström, C H

2014-08-01

The study explores whether the cerebral biochemical pattern in patients treated with hemicraniectomy after large middle cerebral artery infarcts reflects ongoing ischemia or non-ischemic mitochondrial dysfunction. The study includes 44 patients treated with decompressive hemicraniectomy (DCH) due to malignant middle cerebral artery infarctions. Chemical variables related to energy metabolism obtained by microdialysis were analyzed in the infarcted tissue and in the contralateral hemisphere from the time of DCH until 96 h after DCH. Reperfusion of the infarcted tissue was documented in a previous report. Cerebral lactate/pyruvate ratio (L/P) and lactate were significantly elevated in the infarcted tissue compared to the non-infarcted hemisphere (p < 0.05). From 12 to 96 h after DCH the pyruvate level was significantly higher in the infarcted tissue than in the non-infarcted hemisphere (p < 0.05). After a prolonged period of ischemia and subsequent reperfusion, cerebral tissue shows signs of protracted mitochondrial dysfunction, characterized by a marked increase in cerebral lactate level with a normal or increased cerebral pyruvate level resulting in an increased LP-ratio. This biochemical pattern contrasts to cerebral ischemia, which is characterized by a marked decrease in cerebral pyruvate. The study supports the hypothesis that it is possible to diagnose cerebral mitochondrial dysfunction and to separate it from cerebral ischemia by microdialysis and bed-side biochemical analysis.

Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.

PubMed

Tozzi, Alessandro; de Iure, Antonio; Bagetta, Vincenza; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Costa, Cinzia; Di Filippo, Massimiliano; Ghiglieri, Veronica; Latagliata, Emanuele Claudio; Wegrzynowicz, Michal; Decressac, Mickael; Giampà, Carmela; Dalley, Jeffrey W; Xia, Jing; Gardoni, Fabrizio; Mellone, Manuela; El-Agnaf, Omar Mukhtar; Ardah, Mustafa Taleb; Puglisi-Allegra, Stefano; Björklund, Anders; Spillantini, Maria Grazia; Picconi, Barbara; Calabresi, Paolo

2016-03-01

Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Neuroanatomy and neurophysiology related to sexual dysfunction in male neurogenic patients with lesions to the spinal cord or peripheral nerves.

PubMed

Everaert, K; de Waard, W I Q; Van Hoof, T; Kiekens, C; Mulliez, T; D'herde, C

2010-03-01

Review article. The neuroanatomy and physiology of psychogenic erection, cholinergic versus adrenergic innervation of emission and the predictability of outcome of vibration and electroejaculation require a review and synthesis. University Hospital Belgium. We reviewed the literature with PubMed 1973-2008. Erection, emission and ejaculation are separate phenomena and have different innervations. It is important to realize, which are the afferents and efferents and where the motor neuron of the end organ is located. When interpreting a specific lesion it is important to understand if postsynaptic fibres are intact or not. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. For vibratory-evoked ejaculation, the reflex arch must be complete; for electroejaculation, the postsynaptic neurons (paravertebral ganglia) must be intact. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. In neurogenic disease, a good knowledge of neuroanatomy and physiology makes understanding of sexual dysfunction possible and predictable. The minimal requirement for the success of penile vibration is a preserved reflex arch and the minimal requirement for the success of electroejaculation is the existence of intact post-ganglionic fibres.

Urtica dioica leaves modulates muscarinic cholinergic system in the hippocampus of streptozotocin-induced diabetic mice.

PubMed

Patel, Sita Sharan; Parashar, Arun; Udayabanu, Malairaman

2015-06-01

Diabetes mellitus is a chronic metabolic disorder and has been associated with cognitive dysfunction. In our earlier study, chronic Urtica dioica (UD) treatment significantly ameliorated diabetes induced associative and spatial memory deficit in mice. The present study was designed to explore the effect of UD leaves extract on muscarinic cholinergic system, which has long been known to be involved in cognition. Streptozotocin (STZ) (50 mg/kg, i.p., consecutively for 5 days) was used to induce diabetes followed by treatment with UD extract (50 mg/kg, oral) or rosiglitazone (5 mg/kg, oral) for 8 weeks. STZ-induced diabetic mice showed significant reduction in hippocampal muscarinic acetylcholine receptor-1 and choline acetyltransferase expressions. Chronic diabetes significantly up-regulated the protein expression of acetylcholinesterase associated with oxidative stress in hippocampus. Besides, STZ-induced diabetic mice showed hypolocomotion with up-regulation of muscarinic acetylcholine receptor-4 expression in striatum. Chronic UD treatment significantly attenuated the cholinergic dysfunction and oxidative stress in the hippocampus of diabetic mice. UD had no effect on locomotor activity and muscarinic acetylcholine receptor-4 expression in striatum. In conclusion, UD leaves extract has potential to reverse diabetes mediated alteration in muscarinic cholinergic system in hippocampus and thereby improve memory functions.

Electroacupuncture brain protection during ischemic stroke: A role for the parasympathetic nervous system.

PubMed

Chi, Laiting; Du, Kairong; Liu, Dongdong; Bo, Yulong; Li, Wenzhi

2018-03-01

The demand for using parasympathetic activation for stroke therapy is unmet. In the current study, we investigated whether the neuroprotection provided by electroacupuncture (EA) in an experimental stroke model was associated with activation of the parasympathetic nervous system (PNS). The results showed that parasympathetic dysfunction (PD), performed as unilateral vagotomy combined with peripheral atropine, attenuated both the functional benefits of EA and its effects in improving cerebral perfusion, reducing infarct volume, and hindering apoptosis, neuronal and peripheral inflammation, and oxidative stress. Most importantly, EA rats showed a dramatically less reduction in the mRNA level of choline acetyltransferase, five subtypes of muscarinic receptors and α7nAChR, suggesting the inhibition of the impairment of the central cholinergic system; EA also activated dorsal motor nucleus of the vagus, the largest source of parasympathetic pre-ganglionic neurons in the lower brainstem (detected by c-fos immunohistochemistry), and PD suppressed these changes. These findings indicated EA may serve as an alternative modality of PNS activation for stroke therapy.

Experimental and clinical study of EHF treatment of vascular-vestibular dysfunction

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

Mal`tsev, A.E.; Abakarov, A.T.; Istomin, V.S.

1994-07-01

The authors present the results of a study of the effectiveness of EHF radiation on the cerebral hemodynamics, bioelectrical activity of the cerebral cortex, and functional state of the vestibular analyzer in chronic studies of cats using a model of vascular-vestibular dysfunction. The clinical part of the work reflects the results of studies of the functional state of cerebral blood circulation and the vestibular analyzer during the EHF treatment of angiovertebrogenic vestibular dysfunction in a background of initial manifestations of cerebral blood supply deficiency (angiodistonic variant).

Optogenetic stimulation of cholinergic projection neurons as an alternative for deep brain stimulation for Alzheimer's treatment

NASA Astrophysics Data System (ADS)

Mancuso, James; Chen, Yuanxin; Zhao, Zhen; Li, Xuping; Xue, Zhong; Wong, Stephen T. C.

2013-03-01

Deep brain stimulation (DBS) of the cholinergic nuclei has emerged as a powerful potential treatment for neurodegenerative disease and is currently in a clinical trial for Alzheimer's therapy. While effective in treatment for a number of conditions from depression to epilepsy, DBS remains somewhat unpredictable due to the heterogeneity of the projection neurons that are activated, including glutamatergic, GABAergic, and cholinergic neurons, leading to unacceptable side effects ranging from apathy to depression or even suicidal behavior. It would be highly advantageous to confine stimulation to specific populations of neurons, particularly in brain diseases involving complex network interactions such as Alzheimer's. Optogenetics, now firmly established as an effective approach to render genetically-defined populations of cells sensitive to light activation including mice expressing Channelrhodopsin-2 specifically in cholinergic neurons, provides just this opportunity. Here we characterize the light activation properties and cell density of cholinergic neurons in healthy mice and mouse models of Alzheimer's disease in order to evaluate the feasibility of using optogenetic modulation of cholinergic synaptic activity to slow or reverse neurodegeneration. This paper is one of the very first reports to suggest that, despite the anatomical depth of their cell bodies, cholinergic projection neurons provide a better target for systems level optogenetic modulation than cholinergic interneurons found in various brain regions including striatum and the cerebral cortex. Additionally, basal forebrain channelrhodopsin-expressing cholinergic neurons are shown to exhibit normal distribution at 60 days and normal light activation at 40 days, the latest timepoints observed. The data collected form the basis of ongoing computational modeling of light stimulation of entire populations of cholinergic neurons.

Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats.

PubMed

Yadav, Rajesh S; Chandravanshi, Lalit P; Shukla, Rajendra K; Sankhwar, Madhu L; Ansari, Reyaz W; Shukla, Pradeep K; Pant, Aditya B; Khanna, Vinay K

2011-12-01

Our recent studies have shown that curcumin protects arsenic induced neurotoxicity by modulating oxidative stress, neurotransmitter levels and dopaminergic system in rats. As chronic exposure to arsenic has been associated with cognitive deficits in humans, the present study has been carried out to implore the neuroprotective potential of curcumin in arsenic induced cholinergic dysfunctions in rats. Rats treated with arsenic (sodium arsenite, 20mg/kg body weight, p.o., 28 days) exhibited a significant decrease in the learning activity, assessed by passive avoidance response associated with decreased binding of (3)H-QNB, known to label muscarinic-cholinergic receptors in hippocampus (54%) and frontal cortex (27%) as compared to controls. Decrease in the activity of acetylcholinesterase in hippocampus (46%) and frontal cortex (33%), staining of Nissl body, immunoreactivity of choline acetyltransferase (ChAT) and expression of ChAT protein in hippocampal region was also observed in arsenic treated rats as compared to controls. Simultaneous treatment with arsenic and curcumin (100mg/kg body weight, p.o., 28 days) increased learning and memory performance associated with increased binding of (3)H-QNB in hippocampus (54%), frontal cortex (25%) and activity of acetylcholinesterase in hippocampus (41%) and frontal cortex (29%) as compared to arsenic treated rats. Increase in the expression of ChAT protein, immunoreactivity of ChAT and staining of Nissl body in hippocampal region was also observed in rats simultaneously treated with arsenic and curcumin as compared to those treated with arsenic alone. The results of the present study suggest that curcumin significantly modulates arsenic induced cholinergic dysfunctions in brain and also exhibits neuroprotective efficacy of curcumin. Copyright © 2011 Elsevier Inc. All rights reserved.

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum.

PubMed

Mattsson, Anna; Olson, Lars; Svensson, Torgny H; Schilström, Björn

2007-11-01

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging

PubMed Central

Toth, Peter; Tarantini, Stefano; Csiszar, Anna

2017-01-01

Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including Alzheimer’s disease. Understanding and targeting the age-related pathophysiological mechanisms that underlie vascular contributions to cognitive impairment and dementia (VCID) are expected to have a major role in preserving brain health in older individuals. Maintenance of cerebral perfusion, protecting the microcirculation from high pressure-induced damage and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. This overview discusses age-related alterations in three main regulatory paradigms involved in the regulation of cerebral blood flow (CBF): cerebral autoregulation/myogenic constriction, endothelium-dependent vasomotor function, and neurovascular coupling responses responsible for functional hyperemia. The pathophysiological consequences of cerebral microvascular dysregulation in aging are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages, microvascular rarefaction, and ischemic neuronal dysfunction and damage. Due to the widespread attention that VCID has captured in recent years, the evidence for the causal role of cerebral microvascular dysregulation in cognitive decline is critically examined. PMID:27793855

Idiopathic pure sudomotor failure and cholinergic urticaria in a patient after acute infectious mononucleosis infection.

PubMed

Chin, Y-Y; Chang, T C-C; Chang, C-H

2013-03-01

Idiopathic pure sudomotor failure (IPSF) is a subgroup of acquired idiopathic generalized anhidrosis, which is characterized by early age of onset, acute or sudden onset, concomitant sharp pain or cholinergic urticaria over the entire body, absence of autonomic dysfunction other than generalized anhidrosis, raised serum IgE level, and marked response to steroid. The aetiology of IPSF is still not well understood, but is thought to be caused by interference in cholinergic transmission in the eccrine glands of skin. IPSF after viral infection has rarely been reported in the literature. We describe a patient who developed generalized anhidrosis and cholinergic urticaria accompanied by heat intolerance after infectious mononucleosis infection. This is the first such case, to our knowledge, and the patient was successfully treated with steroid pulse therapy. © The Author(s). CED © 2012 British Association of Dermatologists.

The involvement of cholinergic and noradrenergic systems in behavioral recovery following oxotremorine treatment to chronically stressed rats.

PubMed

Srikumar, B N; Raju, T R; Shankaranarayana Rao, B S

2006-12-01

Chronic stress in rats has been shown to impair learning and memory, and precipitate several affective disorders like depression and anxiety. The mechanisms involved in these stress-induced disorders and the possible reversal are poorly understood, thus limiting the number of drugs available for their treatment. Our earlier studies suggest cholinergic dysfunction as the underlying cause in the behavioral deficits following stress. Muscarinic cholinergic agonist, oxotremorine is demonstrated to have a beneficial effect in reversing brain injury-induced behavioral dysfunction. In this study, we have evaluated the effect of oxotremorine treatment on chronic restraint stress-induced cognitive deficits. Rats were subjected to restraint stress (6 h/day) for 21 days followed by oxotremorine treatment for 10 days. Spatial learning and memory was assessed in a partially baited eight-arm radial maze task. Stressed rats exhibited impairment in performance, with decreased percentage of correct choices and an increase in the number of reference memory errors (RMEs). Oxotremorine treatment (0.1 or 0.2 mg/kg, i.p.) to stressed rats resulted in a significant increase in the percent correct choices and a decrease in the number of RMEs compared with stress as well as the stress+vehicle-treated groups. In the retention test, oxotremorine treated rats committed less RMEs compared with the stress group. Chronic restraint stress decreased acetylcholinesterase (AChE) activity in the hippocampus, frontal cortex and septum, which was reversed by both the doses of oxotremorine. Further, oxotremorine treatment also restored the norepinephrine levels in the hippocampus and frontal cortex. Thus, this study demonstrates the potential of cholinergic muscarinic agonists and the involvement of both cholinergic and noradrenergic systems in the reversal of stress-induced learning and memory deficits.

The role of cerebral hyperperfusion in postoperative neurologic dysfunction after left ventricular assist device implantation for end-stage heart failure.

PubMed

Lietz, Katherine; Brown, Kevin; Ali, Syed S; Colvin-Adams, Monica; Boyle, Andrew J; Anderson, David; Weinberg, Alan D; Miller, Leslie W; Park, Soon; John, Ranjit; Lazar, Ronald M

2009-04-01

Cerebral hyperperfusion is a life-threatening syndrome that can occur in patients with chronically hypoperfused cerebral vasculature whose normal cerebral circulation was re-established after carotid endarterectomy or angioplasty. We sought to determine whether the abrupt restoration of perfusion to the brain after left ventricular assist device (LVAD) implantation produced similar syndromes. We studied the role of increased systemic flow after LVAD implantation on neurologic dysfunction in 69 consecutive HeartMate XVE LVAD (Thoratec, Pleasanton, Calif) recipients from October 2001 through June 2006. Neurologic dysfunction was defined as postoperative permanent or transient central change in neurologic status, including confusion, focal neurologic deficits, visual changes, seizures, or coma for more than 24 hours within 30 days after LVAD implantation. We found that 19 (27.5%) patients had neurologic dysfunction, including encephalopathy (n = 11), coma (n = 3), and other complications (n = 5). The multivariate analysis showed that an increase in cardiac index from the preoperative baseline value (relative risk, 1.33 per 25% cardiac index increase; P = .01) and a previous coronary bypass operation (relative risk, 4.53; P = .02) were the only independent predictors of neurologic dysfunction. Reduction of left ventricular assist device flow in 16 of the 19 symptomatic patients led to improvement of symptoms in 14 (87%) patients. Our findings showed that normal flow might overwhelm cerebral autoregulation in patients with severe heart failure, suggesting that cerebral hyperperfusion is possible in recipients of mechanical circulatory support with neurologic dysfunction.

Cholinergic autonomic dysfunction in veterans with Gulf War illness: confirmation in a population-based sample.

PubMed

Haley, Robert W; Charuvastra, Elizabeth; Shell, William E; Buhner, David M; Marshall, W Wesley; Biggs, Melanie M; Hopkins, Steve C; Wolfe, Gil I; Vernino, Steven

2013-02-01

The authors of prior small studies raised the hypothesis that symptoms in veterans of the 1991 Gulf War, such as chronic diarrhea, dizziness, fatigue, and sexual dysfunction, are due to cholinergic autonomic dysfunction. To perform a confirmatory test of this prestated hypothesis in a larger, representative sample of Gulf War veterans. Nested case-control study. Clinical and Translational Research Center, University of Texas Southwestern Medical Center, Dallas. Representative samples of Gulf War veterans meeting a validated case definition of Gulf War illness with 3 variants (called syndromes 1-3) and a control group, all selected randomly from the US Military Health Survey. Validated domain scales from the Autonomic Symptom Profile questionnaire, the Composite Autonomic Severity Score, and high-frequency heart rate variability from a 24-hour electrocardiogram. The Autonomic Symptom Profile scales were significantly elevated in all 3 syndrome groups (P< .001), primarily due to elevation of the orthostatic intolerance, secretomotor, upper gastrointestinal dysmotility, sleep dysfunction, urinary, and autonomic diarrhea symptom domains. The Composite Autonomic Severity Score was also higher in the 3 syndrome groups (P= .045), especially in syndrome 2, primarily due to a significant reduction in sudomotor function as measured by the Quantitative Sudomotor Axon Reflex Test, most significantly in the foot; the score was intermediate in the ankle and upper leg and was nonsignificant in the arm, indicating a peripheral nerve length-related deficit. The normal increase in high-frequency heart rate variability at night was absent or blunted in all 3 syndrome groups (P< .001). Autonomic symptoms are associated with objective, predominantly cholinergic autonomic deficits in the population of Gulf War veterans.

Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus

PubMed Central

Zhang, Ying; Cao, Shu-Xia; Sun, Peng; He, Hai-Yang; Yang, Ci-Hang; Chen, Xiao-Juan; Shen, Chen-Jie; Wang, Xiao-Dong; Chen, Zhong; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

2016-01-01

Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2−/y) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2−/y mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2−/y mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes. PMID:27103432

Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus.

PubMed

Zhang, Ying; Cao, Shu-Xia; Sun, Peng; He, Hai-Yang; Yang, Ci-Hang; Chen, Xiao-Juan; Shen, Chen-Jie; Wang, Xiao-Dong; Chen, Zhong; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

2016-06-01

Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.

Incidence of the WAIS-R Fuld profile in HIV-1 infection.

PubMed

van Gorp, W G; Tulin, S J; Evans, G; Satz, P

1990-10-01

The incidence of a WAIS-R subtest "marker" sensitive to cholinergic dysfunction was assessed in a sample 116 homosexual males infected with HIV (Acquired Immunodeficiency Syndrome [AIDS] N = 40; AIDS Related Complex [ARC], N = 76). The incidence of positive profiles was low in the overall sample (11/116, 9%), and significantly lower than incidence rates reported for known cholinergic deficient groups (Alzheimer's disease; scopolamine). However, significantly more AIDS patients (8/40, 20%) than ARC patients (3/76, 4%) demonstrated positive profiles. These results suggest that, as a group, persons with ARC or AIDS do not show an increased incidence of the Fuld profile associated with cholinergic disruption, and offer continued support for diagnostic specificity of the Fuld formula for Alzheimer's disease.

Extinction and recovery of an avoidance memory impaired by scopolamine.

PubMed

Navarro, N M; Krawczyk, M C; Boccia, M M; Blake, M G

2017-03-15

Pre-training administration of scopolamine (SCP) resembles situations of cholinergic dysfunction, leading to memory impairment of mice trained in an inhibitory avoidance task. We suggest here that SCP does not impair memory formation, but acquisition is affected in a way that reduces the strength of the stored memory, thus making this memory less able to control behavior when tested. Hence, a memory trace is stored, but is poorly expressed during the test. Although weakly expressed, this memory shows extinction during successive tests, and can be strengthened by using a reminder. Our results indicate that memories stored under cholinergic dysfunction conditions seem absent or lost, but are in fact present and experience common memory processes, such as extinction, and could be even recovered by using appropriate protocols. Copyright © 2017 Elsevier Inc. All rights reserved.

Isoflurane prevents neurocognitive dysfunction after cardiopulmonary bypass in rats.

PubMed

Li, Wen; Zheng, Beijie; Xu, Huan; Deng, Yuxiao; Wang, Shuyan; Wang, Xiangrui; Su, Diansan

2013-06-01

Postoperative cognitive dysfunction occurs frequently after cardiac surgeries with cardiopulmonary bypass (CPB). Available data from rat CPB models are conflicting. However, none of them was designed to investigate the role of isoflurane (the main anesthetic in all of these studies) in the neurocognitive dysfunction after CPB. Isoflurane has documented neuroprotective effects so the present authors hypothesized that isoflurane prevents the neurocognitive dysfunction in rats after CPB. A prospective, interventional study. A university research laboratory. Male Sprague-Dawley rats. Male Sprague-Dawley rats were divided into 5 groups: the isoflurane CPB group, the animals were anesthetized with isoflurane and underwent 60 minutes of normothermic CPB; the chloral hydrate CPB group, the animals were anesthetized with chloral hydrate and underwent 60 minutes of normothermic CPB; the isoflurane sham group, the animals were subjected only to cannulation and the same duration of anesthesia but no CPB; the chloral hydrate sham group, the animals received only cannulation and the same duration of anesthesia but no CPB; and the naive group, the animals received no treatment. The neurocognitive function of all rats was measured on days 4 to 6 (short-term) and 31 to 33 after CPB (long-term). After the behavior tests, the animals were sacrificed, and the brain was harvested for the measurement of acetylcholinesterase (AChE) and choline acetyltransferase protein levels. Short-term (days 4-6 after CPB) learning and memory were impaired after CPB when the animals were anesthetized with chloral hydrate. When isoflurane was used, the learning and memory did not change after CPB. No long-term (days 31-33 after CPB) neurocognitive changes were found after CPB. AChE decreased significantly after isoflurane anesthesia regardless of whether CPB was performed. Isoflurane prevented the neurocognitive dysfunction induced by CPB, which might involve the cerebral cholinergic system. Copyright © 2013 Elsevier Inc. All rights reserved.

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β-amyloid in ageing and Alzheimer's disease.

PubMed

Weinreb, Orly; Amit, Tamar; Bar-Am, Orit; Youdim, Moussa B H

2016-07-01

Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid β peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the Faculty of Medicine and Director of Eve Topf Center of Excellence in Technion-Israel Institute of Technology, and Chief Scientific Officer of ABITAL Pharma Pipeline Ltd., at the occasion of his 75th birthday. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. © 2015 The British Pharmacological Society.

BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer's disease.

PubMed

Burke, Rebecca M; Norman, Timothy A; Haydar, Tarik F; Slack, Barbara E; Leeman, Susan E; Blusztajn, Jan Krzysztof; Mellott, Tiffany J

2013-11-26

Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aβ42-positive amyloid plaques in the hippocampus and cerebral cortex of 5- and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aβ42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.

Brain cholinergic involvement during the rapid development of tolerance to morphine

NASA Technical Reports Server (NTRS)

Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

1987-01-01

The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

Cholinergic, serotoninergic and peptidergic components of the nervous system of Discocotyle sagittata (Monogenea:Polyopisthocotylea).

PubMed

Cable, J; Marks, N J; Halton, D W; Shaw, C; Johnston, C F; Tinsley, R C; Gannicott, A M

1996-12-01

Cholinergic, serotoninergic (5-HT) and peptidergic neuronal pathways have been demonstrated in both central and peripheral nervous systems of adult Discocotyle sagittata, using enzyme histochemistry and indirect immunocytochemistry in conjunction with confocal scanning laser microscopy. Antisera to 2 native flatworm neuropeptides, neuropeptide F and the FMRFamide-related peptide (FaRP), GNFFRFamide, were employed to detect peptide immunoreactivity. The CNS is composed of paired cerebral ganglia and connecting dorsal commissure, together with several paired longitudinal nerve cords. The main longitudinal nerve cords (lateral, ventral and dorsal) are interconnected at intervals by a series of annular cross-connectives, producing a ladder-like arrangement typical of the platyhelminth nervous system. At the level of the haptor, the ventral cords provide nerve roots which innervate each of the 9 clamps. Cholinergic and peptidergic neuronal organisation was similar, but distinct from that of the serotoninergic components. The PNS and reproductive system are predominantly innervated by peptidergic neurones.

Increased interactions between PKA and NF-κB signaling in the hippocampus following loss of cholinergic input.

PubMed

Lim, C S; Hwang, Y K; Kim, D; Cho, S H; Bañuelos, C; Bizon, J L; Han, J-S

2011-09-29

Neuropsychiatric disorders such as depression are frequently associated with Alzheimer's disease (AD) and the degeneration of cholinergic basal forebrain neurons and reductions in acetylcholine that occur in AD have been identified as potential mediators of these secondary neuropsychiatric symptomologies. Indeed, removal of cholinergic innervation to the hippocampus via selective immunolesions of septohippocampal cholinergic neurons induces dysfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis and decreases glucocorticoid receptor expression (GR). A subsequent study showed that loss of cholinergic input decreases the activity of the catalytic subunit of protein kinase A (PKAc) and lessens the interaction of protein kinase A (PKA) with GR. Because cross-coupling between nuclear factor-κB (NF-κB) p65 and GR depends on PKA signaling, the present study was conducted to evaluate the status of NF-κB as well as interactions of PKA with NF-κB in the hippocampus following cholinergic denervation. Expression of cytosolic NF-κB p65 was diminished and IκB was degraded in the hippocampus of cholinergic immunolesioned rats compared to the controls. Immunolesions also increased NF-κB p65 Ser276 phosphorylation, as well as interactions between PKAc and NF-κB p65. These results indicate that loss of cholinergic input to the hippocampus results in decreased PKA activity and increased NF-κB activity. Such altered signaling may contribute to psychiatric symptoms, including depression, in patients with AD. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

The Cholinergic Signaling Responsible for the Expression of a Memory-Related Protein in Primary Rat Cortical Neurons.

PubMed

Chen, Tsan-Ju; Chen, Shun-Sheng; Wang, Dean-Chuan; Hung, Hui-Shan

2016-11-01

Cholinergic dysfunction in the brain is closely related to cognitive impairment including memory loss. In addition to the degeneration of basal forebrain cholinergic neurons, deficits in the cholinergic receptor signaling may also play an important role. In the present study, to examine the cholinergic signaling pathways responsible for the induction of a memory-related postsynaptic protein, a cholinergic agonist carbachol was used to induce the expression of activity-regulated cytoskeleton associated protein (Arc) in primary rat cortical neurons. After pretreating neurons with various antagonists or inhibitors, the levels of carbachol-induced Arc protein expression were detected by Western blot analysis. The results show that carbachol induces Arc protein expression mainly through activating M1 acetylcholine receptors and the downstream phospholipase C pathway, which may lead to the activation of the MAPK/ERK signaling pathway. Importantly, carbachol-mediated M2 receptor activation exerts negative effects on Arc protein expression and thus counteracts the enhanced effects of M1 activation. Furthermore, it is suggested for the first time that M1-mediated enhancement of N-methyl-D-aspartate receptor (NMDAR) responses, leading to Ca(2+) entry through NMDARs, contributes to carbachol-induced Arc protein expression. These findings reveal a more complete cholinergic signaling that is responsible for carbachol-induced Arc protein expression, and thus provide more information for developing treatments that can modulate cholinergic signaling and consequently alleviate cognitive impairment. J. Cell. Physiol. 231: 2428-2438, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Selective preservation of cholinergic MeCP2 rescues specific Rett-syndrome-like phenotypes in MeCP2stop mice.

PubMed

Zhou, Huanhuan; Wu, Wei; Zhang, Ying; He, Haiyang; Yuan, Zhefeng; Zhu, Zhiwei; Zhao, Zhengyan

2017-03-30

RTT is a neurodevelopmental disorder characterized by growth regression, motor dysfunction, stereotypic hand movements, and autism features. Typical Rett syndrome (RTT) is predominantly caused by mutations in X-linked MeCP2 gene which encodes methyl-CpG-binding protein 2 (MeCP2). The brain-abundant MeCP2 protein mainly functions as a transcriptional regulator for neurodevelopment-associated genes. Specific functions of MeCP2 in certain neuron types remain to be known. Although cholinergic system is an important modulating system in brain, how MeCP2 in cholinergic neurons contribute to RTT has not been clearly understood. Here we use a mouse model with selectively activated endogenous MeCP2 in cholinergic neurons in otherwise MeCP2 stop mice to determine the cholinergic MeCP2 effects on rescuing the RTT-like phenotypes. We found cholinergic MeCP2 preservation could reverse some aspects of the RTT-like phenotypes in mice including hypolocomotion and increased anxiety level, and delay the onset of underweight, instead of improving the hypersocial abnormality and the poor general conditions such as short lifespan, low brain weight, and increasing severity score. Our findings suggest that selective activation of cholinergic MeCP2 is sufficient to reverse the locomotor impairment and increased anxiety-like behaviors at least in early symptomatic stage, supporting future development of RTT therapies associated with cholinergic system. Copyright © 2017 Elsevier B.V. All rights reserved.

Cholinergic Overstimulation Attenuates Rule Selectivity in Macaque Prefrontal Cortex.

PubMed

Major, Alex J; Vijayraghavan, Susheel; Everling, Stefan

2018-01-31

Acetylcholine is released in the prefrontal cortex (PFC) and is a key modulator of cognitive performance in primates. Cholinergic stimulation has been shown to have beneficial effects on performance of cognitive tasks, and cholinergic receptors are being actively explored as promising targets for ameliorating cognitive deficits in Alzheimer's disease. We hypothesized that cholinergic stimulation of PFC during performance of a cognitive task would augment neuronal activity and neuronal coding of task attributes. We iontophoretically applied the general cholinergic receptor agonist carbachol onto neurons in dorsolateral PFC (DLPFC) of male rhesus macaques performing rule-guided prosaccades and antisaccades, a well established oculomotor task for testing cognitive control. Carbachol application had heterogeneous effects on neuronal excitability, with both excitation and suppression observed in significant proportions. Contrary to our prediction, neurons with rule-selective activity exhibited a reduction in selectivity during carbachol application. Cholinergic stimulation disrupted rule selectivity regardless of whether it had suppressive or excitatory effects on these neurons. In addition, cholinergic stimulation excited putative pyramidal neurons, whereas the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to nonspecific increases in activity. Our results suggest excessive cholinergic stimulation has detrimental effects on DLPFC representations of task attributes. These findings delineate the complexity and heterogeneity of neuromodulation of cerebral cortex by cholinergic stimulation, an area of active exploration with respect to the development of cognitive enhancers. SIGNIFICANCE STATEMENT The neurotransmitter acetylcholine is known to be important for cognitive processes in the prefrontal cortex. Removal of acetylcholine from prefrontal cortex can disrupt short-term memory performance and is reminiscent of Alzheimer's disease, which is characterized by degeneration of acetylcholine-producing neurons. Stimulation of cholinergic receptors is being explored to create cognitive enhancers for the treatment of Alzheimer's disease and other psychiatric diseases. Here, we stimulated cholinergic receptors in prefrontal cortex and examined its effects on neurons that are engaged in cognitive behavior. Surprisingly, cholinergic stimulation decreased neurons' ability to discriminate between rules. This work suggests that overstimulation of acetylcholine receptors could disrupt neuronal processing during cognition and is relevant to the design of cognitive enhancers based on stimulating the cholinergic system. Copyright © 2018 the authors 0270-6474/18/381137-14$15.00/0.

Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

PubMed Central

Ramanathan, Dhakshin S.; Conner, James M.; Anilkumar, Arjun A.

2014-01-01

Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia. PMID:25505106

Lack of effect of oral choline supplement on the concentrations of choline metabolites in human brain.

PubMed

Tan, J; Bluml, S; Hoang, T; Dubowitz, D; Mevenkamp, G; Ross, B

1998-06-01

Recent reports suggest that oral choline supplement may alter the cerebral choline/creatine (Cho/Cr) ratio and might be used to treat neurodegenerative disorders of cholinergic transmission. Using both 1H and 31P MRS, we reexamined the Cho/Cr ratio and quantified cerebral choline and its major constituents: phosphoethanolamine (PE), phosphorylcholine (PC), glycerophosphorylethanolamine (GPE), and glycerophosphorylcholine (GPC). In the four brain locations examined, no significant increases in Cho/Cr, [Cho], or in its major constituents were found in response to an oral challenge of 50 mg/kg of choline bitartrate. Oral choline did not significantly affect human cerebral metabolism in the short term.

The effects of dimethylaminoethanol (deanol) on cerebral cortical neurons.

PubMed

Kostopoulos, G K; Phillis, J W

1975-01-01

2-Dimethylaminoethanol and acetylcholine were iontophoretically tested on deep, spontaneously firing, neurons of the rat cerebral cortex. All identified corticospinal cells and 71% of the unidentified ones were excited by Deanol. Eight percent of the latter group were inhibited. All but one neuron responded similarly to ACh and Deanol, when both substances were tested on the same neuron. Atropine reversibly blocked these responses. The implications of these observations are discussed with regard to cholinergic synapses in the brain and the rationalization of the therapeutic use of Deanol.

Zic2 hypomorphic mutant mice as a schizophrenia model and ZIC2 mutations identified in schizophrenia patients

PubMed Central

Hatayama, Minoru; Ishiguro, Akira; Iwayama, Yoshimi; Takashima, Noriko; Sakoori, Kazuto; Toyota, Tomoko; Nozaki, Yayoi; Odaka, Yuri S.; Yamada, Kazuyuki; Yoshikawa, Takeo; Aruga, Jun

2011-01-01

ZIC2 is a causal gene for holoprosencephaly and encodes a zinc-finger-type transcriptional regulator. We characterized Zic2kd/+ mice with a moderate (40%) reduction in Zic2 expression. Zic2kd/+ mice showed increased locomotor activity in novel environments, cognitive and sensorimotor gating dysfunctions, and social behavioral abnormalities. Zic2kd/+ brain involved enlargement of the lateral ventricle, thinning of the cerebral cortex and corpus callosum, and decreased number of cholinergic neurons in the basal forebrain. Because these features are reminiscent of schizophrenia, we examined ZIC2 variant-carrying allele frequencies in schizophrenia patients and in controls in the Japanese population. Among three novel missense mutations in ZIC2, R409P was only found in schizophrenia patients, and was located in a strongly conserved position of the zinc finger domain. Mouse Zic2 with the corresponding mutation showed lowered transcription-activating capacity and had impaired target DNA-binding and co-factor-binding capacities. These results warrant further study of ZIC2 in the pathogenesis of schizophrenia. PMID:22355535

Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

PubMed Central

Pappas, Samuel S; Darr, Katherine; Holley, Sandra M; Cepeda, Carlos; Mabrouk, Omar S; Wong, Jenny-Marie T; LeWitt, Tessa M; Paudel, Reema; Houlden, Henry; Kennedy, Robert T; Levine, Michael S; Dauer, William T

2015-01-01

Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model. DOI: http://dx.doi.org/10.7554/eLife.08352.001 PMID:26052670

Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation.

PubMed

Micheau, J; Durkin, T P; Destrade, C; Rolland, Y; Jaffard, R

1985-08-01

Thiamine deficiency in both man and animals is known to produce memory dysfunction and cognitive disorders which have been related to an impairment of cholinergic activity. The present experiment was aimed at testing whether, inversely, chronic administration of large doses of sulbutiamine would have a facilitative effect on memory and would induce changes in central cholinergic activity. Accordingly mice received 300 mg/kg of sulbutiamine daily for 10 days. They were then submitted to an appetitive operant level press conditioning test. When compared to control subjects, sulbutiamine treated mice learned the task at the same rate in a single session but showed greatly improved performance when tested 24 hr after partial acquisition of the same task. Parallel neurochemical investigations showed that the treatment induced a slight (+ 10%) but significant increase in hippocampal sodium-dependent high affinity choline uptake. The present findings and previous results suggest that sulbutiamine improves memory formation and that this behavioral effect could be mediated by an increase in hippocampal cholinergic activity.

The Efficacy of the Canter Background Interference Procedure in Identifying Children with Cerebral Dysfunction

ERIC Educational Resources Information Center

Adams, Jerry; Kenny, Thomas J.

1973-01-01

In this study, BIP records previously reported by Kenny (1971) were reused to determine the accuracy of identification of children with cerebral dysfunction and to update the results of using the revised BIP scoring system. (Author)

Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice.

PubMed

Milner, Eric; Zhou, Meng-Liang; Johnson, Andrew W; Vellimana, Ananth K; Greenberg, Jacob K; Holtzman, David M; Han, Byung Hee; Zipfel, Gregory J

2014-10-01

We and others have shown that soluble amyloid β-peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared with young APP mice lacking CAA. Amyloid β-peptide in young APP mice also increases infarction after focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits after transient middle cerebral artery occlusion in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater CBF compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than amyloid β-peptide alone, leading to intra- and postischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury. © 2014 American Heart Association, Inc.

In-vivo measurements of regional acetylcholine esterase activity in degenerative dementia: comparison with blood flow and glucose metabolism.

PubMed

Herholz, K; Bauer, B; Wienhard, K; Kracht, L; Mielke, R; Lenz, M O; Strotmann, T; Heiss, W D

2000-01-01

Memory and attention are cognitive functions that depend heavily on the cholinergic system. Local activity of acetylcholine esterase (AChE) is an indicator of its integrity. Using a recently developed tracer for positron emission tomography (PET), C-11-labeled N-methyl-4-piperidyl-acetate (C11-MP4A), we measured regional AChE activity in 4 non-demented subjects, 4 patients with dementia of Alzheimer type (DAT) and 1 patient with senile dementia of Lewy body type (SDLT), and compared the findings with measurements of blood flow (CBF) and glucose metabolism (CMRGlc). Initial tracer extraction was closely related to CBF. AChE activity was reduced significantly in all brain regions in demented subjects, whereas reduction of CMRGlc and CBF was more limited to temporo-parietal association areas. AChE activity in SDLT was in the lower range of values in DAT. Our results indicate that, compared to non-demented controls, there is a global reduction of cortical AChE activity in dementia. Dementia, cholinergic system, acetylcholine esterase, positron emission tomography, cerebral blood flow, cerebral glucose metabolism.

Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors

PubMed Central

Zaghloul, Nahla; Addorisio, Meghan E.; Silverman, Harold A.; Patel, Hardik L.; Valdés-Ferrer, Sergio I.; Ayasolla, Kamesh R.; Lehner, Kurt R.; Olofsson, Peder S.; Nasim, Mansoor; Metz, Christine N.; Wang, Ping; Ahmed, Mohamed; Chavan, Sangeeta S.; Diamond, Betty; Tracey, Kevin J.; Pavlov, Valentin A.

2017-01-01

Sepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among sepsis survivors discharged from the hospital. There is no clear strategy for managing this lethal chronic sepsis illness, which is associated with severe functional disabilities and cognitive deterioration. Providing insight into the underlying pathophysiology is desperately needed to direct new therapeutic approaches. Previous studies have shown that brain cholinergic signaling importantly regulates cognition and inflammation. Here, we studied the relationship between peripheral immunometabolic alterations and brain cholinergic and inflammatory states in mouse survivors of cecal ligation and puncture (CLP)-induced sepsis. Within 6 days, CLP resulted in 50% mortality vs. 100% survival in sham-operated controls. As compared to sham controls, sepsis survivors had significantly lower body weight, higher serum TNF, interleukin (IL)-1β, IL-6, CXCL1, IL-10, and HMGB1 levels, a lower TNF response to LPS challenge, and lower serum insulin, leptin, and plasminogen activator inhibitor-1 levels on day 14. In the basal forebrain of mouse sepsis survivors, the number of cholinergic [choline acetyltransferase (ChAT)-positive] neurons was significantly reduced. In the hippocampus and the cortex of mouse sepsis survivors, the activity of acetylcholinesterase (AChE), the enzyme that degrades acetylcholine, as well as the expression of its encoding gene were significantly increased. In addition, the expression of the gene encoding the M1 muscarinic acetylcholine receptor was decreased in the hippocampus. In parallel with these forebrain cholinergic alterations, microglial activation (in the cortex) and increased Il1b and Il6 gene expression (in the cortex), and Il1b gene expression (in the hippocampus) were observed in mouse sepsis survivors. Furthermore, microglial activation was linked to decreased cortical ChAT protein expression and increased AChE activity. These results reinforce the notion of persistent inflammation-immunosuppression and catabolic syndrome in sepsis survivors and characterize a previously unrecognized relationship between forebrain cholinergic dysfunction and neuroinflammation in sepsis survivors. This insight is of interest for new therapeutic approaches that focus on brain cholinergic signaling for patients with chronic sepsis illness, a problem with no specific treatment. PMID:29326685

Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions.

PubMed

Roy, Ashbeel; Dakroub, Mouhamed; Tezini, Geisa C S V; Liu, Yin; Guatimosim, Silvia; Feng, Qingping; Salgado, Helio C; Prado, Vania F; Prado, Marco A M; Gros, Robert

2016-02-01

Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. We used mice with genetic deletion of cardiomyocyte-specific VAChT or ChAT and mice overexpressing VAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction compared with angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P < 0.05) in Ang II-treated VAChT-deficient mice (3.61 ± 0.64%) compared with wild-type animals (2.24 ± 0.11%). In contrast, VAChT overexpressing mice did not display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure. © FASEB.

Nicotinic Cholinergic Receptor Binding Sites in the Brain: Regulation in vivo

NASA Astrophysics Data System (ADS)

Schwartz, Rochelle D.; Kellar, Kenneth J.

1983-04-01

Tritiated acetylcholine was used to measure binding sites with characteristics of nicotinic cholinergic receptors in rat brain. Regulation of the binding sites in vivo was examined by administering two drugs that stimulate nicotinic receptors directly or indirectly. After 10 days of exposure to the cholinesterase inhibitor diisopropyl fluorophosphate, binding of tritiated acetylcholine in the cerebral cortex was decreased. However, after repeated administration of nicotine for 10 days, binding of tritiated acetylcholine in the cortex was increased. Saturation analysis of tritiated acetylcholine binding in the cortices of rats treated with diisopropyl fluorophosphate or nicotine indicated that the number of binding sites decreased and increased, respectively, while the affinity of the sites was unaltered.

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

PubMed Central

Jaunarajs, K.L. Eskow; Bonsi, P.; Chesselet, M.F.; Standaert, D.G.; Pisani, A.

2015-01-01

Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestion of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia. PMID:25697043

The memory-ameliorating effects of Artemisia princeps var. orientalis against cholinergic dysfunction in mice.

PubMed

Liu, Xiaotong; Kim, Dong Hyun; Kim, Jong Min; Park, Se Jin; Cai, Mudan; Jang, Dae Sik; Ryu, Jong Hoon

2012-01-01

Artemisia princeps var. orientalis (Compositae) is widely distributed in China, Japan and Korea and is known to have anti-inflammatory and anti-oxidative activities. The ethyl acetate fraction of ethanolic extract of A. princeps var. orientalis (AEA) was found to inhibit acetylcholinesterase activity in a dose-dependent manner in vitro (IC(50) value: 541.4 ± 67.5 μg/ml). Therefore, we investigated the effects of AEA on scopolamine-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. AEA (100 or 200 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (p < 0.05). In the Morris water maze task, AEA (200 mg/kg, p.o.) significantly shortened escape latencies in training trials and increased both swimming time spent in the target zone and probe crossing numbers during the probe trial as compared with scopolamine-treated mice (p < 0.05). Additionally, the ameliorating effect of AEA on scopolamine-induced memory impairment was antagonized by a subeffective dose of MK-801. These results suggest that AEA could be an effective treatment against cholinergic dysfunction and its effect is mediated by the enhancement of the cholinergic neurotransmitter system via NMDA receptor signaling or acetylcholinesterase inhibition.

Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter.

PubMed

English, Brett A; Appalsamy, Martin; Diedrich, Andre; Ruggiero, Alicia M; Lund, David; Wright, Jane; Keller, Nancy R; Louderback, Katherine M; Robertson, David; Blakely, Randy D

2010-09-01

Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT(-/-)) mice exhibit early postnatal lethality, CHT heterozygous (CHT(+/-)) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT(+/-) mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT(+/-) mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT(+/-) mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease.

Cholinergic and dopaminergic activities in senile dementia of Lewy body type.

PubMed

Perry, E K; Marshall, E; Perry, R H; Irving, D; Smith, C J; Blessed, G; Fairbairn, A F

1990-01-01

Analyses of brain tissue in a recently identified group of elderly demented patients suggest a neurochemical basis for some of the clinical features. Senile dementia of the Lewy body type (SDLT) can be distinguished from classical Alzheimer disease (AD) clinically by its acute presentation with confusion frequently accompanied by visual hallucinations, and neuropathologically by the presence of Lewy bodies and senile plaques (but not generally neurofibrillary tangles) in the cerebral cortex. Reductions in the cortical cholinergic enzyme choline acetyltransferase were more pronounced in individuals with (80%) compared to those without (50%) hallucinations and correlated strongly with mental test scores in the group as a whole. In the caudate nucleus, dopamine levels were related to the number of neurons in the substantia nigra, there being a 40-60% loss of both in SDLT--probably accounting for mild extrapyramidal features in some of these cases--compared with an 80% loss in Parkinson disease and no change in AD. The cholinergic correlates of mental impairment in SDLT together with the relative absence of cortical neurofibrillary tangles and evidence for postsynaptic cholinergic receptor compensation raise the question of whether this type of dementia may be more amenable to cholinotherapy than classical AD.

[Focal cerebral ischemia in rats with estrogen deficiency and endothelial dysfunction].

PubMed

Litvinov, A A; Volotova, E V; Kurkin, D V; Logvinova, E O; Darmanyan, A P; Tyurenkov, I N

2017-01-01

To assess an effect of ovariectomy (OE) on the cerebral blood flow, endothelium-dependent vasodilation, neurological, cognitive and locomotor deficit as markers of brain damage after focal ischemia in rats. The study was conducted in 48 female Wistar rats. Ovariectomy was performed with ovaries and uterine body extirpation, cerebral ischemia was performed by middle cerebral artery occlusion (MCAO) in rats. To assess brain damage, Combs and Garcia scores, 'open field' test (OFT), 'extrapolatory escape test' (EET), 'passive avoidance test' (PAT), 'beam-walking test' were used. Cerebral blood flow was measured using ultrasonic flowmetry. After 7 days of MCAO, the cerebral blood flow in ovarioectomized animals was reduced by 20% compared to sham-ovariectomized animals. Ovariectomized animals with MCAO showed a three-fold endothelium-dependent vasodilation reduction (the reaction of cerebral vessels to the introduction of acetylcholine and N-L-arginine), indicating the presence of severe endothelial dysfunction. In ovarioectomized animals, the cerebral blood flow was reduced by 34% compared to sham-operated animals. MCAO and OE taken together resulted in more than 2-fold increase in neurological, motor disturbances, 3-fold decrease in motor activity of the animals in the OP test. Focal ischemia in ovarioectomized animals with endothelial dysfunction led to memory decrease by 1/5 fold in PAT and by 2-fold in EET.

Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

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

Srivastava, Pranay; Yadav, Rajesh S.; Department of Crimnology and Forensic Science, Harisingh Gour University, Sagar 470 003

Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenicmore » exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected by curcumin • Functional and structural changes in mitochondria by arsenic protected by curcumin.« less

Oromotor Dysfunction and Communication Impairments in Children with Cerebral Palsy: A Register Study

ERIC Educational Resources Information Center

Parkes, Jackie; Hill, Nan; Platt, Mary Jane; Donnelly, Caroline

2010-01-01

Aim: To report the prevalence, clinical associations, and trends over time of oromotor dysfunction and communication impairments in children with cerebral palsy (CP). Method: Multiple sources of ascertainment were used and children followed up with a standardized assessment including motor speech problems, swallowing/chewing difficulties,…

Altered nocifensive behavior in animal models of autism spectrum disorder: the role of the nicotinic cholinergic system

PubMed Central

Wang, Li; Almeida, Luis E.F.; Nettleton, Margaret; Khaibullina, Alfia; Albani, Sarah; Kamimura, Sayuri; Nouraie, Mehdi; Quezado, Zenaide M.N.

2016-01-01

Caretakers and clinicians alike have long recognized that individuals with autism spectrum disorder (ASD) can have altered sensory processing, which can contribute to its core symptoms. However, the pathobiology of sensory alterations in ASD is poorly understood. Here we examined nocifensive behavior in ASD mouse models, the BTBR T+Itpr3tf/J (BTBR) and the fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also examined the effects of nicotine on nocifensive behavior given that nicotine, a nicotinic cholinergic receptor (nAChR) agonist that has antinociceptive effects and was shown to improve social deficits and decrease repetitive behaviors in BTBR mice. Compared to respective controls, both BTBR and Fmr1-KO had hyporesponsiveness to noxious thermal stimuli and electrical stimulation of C-sensory fibers, normal responsiveness to electrical stimulation of Aβ- and Aδ-fiber, and hyperresponsiveness to visceral pain after acetic acid intraperitoneal injection. In BTBR, nicotine at lower doses increased, whereas at higher doses, it decreased hotplate latency compared to vehicle. In a significantly different effect pattern, in control mice, nicotine had antinociceptive effects to noxious heat only at the high dose. Interestingly, these nocifensive behavior alterations and differential responses to nicotine antinociceptive effects in BTBR mice were associated with significant downregulation of α3, α4, α5, α7, β2, β3, and β4 nAChR subunits in several cerebral regions both, during embryonic development and adulthood. Taken together, these findings further implicate nAChRs in behaviors alterations in the BTBR model and lend support to the hypothesis that nAChRs may be a target for treatment of behavior deficits and sensory dysfunction in ASD. PMID:27638450

Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

PubMed Central

Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

2014-01-01

The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically projecting GABAergic/PV neurons. PMID:24553925

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome

PubMed Central

Powers, Brian E.; Velazquez, Ramon; Kelley, Christy M.; Ash, Jessica A.; Strawderman, Myla S.; Alldred, Melissa J.; Ginsberg, Stephen D.; Mufson, Elliott J.

2016-01-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs. PMID:26719290

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome.

PubMed

Powers, Brian E; Velazquez, Ramon; Kelley, Christy M; Ash, Jessica A; Strawderman, Myla S; Alldred, Melissa J; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J

2016-12-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs.

Raven's Coloured Progressive Matrices as a Measure of Cognitive Functioning in Cerebral Palsy

ERIC Educational Resources Information Center

Pueyo, R.; Junque, C.; Vendrell, P.; Narberhaus, A.; Segarra, D.

2008-01-01

Background: Cognitive dysfunction is frequent in Cerebral Palsy (CP). CP motor impairment and associated speech deficits often hinder cognitive assessment, with the result being that not all CP studies consider cognitive dysfunction. Raven's Coloured Progressive Matrices is a simple, rapid test which can be used in persons with severe motor…

Identification of the origin of adrenergic and cholinergic nerve fibers within the superior hypogastric plexus of the human fetus

PubMed Central

Zaitouna, Mazen; Alsaid, Bayan; Diallo, Djibril; Benoit, Gérard; Bessede, Thomas

2013-01-01

Nerve fibers contributing to the superior hypogastric plexus (SHP) and the hypogastric nerves (HN) are currently considered to comprise an adrenergic part of the autonomic nervous system located between vertebrae (T1 and L2), with cholinergic aspects originating from the second to fourth sacral spinal segments (S2, S3 and S4). The aim of this study was to identify the origin and the nature of the nerve fibers within the SHP and the HN, especially the cholinergic fibers, using computer-assisted anatomic dissection (CAAD). Serial histological sections were performed at the level of the lumbar spine and pelvis in five human fetuses between 14 and 30 weeks of gestation. Sections were treated with histological staining [hematoxylin-eosin (HE) and Masson's trichrome (TriM)] and with immunohistochemical methods to detect nerve fibers (anti-S100), adrenergic fibers (anti-TH), cholinergic fibers (anti-VAChT) and nitrergic fibers (anti-nNOS). The sections were then digitalized using a high-resolution scanner and the 3D images were reconstructed using winsurf software. These experiments revealed the coexistence of adrenergic and cholinergic fibers within the SHP and the HNs. One-third of these cholinergic fibers were nitrergic fibers [anti-VACHT (+)/anti-NOS (+)] and potentially pro-erectile, while the others were non-nitrergic [anti-VACHT (+)/anti-NOS (−)]. We found these cholinergic fibers arose from the lumbar nerve roots. This study described the nature of the SHP nerve fibers which gives a better understanding of the urinary and sexual dysfunctions after surgical injuries. PMID:23668336

Lentiviral Infection of Rhesus Macaques Causes Long-Term Injury to Cortical and Hippocampal Projections of Prostaglandin-Expressing Cholinergic Basal Forebrain Neurons

PubMed Central

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E.

2011-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human HIV-AIDS and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenases 1 and 2 (COX1 and 2) in brains of SIV-infected macaques with and without encephalitis and antiretroviral therapy, and uninfected controls. COX1 but not COX2 was co-expressed with markers of cholinergic phenotype, i.e. choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human samples. COX1 was decreased in basal forebrain neurons in macaques with AIDS vs. uninfected and asymptomatic SIV-infected macaques. VAChT-positive fiber density was reduced in frontal, parietal and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2′,3′-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent, irreversible brain damage. PMID:22157616

Effects of [6]-shogaol on cholinergic signaling in HT22 cells following neuronal damage induced by hydrogen peroxide.

PubMed

Shim, Sehwan; Kwon, Jungkee

2012-05-01

Cholinergic neurons play a major role in memory and attention. The dysfunction and death of these neurons, especially in the hippocampus, are thought to contribute to the pathophysiology of memory deficits associated with Alzheimer's disease (AD). Therefore, studying the cholinergic properties and cell survival may help in treating this disease. We investigated the possible effects of [6]-shogaol on cholinergic signaling in HT22 hippocampal neuronal cells. HT22 cells express essential cholinergic markers, including choline acetyltransferase (ChAT) and choline transporter (ChTp). HT22 cells treated with H(2)O(2) for 3h showed an increase in ROS production (35%). These features were partly recovered by [6]-shogaol. Treating H(2)O(2)-treated HT22 cells with [6]-shogaol markedly increased the expression of ChAT and ChTp, an effect similar to that of brain-derived neurotrophic factor (BDNF). Furthermore, K-252a, an inhibitor of the BDNF receptor Trk B, attenuated the effects of both [6]-shogaol and BDNF. These data suggest that [6]-shogaol protects neurons by increasing ChAT and ChTp expression through a BDNF increase and thus may be useful for treating neurodegenerative diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

Novel strains of mice deficient for the vesicular acetylcholine transporter: insights on transcriptional regulation and control of locomotor behavior.

PubMed

Martins-Silva, Cristina; De Jaeger, Xavier; Guzman, Monica S; Lima, Ricardo D F; Santos, Magda S; Kushmerick, Christopher; Gomez, Marcus V; Caron, Marc G; Prado, Marco A M; Prado, Vania F

2011-03-10

Defining the contribution of acetylcholine to specific behaviors has been challenging, mainly because of the difficulty in generating suitable animal models of cholinergic dysfunction. We have recently shown that, by targeting the vesicular acetylcholine transporter (VAChT) gene, it is possible to generate genetically modified mice with cholinergic deficiency. Here we describe novel VAChT mutant lines. VAChT gene is embedded within the first intron of the choline acetyltransferase (ChAT) gene, which provides a unique arrangement and regulation for these two genes. We generated a VAChT allele that is flanked by loxP sequences and carries the resistance cassette placed in a ChAT intronic region (FloxNeo allele). We show that mice with the FloxNeo allele exhibit differential VAChT expression in distinct neuronal populations. These mice show relatively intact VAChT expression in somatomotor cholinergic neurons, but pronounced decrease in other cholinergic neurons in the brain. VAChT mutant mice present preserved neuromuscular function, but altered brain cholinergic function and are hyperactive. Genetic removal of the resistance cassette rescues VAChT expression and the hyperactivity phenotype. These results suggest that release of ACh in the brain is normally required to "turn down" neuronal circuits controlling locomotion.

Impaired Cerebral Mitochondrial Oxidative Phosphorylation Function in a Rat Model of Ventricular Fibrillation and Cardiopulmonary Resuscitation

PubMed Central

Fu, Yue; Xu, Wen; Jiang, Longyuan; Huang, Zitong

2014-01-01

Postcardiac arrest brain injury significantly contributes to mortality and morbidity in patients suffering from cardiac arrest (CA). Evidence that shows that mitochondrial dysfunction appears to be a key factor in tissue damage after ischemia/reperfusion is accumulating. However, limited data are available regarding the cerebral mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) and its relationship to the alterations of high-energy phosphate. Here, we sought to identify alterations of mitochondrial morphology and oxidative phosphorylation function as well as high-energy phosphates during CA and CPR in a rat model of ventricular fibrillation (VF). We found that impairment of mitochondrial respiration and partial depletion of adenosine triphosphate (ATP) and phosphocreatine (PCr) developed in the cerebral cortex and hippocampus following a prolonged cardiac arrest. Optimal CPR might ameliorate the deranged phosphorus metabolism and preserve mitochondrial function. No obvious ultrastructural abnormalities of mitochondria have been found during CA. We conclude that CA causes cerebral mitochondrial dysfunction along with decay of high-energy phosphates, which would be mitigated with CPR. This study may broaden our understanding of the pathogenic processes underlying global cerebral ischemic injury and provide a potential therapeutic strategy that aimed at preserving cerebral mitochondrial function during CA. PMID:24696844

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness.

PubMed

Hubbard, Nicholas A; Hutchison, Joanna L; Motes, Michael A; Shokri-Kojori, Ehsan; Bennett, Ilana J; Brigante, Ryan M; Haley, Robert W; Rypma, Bart

2014-05-01

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM.

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness

PubMed Central

Hubbard, Nicholas A.; Hutchison, Joanna L.; Motes, Michael A.; Shokri-Kojori, Ehsan; Bennett, Ilana J.; Brigante, Ryan M.; Haley, Robert W.; Rypma, Bart

2015-01-01

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM. PMID:25767746

Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria

PubMed Central

Freeman, Brandi D.; Martins, Yuri C.; Akide-Ndunge, Oscar B.; Bruno, Fernando P.; Wang, Hua; Tanowitz, Herbert B.; Spray, David C.; Desruisseaux, Mahalia S.

2016-01-01

Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria. PMID:27031954

Gap junctional intercellular communication dysfunction mediates the cognitive impairment induced by cerebral ischemia-reperfusion injury: PI3K/Akt pathway involved.

PubMed

Zhou, Shujun; Fang, Zheng; Wang, Gui; Wu, Song

2017-01-01

Cerebral ischemia/reperfusion (I/R) injury causes hippocampal apoptosis and cognitive impairment, and the dysfunction of gap junction intercellular communication (GJIC) may contribute to the cognitive impairment. We aim to examine the impact of cerebral I/R injury on cognitive impairment, the role of GJIC dysfunction in the rat hippocampus and the involvement of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway. Rats were subjected to a cerebral I/R procedure and underwent cognitive assessment with the novel object recognition and Morris Water Maze tasks. The distance of Lucifer Yellow dye transfer and the Cx43 protein were examined to measure GJIC. Neural apoptosis was assessed with the terminal deoxynucleotide-transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) method. After rats received inhibitors of the PI3K/Akt pathway, GJIC and cognitive ability were measured again. GJIC promotion by ZP123 significantly reversed cognitive impairment and hippocampal apoptosis induced by cerebral I/R, while the inhibition of GJIC by octanol significantly facilitated cognitive impairment and hippocampal apoptosis. The phosphorylation of Akt was enhanced by cerebral I/R and octanol but inhibited by ZP123. The inhibition of the PI3K/Akt pathway significantly suppressed GJIC and cognitive impairment. The PI3K/Akt pathway is involved in cognitive impairment caused by gap junctional communication dysfunction in the rat hippocampus after ischemia-reperfusion injury.

Evidence of central cholinergic mechanisms in the appearance of affective aggressive behaviour: dissociation of aggression from autonomic and motor phenomena.

PubMed

Beleslin, D B; Samardzić, R

1979-04-11

Carbachol, muscarine, eserine and neostigmine injected into the cerebral ventricles of conscious cats evoked emotional behaviour with aggression, autonomic and motor phenomena as well as clonic-tonic convulsions. The main and the most impressive feature of the gross behavioural effects of intraventricular carbachol, muscarine, eserine and neostigmine in conscious cats was the affective type of aggression. However, neostigmine produced aggressive behaviour only in about one-quarter of the experiments. After intraventricular hemicholinium-3 and triethylcholine carbachol, muscarine, eserine and neostigmine elicited autonomic and motor phenomena. In these cats cholinomimetics and anticholinesterases evoked only slight hissing and snarling. Choline administered into the cerebral ventricles of hemicholinium-3 and triethylcholine-treated cats restored the emotional behaviour with aggression, autonomic and motor phenomena as well as clonic-tonic convulsions to intraventricular carbachol, muscarine, eserine and neostigmine. The restored gross behavioural changes to eserine were almost of the same intensity, while those to carbachol and muscarine were of lesser intensity than in control cats. From these experiments it is concluded that cholinergic neurones are involved in the appearance of the affective type of aggression resulting from intraventricular carbachol, muscarine, eserine and neostigmine.

Event-Related Potential Patterns Associated with Hyperarousal in Gulf War Illness Syndrome Groups

PubMed Central

Tillman, Gail D.; Calley, Clifford S.; Green, Timothy A.; Buhl, Virginia I.; Biggs, Melanie M.; Spence, Jeffrey S.; Briggs, Richard W.; Haley, Robert W.; Hart, John; Kraut, Michael A.

2012-01-01

An exaggerated response to emotional stimuli is one of several symptoms widely reported by veterans of the 1991 Persian Gulf War. Many have attributed these symptoms to post-war stress; others have attributed the symptoms to deployment-related exposures and associated damage to cholinergic, dopaminergic, and white matter systems. We collected event-related potential (ERP) data from 20 veterans meeting Haley criteria for Gulf War Syndromes 1–3 and from 8 matched Gulf War veteran controls, who were deployed but not symptomatic, while they performed an auditory three-condition oddball task with gunshot and lion roar sounds as the distractor stimuli. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans; different ERP profiles emerged to account for their hyperarousability. Syndromes 2 and 3, who have previously shown brainstem abnormalities, show significantly stronger auditory P1 amplitudes, purported to indicate compromised cholinergic inhibitory gating in the reticular activating system. Syndromes 1 and 2, who have previously shown basal ganglia dysfunction, show significantly weaker P3a response to distractor stimuli, purported to indicate dysfunction of the dopaminergic contribution to their ability to inhibit distraction by irrelevant stimuli. All three syndrome groups showed an attenuated P3b to target stimuli, which could be secondary to both cholinergic and dopaminergic contributions or disruption of white matter integrity. PMID:22691951

Involvement of Cholinergic Dysfunction and Oxidative Damage in the Effects of Simulated Weightlessness on Learning and Memory in Rats

PubMed Central

Wang, Qiong; Lv, Ke; Wang, Tingmei; Wang, Yanli; Ji, Guohua; Cao, Hongqing; Kan, Guanghan

2018-01-01

The present study aimed to determine how the learning and memory gradually change with the prolonged hindlimb unloading (HU) treatment in rats. Different HU durations (7 d, 14 d, 21 d, and 28 d) in Sprague-Dawley (SD) rats were implemented. Cognitive function was assessed using the Morris water maze (MWM) and the shuttle box test. Additionally, parameters about cholinergic activity and oxidative stress were tested. Results showed that longer-than-14 d HU led to the inferior performances in the behavioral tasks. Besides, acetylcholine esterase (AChE) activity, malondialdehyde (MDA) level in brain, reactive oxygen species (ROS), and 8-hydroxy-2-deoxyguanosine (8-OHdG) concentrations of HU rats were significantly increased. Furthermore, choline acetyltransferase (ChAT), superoxide dismutase (SOD), and catalase (CAT) activity in brain were notably attenuated. Most of these effects were more pronounced after longer exposure (21 d and 28 d) to HU, although some indicators had their own characteristics of change. These results indicate that cholinergic dysfunction and oxidative damage were involved in the learning and memory impairments induced by longer-than-14 d HU. Moreover, the negative effects of HU tend to be augmented as the HU duration becomes longer. The results may be helpful to present possible biochemical targets for countermeasures development regarding the memory deficits under extreme environmental conditions. PMID:29581965

Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter

PubMed Central

English, Brett A.; Appalsamy, Martin; Diedrich, Andre; Ruggiero, Alicia M.; Lund, David; Wright, Jane; Keller, Nancy R.; Louderback, Katherine M.; Robertson, David

2010-01-01

Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT−/−) mice exhibit early postnatal lethality, CHT heterozygous (CHT+/−) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT+/− mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT+/− mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT+/− mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease. PMID:20601463

The Risk of Neurological Dysfunctions after Deep Hypothermic Circulatory Arrest with Retrograde Cerebral Perfusion.

PubMed

Gatti, Giuseppe; Benussi, Bernardo; Currò, Placido; Forti, Gabriella; Rauber, Elisabetta; Minati, Alessandro; Gabrielli, Marco; Tognolli, Umberto; Sinagra, Gianfranco; Pappalardo, Aniello

2017-12-01

Retrograde cerebral perfusion (RCP) is a brain protection technique that is adopted generally for anticipated short periods of deep hypothermic circulatory arrest (DHCA). However, the real impact of this technique on cerebral protection during DHCA remains a controversial issue. For 344 (59.5%) of 578 consecutive patients (mean age, 66.9 ± 10.9 years) who underwent cardiovascular surgery under DHCA at the present authors' institution (1999-2015), RCP was the sole technique of cerebral protection that was adopted in addition to deep hypothermia. Surgery of the thoracic aorta was performed in 95.9% of these RCP patients; in 92 cases there was an aortic arch involvement. Outcomes were reviewed retrospectively. The focus was on postoperative neurological dysfunctions. There were 33 (9.6%) in-hospital deaths. Thirty-one (9%) patients had permanent neurological dysfunctions and 66 (19.1%) transitory neurological dysfunctions alone. Age older than 74 years (odds ratio [OR], 1.88, P = .023), surgery for acute aortic dissection (OR, 2.57; P = .0009), and DHCA time longer than 25 minutes (OR, 2.44; P = .0021) were predictors of neurological dysfunctions. The 10-year nonparametric estimate of freedom from all-cause death was 61.8% (95% confidence interval, 57.8%-65.8%). Permanent postoperative neurological dysfunctions were risk factors for cardiac or cerebrovascular death (hazard ratio, 2.6; P = .039) even after an adjusted survival analysis (P < .04). According to the study findings, RCP, in addition to deep hypothermia, combines with a low risk of neurological dysfunctions provided that DHCA length is 25 minutes or less. Permanent postoperative neurological dysfunctions are predictors of poor late survival. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Short-term ethanol exposure causes imbalanced neurotrophic factor allocation in the basal forebrain cholinergic system: a novel insight into understanding the initial processes of alcohol addiction.

PubMed

Miki, Takanori; Kusaka, Takashi; Yokoyama, Toshifumi; Ohta, Ken-ichi; Suzuki, Shingo; Warita, Katsuhiko; Jamal, Mostofa; Wang, Zhi-Yu; Ueki, Masaaki; Liu, Jun-Qian; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

2014-02-01

Alcohol ingestion affects both motor and cognitive functions. One brain system that is influenced by ethanol is the basal forebrain (BF) cholinergic projection system, which projects to diverse neocortical and limbic areas. The BF is associated with memory and cognitive function. Our primary interest is the examination of how regions that receive BF cholinergic projections are influenced by short-term ethanol exposure through alterations in the mRNA levels of neurotrophic factors [nerve growth factor/TrkA, brain-derived neurotrophic factor/TrkB, and glial-derived neurotrophic factor (GDNF)/GDNF family receptor α1]. Male BALB/C mice were fed a liquid diet containing 5 % (v/v) ethanol. Pair-fed control mice were maintained on an identical liquid diet, except that the ethanol was isocalorically substituted with sucrose. Mice exhibiting signs of ethanol intoxication (stages 1-2) were used for real-time reverse transcription-polymerase chain reaction analyses. Among the BF cholinergic projection regions, decreased levels of GDNF mRNA and increased levels of TrkB mRNA were observed in the basal nucleus, and increased levels of TrkB mRNA were observed in the cerebral cortex. There were no significant alterations in the levels of expression of relevant neurotrophic factors in the septal nucleus and hippocampus. Given that neurotrophic factors function in retrograde/anterograde or autocrine/paracrine mechanisms and that BF cholinergic projection regions are neuroanatomically connected, these findings suggested that an imbalanced allocation of neurotrophic factor ligands and receptors is an initial phenomenon in alcohol addiction. The exact mechanisms underlying this phenomenon in the BF cholinergic system are unknown. However, our results provide a novel notion for the understanding of the initial processes in alcohol addiction.

Effects of muscarinic blockade in perirhinal cortex during visual recognition

PubMed Central

Tang, Yi; Mishkin, Mortimer; Aigner, Thomas G.

1997-01-01

Stimulus recognition in monkeys is severely impaired by destruction or dysfunction of the perirhinal cortex and also by systemic administration of the cholinergic-muscarinic receptor blocker, scopolamine. These two effects are shown here to be linked: Stimulus recognition was found to be significantly impaired after bilateral microinjection of scopolamine directly into the perirhinal cortex, but not after equivalent injections into the laterally adjacent visual area TE or into the dentate gyrus of the overlying hippocampal formation. The results suggest that the formation of stimulus memories depends critically on cholinergic-muscarinic activation of the perirhinal area, providing a new clue to how stimulus representations are stored. PMID:9356507

Neurogenic Lower Urinary Tract Dysfunction in Adults with Cerebral Palsy: Outcomes following a Conservative Management Approach.

PubMed

Goldfarb, Robert A; Pisansky, Andrew; Fleck, Joseph; Hoversten, Patrick; Cotter, Katherine J; Katorski, Jenna; Liberman, Daniel; Elliott, Sean P

2016-04-01

Cerebral palsy is characterized by motor impairment following injury to the developing brain. Neurogenic lower urinary tract dysfunction is estimated to affect at least a third of children with cerebral palsy. However there are limited data as patients transition to adulthood. We sought to describe the symptoms, sequelae and management of neurogenic lower urinary tract dysfunction in adults with cerebral palsy. We retrospectively reviewed the charts of adult patients with cerebral palsy between 2011 and 2014. Patients with prior bladder reconstruction or catheterization based bladder drainage were excluded from study. Cerebral palsy severity was determined using GMFCS (Gross Motor Function Classification System). A conservative evaluation and treatment paradigm was used. Noninvasive treatments were encouraged. Specifically clean intermittent catheterization, which is often not feasible, is avoided unless urinary retention, hydronephrosis or refractory lower urinary tract symptoms develop. There were 121 patients included in final analysis. Median age was 25 and 61 patients (50%) had GMFCS level V. Noninvasive management failed in 28 of 121 patients (23%) as defined by hydronephrosis in 9, persistent urinary retention in 10 and refractory lower urinary tract symptoms/incontinence in 9. Urethral clean intermittent catheterization was poorly tolerated. Of all patients 25% showed evidence of urolithiasis during the study period. Surgical intervention was rare and associated with significant morbidity. Adults with cerebral palsy may present with variable signs and symptoms of neurogenic lower urinary tract dysfunction. Conservative treatment was successful in more than 75% of patients. Clean intermittent catheterization was poorly tolerated in patients in whom conservative treatment failed. Surgical intervention was rarely indicated and it should be reserved for select individuals. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Lentiviral infection of rhesus macaques causes long-term injury to cortical and hippocampal projections of prostaglandin-expressing cholinergic basal forebrain neurons.

PubMed

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E

2012-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human immunodeficiency virus-acquired immunodeficiency syndrome (AIDS) and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenase isotypes 1 and 2 (COX1 and COX2) in the brains of SIV-infected macaques with or without encephalitis and antiretroviral therapy and uninfected controls.Cyclooxygenase isotype 1, but not COX2, was coexpressed with markers of cholinergic phenotype, that is, choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human, brain. Cyclooxygenase isotype 1 was decreased in basal forebrain neurons in macaques with AIDS versus uninfected and asymptomatic SIV-infected macaques. The VAChT-positive fiber density was reduced in frontal, parietal, and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2',3'-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results further imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent irreversible brain damage.

Cerebral Visual Impairment: Which Perceptive Visual Dysfunctions Can Be Expected in Children with Brain Damage? A Systematic Review

ERIC Educational Resources Information Center

Boot, F. H.; Pel, J. J. M.; van der Steen, J.; Evenhuis, H. M.

2010-01-01

The current definition of Cerebral Visual Impairment (CVI) includes all visual dysfunctions caused by damage to, or malfunctioning of, the retrochiasmatic visual pathways in the absence of damage to the anterior visual pathways or any major ocular disease. CVI is diagnosed by exclusion and the existence of many different causes and symptoms make…

Neonatal treatment with scopolamine butylbromide prevents metabolic dysfunction in male rats

PubMed Central

Malta, Ananda; Souza, Aline Amenencia de; Ribeiro, Tatiane Aparecida; Francisco, Flávio Andrade; Pavanello, Audrei; Prates, Kelly Valério; Tófolo, Laize Peron; Miranda, Rosiane Aparecida; Oliveira, Júlio Cezar de; Martins, Isabela Peixoto; Previate, Carina; Gomes, Rodrigo Mello; Franco, Claudinéia Conationi da Silva; Natali, Maria Raquel Marçal; Palma-Rigo, Kesia; Mathias, Paulo Cezar de Freitas

2016-01-01

We tested whether treatment with a cholinergic antagonist could reduce insulin levels in early postnatal life and attenuate metabolic dysfunctions induced by early overfeeding in adult male rats. Wistar rats raised in small litters (SLs, 3 pups/dam) and normal litters (NLs, 9 pups/dam) were used in models of early overfeeding and normal feeding, respectively. During the first 12 days of lactation, animals in the SL and NL groups received scopolamine butylbromide (B), while the controls received saline (S) injections. The drug treatment decreased insulin levels in pups from both groups, and as adults, these animals showed improvements in glucose tolerance, insulin sensitivity, vagus nerve activity, fat tissue accretion, insulinemia, leptinemia, body weight gain and food intake. Low glucose and cholinergic insulinotropic effects were observed in pancreatic islets from both groups. Low protein expression was observed for the muscarinic M3 acetylcholine receptor subtype (M3mAChR), although M2mAChR subtype expression was increased in SL-B islets. In addition, beta-cell density was reduced in drug-treated rats. These results indicate that early postnatal scopolamine butylbromide treatment inhibits early overfeeding-induced metabolic dysfunctions in adult rats, which might be caused by insulin decreases during lactation, associated with reduced parasympathetic activity and expression of M3mAChR in pancreatic islets. PMID:27561682

Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: Relationship with spatial impairment

PubMed Central

Bañuelos, C.; LaSarge, C. L.; McQuail, J. A.; Hartman, J. J.; Gilbert, R. J.; Ormerod, B. K.; Bizon, J. L.

2013-01-01

Both cholinergic and GABAergic projections from the rostral basal forebrain have been implicated in hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in co-distributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase (ChAT) immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 (GAD67) immunopositive) neurons, and total (NeuN immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline. PMID:22817834

Characterization of cholinergic muscarinic receptor-stimulated phosphoinositide metabolism in brain from immature rats

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

Balduini, W.; Murphy, S.D.; Costa, L.G.

Hydrolysis of phosphoinositides elicited by stimulation of cholinergic muscarinic receptors has been studied in brain from neonatal (7-day-old) rats in order to determine: (1) whether the neonatal rat could provide a good model system to study this signal-transduction pathway; and (2) whether potential differences with adult nerve tissue would explain the differential, age-related effects of cholinergic agonists. Accumulation of (3H) inositol phosphates in (3H)inositol prelabeled slices from neonatal and adult rats was measured as an index of phosphoinositide metabolism. Full (acetylcholine, methacholine, carbachol) and partial (oxotremorine, bethanechol) agonists had qualitatively similar, albeit quantitatively different, effects in neonatal and adult rats.more » Atropine and pirenzepine effectively blocked the carbachol-induced response with inhibition constants of 1.2 and 20.7 nM, respectively. In all brain areas, response to all agonists was higher in neonatal than adult rats, and in hippocampus and cerebral cortex the response was higher than in cerebellum or brainstem. The relative intrinsic activity of partial agonists was higher in the latter two areas (0.6-0.7) than in the former two (0.3-0.4). Carbachol-stimulated phosphoinositide metabolism in brain areas correlated well with the binding of (3H)QNB (r2 = 0.627) and, particularly, with (3H)pirenzepine (r2 = 0.911). In cerebral cortex the effect of carbachol was additive to that of norepinephrine and glutamate. The presence of calcium (250-500 microM) was necessary for maximal response to carbachol to be elicited; the EC50 value for Ca2+ was 65.4 microM. Addition of EDTA completely abolished the response. Removal of sodium ions from the incubation medium reduced the response to carbachol by 50%.« less

Effects of aniracetam on one-trial passive avoidance tests and cholinergic neurons in discrete brain regions of rats.

PubMed

Toide, K

1989-01-01

Using rats in one-trial passive avoidance tests, the anti-amnesic effects of the nootropic drug aniracetam were investigated; moreover, the action of aniracetam upon the cholinergic system in the brain was studied. In one-trial passive avoidance tests, aniracetam prolonged significantly the retention time for 100 mg/kg, p.o. However, the retention-prolonging effect was diminished when the dose was increased to 300 mg/kg p.o. Investigation of the action of the drug upon the cholinergic system revealed that ACh and choline content in the corpus striatum was not increased by any doses of aniracetam. ACh content in the hippocampus was increased by doses of 100-300 mg/kg, p.o., but choline was not significantly increased by any doses, while in the cerebral cortex ACh content was significantly increased by a dose of 300 mg/kg, p.o. In addition, the decrease in hippocampal ACh and choline content following an injection of scopolamine was lessened by aniracetam 100 mg/kg, p.o. and 100-300 mg/kg, respectively. In order to elucidate the mechanism of these actions of aniracetam, the ACh-releasing action and changes in choline content of the extracellular spaces in the hippocampus were investigated, but no effects were observed. The results obtained indicate that aniracetam has an inhibitory effect upon scopolamine-induced amnesia. The mechanism of this effect may be an action upon the cholinergic system; therefore, some action with respect to the impairment of cholinergic neurotransmission in the hippocampus induced by scopolamine appears to be of particular importance.

Frequency of Inverted Electrocardiographic T Waves (Cerebral T Waves) in Patients With Acute Strokes and Their Relation to Left Ventricular Wall Motion Abnormalities.

PubMed

Stone, Jeremy; Mor-Avi, Victor; Ardelt, Agnieszka; Lang, Roberto M

2018-01-01

Transient, symmetric, and deep inverted electrocardiogram (ECG) T waves in the setting of stroke, commonly referred to as cerebral T waves, are rare, and the underlying mechanism is unclear. Our study aimed to test the hypothesis that cerebral T waves are associated with transient cardiac dysfunction. This retrospective study included 800 patients admitted with the primary diagnosis of hemorrhagic or ischemic stroke. ECGs were examined for cerebral T waves, defined as T-wave inversion of ≥5 mm depth in ≥4 contiguous precordial leads. Echocardiograms of those meeting these criteria were examined for the presence of left ventricular (LV) wall motion abnormalities. Follow-up evaluation included both ECG and echocardiogram. Of the 800 patients, 17 had cerebral T waves on ECG (2.1%). All 17 patients had ischemic strokes, of which 11 were in the middle cerebral artery distribution (65%), and 2 were cerebellar (12%), whereas the remaining 4 involved other locations. Follow-up ECG showed resolution of the T-wave changes in all 17 patients. Of these patients, 14 (82%) had normal wall motion, and 3 had transient wall motion abnormalities (18%). Two of these patients had Takotsubo-like cardiomyopathy with apical ballooning, and the third had globally reduced LV function. Coronary angiography showed no significant disease to explain the LV dysfunction. In summary, in our cohort of patients with acute stroke, cerebral T waves were rare and occurred only in ischemic stroke. Eighteen percent of patients with cerebral T waves had significant transient wall motion abnormalities. Patients with stroke with cerebral T waves, especially in those with ischemic strokes, should be assessed for cardiac dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

Mitochondrial dysfunction and organophosphorus compounds

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

Karami-Mohajeri, Somayyeh; Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Kerman University of Medical Sciences, Kerman; Abdollahi, Mohammad, E-mail: Mohammad.Abdollahi@UToronto.Ca

2013-07-01

Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen frommore » dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP.« less

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages.

PubMed

Jiang, Wei; Li, Daojing; Han, Ranran; Zhang, Chao; Jin, Wei-Na; Wood, Kristofer; Liu, Qiang; Shi, Fu-Dong; Hao, Junwei

2017-07-25

The nonneural cholinergic system of immune cells is pivotal for the maintenance of immunological homeostasis. Here we demonstrate the expression of choline acetyltransferase (ChAT) and cholinergic enzymes in murine natural killer (NK) cells. The capacity for acetylcholine synthesis by NK cells increased markedly under inflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), in which ChAT expression escalated along with the maturation of NK cells. ChAT + and ChAT - NK cells displayed distinctive features in terms of cytotoxicity and chemokine/cytokine production. Transfer of ChAT + NK cells into the cerebral ventricles of CX3CR1 -/- mice reduced brain and spinal cord damage after EAE induction, and decreased the numbers of CNS-infiltrating CCR2 + Ly6C hi monocytes. ChAT + NK cells killed CCR2 + Ly6C hi monocytes directly via the disruption of tolerance and inhibited the production of proinflammatory cytokines. Interestingly, ChAT + NK cells and CCR2 + Ly6C hi monocytes formed immune synapses; moreover, the impact of ChAT + NK cells was mediated by α7-nicotinic acetylcholine receptors. Finally, the NK cell cholinergic system up-regulated in response to autoimmune activation in multiple sclerosis, perhaps reflecting the severity of disease. Therefore, this study extends our understanding of the nonneural cholinergic system and the protective immune effect of acetylcholine-producing NK cells in autoimmune diseases.

The Ror receptor tyrosine kinase CAM-1 is required for ACR-16-mediated synaptic transmission at the C. elegans neuromuscular junction.

PubMed

Francis, Michael M; Evans, Susan P; Jensen, Michael; Madsen, David M; Mancuso, Joel; Norman, Kenneth R; Maricq, Andres Villu

2005-05-19

Nicotinic (cholinergic) neurotransmission plays a critical role in the vertebrate nervous system, underlies nicotine addiction, and nicotinic receptor dysfunction leads to neurological disorders. The C. elegans neuromuscular junction (NMJ) shares many characteristics with neuronal synapses, including multiple classes of postsynaptic currents. Here, we identify two genes required for the major excitatory current found at the C. elegans NMJ: acr-16, which encodes a nicotinic AChR subunit homologous to the vertebrate alpha7 subunit, and cam-1, which encodes a Ror receptor tyrosine kinase. acr-16 mutants lack fast cholinergic current at the NMJ and exhibit synthetic behavioral deficits with other known AChR mutants. In cam-1 mutants, ACR-16 is mislocalized and ACR-16-dependent currents are disrupted. The postsynaptic deficit in cam-1 mutants is accompanied by alterations in the distribution of cholinergic vesicles and associated synaptic proteins. We hypothesize that CAM-1 contributes to the localization or stabilization of postsynaptic ACR-16 receptors and presynaptic release sites.

Alpha-lipoic acid protects oxidative stress, changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats.

PubMed

Dwivedi, Nidhi; Flora, Govinder; Kushwaha, Pramod; Flora, Swaran J S

2014-01-01

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50 ppm sodium arsenite in drinking water or in combination with DDVP (4 mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid. Copyright © 2013 Elsevier B.V. All rights reserved.

Identifying and characterising cerebral visual impairment in children: a review.

PubMed

Philip, Swetha Sara; Dutton, Gordon N

2014-05-01

Cerebral visual impairment (CVI) comprises visual malfunction due to retro-chiasmal visual and visual association pathway pathology. This can be isolated or accompany anterior visual pathway dysfunction. It is a major cause of low vision in children in the developed and developing world due to increasing survival in paediatric and neonatal care. CVI can present in many combinations and degrees. There are multiple causes and it is common in children with cerebral palsy. CVI can be identified easily, if a structured approach to history-taking is employed. This review describes the features of CVI and describes practical management strategies aimed at helping affected children. A literature review was undertaken using 'Medline' and 'Pubmed'. Search terms included cerebral visual impairment, cortical visual impairment, dorsal stream dysfunction and visual function in cerebral palsy. © 2014 The Authors. Clinical and Experimental Optometry © 2014 Optometrists Association Australia.

Cerebral blood flow modulation by Basal forebrain or whisker stimulation can occur independently of large cytosolic Ca2+ signaling in astrocytes.

PubMed

Takata, Norio; Nagai, Terumi; Ozawa, Katsuya; Oe, Yuki; Mikoshiba, Katsuhiko; Hirase, Hajime

2013-01-01

We report that a brief electrical stimulation of the nucleus basalis of Meynert (NBM), the primary source of cholinergic projection to the cerebral cortex, induces a biphasic cerebral cortical blood flow (CBF) response in the somatosensory cortex of C57BL/6J mice. This CBF response, measured by laser Doppler flowmetry, was attenuated by the muscarinic type acetylcholine receptor antagonist atropine, suggesting a possible involvement of astrocytes in this type of CBF modulation. However, we find that IP3R2 knockout mice, which lack cytosolic Ca2+ surges in astrocytes, show similar CBF changes. Moreover, whisker stimulation resulted in similar degrees of CBF increase in IP3R2 knockout mice and the background strain C57BL/6J. Our results show that neural activity-driven CBF modulation could occur without large cytosolic increases of Ca2+ in astrocytes.

Evaluation of cerebral-cardiac syndrome using echocardiography in a canine model of acute traumatic brain injury.

PubMed

Qian, Rong; Yang, Weizhong; Wang, Xiumei; Xu, Zhen; Liu, Xiaodong; Sun, Bing

2015-01-01

Previous studies have confirmed that traumatic brain injury (TBI) can induce general adaptation syndrome (GAS), which subsequently results in myocardial dysfunction and damage in some patients with acute TBI; this condition is also termed as cerebral-cardiac syndrome. However, most clinicians ignore the detection and treatment of myocardial dysfunction, and instead concentrate only on the serious neural damage that is observed in acute TBI, which is one of the most important fatal factors. Therefore, clarification is urgently needed regarding the relationship between TBI and myocardial dysfunction. In the present study, we evaluated 18 canine models of acute TBI, by using real-time myocardial contrast echocardiography and strain rate imaging to accurately evaluate myocardial function and regional microcirculation, including the strain rate of the different myocardial segments, time-amplitude curves, mean ascending slope of the curve, and local myocardial blood flow. Our results suggest that acute TBI often results in cerebral-cardiac syndrome, which rapidly progresses to the serious stage within 3 days. This study is the first to provide comprehensive ultrasonic characteristics of cerebral-cardiac syndrome in an animal model of TBI.

The Brainstem Tau Cytoskeletal Pathology of Alzheimer's Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance.

PubMed

Rüb, Udo; Stratmann, Katharina; Heinsen, Helmut; Turco, Domenico Del; Seidel, Kay; Dunnen, Wilfred den; Korf, Horst-Werner

2016-01-01

The human brainstem is involved in the regulation of the sleep/waking cycle and normal sleep architectonics and is crucial for the performance of a variety of somatomotor, vital autonomic, oculomotor, vestibular, auditory, ingestive and somatosensory functions. It harbors the origins of the ascending dopaminergic, cholinergic, noradrenergic, serotonergic systems, as well the home base of the descending serotonergic system. In contrast to the cerebral cortex the affection of the brainstem in Alzheimer's disease (AD) by the neurofibrillary or tau cytoskeletal pathology was recognized only approximately fourty years ago in initial brainstem studies. Detailed pathoanatomical investigations of silver stained or tau immunostained brainstem tissue sections revealed nerve cell loss and prominent ADrelated cytoskeletal changes in the raphe nuclei, locus coeruleus, and in the compact parts of the substantia nigra and pedunculopontine nucleus. An additional conspicuous AD-related cytoskeletal pathology was also detected in the auditory brainstem system of AD patients (i.e. inferior colliculus, superior olive, dorsal cochlear nucleus), in the oculomotor brainstem network (i.e. rostral interstitial nucleus of the medial longitudinal fascicle, Edinger-Westphal nucleus, reticulotegmental nucleus of pons), autonomic system (i.e. central and periaqueductal grays, parabrachial nuclei, gigantocellular reticular nucleus, dorsal motor vagal and solitary nuclei, intermediate reticular zone). The alterations in these brainstem nuclei offered for the first time adequate explanations for a variety of less understood disease symptoms of AD patients: Parkinsonian extrapyramidal motor signs, depression, hallucinations, dysfunctions of the sleep/wake cycle, changes in sleeping patterns, attentional deficits, exaggerated pupil dilatation, autonomic dysfunctions, impairments of horizontal and vertical saccades, dysfunctional smooth pursuits. The very early occurrence of the AD-related cytoskeletal pathology in some of these brainstem nuclei points to a major and strategic role of the brainstem in the induction and brain spread of the AD-related cytoskeletal pathology.

Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria.

PubMed

Holmberg, Dag; Franzén-Röhl, Elisabeth; Idro, Richard; Opoka, Robert O; Bangirana, Paul; Sellgren, Carl M; Wickström, Ronny; Färnert, Anna; Schwieler, Lilly; Engberg, Göran; John, Chandy C

2017-07-28

One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated. Cerebrospinal fluid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cognitive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren's Children's Hospital were quantified and used for comparison. Children with CM had significantly higher CSF concentration of kynurenine and KYNA than Swedish children (P < 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respectively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old. CSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of attention and cognition.

Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: A Chronic Effects of Neurotrauma Consortium Study

PubMed Central

Mufson, Elliott J.; Perez, Sylvia E.; Nadeem, Muhammad; Mahady, Laura; Kanaan, Nicholas M.; Abrahamson, Eric E.; Ikonomovic, Milos D.; Crawford, Fiona; Alvarez, Victor; Stein, Thor; McKee, Ann C.

2017-01-01

Objective To test the hypothesis that the nucleus basalis of Meynert (nbM), a cholinergic basal forebrain (CBF) cortical projection system, develops neurofibrillary tangles (NFTs) during the progressive pathological stages of chronic traumatic encephalopathy (CTE) in the brain of athletes. Method To characterize NFT pathology we used tau- antibodies marking early, intermediate, and late stages of NFT development in cholinergic basal forebrain tissue obtained at autopsy from eighteen former athletes and veterans with a history of repetitive mild traumatic brain injury (TBI). Results We found evidence that cholinergic nbM neurons develop intracellular tau-immunoreactive changes progressively across the pathological stages of CTE. In particular, there was an increase in pretangle (phosphorylated pS422) and oligomeric (TOC1 and TNT1) forms of tau in stage IV compared to stage II CTE cases. The nbM neurons also displayed pathologic TDP-43 inclusions and diffuse extracellular and vascular amyloid-β (Aβ) deposits in CTE. A higher percent of pS422/p75NTR, pS422 and TNT1 labeled neurons were significantly correlated with age at symptom onset, interval between symptom onset and death and age at death. Conclusion The development of NFTs within the nbM neurons could contribute to the basal forebrain cortical cholinergic disconnection in CTE. Further studies are needed to determine the mechanism driving NFT formation in the nbM neurons and its relation to chronic cognitive dysfunction in CTE. PMID:27834536

Changes in Ca(2+) channel expression upon differentiation of SN56 cholinergic cells.

PubMed

Kushmerick, C; Romano-Silva, M A; Gomez, M V; Prado, M A

2001-10-19

The SN56 cell line, a fusion of septal neurons and neuroblastoma cells, has been used as a model for central cholinergic neurons. These cells show increased expression of cholinergic neurochemical features upon differentiation, but little is known about how differentiation affects their electrophysiological properties. We examined the changes in Ca(2+) channel expression that occur as these cells undergo morphological differentiation in response to serum withdrawal and exposure to dibutyryl-cAMP. Undifferentiated cells expressed a T-type current with biophysical and pharmacological properties similar, although not identical, to those reported for the current generated by the alpha(1H) (CaV3.2) Ca(2+) channel subunit. Differentiated cells expressed, in addition to this T-type current, high voltage activated currents which were inhibited 38% by the L-type channel antagonist nifedipine (5 microM), 37% by the N-type channel antagonist omega-conotoxin-GVIA (1 microM), and 15% by the P/Q-type channel antagonist omega-agatoxin-IVA (200 nM). Current resistant to these inhibitors accounted for 15% of the high voltage activated current in differentiated SN56 cells. Our data demonstrate that differentiation increases the expression of neuronal type voltage gated Ca(2+) channels in this cell line, and that the channels expressed are comparable to those reported for native basal forebrain cholinergic neurons. This cell line should thus provide a useful model system to study the relationship between calcium currents and cholinergic function and dysfunction.

Effects of Aged Garlic Extract on Cholinergic, Glutamatergic and GABAergic Systems with Regard to Cognitive Impairment in Aβ-Induced Rats

PubMed Central

Thorajak, Piyaporn; Pannangrong, Wanassanun; Umka Welbat, Jariya; Chaijaroonkhanarak, Wunnee; Sripanidkulchai, Kittisak; Sripanidkulchai, Bungorn

2017-01-01

Alzheimer’s disease (AD) has been linked to the degeneration of central cholinergic and glutamatergic transmission, which correlates with progressive memory loss and the accumulation of amyloid-β (Aβ). It has been claimed that aged garlic extract (AGE) has a beneficial effect in preventing neurodegeneration in AD. Therefore, the objective of this study was to investigate the effects of AGE on Aβ-induced cognitive dysfunction with a biochemical basis in the cholinergic, glutamatergic, and GABAergic systems in rats. Adult male Wistar rats were orally administered three doses of AGE (125, 250, and 500 mg/kg) daily for 65 days. At day 56, they were injected with 1 μL of aggregated Aβ (1–42) into each lateral ventricle, bilaterally. After six days of Aβ injection, the rats’ working and reference memory was tested using a radial arm maze. The rats were then euthanized to investigate any changes to the cholinergic neurons, vesicular glutamate transporter 1 and 2 proteins (VGLUT1 and VGLUT2), and glutamate decarboxylase (GAD) in the hippocampus. The results showed that AGE significantly improved the working memory and tended to improve the reference memory in cognitively-impaired rats. In addition, AGE significantly ameliorated the loss of cholinergic neurons and increased the VGLUT1 and GAD levels in the hippocampus of rat brains with Aβ-induced toxicity. In contrast, the VGLUT2 protein levels did not change in any of the treated groups. We concluded that AGE was able to attenuate the impairment of working memory via the modification of cholinergic neurons, VGLUT1, and GAD in the hippocampus of Aβ-induced rats. PMID:28671572

Trail Making Test Elucidates Neural Substrates of Specific Poststroke Executive Dysfunctions.

PubMed

Muir, Ryan T; Lam, Benjamin; Honjo, Kie; Harry, Robin D; McNeely, Alicia A; Gao, Fu-Qiang; Ramirez, Joel; Scott, Christopher J M; Ganda, Anoop; Zhao, Jiali; Zhou, X Joe; Graham, Simon J; Rangwala, Novena; Gibson, Erin; Lobaugh, Nancy J; Kiss, Alex; Stuss, Donald T; Nyenhuis, David L; Lee, Byung-Chul; Kang, Yeonwook; Black, Sandra E

2015-10-01

Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute-subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. Multiple linear regression analyses were completed. Although larger infarcts (β=0.37, P<0.0001) were associated with slower processing speed, cholinergic hyperintensities projections scale severity (β=0.39, P<0.0001) was associated with all metrics of set shifting. Left superior longitudinal fasciculus damage, however, was only associated with the difference score (β=0.17, P=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting. © 2015 American Heart Association, Inc.

Endothelial dysfunction and amyloid-β-induced neurovascular alterations

PubMed Central

Koizumi, Kenzo; Wang, Gang; Park, Laibaik

2015-01-01

Alzheimer's disease (AD) and cerebrovascular diseases share common vascular risk factors that have disastrous effects on cerebrovascular regulation. Endothelial cells, lining inner walls of cerebral blood vessels, form a dynamic interface between the blood and the brain and are critical for the maintenance of neurovascular homeostasis. Accordingly, injury in endothelial cells is regarded as one of the earliest symptoms of impaired vasoregulatory mechanisms. Extracellular buildup of amyloid-β (Aβ) is a central pathogenic factor in AD. Aβ exerts potent detrimental effects on cerebral blood vessels and impairs endothelial structure and function. Recent evidence implicates vascular oxidative stress and activation of the nonselective cationic channel transient receptor potential melastatin (TRPM)-2 on endothelial cells in the mechanisms of Aβ-induced neurovascular dysfunction. Thus, Aβ triggers opening of TRPM2 channels in endothelial cells leading to intracellular Ca2+ overload and vasomotor dysfunction. The cerebrovascular dysfunction may contribute to AD pathogenesis by reducing the cerebral blood supply, leading to increased susceptibility to vascular insufficiency, and by promoting Aβ accumulation. The recent realization that vascular factors contribute to AD pathobiology suggests new targets for the prevention and treatment of this devastating disease. PMID:26328781

Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine -- a PDE1 inhibitor.

PubMed

Deshmukh, Rahul; Sharma, Vivek; Mehan, Sidharth; Sharma, Nidhi; Bedi, K L

2009-10-12

Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. The present study was designed to investigate the effect of vinpocetine (PDE1 inhibitor) on intracerebroventricular (i.c.v.) streptozotocin induced experimental sporadic dementia of Alzheimer's type. Infusion of streptozotocin impaired learning and memory, increased oxidative-nitritive stress and induced cholinergic hypofunction in rats. Chronic treatment with vinpocetine (5, 10 and 20 mg/kg i.p.) for 21 days following first i.c.v. streptozotocin infusion significantly improved learning and memory in Morris water maze and passive avoidance paradigms. Further, vinpocetine significantly reduced the oxidative-nitritive stress, as evidenced by decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced glutathione (GSH) levels. Significant increase in acetylcholinesterase activity and lactate dehydrogenase levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Chronic treatment with vinpocetine also reduced significantly the increase in acetylcholinesterase activity and lactate dehydrogenase levels indicating restorative capacity of vinpocetine with respect to cholinergic functions and preventing the neuronal damage. The observed beneficial effects of vinpocetine on spatial memory may be due to its ability to favorably modulate cholinergic functions, prevent neuronal cell damage and possibly through its antioxidant mechanism also.

[Oral motor dysfunction, feeding problems and nutritional status in children with cerebral palsy].

PubMed

Hou, Mei; Fu, Ping; Zhao, Jian-hui; Lan, Kun; Zhang, Hong

2004-10-01

This study was undertaken to investigate the clinical features of oral motor dysfunction and feeding problems as well as the nutritional status of children with cerebral palsy (CP). Fifty-nine CP children, 39 boys and 20 girls, mean age 31 months (20 to 72 months), were recruited. Their parents were interviewed for high risk factors and feeding history. Each case was assessed for oral motor and feeding problems based on oral motor and feeding skill score; for nutritional status by measurement of weight, height; neurologically for type of cerebral palsy and for developmental age by Gesell's developmental scale. Equal number of age and sex matched controls were included for comparison of nutritional status, oral motor and feeding skill score. Among 59 patients, 51 cases had oral motor dysfunction and 55 cases had feeding problems including all athtosis, spastic tetraplegia, and 16 had spastic diplegia. The scores of both the mean oral motor function and feeding skill of CP children were significantly lower than those of the controls (P < 0.001). Main food of children with cerebral palsy consisted of liquid and semisolid diet. Body weight and height below the 25th percentile were found in 13 cases and 19 cases, respectively. The majority of the children with cerebral palsy had oral motor dysfunction and feeding problems which appeared in early age and disturbed the growth and nutritional status. Thorough assessment for oral motor function, feeding problems and nutritional status of CP children is indicated in order to start timely rehabilitation and nutritional interventions which can significantly improve their nutritional status and quality of life.

Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats.

PubMed

Abdou, Heba M; Yousef, Mokhtar I; El Mekkawy, Desouki A; Al-Shami, Ahmed S

2016-08-01

The present study was carried out to evaluate the potential protective role of co-administration of Ginkgo biloba, Trifolium pretenseagainst sodium arsenite-induced neurotoxicity in different parts of brain (Cerebral cortex, Hippocampus, striatum and Hind brain) and in the spinal cord of rats. Sodium arsenite caused impairment in the acquisition and learning in all the behavioral tasks and caused significant increase in tumor necrosis factor-α,thiobarbituric acid-reactive substances andlipid profile, while caused significant decrease in glutathione, total thiol content, total antioxidant capacity, acetylcholinesterase, monoamine oxidase and ATPases activities. These results were confirmed by histopathological, fluorescence and scanning electron microscopy examination of different regions of brain. From these results sodium arsenite-induced neurodegenerative disorder in different regions of brain and spinal cord and this could be mediated through modifying the intracellular brain ions homeostasis, cholinergic dysfunction and oxidative damage. The presence of Ginkgo biloba and/orTrifolium pretense with sodium arsenite minimized its neurological damages. It was pronounced that using Ginkgo biloba and Trifolium pretense in combination was more effective as protective agents compared to use eachone of them alone. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cholinergic abnormalities in autism: is there a rationale for selective nicotinic agonist interventions?

PubMed

Deutsch, Stephen I; Urbano, Maria R; Neumann, Serina A; Burket, Jessica A; Katz, Elionora

2010-05-01

The core dysfunctions of autism spectrum disorders, which include autistic disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified, include deficits in socialization and communication and a need for the preservation of "sameness;" intellectual impairment and epilepsy are common comorbidities. Data suggest that pathological involvement of cholinergic nuclei and altered expression of acetylcholine receptors, particularly nicotinic acetylcholine receptors, occur in brain of persons with autistic disorder. However, many of these studies involved postmortem tissue from small samples of primarily adult persons. Thus, the findings may reflect compensatory changes and may relate more closely to intellectual impairment and the confounding effects of seizures and medications, as opposed to the core dysfunctions of autism. Nonetheless, because of the roles played by acetylcholine receptors in general, and nicotinic acetylcholine receptors in particular, in normal processes of attention, cognition, and memory, selective cholinergic interventions should be explored for possible therapeutic effects. Additionally, there are electrophysiological data that complement the clinical observations of frequent comorbid seizure disorders in these patients, suggesting a disturbance in the balance of excitatory and inhibitory tone in the brains of persons with autistic disorders. Conceivably, because the alpha7 nicotinic acetylcholine receptor is located on the surface of gamma-aminobutyric acid inhibitory neurons, selective stimulation of this receptor would promote gamma-aminobutyric acid's release and restore diminished inhibitory tone. The development of agonists and partial agonists for nicotinic acetylcholine receptors and positive allosteric modulators that enhance the efficiency of coupling between the binding of agonist and channel opening should facilitate consideration of clinical trials.

Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia.

PubMed

Besnard, Marianne; Eyrolle-Guignot, Dominique; Guillemette-Artur, Prisca; Lastère, Stéphane; Bost-Bezeaud, Frédérique; Marcelis, Ludivine; Abadie, Véronique; Garel, Catherine; Moutard, Marie-Laure; Jouannic, Jean-Marie; Rozenberg, Flore; Leparc-Goffart, Isabelle; Mallet, Henri-Pierre

2016-01-01

We detected an unusual increase in congenital cerebral malformations and dysfunction in fetuses and newborns in French Polynesia, following an epidemic of Zika virus (ZIKV), from October 2013 to March 2014. A retrospective review identified 19 cases, including eight with major brain lesions and severe microcephaly, six with severe cerebral lesions without microcephaly and five with brainstem dysfunction without visible malformations. Imaging revealed profound neurological lesions (septal and callosal disruption, ventriculomegaly, abnormal neuronal migration, cerebellar hypoplasia, occipital pseudocysts, brain calcifications). Amniotic fluid was drawn from seven cases at gestation weeks 20 to 29. ZIKV RNA was detected by RT-PCR and infectious ZIKV isolates were obtained in four of five microcephalic, but not in two non-microcephalic cases with severe brain lesions. Medical termination of pregnancy was performed in eleven cases; two cases with brainstem dysfunction died in the first months of life; six cases are alive, with severe neurological impairment. The results show that four of seven tested fetuses with major neurological injuries were infected with ZIKV in utero. For other non-microcephalic, congenital abnormalities we were not able to prove or exclude ZIKV infection retrospectively. The unusual occurrence of brain malformations or dysfunction without microcephaly following a ZIKV outbreak needs further studies.

Drug-induced sexual dysfunction.

PubMed

Aldridge, S A

1982-01-01

Commonly used drugs that may cause sexual dysfunction are reviewed. The anatomy and physiology of the normal sexual response are reviewed. The influence of drugs on neurogenic, hormonal, and vascular mechanisms may result in diminished libido, impotence, ejaculatory and orgasmic difficulties, inhibited vaginal lubrication, menstrual irregularities, and gynecomastia in men or painful breast enlargement in women. Parasympatholytic agents, which interfere with cholinergic transmission, may affect erectile potency, while adrenergic inhibiting agents may interfere with ejaculatory control. Central nervous system depressants or sedating drugs, drugs producing hyperprolactinemia, and antiandrogenic drugs also may affect the normal sexual response. Drugs such as antihypertensive and antipsychotic agents may induce sexual dysfunction that can result in patient noncompliance. Usually, drug-induced side effects are reversible with discontinuation of the offending agent.

Theory of Mind and Irony Comprehension in Children with Cerebral Palsy

ERIC Educational Resources Information Center

Caillies, Stephanie; Hody, Anais; Calmus, Arnaud

2012-01-01

The main goal of the present study was to characterise the pragmatic abilities of French children with cerebral palsy through their understanding of irony and other people's mental states. We predicted that children with cerebral palsy would have difficulty understanding false-belief and ironic remarks, due to the executive dysfunction that…

Effects of AF64A on gene expression of choline acetyltransferase (ChAT) in the septo-hippocampal pathway and striatum in vivo.

PubMed

Fan, Q I; Hanin, I

1999-01-01

AF64A (ethylcholine mustard aziridinium ion) was stereotaxically administered bilaterally (1 nmol/side) into rat lateral cerebral ventricles. Choline acetyltransferase (ChAT) activity and ChAT mRNA levels were measured at predetermined time points in the septo-hippocampal pathway and striatum, both well identified as rich in cholinergic neurons. AF64A caused a rapid but transient increase in ChAT mRNA (167%, P < 0.05) and ChAT activity (164%, P < 0.01) in the septum. By day 7 post treatment, there was a significant decrease in ChAT mRNA (42.5% of control, P < 0.05) in the septum although the ChAT activity still stayed high. This decreased ChAT mRNA level in the septum lasted for at least four weeks, and was paralleled by a long-lasting decrease in ChAT activity in the hippocampus. In the striatum, on the other hand, there were no observed changes in either ChAT activity or ChAT mRNA. These data suggest that the long term effect of AF64A on the septo-hippocampal cholinergic pathway may, at least in part, be due to an action of AF64A on gene expression in the cholinergic neuron. The difference in the response to AF64A between the septo-hippocampal and striatal cholinergic systems might be due to their difference in neuron types.

Cognitive outcome of cerebral fat embolism.

PubMed

Manousakis, Georgios; Han, Dong Y; Backonja, Miroslav

2012-11-01

Cerebral fat embolism is an uncommon but serious complication of long-bone fracture. We report a young adult patient who sustained fat embolism after a femoral fracture. He developed stupor and coma within 24 hours from his injury. His acute recovery was characterized by marked frontal dysfunction. A comprehensive neuropsychological evaluation 4 months later revealed overall normal cognitive function, except for mild residual frontal dysfunction and weakness of verbal memory. Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Investigation of the role of non-selective calcium channel blocker (flunarizine) on cerebral ischemic-reperfusion associated cognitive dysfunction in aged mice.

PubMed

Gulati, Puja; Muthuraman, Arunachalam; Kaur, Parneet

2015-04-01

The present study was designed to investigate the role of flunarizine (a non-selective calcium channel blocker) on cerebral ischemic-reperfusion associated cognitive dysfunction in aged mice. Bilateral carotid artery occlusion of 12min followed by reperfusion for 24h was given to induce cerebral injury in male Swiss mice. The assessment of learning & memory was performed by Morris water maze test; motor in-coordination was evaluated by rota rod, lateral push and inclined beam walking tests; cerebral infarct size was quantified by triphenyltetrazolium chloride staining. In addition, reduced glutathione (GSH), total calcium and acetylcholinesterase (AChE) activity were also estimated in aged brain tissue. Donepezil treated group served as a positive control in this study. Ischemia reperfusion (I/R) injury produced significant increase in cerebral infarct size. A significant loss of memory along with impairment of motor performance was also noted. Further, I/R injury also produced significant increase in levels of total calcium, AChE activity and decrease in GSH levels. Pretreatment of flunarizine significantly attenuated I/R induced infarct size, behavioral and biochemical changes. Hence, it may be concluded that, a non-selective calcium channel blocker can be useful in I/R associated cognitive dysfunction due to its anti-oxidant, anti-infarct and modulatory actions of neurotransmitters & calcium channels. Copyright © 2015 Elsevier Inc. All rights reserved.

ChAT-ChR2-EYFP mice have enhanced motor endurance but show deficits in attention and several additional cognitive domains.

PubMed

Kolisnyk, Benjamin; Guzman, Monica S; Raulic, Sanda; Fan, Jue; Magalhães, Ana C; Feng, Guoping; Gros, Robert; Prado, Vania F; Prado, Marco A M

2013-06-19

Acetylcholine (ACh) is an important neuromodulator in the nervous system implicated in many forms of cognitive and motor processing. Recent studies have used bacterial artificial chromosome (BAC) transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2-EYFP) to dissect cholinergic circuit connectivity and function using optogenetic approaches. We report that a mouse line used for this purpose also carries several copies of the vesicular acetylcholine transporter gene (VAChT), which leads to overexpression of functional VAChT and consequently increased cholinergic tone. We demonstrate that these mice have marked improvement in motor endurance. However, they also present severe cognitive deficits, including attention deficits and dysfunction in working memory and spatial memory. These results suggest that increased VAChT expression may disrupt critical steps in information processing. Our studies demonstrate that ChAT-ChR2-EYFP mice show altered cholinergic tone that fundamentally differentiates them from wild-type mice.

Intrinsic Cholinergic Mechanisms Regulating Cerebral Blood Flow as a Target for Organophosphate Action

DTIC Science & Technology

1988-10-01

acetyltransferase (ChAT), the ACh- C= synthesizing enzyme. ChAT-immunoreactive cell bodies and processes were localized to autonomic or limbic nuclei throughout...the neuraxis and close appositions with brainstemn microvessels and ependymal cells . Moreover, theA DO , U03 Eoirlo oil ov wavs I 69LET9 SCCUmTYV...spinal preganglionic neurons of the intermediolateral cell columns ([ML). ChAT-immunoreactive cell bodies and processes were localized to autonomic or

Localization of multiple neurotransmitters in surgically derived specimens of human atrial ganglia.

PubMed

Hoover, D B; Isaacs, E R; Jacques, F; Hoard, J L; Pagé, P; Armour, J A

2009-12-15

Dysfunction of the intrinsic cardiac nervous system is implicated in the genesis of atrial and ventricular arrhythmias. While this system has been studied extensively in animal models, far less is known about the intrinsic cardiac nervous system of humans. This study was initiated to anatomically identify neurotransmitters associated with the right atrial ganglionated plexus (RAGP) of the human heart. Biopsies of epicardial fat containing a portion of the RAGP were collected from eight patients during cardiothoracic surgery and processed for immunofluorescent detection of specific neuronal markers. Colocalization of markers was evaluated by confocal microscopy. Most intrinsic cardiac neuronal somata displayed immunoreactivity for the cholinergic marker choline acetyltransferase and the nitrergic marker neuronal nitric oxide synthase. A subpopulation of intrinsic cardiac neurons also stained for noradrenergic markers. While most intrinsic cardiac neurons received cholinergic innervation evident as punctate immunostaining for the high affinity choline transporter, some lacked cholinergic inputs. Moreover, peptidergic, nitrergic, and noradrenergic nerves provided substantial innervation of intrinsic cardiac ganglia. These findings demonstrate that the human RAGP has a complex neurochemical anatomy, which includes the presence of a dual cholinergic/nitrergic phenotype for most of its neurons, the presence of noradrenergic markers in a subpopulation of neurons, and innervation by a host of neurochemically distinct nerves. The putative role of multiple neurotransmitters in controlling intrinsic cardiac neurons and mediating efferent signaling to the heart indicates the possibility of novel therapeutic targets for arrhythmia prevention.

Blood-brain barrier dysfunction in brain diseases: clinical experience.

PubMed

Schoknecht, Karl; Shalev, Hadar

2012-11-01

The blood-brain barrier, a unique feature of the cerebral vasculature, is gaining attention as a feature in common neurologic disorders including stroke, traumatic brain injury, epilepsy, and schizophrenia. Although acute blood-brain barrier dysfunction can induce cerebral edema, seizures, or neuropsychiatric symptoms, epileptogenesis and cognitive decline are among the chronic effects. The mechanisms underlying blood-brain barrier dysfunction are diverse and may range from physical endothelial damage in traumatic brain injury to degradation of extracellular matrix proteins via matrix metalloproteinases as part of an inflammatory response. Clinically, blood-brain barrier dysfunction is often detected using contrast-enhanced imaging. However, these techniques do not give any insights into the underlying mechanism. Elucidating the specific pathways of blood-brain barrier dysfunction at different time points and in different brain diseases using novel imaging techniques promises a more accurate blood-brain barrier terminology as well as new treatment options and personalized treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Neuro-Ophthalmological Disorders in Cerebral Palsy: Ophthalmological, Oculomotor, and Visual Aspects

ERIC Educational Resources Information Center

Fazzi, Elisa; Signorini, Sabrina G.; La Piana, Roberta; Bertone, Chiara; Misefari, Walter; Galli, Jessica; Balottin, Umberto; Bianchi, Paolo Emilio

2012-01-01

Aim: Cerebral visual impairment (CVI) is a disorder caused by damage to the retrogeniculate visual pathways. Cerebral palsy (CP) and CVI share a common origin: 60 to 70% of children with CP also have CVI. We set out to describe visual dysfunction in children with CP. A further aim was to establish whether different types of CP are associated with…

Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice.

PubMed

Takuma, K; Mizoguchi, H; Funatsu, Y; Hoshina, Y; Himeno, Y; Fukuzaki, E; Kitahara, Y; Arai, S; Ibi, D; Kamei, H; Matsuda, T; Koike, K; Inoue, M; Nagai, T; Yamada, K

2012-04-05

We have recently found that the combination of ovariectomy (OVX) and chronic restraint stress (CS) causes hippocampal pyramidal cell loss and cognitive dysfunction in female rats and that estrogen replacement prevents the OVX/CS-induced morphological and behavioral changes. In this study, to clarify the mechanisms underlying the OVX/CS-mediated memory impairment further, we examined the roles of cholinergic systems in the OVX/CS-induced memory impairment in mice. Female Slc:ICR strain mice were randomly divided into two groups: OVX and sham-operated groups. Two weeks after the operation, the mice of each group were further assigned to CS (6 h/day) or non-stress group. Following the 3-week-stress period, all mice were subjected to contextual fear conditioning, and context- and tone-dependent memory tests were conducted 1 or 24 h after the conditioning. Overburden with 3 weeks of CS from 2 weeks after OVX impaired context- and tone-dependent freezing and the OVX/CS caused significant Nissl-stained neuron-like cell loss in the hippocampal CA3 region, although OVX and CS alone did not cause such behavioral and histological changes. Replacement of 17β-estradiol for 5 weeks after OVX suppressed OVX/CS-induced memory impairment and hippocampal Nissl-positive cell loss. Furthermore, the OVX/CS mice exhibited a significant decrease in choline acetyltransferase in the hippocampus compared with other groups. The cholinesterase inhibitors donepezil and galantamine ameliorated OVX/CS-induced memory impairment. These data suggest that cholinergic dysfunction may be involved in the OVX/CS-induced conditioned fear memory impairment. Overall, our findings suggest that the OVX/CS mouse model is useful to study the mechanisms underlying estrogen loss-induced memory deficits. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of alpha-lipoic acid on spatial learning and memory, oxidative stress, and central cholinergic system in a rat model of vascular dementia.

PubMed

Zhao, Ran-Ran; Xu, Fei; Xu, Xiao-Chen; Tan, Guo-Jun; Liu, Liang-Min; Wu, Ning; Zhang, Wen-Zhong; Liu, Ji-Xiang

2015-02-05

Brain oxidative stress due to chronic cerebral hypoperfusion was considered to be the major risk factor in the pathogenesis of vascular dementia. In this study, we investigated the protective efficacy of alpha-lipoic acid, an antioxidant, against vascular dementia in rats, as well as the potential mechanism. Bilateral common carotid arteries occlusion (BCCAO) induced severe cognitive deficits tested by Morris water maze (MWM), along with oxidative stress and disturbance of central cholinergic system. However, administration of alpha-lipoic acid (50mg/kg, i.p.) for 28 days significantly restored cognitive deficits induced by BCCAO. Biochemical determination revealed that alpha-lipoic acid markedly decreased the production of malondialdehyde (MDA) and the generation of reactive oxidative species (ROS), and increased the level of reduced glutathione (GSH) in the hippocampal tissue. Additionally, alpha-lipoic acid raised the level of acetylcholine (ACh) and choline acetyltransferase (ChAT) and decreased the activity of acetycholinesterase (AChE) in the hippocampus. These results indicated that treatment with alpha-lipoic acid significantly improved behavioral alterations, protected against oxidative stress, and restored central cholinergic system in the rat model of vascular dementia induced by BCCAO. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Recovery of an injured fornix in a stroke patient.

PubMed

Yeo, Sang Seok; Jang, Sung Ho

2013-11-01

Knowledge about recovery of an injured fornix following brain injury is limited. We describe here a patient who showed recovery of an injured fornix following stroke. A 57-year-old female patient underwent coiling for a ruptured anterior communicating cerebral artery aneurysm, and conservative management for subarachnoid and intraventricular haemorrhage. The patient showed severe cognitive impairment 6 weeks after onset. However, her cognition showed continuous improvement with time; based on the Mini-Mental State Examination and the Memory Assessment Scale, her cognition was within the normal range 7 months after onset. Findings from diffusion tensor tractography at 6 weeks and 7 months showed discontinuations in both columns of the fornix. The proximal portion of both crus also showed discontinuation on diffusion tensor tractography at 6 weeks and 7 months; however, on 7-month diffusion tensor tractography, the end of the fornical body was shown to be connected to the splenium of the corpus callosum and then branched to the right medial temporal lobe and right thalamus. The unusual neural connection between the injured fornix and the thalamus appears to be a recovery phenomenon, which allows the injured fornix and the medial temporal lobe to obtain cholinergic innervation from cholinergic nuclei in the brainstem rather than from cholinergic nuclei in the basal forebrain.

Intrinsic Cholinergic Mechanisms Regulating Cerebral Blood Flow as a Target for Organo Phosphate Action.

DTIC Science & Technology

1986-10-01

Associates) onto a 10 um ODS column (4.6 x 100 mm). The mobile phase was 96% 0.01 M sodium acetate (pH = 5.0) containing 30 mg/liter 1-octanesulfonic acid...the biological samples, each sample was evaporated and reconstituted in 30 ul of mobile phase. As for the standards, 20 ul aliquots were analyzed...were not significantly reduced by atropine (Fig. 5). B. Effect of Topical Aplication of Atropine on the Cerebrovasodilation Elicited by Hypercarbia

Nerve growth factor metabolic dysfunction in Down’s syndrome brains

PubMed Central

Iulita, M. Florencia; Do Carmo, Sonia; Ower, Alison K.; Fortress, Ashley M.; Aguilar, Lisi Flores; Hanna, Michael; Wisniewski, Thomas; Granholm, Ann-Charlotte; Buhusi, Mona; Busciglio, Jorge

2014-01-01

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer’s disease and Down’s syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer’s disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF’s extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down’s syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down’s syndrome and age-matched controls (age range 31–68 years). We further examined primary cultures of human foetal Down’s syndrome cortex (17–21 gestational age weeks) and brains from Ts65Dn mice (12–22 months), a widely used animal model of Down’s syndrome. We report a significant increase in proNGF levels in human and mouse Down’s syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down’s syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down’s syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down’s syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer’s disease and Down’s syndrome. PMID:24519975

[Role of cerebral hemodynamics in the mechanism of development of acquired myopia in schoolchildren].

PubMed

Iastrebtseva, T A; Demidova, T E; Polikarpova, V E

2008-01-01

Rheoencephalography was used to study cerebral venous circulation in 199 schoolchildren aged 12-15 years who had emmetropia, pseudomyopia, and myopia. Tonometry was carried out in 39 persons. Cerebral venous hemodynamic dysfunction was more frequently encountered in schoolchildren with myopia than in those with emmetropia. Intraocular pressure was significantly higher only in schoolchildren with high myopia than in the controls.

Glucocorticoid Programing of the Mesopontine Cholinergic System

PubMed Central

Borges, Sónia; Coimbra, Bárbara; Soares-Cunha, Carina; Ventura-Silva, Ana P.; Pinto, Luisa; Carvalho, Miguel M.; Pêgo, José-Miguel; Rodrigues, Ana João; Sousa, Nuno

2013-01-01

Stress perception, response, adaptation, and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids (GCs) is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programing intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety, and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to GCs (in utero glucocorticoid exposure, iuGC) present hyperanxiety, increased fear behavior, and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22 kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT), in the initiation of 22 kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT) expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individual stress vulnerability threshold. PMID:24379803

Safety and efficacy of retrograde cerebral perfusion as an adjunct for cerebral protection during surgery on the aortic arch.

PubMed

Girardi, Leonard N; Shavladze, Nikolay; Sedrakyan, Art; Neragi-Miandoab, Siyamek

2014-12-01

The best adjunct for cerebral protection during aortic arch reconstruction remains controversial. Retrograde cerebral perfusion (RCP) as an adjunct to profound hypothermic circulatory arrest (PHCA) extends the tolerable period of brain ischemia by flushing emboli and air from the cerebral circulation while maintaining hypothermia. We examined our experience with RCP to determine its efficacy in patients undergoing complex arch reconstruction. We retrospectively evaluated 879 patients undergoing arch reconstruction using RCP from July 1997 to March 2013. Perioperative risk factors were analyzed as predictors of neurologic injury and mortality. Survival for the type of arch reconstruction and for the interval of PHCA was calculated. Of the 879 patients, 671 underwent hemiarch and 208 total arch replacement. The mean age was 65 ± 13.3 years, and 61.6% were men. The total arch patients had longer mean periods of PHCA (39 vs 21 minutes, P < .001) and RCP (37 vs 19 minutes, P < .001). However, the incidence of transient neurologic dysfunction (3.0% vs 2.4%, P < .813) and permanent neurologic dysfunction (1.3% vs 1.9%, P < .519) was similar for both techniques. Mortality was greater in the hemiarch group (4.8% vs 0.5%, P < .003). Patients requiring >40 minutes of PHCA had outcomes similar to those requiring less. The 1-, 5-, and 10-year survival was similar, regardless of the procedure performed or interval of PHCA. RCP is a safe and effective adjunct for cerebral protection during arch surgery. Patients requiring more extensive arch reconstruction are not at greater risk of permanent neurologic dysfunction or perioperative mortality. Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Cholinergic modulation of dopaminergic neurons in the mouse olfactory bulb.

PubMed

Pignatelli, Angela; Belluzzi, Ottorino

2008-04-01

Considerable evidence exists for an extrinsic cholinergic influence in the maturation and function of the main olfactory bulb. In this study, we addressed the muscarinic modulation of dopaminergic neurons in this structure. We used different patch-clamp techniques to characterize the diverse roles of muscarinic agonists on identified dopaminergic neurons in a transgenic animal model expressing a reporter protein (green fluorescent protein) under the tyrosine hydroxylase promoter. Bath application of acetylcholine (1 mM) in slices and in enzymatically dissociated cells reduced the spontaneous firing of dopaminergic neurons recorded in cell-attached mode. In whole-cell configuration no effect of the agonist was observed, unless using the perforated patch technique, thus suggesting the involvement of a diffusible second messenger. The effect was mediated by metabotropic receptors as it was blocked by atropine and mimicked by the m2 agonist oxotremorine (10 muM). The reduction of periglomerular cell firing by muscarinic activation results from a membrane-potential hyperpolarization caused by activation of a potassium conductance. This modulation of dopaminergic interneurons may be important in the processing of sensory information and may be relevant to understand the mechanisms underlying the olfactory dysfunctions occurring in neurodegenerative diseases affecting the dopaminergic and/or cholinergic systems.

Spatial learning in rats: correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage.

PubMed

Mandel, R J; Gage, F H; Thal, L J

1989-06-01

Rats display an acquisition deficit in a circular water maze following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). Experiments were therefore performed to determine if acquisition behavior on this task could predict the degree of cortical cholinergic deafferentation and if the acquisition deficit could be pharmacologically reversed. Performance on acquisition was highly correlated with the lesion-induced reduction in cortical choline acetyltransferase (ChAT) activity. Accuracy of spatial behavior was highly correlated to percentage ChAT depletion (r = 0.75). Neither lesioned rats nor controls displayed a retention deficit after a 9-day interval, nor did either group display a passive-avoidance retention deficit. To test the causal relationship between cholinergic dysfunction and spatial behavior, the central nervous system cholinergic enhancer nerve growth factor (NGF) was intraventricularly infused for 4 weeks. NGF infusion resulted in improved acquisition of the water maze task compared to NBM-lesioned rats receiving vehicle infusion and untreated rats with NBM lesions. These studies indicate that the decrease in cortical ChAT activity is likely to be responsible for the observed acquisition deficit and that pharmacological manipulations can be successfully used to improve behavior following NBM lesions.

Canagliflozin prevents scopolamine-induced memory impairment in rats: Comparison with galantamine hydrobromide action.

PubMed

Arafa, Nadia M S; Ali, Elham H A; Hassan, Mohamed Kamel

2017-11-01

Canagliflozin (CAN) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated to improve glycemic control in adults with type 2 diabetes mellitus. There is a little information about its effect on the cholinergic system that proposed mechanism for memory improvement occurring by SGLT2 drugs. This study aimed to estimate the effect of CAN as compared to galantamine (GAL) treatments for two weeks on scopolamine hydrobromide (SCO)-induced memory dysfunction in experimental rats. Animals divided into six groups; control (CON), CAN, GAL, SCO, SCO + CAN and SCO + GAL. Results indicated significant decrease in body weights of the CAN groups as compared to control values. Moreover, in the SCO + CAN and SCO + GAL the number of arm entry and number of correct alternation in Y maze task increased and showed improvement in the water maze task, acetylcholinesterase (AChE) activities decreased significantly, while monoamines levels significantly increased compared with the SCO group values. Results also recorded acetylcholine M1 receptor (M1 mAChR) in SCO + CAN or SCO + GAL groups in comparison with the SCO group. The study suggested that canagliflozin might improve memory dysfunction induced by scopolamine hydrobromide via cholinergic and monoamines system. Copyright © 2017 Elsevier B.V. All rights reserved.

Prefrontal gray matter morphology mediates the association between serum anticholinergicity and cognitive functioning in early course schizophrenia.

PubMed

Wojtalik, Jessica A; Eack, Shaun M; Pollock, Bruce G; Keshavan, Matcheri S

2012-11-30

Antipsychotic and other medications used in the treatment of schizophrenia place a burden on the cholinergic subsystems of the brain, which have been associated with increased cognitive impairment in the disorder. This study sought to examine the neurobiologic correlates of the association between serum anticholinergic activity (SAA) and cognitive impairments in early schizophrenia. Neurocognitive performance on measures of memory and executive function, structural magnetic resonance imaging (MRI) scans, and SAA assays were collected from 47 early course, stabilized outpatients with schizophrenia or schizoaffective disorder. Voxel-based morphometry analyses employing general linear models, adjusting for demographic and illness-related confounds, were used to investigate the associations between SAA, gray matter morphology, and neurocognitive impairment. SAA was related to working memory and executive function impairments. Higher SAA was significantly associated with lower gray matter density in broad regions of the frontal and medial-temporal lobes, including the dorsolateral prefrontal cortex (DLPFC), hippocampus, and striatum. Lower gray matter volume in the left DLPFC was found to significantly mediate the association between SAA and working memory impairment. Disease- and/or medication-related cholinergic dysfunction may be associated with brain volume abnormalities in early course schizophrenia, which may account for the association between SAA and cognitive dysfunction in the disorder. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Similar cerebral protective effectiveness of antegrade and retrograde cerebral perfusion combined with deep hypothermia circulatory arrest in aortic arch surgery: a meta-analysis and systematic review of 5060 patients.

PubMed

Hu, Zhipeng; Wang, Zhiwei; Ren, Zongli; Wu, Hongbing; Zhang, Min; Zhang, Hao; Hu, Xiaoping

2014-08-01

Our objective was to determine if antegrade cerebral perfusion (ACP) and retrograde cerebral perfusion (RCP) combined with deep hypothermia circulatory arrest in aortic arch surgery results in different mortality and neurologic outcomes. The Cochrane Library, Medline, EMBASE, CINAHL, Web of Science, and the Chinese Biomedical Database were searched for studies reporting on postoperative strokes, permanent neurologic dysfunction, temporary neurologic dysfunction, and all causes mortality within 30 days postoperation in aortic arch surgery. Meta-analysis for effect size, t test, and I(2) for detecting heterogeneity and sensitivity analysis for assessing the relative influence of each study was performed. Fifteen included studies encompassed a total of 5060 patients of whom 2855 were treated with deep hypothermic circulatory arrest plus ACP and 1897 were treated with deep hypothermic circulatory arrest plus RCP. Pooled analysis showed no significant statistical difference (P > .01) of 30-day mortality, permanent neurologic dysfunction, and transient neurologic dysfunction in the 2 groups. Before sensitivity analysis, postoperative stroke incidence in the ACP group was higher than in the RCP group (7.2% vs 4.7%; P < .01). After a study that included a different percentage of patients with a history of central neurologic events in the 2 groups was ruled out, postoperative stroke incidence in the 2 groups also showed no significant statistical difference (P > .01). ACP and RCP provide similar cerebral protective effectiveness combined with deep hypothermia circulatory arrest and could be selected according to the actual condition in aortic arch surgery. A high-quality randomized controlled trial is urgently needed to confirm this conclusion, especially for stroke morbidity following ACP or RCP. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Biomarkers and Brain Mechanisms of Gulf War Illness

DTIC Science & Technology

2017-09-01

serve as biomarkers of the disorder. 15. SUBJECT TERMS Gulf War illness, neuroinflammation, oxidative stress , mitochondrial dysfunction, magnetic...Oxidative Stress , Mitochondrial Dysfunction; Magnetic Resonance Imaging, Positron Emission Tomography Page | 5 Subtask 2: Develop complementary or...30 Major Task 3: To conduct 1H and 31P MRS studies for assessment of oxidative stress and mitochondrial dysfunction in vivo. Assess cerebral blood

Neurovascular signaling in the brain and the pathological consequences of hypertension

PubMed Central

Dunn, Kathryn M.

2013-01-01

The execution and maintenance of all brain functions are dependent on a continuous flow of blood to meet the metabolic needs of the tissue. To ensure the delivery of resources required for neural processing and the maintenance of neural homeostasis, the cerebral vasculature is elaborately and extensively regulated by signaling from neurons, glia, interneurons, and perivascular nerves. Hypertension is associated with impaired neurovascular regulation of the cerebral circulation and culminates in neurodegeneration and cognitive dysfunction. Here, we review the physiological processes of neurovascular signaling in the brain and discuss mechanisms of hypertensive neurovascular dysfunction. PMID:24163077

Activation of PPAR-γ by pioglitazone attenuates oxidative stress in aging rat cerebral arteries through upregulating UCP2.

PubMed

Wang, Peijian; Li, Binghu; Cai, Guocai; Huang, Mingqing; Jiang, Licheng; Pu, Jing; Li, Lu; Wu, Qi; Zuo, Li; Wang, Qiulin; Zhou, Peng

2014-12-01

Increasing amounts of evidence implicate oxidative stress as having a pivotal role in age-related cerebrovascular dysfunction, which is an important risk factor for the development of cerebrovascular disease. Previous studies have shown that the activation of the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) in vascular endothelial cells results in an improvement of vascular function. Pioglitazone, a well-known PPAR-γ agonist, protects against oxidative stress in the rostral ventrolateral medulla by the upregulation of mitochondrial uncoupling protein 2 (UCP2). In this study, we sought to explore the effects and the underlying mechanisms of pioglitazone on age-related oxidative stress elevation and cerebrovascular dysfunction in aging rat cerebral arteries. A natural aging model was constructed and used in these experiments. One-month oral administration of pioglitazone (20 mg·kg·d) ameliorated the production of reactive oxygen species, promoted endothelial nitric oxide synthase phosphorylation and increased the nitric oxide available, thus improving endothelium-dependent relaxation in aging rat cerebral arteries. One-month pioglitazone administration also restored PPAR-γ expression and increased the levels of UCP2 in aging rat cerebral arteries. Using in vitro studies, we demonstrated that pioglitazone attenuated reactive oxygen species levels in aging human umbilical vein endothelial cells through PPAR-γ activation. Furthermore, we found that this occurs in an UCP2-dependent manner. Our study demonstrated that the activation of PPAR-γ by pioglitazone protected against oxidative stress damage in aging cerebral arteries by upregulating UCP2. PPAR-γ may be a new target in treating age-related cerebrovascular dysfunction.

[Condition of neurohumoral regulation of bronchial tone and gallbladder in patients with chronic cholecystitis and chronic obstructive pulmonary disease].

PubMed

Dudka, T V; Khukhlina, O S; Dudka, I V

2014-01-01

SUMMARY The paper presents data from a study of the neuroendocrine regulation of nonstriated muscles, bronchial tree and the gallbladder tones by means of an assessment of the adrenergic and cholinergic systems state in patients, suffering from chronic obstructive pulmonary disease and chronic acalculous cholecystitis. Adrenergic and cholinergic activities as well as cortisol secretion have significantly changed. To study the features of adrenergic and cholinergic regulations of bronchial tone and that of the gallbladder in patients with combined course of chronic acalculous cholecystitis and chronic obstructive pulmonary disease. 92 patients were involved in the study: 30 patients with COPD (1st group), 30 patients with COPD of comorbid CAC in the acute phase (2nd group), 32 patients with CAC in the acute phase (3rd group) and a control group--30 practically healthy individuals (PHI) of the respective age. All the patients with COPD and COPD combined with CAC had a marked predominance of the parasympathetic nervous system, as evidenced by the established significant decrease of CDE (Table) in patients with isolated COPD is 1.4 times (p < 0.05), in patients with COPD combined with CAC--there was more intense inhibition of enzyme activity--in 1.8 times (p < 0.05) and in patients with CAC of the 3rd group there were identical changes--a decreased activity of CDE in 1.6 times (p < 0.05) with significant intergroup differences between the groups (p < 0.05). An analysis of the studies showed significant changes in the CDE of the surveyed individuals. For instance, the CDA in the individuals of groups 1 and 2 was lower by 1.6 and 2.4 times respectively (p < 0.001) than in the group of PHI; in the patients of the 3rd group--the changes were minor--a decline of 14.6% (p < 0.05) compared with practically healthy individuals (Table). Participation of sympathoadrenal system in the pathogenesis of COPD occurrence has been proved, however, in patients with COPD and CAC, the ability to deposit CA, when combined with CAC has significantly dropped. The study of cortisol density in the blood serum of the patients under examination showed its significant drop in all groups observed. For instance, the first group patients' blood contained 2.7 times (p < 0.05) less cortisol than that of PHI; in the patients of the second group the inhibition of the functional state of the adrenal cortex was even more intense--cortisol was lower than its index in the control group by 3.7 times (p < 0.05); the 3d group patients had the maximum drop in cortisol secretion by 1.7 times (p < 0.05) with reliable intergroup difference. The base of regulatory neuroendocrine and paracrine mecganisms imbalance, contributing to a development of COPD, is the cholinergic imbalance (reduction in blood acetylcholinesterase activity, hypertensive sphincter of Oddi dysfunction), adrenergic imbalance, reduction in catecholamine-depositing erythrocytes function, hypokinetic gallbladder dysfunction, adrenal dysfunction (decreased cortisol levels) that contribute to the development and progression of chronic cholecystitis against a background of hypokinetic gallbladder dysfunction.

Virtual Reality Goes to War: A Brief Review of the Future of Military Behavioral Healthcare

DTIC Science & Technology

2011-05-07

functional skill training and motor rehabilitation with patients having central nervous system dysfunction (e.g., stroke, TBI, SCI, cerebral palsy ...Improvement in cerebral function with treatment of posttraumatic stress disorder. Annals of the New York Academy of Sciences (NYAS), 1208, 142–149. Schneider

Metabolomics-based mechanisms exploration of Huang-Lian Jie-Du decoction on cerebral ischemia via UPLC-Q-TOF/MS analysis on rat serum.

PubMed

Zhu, Baojie; Cao, Huiting; Sun, Limin; Li, Bo; Guo, Liwei; Duan, Jinao; Zhu, Huaxu; Zhang, Qichun

2018-04-24

Huang-Lian Jie-Du decoction (HLJDD), a traditional formula of Chinese medicine constituted with Rhizoma Coptidis, RadixScutellariae, CortexPhellodendri amurensis and Fructus Gardeniae, exhibits unambiguous therapeutic effect on cerebral ischemia via multi-targets action. Further investigation, however, is still required to explore the relationship between those mechanisms and targets through system approaches. Rats of cerebral ischemia were completed by middle cerebral artery occlusion (MCAO) with reperfusion. Following evaluation of pharmacological actions of HLJDD on MCAO rats, the plasma samples from rats of control, MCAO and HLJDD-treated MCAO groups were prepared strictly and subjected to ultra-performance liquid chromatography quadrupole time of flight mass spectrometry for metabolites analysis. The raw mass data were imported to MassLynx software for peak detection and alignment, and further introduced to EZinfo 2.0 software for orthogonal projection to latent structures analysis, principal component analysis and partial least-squares-discriminant analysis. The metabolic pathways assay of those potential biomarkers were performed with MetaboAnalyst through the online database, HMDB, Metlin, KEGG and SMPD. Those intriguing metabolic pathways were further investigated via biochemical assay. HLJDD ameliorated the MCAO-induce cerebral damage and blocked the severe inflammation response. There were nineteen different biomarkers identified among control, MCAO and HLJDD-treated MCAO groups. Ten metabolic pathways were proposed from these significant metabolites. Incorporation with the biochemical assay of cerebral tissue, modulation of metabolic stress, regulation glutamate/GABA-glutamine cycle and enhancement of cholinergic neurons function were explored that involved in the actions of HLJDD on cerebral ischemia. HLJDD achieves therapeutic action on cerebral ischemia via coordinating the basic pathophysiological network of metabolic stress, glutamate metabolism, and acetylcholine levels and function. Copyright © 2018 Elsevier B.V. All rights reserved.

Methamidophos Exposure During the Early Postnatal Period of Mice: Immediate and Late-Emergent Effects on the Cholinergic and Serotonergic Systems and Behavior

PubMed Central

Abreu-Villaça, Yael

2013-01-01

Organophosphates (OPs) are among the most used pesticides. Although some OPs have had their use progressively more restricted, other OPs are being used without sufficient investigation of their effects. Here, we investigated the immediate neurochemical and delayed neurochemical and behavioral actions of the OP methamidophos to verify whether there are concerns regarding exposure during early postnatal development. From the third to the nineth postnatal day (PN), Swiss mice were sc injected with methamidophos (1mg/kg). At PN10, we assessed cholinergic and serotonergic biomarkers in the cerebral cortex and brainstem. From PN60 to PN63, mice were submitted to a battery of behavioral tests and subsequently to biochemical analyses. At PN10, the effects were restricted to females and to the cholinergic system: Methamidophos promoted increased choline transporter binding in the brainstem. At PN63, in the brainstem, there was a decrease in choline transporter, a female-only decrease in 5HT1A and a male-only increase in 5HT2 receptor binding. In the cortex, choline acetyltransferase activity was decreased and 5HT2 receptor binding was increased both in males and females. Methamidophos elicited behavioral alterations, suggestive of increased depressive-like behavior and impaired decision making. There were no significant alterations on anxiety-related measures and on memory/learning. Methamidophos elicited cholinergic and serotonergic alterations that depended on brain region, sex, and age of the animals. These outcomes, together with the behavioral effects, indicate that this OP is deleterious to the developing brain and that alterations are indeed identified long after the end of exposure. PMID:23596261

Methamidophos exposure during the early postnatal period of mice: immediate and late-emergent effects on the cholinergic and serotonergic systems and behavior.

PubMed

Lima, Carla S; Dutra-Tavares, Ana C; Nunes, Fernanda; Nunes-Freitas, André L; Ribeiro-Carvalho, Anderson; Filgueiras, Cláudio C; Manhães, Alex C; Meyer, Armando; Abreu-Villaça, Yael

2013-07-01

Organophosphates (OPs) are among the most used pesticides. Although some OPs have had their use progressively more restricted, other OPs are being used without sufficient investigation of their effects. Here, we investigated the immediate neurochemical and delayed neurochemical and behavioral actions of the OP methamidophos to verify whether there are concerns regarding exposure during early postnatal development. From the third to the nineth postnatal day (PN), Swiss mice were sc injected with methamidophos (1mg/kg). At PN10, we assessed cholinergic and serotonergic biomarkers in the cerebral cortex and brainstem. From PN60 to PN63, mice were submitted to a battery of behavioral tests and subsequently to biochemical analyses. At PN10, the effects were restricted to females and to the cholinergic system: Methamidophos promoted increased choline transporter binding in the brainstem. At PN63, in the brainstem, there was a decrease in choline transporter, a female-only decrease in 5HT1A and a male-only increase in 5HT2 receptor binding. In the cortex, choline acetyltransferase activity was decreased and 5HT2 receptor binding was increased both in males and females. Methamidophos elicited behavioral alterations, suggestive of increased depressive-like behavior and impaired decision making. There were no significant alterations on anxiety-related measures and on memory/learning. Methamidophos elicited cholinergic and serotonergic alterations that depended on brain region, sex, and age of the animals. These outcomes, together with the behavioral effects, indicate that this OP is deleterious to the developing brain and that alterations are indeed identified long after the end of exposure.

Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions.

PubMed

Zhang, Rui; Zhang, Jingzhu; Fang, Lingduo; Li, Xi; Zhao, Yue; Shi, Wanying; An, Li

2014-08-18

Alzheimer's disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and D-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics.

Intrinsic Cholinergic Mechanisms Regulating Cerebral Blood Flow as a Target for Organophosphate Action.

DTIC Science & Technology

1985-10-01

regions one hour 26 following microinjection of YH- choline into the right parietal cortex. II Effect of atropine sulfate (0.3 mg/kg i.v.) on the...Harvard Apparatus model 940). The superfusate consisted of a modified Kreb’s- bicarbonate buffer containing physostigmine to inhibit ACh degradation...in mM: NaCl, 118; CaCI 2 , 1.2; KC01, 4.8; MgSO4, 1.2; NaH 2 PO 4 , 1.2; NaHCO 3 , 25; choline chloride, 0.001; physostigmine, 0.1). The area of the

Bilateral cerebral hemispheric infarction associated with sildenafil citrate (Viagra) use.

PubMed

Kim, K-K; Kim, D G; Ku, Y H; Lee, Y J; Kim, W-C; Kim, O J; Kim, H S

2008-03-01

Sildenafil citrate (Viagra) is one of the frequently prescribed drugs for men with erectile dysfunction. We describe a 52-year-old man with bilateral middle cerebral artery (MCA) territory infarction after sildenafil use. He ingested 100 mg of sildenafil and about 1 h later, he complained of chest discomfort, palpitation and dizziness followed by mental obtundation, global aphasia and left hemiparesis. Brain magnetic resonance imaging documented acute bilateral hemispheric infarction, and cerebral angiography showed occluded bilateral MCA. Despite significant bilateral MCA stenosis and cerebral infarction, systemic hypotension persisted for a day. We presume that cerebral infarction was caused by cardioembolism with sildenafil use.

The role of nicotinic receptors in shaping and functioning of the glutamatergic system: a window into cognitive pathology.

PubMed

Molas, Susanna; Dierssen, Mara

2014-10-01

The involvement of the cholinergic system in learning, memory and attention has long been recognized, although its neurobiological mechanisms are not fully understood. Recent evidence identifies the endogenous cholinergic signaling via nicotinic acetylcholine receptors (nAChRs) as key players in determining the morphological and functional maturation of the glutamatergic system. Here, we review the available experimental and clinical evidence of nAChRs contribution to the establishment of the glutamatergic system, and therefore to cognitive function. We provide some clues of the putative underlying molecular mechanisms and discuss recent human studies that associate genetic variability of the genes encoding nAChR subunits with cognitive disorders. Finally, we discuss the new avenues to therapeutically targeting nAChRs in persons with cognitive dysfunction for which the α7-nAChR subunit is an important etiological mechanism. Copyright © 2014 Elsevier Ltd. All rights reserved.

l-arginine and l-NMMA for assessing cerebral endothelial dysfunction in ischaemic cerebrovascular disease: A systematic review.

PubMed

Karlsson, William K; Sørensen, Caspar G; Kruuse, Christina

2017-01-01

Endothelial dysfunction (ED), in particular cerebral ED, may be an essential biomarker for ischaemic cerebrovascular disease. However, there is no consensus on methods to best estimate cerebral ED. In this systematic review, we evaluate the use of l-arginine and N G -monomethyl-l-arginine (l-NMMA) for assessment of cerebral ED. A systematic search of PubMed, EMBASE and the Cochrane Library was done. We included studies investigating cerebrovascular response to l-arginine or l-NMMA in human subjects with vascular risk factors or ischaemic cerebrovascular disease. Seven studies (315 subjects) were eligible according to inclusion and exclusion criteria. Studies investigated the effect of age (n=2), type 2 diabetes mellitus (DM) (n=1), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (n=1), leukoaraiosis (n=1), and prior ischaemic stroke or transient ischaemic attack (TIA) (n=2) on cerebral ED. Most studies applied transcranial Doppler to quantify cerebral ED. Endothelium-dependent vasodilatation (EDV) induced by l-arginine was impaired in elderly and subjects with leukoaraiosis, but enhanced in CADASIL patients. Studies including subjects with prior ischaemic stroke or TIA reported both enhanced and impaired EDV to l-arginine. Responses to l-NMMA deviated between subjects with type 2 DM and the elderly. We found only few studies investigating cerebral endothelial responses to l-arginine and l-NMMA in subjects with vascular risk factors or ischaemic cerebrovascular disease. Inconsistencies in results were most likely due to variations in methods and included subject populations. In order to use cerebral ED as a prognostic marker, further studies are required to evaluate the association to cerebrovascular disease. © 2016 John Wiley & Sons Australia, Ltd.

Rho-kinase inhibitor and nicotinamide adenine dinucleotide phosphate oxidase inhibitor prevent impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats.

PubMed

Iida, Hiroki; Iida, Mami; Takenaka, Motoyasu; Fukuoka, Naokazu; Dohi, Shuji

2008-06-01

We previously reported that acute cigarette smoking can cause a dysfunction of endothelium-dependent vasodilation in cerebral vessels, and that blocking the angiotensin II (Ang II) type 1 (AT1) receptor with valsartan prevented this impairment. Our aim was to investigate the effects of a Rho-kinase inhibitor (fasudil) and a Nicotinamide Adenine Dinucleotide PHosphate (NADPH) oxidase inhibitor (apocynin) on smoking-induced endothelial dysfunction in cerebral arterioles. In Sprague-Dawley rats, we used a closed cranial window preparation to measure changes in pial vessel diameters following topical acetylcholine (ACh) before smoking. After one-minute smoking, we again examined the arteriolar responses to ACh. Finally, after intravenous fasudil or apocynin pre-treatment we re-examined the vasodilator responses to topical ACh (before and after cigarette smoking). Under control conditions, cerebral arterioles were dose-dependently dilated by topical ACh (10(-6) M and 10(-5) M). One hour after a one-minute smoking (1 mg-nicotine cigarette), 10(-5) M ACh constricted cerebral arterioles. However, one hour after a one-minute smoking, 10(-5) M ACh dilated cerebral pial arteries both in the fasudil pre-treatment and the apocynin pre-treatment groups, responses that were significantly different from those obtained without fasudil or apocynin pre-treatment. Thus, inhibition of Rho-kinase and NADPH oxidase activities may prevent the above smoking-induced impairment of endothelium-dependent vasodilation.

Effect of central muscarinic receptors on passive-avoidance learning deficits induced by prenatal pentylenetetrazol kindling in male offspring.

PubMed

Pourmotabbed, A; Mahmoodi, G; Mahmoodi, S; Mohammadi-Farani, A; Nedaei, S E; Pourmotabbed, T; Pourmotabbed, T

2014-10-24

Occurrence of the epileptic seizures during gestation might affect the neurodevelopment of the fetus resulting in cognitive problems for the child later in life. We have previously reported that prenatal pentylenetetrazol (PTZ)-kindling induces learning and memory deficits in the children born to kindled mothers, later in life but the mechanisms involved in this processes are unknown. The cholinergic system plays a major role in learning and memory. The present study was performed to investigate the possible involvement of central muscarinic cholinergic receptors on learning and memory deficits induced by prenatal PTZ-kindling in male offspring. Pregnant Wistar rats were kindled by repetitive i.p. injection of 25mg/kg of PTZ on day 13 of their pregnancy. The effect of intracerebroventricular (ICV) microinjection of scopolamine and pilocarpine, muscarinic cholinergic receptors antagonist and agonist, respectively on passive-avoidance learning of pups were tested at 12weeks of age using shuttle-box apparatus. Our data showed that the retention latencies of pups that received scopolamine (2 or 3μg) were significantly reduced compared to those received normal saline (p<0.05). Interestingly, post training ICV administration of pilocarpine (2μg) retrieved pups' memory deficits (p<0.001). These results demonstrate for the first time, the importance of the central muscarinic cholinergic receptors in learning and memory deficits in pups born to kindled dams and suggest a central mechanism for the cognitive and memory dysfunction, associated with seizures during pregnancy. Copyright © 2014. Published by Elsevier Ltd.

Peptidergic contribution to posttetanic potentiation at a central synapse of aplysia.

PubMed

Koh, Hae-Young; Weiss, Klaudiusz R

2005-08-01

Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. Although neuropeptides are located in a large number of neurons and many neuropeptides, like PTP, can enhance synaptic transmission, there is a paucity of studies indicating that peptides may actually participate in PTP. Here, we utilize a single central synapse in the feeding circuit of Aplysia to investigate a possible peptidergic contribution to PTP in the CNS. The cholinergic command-like interneuron, cerebral-buccal interneuron 2 (CBI-2), contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that tetanic prestimulation or repeated stimulation of CBI-2, as well as perfusion of FCAP and CP2, increase the size of the cholinergic excitatory postsynaptic potentials (EPSPs) that CBI-2 evokes in the motoneurons B61/62 and shorten the latency to initiate B61/62 firing in response to CBI-2 stimulation. We used temperature-dependent suppression of peptide release and occlusion experiments to examine the possible contribution of FCAP and CP2 to PTP at the CBI-2 to B61/62 synapse. When peptide release was suppressed, perfusion of exogenous peptides increased the size of posttetanic EPSPs. In contrast, when peptide release was not suppressed, exogenous peptides did not enhance the size of posttetanic EPSPs, thus indicating occlusion. Temperature manipulation and occlusion experiments also indicated that peptides extend PTP duration. This peptide-dependent prolongation of PTP has functional consequences in that it extends the duration of time during which the latency to initiate B61/62 firing in response to CBI-2 stimulation is shortened.

Effect of high fat diets on the NTPDase, 5'-nucleotidase and acetylcholinesterase activities in the central nervous system.

PubMed

Kaizer, Rosilene Rodrigues; Spanevello, Rosélia Maria; Costa, Eduarda; Morsch, Vera Maria; Schetinger, Maria Rosa Chitolina

2018-02-01

High fat diets are associated with the promotion of neurological diseases, such as Alzheimer disease (AD). This study aim investigate the high fat diets role to promotion of AD using as biochemistry parameter of status of central nervous system through the NTPDase, 5'-nucleotidase and acetylcholinesterase (AChE) activities in brain of young rats. The intake of high fat diets promotes an inhibition of purinergic and cholinergic functions, mainly in the long-term exposure to saturated and saturated/unsaturated diets. The AChE activity was decreased to supernatant and synaptosomes tissues preparations obtained from cerebral cortex in average of 20%, to both groups exposed to saturated and saturated/unsaturated diets, when compared to the control group. Very similar results were found in hippocampus and cerebellum brain areas. At same time, the adenine nucleotides hydrolysis in synaptosomes of cerebral cortex were decreased to ATP, ADP and AMP after the long-term exposure to high fat diets, as saturated and saturated/unsaturated. The inhibition of ATP hydrolysis was of 26% and 39% to saturated and saturated/unsaturated diets, respectively. ADP hydrolysis was decreased in 20% to saturated diet, and AMP hydrolysis was decreased in 25% and 33% to saturated and saturated/unsaturated diets, respectively, all in comparison to the control. Thus, we can suggest that the effects of high diets on the purinergic and cholinergic nervous system may contribute to accelerate the progressive memory loss, to decline in language and other cognitive disruptions, such as AD patients presents. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

The maturational theory of brain development and cerebral excitability in the multifactorially inherited manic-depressive psychosis and schizophrenia.

PubMed

Saugstad, L F

1994-12-01

An association has been established between the multifactorially inherited rate of physical maturation and the final step in brain development, when some 40% of synapses are eliminated. This may imply that similarly to endocrine disease entities, we have cerebral disease entities at the extremes of the maturational rate continuum. The restriction of prepubertal pruning to excitatory synapses leaving the number of inhibitory ones fairly constant, implies changes in cerebral excitability as a function of rate of maturation (age at puberty). In early maturation there will be an excess in excitatory drive due to prematurely abridged pruning, which compounds a synchronization tendency inherent in excessive synaptic density. Lowering excitatory level with antiepileptics is hypothesized to be a logical treatment in this type of brain dysfunction. In late maturation, a deficit in excitatory drive due to failure to shut down the pruning process associated with a tendency to the breakdown of circuitry and desynchronization, adds to a similar adversity inherent in reduced synaptic density. Raising the excitatory level with convulsants is hypothesized to be the treatment for this type of CNS dysfunction. The maturational theory of Kraepelin's psychoses holds that they are naturally occurring contrasting chemical signaling disorders in the brain at the extremes of the maturational rate continuum: manic depressive psychosis is a disorder of the early maturer and comprises raised cerebral excitability and a raised density of synapses. This is successfully treated with anti-epileptics like sodium valproate and carbamazepin. Schizophrenia is a disorder in late maturation with reduced cerebral excitability and reduced synaptic density. This is accordingly treated with convulsants such as typical and atypical neuroleptics. However, the conventional effective treatments in both disorders act on inhibition only by either lowering or raising inhibitory level. While the neuroleptics drugs are superior anti-psychotics they nevertheless do not affect the deviation in cerebral excitability which would explain why they do not cure. Disturbed circadian rhythms which precede psychotic episodes in manic depressives accord with a primary dysfunction in the CNS, the suprachiasmatic nucleus of the hypothalamus via its direct input the glutamatergic retinohypothalamic tract. The residual deficits in schizophrenia accord with persistently disconnected circuitry and communication which is a consequence of reduced excitatory level and is manifested in insufficient motivation, a reduced drive associated hypofunction, and neuromuscular dysfunction.

Curcumin restores diabetes induced neurochemical changes in the brain stem of Wistar rats.

PubMed

Kumar, Peeyush T; George, Naijil; Antony, Sherin; Paulose, Cheramadathikudiyil Skaria

2013-02-28

Diabetes mellitus, when poorly controlled, leads to debilitating central nervous system (CNS) complications including cognitive deficits, somatosensory and motor dysfunction. The present study investigated curcumin's potential in modulating diabetes induced neurochemical changes in brainstem. Expression analysis of cholinergic, insulin receptor and GLUT-3 in the brainstem of streptozotocin (STZ) induced diabetic rats were studied. Radioreceptor binding assays, gene expression studies and immunohistochemical analysis were done in the brainstem of male Wistar rats. Our result showed that Bmax of total muscarinic and muscarinic M3 receptors were increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. mRNA level of muscarinic M3, α7-nicotinic acetylcholine, insulin receptors, acetylcholine esterase, choline acetyltransferase and GLUT-3 significantly increased and M1 receptor decreased in the brainstem of diabetic rats. Curcumin and insulin treatment restored the alterations and maintained all parameters to near control. The results show that diabetes is associated with significant reduction in brainstem function coupled with altered cholinergic, insulin receptor and GLUT-3 gene expression. The present study indicates beneficial effect of curcumin in diabetic rats by regulating the cholinergic, insulin receptor and GLUT-3 in the brainstem similar to the responses obtained with insulin therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

N-Benzoyl-D-phenylalanine attenuates brain acetylcholinesterase in neonatal streptozotocin-diabetic rats.

PubMed

Ashokkumar, Natarajan; Pari, Leelavinothan; Ramkumar, Kunga Mohan

2006-09-01

The effect of hyperglycaemia due to experimental diabetes in male Wistar rats causes a decrease in the level of acetylcholinesterase (AChE) with significant increase in lipid peroxidative markers: thiobarbituric acid-reactive substances (TBARS) and hydroperoxides in brains of experimental animals. The decreased activity of both salt soluble and detergent soluble acetylcholinesterase observed in diabetes may be attributed to lack of insulin which causes specific alterations in the level of neurotransmitter, thus causing brain dysfunction. Administration of non-sulfonylurea drug N-benzoyl-D-phenylalanine (NBDP) could protect against direct action of lipid peroxidation on brain AChE and in this way it might be useful in the prevention of cholinergic neural dysfunction, which is one of the major complications in diabetes.

Neurologic Complications of Transplantation.

PubMed

Dhar, Rajat

2018-02-01

Neurologic disturbances including encephalopathy, seizures, and focal deficits complicate the course 10-30% of patients undergoing organ or stem cell transplantation. While much or this morbidity is multifactorial and often associated with extra-cerebral dysfunction (e.g., graft dysfunction, metabolic derangements), immunosuppressive drugs also contribute significantly. This can either be through direct toxicity (e.g., posterior reversible encephalopathy syndrome from calcineurin inhibitors such as tacrolimus in the acute postoperative period) or by facilitating opportunistic infections in the months after transplantation. Other neurologic syndromes such as akinetic mutism and osmotic demyelination may also occur. While much of this neurologic dysfunction may be reversible if related to metabolic factors or drug toxicity (and the etiology is recognized and reversed), cases of multifocal cerebral infarction, hemorrhage, or infection may have poor outcomes. As transplant patients survive longer, delayed infections (such as progressive multifocal leukoencephalopathy) and post-transplant malignancies are increasingly reported.

Cerebral serotonin transporter binding is inversely related to body mass index.

PubMed

Erritzoe, D; Frokjaer, V G; Haahr, M T; Kalbitzer, J; Svarer, C; Holst, K K; Hansen, D L; Jernigan, T L; Lehel, S; Knudsen, G M

2010-08-01

Overweight and obesity is a health threat of increasing concern and understanding the neurobiology behind obesity is instrumental to the development of effective treatment regimes. Serotonergic neurotransmission is critically involved in eating behaviour; cerebral level of serotonin (5-HT) in animal models is inversely related to food intake and body weight and some effective anti-obesity agents involve blockade of the serotonin transporter (SERT). We investigated in 60 healthy volunteers body mass index (BMI) and regional cerebral SERT binding as measured with [(11)C]DASB PET. In a linear regression model with adjustment for relevant covariates, we found that cortical and subcortical SERT binding was negatively correlated to BMI (-0.003 to -0.012 BP(ND) unit per kg/m(2)). Tobacco smoking and alcohol consumption did not affect cerebral SERT binding. Several effective anti-obesity drugs encompass blockade of the SERT; yet, our study is the first to demonstrate an abnormally decreased cerebral SERT binding in obese individuals. Whether the SERT has a direct role in the regulation of appetite and eating behaviour or whether the finding is due to a compensatory downregulation of SERT secondary to other dysfunction(s) in the serotonergic transmitter system, such as low baseline serotonin levels, remains to be established. Copyright 2010 Elsevier Inc. All rights reserved.

Tiliacora triandra, an Anti-Intoxication Plant, Improves Memory Impairment, Neurodegeneration, Cholinergic Function, and Oxidative Stress in Hippocampus of Ethanol Dependence Rats.

PubMed

Phunchago, Nattaporn; Wattanathorn, Jintanaporn; Chaisiwamongkol, Kowit

2015-01-01

Oxidative stress plays an important role in brain dysfunctions induced by alcohol. Since less therapeutic agent against cognitive deficit and brain damage induced by chronic alcohol consumption is less available, we aimed to assess the effect of Tiliacora triandra extract, a plant possessing antioxidant activity, on memory impairment, neuron density, cholinergic function, and oxidative stress in hippocampus of alcoholic rats. Male Wistar rats were induced ethanol dependence condition by semivoluntary intake of alcohol for 15 weeks. Alcoholic rats were orally given T. triandra at doses of 100, 200, and 400 mg·kg(-1)BW for 14 days. Memory assessment was performed every 7 days while neuron density, activities of AChE, SOD, CAT, and GSH-Px and, MDA level in hippocampus were assessed at the end of study. Interestingly, the extract mitigated the increased escape latency, AChE and MDA level. The extract also mitigated the decreased retention time, SOD, CAT, and GSH-Px activities, and neurons density in hippocampus induced by alcohol. These data suggested that the extract improved memory deficit in alcoholic rats partly via the decreased oxidative stress and the suppression of AChE. Therefore, T. triandra is the potential reagent for treating brain dysfunction induced by alcohol. However, further researches are necessary to understand the detail mechanism and possible active ingredient.

Pure Misallocation of ''0'' in Number Transcoding: A New Symptom of Right Cerebral Dysfunction

ERIC Educational Resources Information Center

Furumoto, Hideharu

2006-01-01

To account for the mechanism of number transcoding, many authors have proposed various models, for example, semantic-abstract model, lexical-semantic model, triple-code model, and so on. However, almost all of them are based on the symptoms of patients with left cerebral damage. Previously, I reported two Japanese patients with right posterior…

Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke.

PubMed

Alfieri, Alessio; Srivastava, Salil; Siow, Richard C M; Cash, Diana; Modo, Michel; Duchen, Michael R; Fraser, Paul A; Williams, Steven C R; Mann, Giovanni E

2013-12-01

Disruption of the blood-brain barrier (BBB) and cerebral edema are the major pathogenic mechanisms leading to neurological dysfunction and death after ischemic stroke. The brain protects itself against infarction via activation of endogenous antioxidant defense mechanisms, and we here report the first evidence that sulforaphane-mediated preactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) in the cerebral vasculature protects the brain against stroke. To induce ischemic stroke, Sprague-Dawley rats were subjected to 70 min middle cerebral artery occlusion (MCAo) followed by 4, 24, or 72 h reperfusion. Nrf2 and HO-1 protein expression was upregulated in cerebral microvessels of peri-infarct regions after 4-72 h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In naïve rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1h) was associated with increased HO-1 expression in perivascular astrocytes in peri-infarct regions and cerebral endothelium in the infarct core. BBB disruption, lesion progression, as analyzed by MRI, and neurological deficits were reduced by sulforaphane pretreatment. As sulforaphane pretreatment led to a moderate increase in peroxynitrite generation, we suggest that hormetic preconditioning underlies sulforaphane-mediated protection against stroke. In conclusion, we propose that pharmacological or dietary interventions aimed to precondition the brain via activation of the Nrf2 defense pathway in the cerebral microvasculature provide a novel therapeutic approach for preventing BBB breakdown and neurological dysfunction in stroke. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Agraphia of the left hand with dysfunction of the left superior parietal region without callosal lesions.

PubMed

Kinno, Ryuta; Ohashi, Hideaki; Mori, Yukiko; Shiromaru, Azusa; Ono, Kenjiro

2018-03-01

A 28-year-old right-handed man noticed weakness in his legs, three days after an ephedrine overdose. Initial brain magnetic resonance imaging showed lesions in the parietal regions bilaterally. Computed tomography angiography showed segmental and multifocal vasoconstriction of the cerebral arteries. After treatment, clinical and radiological findings resolved, suggesting the patient had reversible cerebral vasoconstriction syndrome with posterior reversible encephalopathy syndrome. However, he had residual agraphia of the left hand. Language testing revealed no difficulties in oral expression, auditory comprehension, understanding of written language, or writing with the right hand. I-123 iodoamphetamine single-photon emission computed tomography showed residual dysfunction in the left superior parietal lobule. There were no apparent signs of other disconnection syndromes or neuroimaging abnormalities in the corpus callosum. We diagnosed left-hand agraphia due to left parietal dysfunction. Our case suggests that left superior parietal dysfunction without callosal lesions is a possible cause of left-hand agraphia. Neural mechanisms for writing with the right or left hand may be separable at the cortical level.

Abnormal white matter tractography of visual pathways detected by high-angular-resolution diffusion imaging (HARDI) corresponds to visual dysfunction in cortical/cerebral visual impairment

PubMed Central

Bauer, Corinna M.; Heidary, Gena; Koo, Bang-Bon; Killiany, Ronald J.; Bex, Peter; Merabet, Lotfi B.

2014-01-01

Cortical (cerebral) visual impairment (CVI) is characterized by visual dysfunction associated with damage to the optic radiations and/or visual cortex. Typically it results from pre- or perinatal hypoxic damage to postchiasmal visual structures and pathways. The neuroanatomical basis of this condition remains poorly understood, particularly with regard to how the resulting maldevelopment of visual processing pathways relates to observations in the clinical setting. We report our investigation of 2 young adults diagnosed with CVI and visual dysfunction characterized by difficulties related to visually guided attention and visuospatial processing. Using high-angular-resolution diffusion imaging (HARDI), we characterized and compared their individual white matter projections of the extrageniculo-striate visual system with a normal-sighted control. Compared to a sighted control, both CVI cases revealed a striking reduction in association fibers, including the inferior frontal-occipital fasciculus as well as superior and inferior longitudinal fasciculi. This reduction in fibers associated with the major pathways implicated in visual processing may provide a neuroanatomical basis for the visual dysfunctions observed in these patients. PMID:25087644

Bihemispheric cerebral FDG PET correlates of cognitive dysfunction as assessed by the CERAD in Alzheimer's disease.

PubMed

Schönknecht, Oskar Dieter Peter; Hunt, Aoife; Toro, Pablo; Guenther, Thomas; Henze, Marcus; Haberkorn, Uwe; Schröder, Johannes

2011-04-01

Alzheimer's disease (AD) is characterized by a variety of cognitive deficits which can be reliably assessed by the neuropsychological test battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), but the cerebral changes underlying the respective cognitive deficits are only partly understood. Measures of severity of dementia in AD as well as delayed episodic memory performance in mild cognitive impairment significantly correlated with bihemispheric cerebral glucose hypometabolism. We therefore hypothesized that the CERAD cognitive battery may represent cerebral dysfunction of both hemispheres in patients with AD. In 32 patients with AD, cerebral glucose metabolism was investigated using positron-emission-tomography with 18Fluorodeoxyglucose (FDG PET) and associated with the test scores of the CERAD cognitive battery by statistical parametric mapping. Episodic memory scores significantly correlated with temporopari etal glucose metabolism of both hemispheres while delayed episodic memory significantly was correlated with the right frontotemporal cortices. Verbal fluency and naming scores significantly correlated with glucose metabolism in left temporoparietal and right frontal cortices, whereas constructional praxis predominantly correlated significantly with the bilateral precuneus. In conclusion, the results of our study demonstrate that not only memory function but also functions of language and constructional praxis in AD are associated with glucose metabolism as revealed by FDG PET in subsets of uni- and bilateral brain areas. The findings of our study for the first time demonstrate that in AD neuropsychological deficits as assessed by the CERAD refer to different cerebral sites of both hemispheres.

Cholinergic Enhancement Increases the Effects of Voluntary Attention but Does Not Affect Involuntary Attention

PubMed Central

Rokem, Ariel; Landau, Ayelet N; Garg, Dave; Prinzmetal, William; Silver, Michael A

2010-01-01

Voluntary visual spatial attention can be allocated in a goal-oriented manner to locations containing behaviorally relevant information. In contrast, involuntary attention is automatically captured by salient events. Allocation of attention is known to be modulated by release of the neurotransmitter acetylcholine (ACh) in cerebral cortex. We used an anti-predictive spatial cueing task to assess the effects of pharmacological enhancement of cholinergic transmission on behavioral measures of voluntary and involuntary attention in healthy human participants. Each trial began with the presentation of a cue in a peripheral location. In 80% of the trials, a target then appeared in a location opposite the cue. In the remaining 20% of trials, the target appeared in the cue location. For trials with short stimulus onset asynchrony (SOA) between cue and target, involuntary capture of attention resulted in shorter reaction times (RTs) to targets presented at the cue location. For long SOA trials, allocation of voluntary attention resulted in the opposite pattern: RTs were shorter when the target appeared in the expected (opposite) location. Each subject participated in two sessions: one in which the cholinesterase inhibitor donepezil was administered to increase synaptic ACh levels and one in which placebo was administered. Donepezil selectively improved performance (reduced RT) for long SOA trials in which targets appeared in the expected location. Thus, cholinergic enhancement augments the benefits of voluntary attention but does not affect involuntary attention, suggesting that they rely on different neurochemical mechanisms. PMID:20811340

Cholinergic mechanisms of analgesia produced by physostigmine, morphine and cold water swimming.

PubMed

Romano, J A; Shih, T M

1983-07-01

This study concerns the cholinergic involvement in three experimental procedures which produce analgesia. Rats were given one of seven treatments: saline (1.0 ml/kg, i.p.); morphine sulfate (3.5, 6.0 or 9.0 mg/kg, i.p.); physostigmine salicylate (0.65 mg/kg, i.p.); warm water swim (3.5 min at 28 degrees C); and cold water swim (3.5 min at 2 degrees C). Each rat was tested on a hot plate (59.1 degrees C) once prior to and 30 min after treatment. Immediately after the last test the rats were killed with focussed microwave radiation. Levels of acetylcholine (ACh) and choline (Ch) in six brain areas (brain stem, cerebral cortex, hippocampus, midbrain, cerebellum and striatum) were analyzed by gas chromatograph-mass spectrometer. Morphine (9.0 mg/kg), physostigmine and cold water swimming caused significant analgesia. Morphine elevated the levels of ACh in the cerebellum and striatum, cold water swimming--in the cerebellum, striatum and cortex, and physostigmine--in the striatum and hippocampus. Levels of choline were elevated by morphine in the cerebellum, cortex and hippocampus, while cold water swimming elevated levels of choline in the cerebellum, cortex, striatum and hippocampus. Physostigmine did not change levels of choline in any of the brain areas studied. These data suggest that the analgetic effects of morphine or cold water swimming may be mediated by components of the cholinergic system that differ from those involved in the analgetic effects of physostigmine.

Arterial Cannulation and Cerebral Perfusion Strategies for Aortic Arch Operations.

PubMed

Foley, Lisa S; Yamanaka, Katsuhiro; Reece, T Brett

2016-12-01

Neurologic injuries following aortic arch operations can be devastating, with stroke occurring in up to 12% of elective operations and significant cerebral dysfunction occurring in up to 25% of cases. The primary challenge unique to aortic arch operations involves interruption of direct perfusion of the brachiocephalic vessels during arch reconstruction. For this reason, neuroprotection is paramount. The 2 main modes of protection are (1) reducing metabolic demand through hypothermia and (2) limiting, or even eliminating, the ischemic period. Preoperative selection of the cerebral perfusion plan for each operation is imperative to maintain maximal diffuse cerebral protection and prevent focal neurologic events. © The Author(s) 2016.

Cerebral fat embolism syndrome after long bone fracture due to gunshot injury.

PubMed

Duran, Latif; Kayhan, Servet; Kati, Celal; Akdemir, Hizir Ufuk; Balci, Kemal; Yavuz, Yucel

2014-03-01

Cerebral fat embolism syndrome is a lethal complication of long-bone fractures and clinically manifasted with respiratory distress, altered mental status, and petechial rash. We presented a 20-year-old male admitted with gun-shot wounds to his left leg. Twenty-four hours after the event, he had generalized tonic clonic seizures, decorticate posture and a Glascow Coma Scale of seven with localization of painful stimuli. Subsequent magnetic resonance imaging of the brain showed a star-field pattern defining multiple lesions of restricted diffusion. On a 4-week follow-up, he had returned to normal neurological function. Despite the severity of the neurological condition upon initial presentation, the case cerebral fat embolism illustrates that, cerebral dysfunction associated with cerebral fat embolism illustrates reversible.

Neurological and psychiatric disorders in thyroid dysfunctions. The role of nuclear medicine: SPECT and PET imaging.

PubMed

Lass, P; Slawek, J; Derejko, M; Rubello, D

2008-06-01

Thyroid dysfunctions may be accompanied by numerous neurological and psychiatric disorders. The most known is cognitive impairment and depression in hypothyroid patients, as well as an increased risk of cerebrovascular accidents. A separate, although a rare entity, is Hashimoto's encephalopathy. In hyperthyroidism there is an increased incidence of psychiatric disorders, including apathetic hyperthyroidism and hyperthyroid dementia. Functional imaging of cerebral blood flow and metabolism helped establish both global and/or regional decrease of both cerebral blood flow and metabolism in hypothyroidism, particularly in regions mediating attention, motor speed and visuospatial processing. Hypothyroid dementia may be mediated by neurocircuitry different from that in major depression. Less is known on flow/metabolism changes in hyperthyroidism. Global blood flow may be slightly increased, with regional deficits of blood flow, particular in hyperthyroid dementia. As presented above radionuclide functional imaging showed some metabolic patterns in thyroid dysfunctions, but still many issues remain unresolved. In particular little is known about the underlying pathology of cognitive impairment and depression in hypothyroidism, which may differ from ones in euthyroid patients. Also little is known about the reversibility of changes in cerebral blood flow following thyroid replacement therapy. In hyperthyroid patients functional imaging might contribute to elucidate the background of apathetic hyperthyroidism and potential different background of psychiatric complications.

Effect of Rhythmic Auditory Stimulation on Controlling Stepping Cadence of Individuals with Mental Retardation and Cerebral Palsy

ERIC Educational Resources Information Center

Varsamis, Panagiotis; Staikopoulos, Konstantinos; Kartasidou, Lefkothea

2012-01-01

One of the purposes of Rhythmic Auditory Stimulation (RAS) is to improve the control of dysfunctional movement patterns. This study aimed to extend the line of research by focussing on secondary students with mental retardation and cerebral palsy. According to the study's assumption, cadence can be controlled through a stable and low signal…

In Search of Dignity: One Family Caring for Their Child's Incontinence

ERIC Educational Resources Information Center

Coelho, Amy

2009-01-01

This article shares a story of a family with a child who has a spastic quadriplegia cerebral palsy, a form of cerebral palsy (CP) that affects all four limbs and torso with debilitating muscle dysfunction. It describes how the family cares for their child's incontinence. It also shares the experience of the child's mother, Kathy, who attributes…

Intra- and Inter-Observer Reliability of the Trunk Impairment Scale for Children with Cerebral Palsy

ERIC Educational Resources Information Center

Saether, Rannei; Jorgensen, Lone

2011-01-01

Standardized scales to evaluate qualities of trunk movements in children with dysfunction are sparse. An examination of the reliability of scales that may be useful in the clinic is important. The aim of this study was to examine the reliability of the Trunk Impairment Scale (TIS) for children with cerebral palsy (CP). Standardized scales are…

Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet

PubMed Central

Bernier, Michel; Wahl, Devin; Ali, Ahmed; Allard, Joanne; Faulkner, Shakeela; Wnorowski, Artur; Sanghvi, Mitesh; Moaddel, Ruin; Alfaras, Irene; Mattison, Julie A.; Tarantini, Stefano; Tucsek, Zsuzsanna; Ungvari, Zoltan; Csiszar, Anna; Pearson, Kevin J.; de Cabo, Rafael

2016-01-01

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress. PMID:27070252

Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet.

PubMed

Bernier, Michel; Wahl, Devin; Ali, Ahmed; Allard, Joanne; Faulkner, Shakeela; Wnorowski, Artur; Sanghvi, Mitesh; Moaddel, Ruin; Alfaras, Irene; Mattison, Julie A; Tarantini, Stefano; Tucsek, Zsuzsanna; Ungvari, Zoltan; Csiszar, Anna; Pearson, Kevin J; de Cabo, Rafael

2016-05-01

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress.

Directed Retrograde Cerebral Protection during Moderate Hypothermic Circulatory Arrest

PubMed Central

Yacoubian, Vahe; Jyrala, Aarne; Kay, Gregory L.

2006-01-01

There are many choices for neurologic protection for aortic arch surgery. Although numerous investigators have challenged the efficacy of retrograde cerebral perfusion, we have had good results with our application of this technique. We performed a retrospective review of 8 consecutive patients who underwent surgery from 1 June 2001 through 31 March 2003; the age range was 33 to 97 years. All patients required circulatory arrest and underwent retrograde cerebral perfusion with use of a tourniquet on the patients' left and right arms above the elbow to direct retrograde flow to the brain. Moderate hypothermia (around 24 °C nasopharyngeal) was used; circulatory arrest time ranged from 27 to 63 minutes. There was 1 late hospital death due to multiple-organ system failure. There were no neurologic complications (stroke or temporary neurologic dysfunction). There was no substantive neurologic or renal dysfunction in this cohort, in which moderate hypothermia was used. These results are comparable to those reported in the literature for similar patients. We conclude that, for patients who require circulatory arrest, directed retrograde cerebral perfusion at moderate nasopharyngeal hypothermia gives results comparable to those reported with other techniques. PMID:17215968

Effects of oxotremorine on local glucose utilization in the rat cerebral cortex

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

Dam, M.; Wamsley, J.K.; Rapoport, S.I.

The (/sup 14/C)2-deoxy-D-glucose technique was used to examine the effects of central muscarinic stimulation on local cerebral glucose utilization (LCGU) in the cerebral cortex of the unanesthetized rat. Systemic administration of the muscarinic agonist oxotremorine (OXO, 0.1 to 1.0 mg/kg, i.p.) increased LCGU in the neocortex, mesocortex, and paleocortex. In the neocortex, OXO was more potent in elevating LCGU of the auditory, frontal, and sensorimotor regions compared with the visual cortex. Within these neocortical regions, OXO effects were greatest in cortical layers IV and V. OXO effects were more dramatic in the neocortex than in the meso- or paleocortex, andmore » no significant effect occurred in the perirhinal and pyriform cortices. OXO-induced LCGU increases were not influenced by methylatropine (1 mg/kg, s.c.) but were antagonized completely by scopolamine (2.5 mg/kg, i.p.). Scopolamine reduced LCGU in layer IV of the auditory cortex and in the retrosplenial cortex. The distribution and magnitude of the cortical LCGU response to OXO apparently were related to the distributions of cholinergic neurochemical markers, especially high affinity muscarinic binding sites.« less

Virtual reality training improves balance function.

PubMed

Mao, Yurong; Chen, Peiming; Li, Le; Huang, Dongfeng

2014-09-01

Virtual reality is a new technology that simulates a three-dimensional virtual world on a computer and enables the generation of visual, audio, and haptic feedback for the full immersion of users. Users can interact with and observe objects in three-dimensional visual space without limitation. At present, virtual reality training has been widely used in rehabilitation therapy for balance dysfunction. This paper summarizes related articles and other articles suggesting that virtual reality training can improve balance dysfunction in patients after neurological diseases. When patients perform virtual reality training, the prefrontal, parietal cortical areas and other motor cortical networks are activated. These activations may be involved in the reconstruction of neurons in the cerebral cortex. Growing evidence from clinical studies reveals that virtual reality training improves the neurological function of patients with spinal cord injury, cerebral palsy and other neurological impairments. These findings suggest that virtual reality training can activate the cerebral cortex and improve the spatial orientation capacity of patients, thus facilitating the cortex to control balance and increase motion function.

Acute presentation of gestational diabetes insipidus with pre-eclampsia complicated by cerebral vasoconstriction: a case report and review of the published work.

PubMed

Mor, Amir; Fuchs, Yael; Zafra, Kathleen; Haberman, Shoshana; Tal, Reshef

2015-08-01

Gestational diabetes insipidus (GDI) is a rare, self-limited complication of pregnancy. As it is related to excess placental vasopressinase enzyme activity, which is metabolized in the liver, GDI is more common in pregnancies complicated by conditions associated with liver dysfunction. We present a case of a 41-year-old woman at 38 weeks' gestation who presented with pre-eclampsia with severe features, including impaired liver function and renal insufficiency. Following cesarean section she was diagnosed with GDI, which was further complicated by cerebral vasoconstriction as demonstrated by magnetic resonance angiography. This case raises the possibility that cerebral vasoconstriction may be related to the cause of GDI. A high index of suspicion of GDI should be maintained in patients who present with typical signs and symptoms, especially in the setting of pregnancy complications associated with liver dysfunction. © 2015 The Authors. Journal of Obstetrics and Gynaecology Research © 2015 Japan Society of Obstetrics and Gynecology.

Virtual reality training improves balance function

PubMed Central

Mao, Yurong; Chen, Peiming; Li, Le; Huang, Dongfeng

2014-01-01

Virtual reality is a new technology that simulates a three-dimensional virtual world on a computer and enables the generation of visual, audio, and haptic feedback for the full immersion of users. Users can interact with and observe objects in three-dimensional visual space without limitation. At present, virtual reality training has been widely used in rehabilitation therapy for balance dysfunction. This paper summarizes related articles and other articles suggesting that virtual reality training can improve balance dysfunction in patients after neurological diseases. When patients perform virtual reality training, the prefrontal, parietal cortical areas and other motor cortical networks are activated. These activations may be involved in the reconstruction of neurons in the cerebral cortex. Growing evidence from clinical studies reveals that virtual reality training improves the neurological function of patients with spinal cord injury, cerebral palsy and other neurological impairments. These findings suggest that virtual reality training can activate the cerebral cortex and improve the spatial orientation capacity of patients, thus facilitating the cortex to control balance and increase motion function. PMID:25368651

The Trail Making Test elucidates neural substrates of specific post-stroke executive dysfunctions

PubMed Central

Muir, Ryan T.; Lam, Benjamin; Honjo, Kie; Harry, Robin D.; McNeely, Alicia A.; Gao, Fu-Qiang; Ramirez, Joel; Scott, Christopher J.M; Ganda, Anoop; Zhao, Jiali; Zhou, X. Joe; Graham, Simon J.; Rangwala, Novena; Gibson, Erin; Lobaugh, Nancy J.; Kiss, Alex; Stuss, Donald T.; Nyenhuis, David L.; Lee, Byung-Chul; Kang, Yeonwook; Black, Sandra E.

2015-01-01

Background and Purpose Post-stroke cognitive impairment (PSCI) is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. Methods One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set-shifting (TMT-B-A difference, proportion, quotient scores and TMT-B set-shifting errors). The TMT was administered to two overt ischemic stroke cohorts from a multinational study: (i) a chronic stroke cohort (N=61) and (ii) an acute-sub-acute stroke cohort (N=45). Volumetric quantification of ischemic stroke and White Matter HyperIntensities (WMH) was done on MRI, along with ratings of involvement of cholinergic projections, using the previously published Cholinergic Hyperintensities Projections Scale (CHIPS). Damage to the superior longitudinal fasciculus (SLF), which co-localizes with some cholinergic projections, was also documented. Results Multiple linear regression analyses were completed. While larger infarcts (β=0.37, p<0.0001) were associated with slower processing speed, CHIPS severity (β=0.39, p<0.0001) was associated with all metrics of set shifting. Left SLF damage, however, was only associated with the difference score (β=0.17, p=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set shifting errors also had greater CHIPS severity. Conclusions In this multinational stroke cohort study, damage to lateral cholinergic pathways and the SLF emerged as significant neuroanatomical correlates for executive deficits in set shifting. PMID:26382176

Inhaled ammonium persulphate inhibits non-adrenergic, non-cholinergic relaxations in the guinea pig isolated trachea.

PubMed

Dellabianca, A; Faniglione, M; De Angelis, S; Colucci, M; Cervio, M; Balestra, B; Tonini, S; Candura, S M

2010-01-01

Persulphates can act both as irritants and sensitizers in inducing occupational asthma. A dysfunction of nervous control regulating the airway tone has been hypothesized as a mechanism underlying bronchoconstriction in asthma. It was the aim of this study to investigate whether inhaled ammonium persulphate affects the non-adrenergic, non-cholinergic (NANC) inhibitory innervation, the cholinergic nerve-mediated contraction or the muscular response to the spasmogens, carbachol or histamine, in the guinea pig epithelium-free, isolated trachea. Male guinea pigs inhaled aerosols containing ammonium persulphate (10 mg/m(3) for 30 min for 5 days during 3 weeks). Control animals inhaled saline aerosol. NANC relaxations to electrical field stimulation at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Drugs inactivating peptide transmission, nitric oxide synthase, carbon monoxide production by haem oxygenase-2 and soluble guanylyl cyclase were used to assess the involvement of various inhibitory neurotransmitters. Carbachol and histamine cumulative concentration-response curves were obtained. In both groups, nitric oxide and carbon monoxide participated to the same extent as inhibitory neurotransmitters. In exposed animals, the tracheal NANC relaxations were reduced to 45.9 +/- 12.1% (p < 0.01). The cholinergic nerve-mediated contractions to electrical field stimulation and the muscular response to histamine were not modified by ammonium persulphate exposure. The muscular response to carbachol was unaffected up to 1 microM. Conversely, the response to the maximal concentration of carbachol (3 microM) was increased (p < 0.01). Ammonium persulphate inhalation at high concentrations impairs the nervous NANC inhibitory control in the guinea pig airways. This may represent a novel mechanism contributing to persulphate-induced asthma. Copyright 2009 S. Karger AG, Basel.

SN56 neuronal cell death after 24 h and 14 days chlorpyrifos exposure through glutamate transmission dysfunction, increase of GSK-3β enzyme, β-amyloid and tau protein levels.

PubMed

Moyano, Paula; Frejo, María Teresa; Anadon, María José; García, José Manuel; Díaz, María Jesús; Lobo, Margarita; Sola, Emma; García, Jimena; Del Pino, Javier

2018-06-01

Chlorpyrifos (CPF) is an organophosphate insecticide described to induce cognitive disorders, both after acute and repeated administration. However, the mechanisms through which it induces these effects are unknown. CPF has been reported to produce basal forebrain cholinergic neuronal cell death, involved on learning and memory regulation, which could be the cause of such cognitive disorders. Neuronal cell death was partially mediated by oxidative stress generation, P75 NTR and α 7 -nAChRs gene expression alteration triggered through acetylcholinesterase (AChE) variants disruption, suggesting other mechanisms are involved. In this regard, CPF induces Aβ and tau proteins production and activation of GSK3β enzyme and alters glutamatergic transmission, which have been related with basal forebrain cholinergic neuronal cell death and development of cognitive disorders. According to these data, we hypothesized that CPF induces basal forebrain cholinergic neuronal cell death through induction of Aβ and tau proteins production, activation of GSK-3β enzyme and disruption of glutamatergic transmission. We evaluated this hypothesis in septal SN56 basal forebrain cholinergic neurons, after 24 h and 14 days CPF exposure. This study shows that CPF increases glutamate levels, upregulates GSK-3β gene expression, and increases the production of Aβ and phosphorylated tau proteins and all these effects reduced cell viability. CPF increases glutaminase activity and upregulates the VGLUT1 gene expression, which could mediate the disruption of glutamatergic transmission. Our present results provide new understanding of the mechanisms contributing to the harmful effects of CPF, and its possible relevance in the pathogenesis of neurodegenerative diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention

PubMed Central

Lindner, Michael; Bell, Tiffany; Iqbal, Somya; Mullins, Paul Gerald

2017-01-01

Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans. PMID:28192451

Biflorin Ameliorates Memory Impairments Induced by Cholinergic Blockade in Mice

PubMed Central

Jeon, Se Jin; Kim, Boseong; Ryu, Byeol; Kim, Eunji; Lee, Sunhee; Jang, Dae Sik; Ryu, Jong Hoon

2017-01-01

To examine the effect of biflorin, a component of Syzygium aromaticum, on memory deficit, we introduced a scopolamine-induced cognitive deficit mouse model. A single administration of biflorin increased latency time in the passive avoidance task, ameliorated alternation behavior in the Y-maze, and increased exploration time in the Morris water maze task, indicating the improvement of cognitive behaviors against cholinergic dysfunction. The biflorin-induced reverse of latency in the scopolamine-treated group was attenuated by MK-801, an NMDA receptor antagonist. Biflorin also enhanced cognitive function in a naïve mouse model. To understand the mechanism of biflorin for memory amelioration, we performed Western blot. Biflorin increased the activation of protein kinase C-ζ and its downstream signaling molecules in the hippocampus. These results suggest that biflorin ameliorates drug-induced memory impairment by modulation of protein kinase C-ζ signaling in mice, implying that biflorin could function as a possible therapeutic agent for the treatment of cognitive problems. PMID:27829270

Combined treatment of methylprednisolone pulse and memantine hydrochloride prompts recovery from neurological dysfunction and cerebral hypoperfusion in carbon monoxide poisoning: a case report.

PubMed

Iwamoto, Konosuke; Ikeda, Ken; Mizumura, Sunao; Tachiki, Kazuhiro; Yanagihashi, Masaru; Iwasaki, Yasuo

2014-03-01

A 49-year-old healthy man developed sudden unconsciousness under inadequate ventilation. Blood gas analysis showed carboxyhemoglobin of 7.3%. After normobaric oxygen therapy, he recovered completely 7 days later. At 3 weeks after carbon monoxide (CO) exposures, memory and gait disturbances appeared. Neurological examination revealed Mini-Mental State Examination (MMSE) score of 5 of 30 points, leg hyper-reflexia with Babinski signs, and Parkinsonism. Brain fluid-attenuated inversion recovery imaging disclosed symmetric hypointense lesions in the thalamus and the globus pallidus, and hyperintense lesions in the cerebral white matter. Brain single-photon emission tomography (SPECT) scanning with (99m)Technesium-ethyl cysteinate dimer displayed marked hypoperfusion in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. He was diagnosed as CO poisoning and treated with hyperbaric oxygen therapy. The neurological deficits were not ameliorated. At 9 weeks after neurological onset, methylprednisolone (1000 mg/day, intravenous, 3 days) and memantine hydrochloride (20 mg/day, per os) were administered. Three days later, MMSE score was increased from 3 to 20 points. Neurological examination was normal 3 weeks later. Brain SPECT exhibited 20% increase of regional cerebral blood flows in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. These clinicoradiological changes supported that the treatment with steroid pulse and memantine hydrochloride could prompt recovery from neurological dysfunction and cerebral hypoperfusion. Further clinical trials are warranted whether such combined therapy can attenuate neurological deficits and cerebral hypoperfusion in patients with CO poisoning. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

(-)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury.

PubMed

Chang, Cheng-Fu; Lai, Jing-Huei; Wu, John Chung-Che; Greig, Nigel H; Becker, Robert E; Luo, Yu; Chen, Yen-Hua; Kang, Shuo-Jhen; Chiang, Yung-Hsiao; Chen, Kai-Yun

2017-12-15

Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury. Published by Elsevier B.V.

Relationship of bladder dysfunction with upper urinary tract deterioration in cerebral palsy.

PubMed

Gündoğdu, Gökhan; Kömür, Mustafa; Avlan, Dinçer; Sarı, Ferda Bacaksızlar; Delibaş, Ali; Taşdelen, Bahar; Naycı, Ali; Okuyaz, Cetin

2013-10-01

Although lower urinary tract dysfunction (LUTD) in patients with cerebral palsy (CP) has been previously documented by clinical observations and urodynamic tests, its correlation with upper urinary tract deterioration (UUTD) has not been demonstrated. This paper documents symptoms and urodynamic findings of LUTD and their relationship with UUTD in 33 children with CP. By sonography, 4 of these children were found to have UUTD. Age was found to correlate with UUTD, but gender difference and mental or motor functions did not. When comparing urinary symptoms with UUTD, incontinence (n = 31) did not correlate, but on the other hand symptoms of detrusor sphincter dyssynergia (interrupted voiding, urinary retention, hesitancy; n = 5) and culture proven febrile urinary tract infections (n = 4) did. Abnormal urodynamics findings were not diagnostic. We conclude that, apart from incontinence, dysfunctional voiding symptoms and febrile urinary tract infections are valuable indicators of UUTD. Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Cerebral fat embolism syndrome after long bone fracture due to gunshot injury

PubMed Central

Duran, Latif; Kayhan, Servet; Kati, Celal; Akdemir, Hizir Ufuk; Balci, Kemal; Yavuz, Yucel

2014-01-01

Cerebral fat embolism syndrome is a lethal complication of long-bone fractures and clinically manifasted with respiratory distress, altered mental status, and petechial rash. We presented a 20-year-old male admitted with gun-shot wounds to his left leg. Twenty-four hours after the event, he had generalized tonic clonic seizures, decorticate posture and a Glascow Coma Scale of seven with localization of painful stimuli. Subsequent magnetic resonance imaging of the brain showed a star-field pattern defining multiple lesions of restricted diffusion. On a 4-week follow-up, he had returned to normal neurological function. Despite the severity of the neurological condition upon initial presentation, the case cerebral fat embolism illustrates that, cerebral dysfunction associated with cerebral fat embolism illustrates reversible. PMID:24701067

Cerebral Metabolism and the Role of Glucose Control in Acute Traumatic Brain Injury.

PubMed

Buitrago Blanco, Manuel M; Prashant, Giyarpuram N; Vespa, Paul M

2016-10-01

This article reviews key concepts of cerebral glucose metabolism, neurologic outcomes in clinical trials, the biology of the neurovascular unit and its involvement in secondary brain injury after traumatic brain insults, and current scientific and clinical data that demonstrate a better understanding of the biology of metabolic dysfunction in the brain, a concept now known as cerebral metabolic energy crisis. The use of neuromonitoring techniques to better understand the pathophysiology of the metabolic crisis is reviewed and a model that summarizes the triphasic view of cerebral metabolic disturbance supported by existing scientific data is outlined. The evidence is summarized and a template for future research provided. Copyright © 2016 Elsevier Inc. All rights reserved.

6,7,4'-Trihydroxyisoflavone, a major metabolite of daidzein, improves learning and memory via the cholinergic system and the p-CREB/BDNF signaling pathway in mice.

PubMed

Ko, Yong-Hyun; Kim, Sun Yeou; Lee, Seok-Yong; Jang, Choon-Gon

2018-05-05

Daidzein is one of the major isoflavfones found in soy food and plants. Following ingestion, daidzein is readily converted to hydroxylated metabolites in the human body. 6,7,4'-Trihydroxyisoflavone (THIF), one of the metabolites of daidzein, has several pharmacological activities, including anti-cancer and anti-obesity properties. However, no reports exist on the effects of 6,7,4'-THIF for cognitive function in mice. The present study aimed to investigate the effects of 6,7,4'-THIF against scopolamine-induced learning and memory impairments using the Y-maze and passive avoidance test. A single administration of 6,7,4'-THIF significantly improved scopolamine-induced cognitive dysfunction in these in vivo tests. Moreover, treatment with 6,7,4'-THIF alone enhanced learning and memory performance in the same behavioral tests. Molecular studies showed that 6,7,4'-THIF significantly inhibited acetylcholinesterase and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus of scopolamine-induced mice. In addition, immunohistochemistry and Western blot results revealed that 6,7,4'-THIF significantly increased brain-derived neurotrophic factor (BDNF) and phosphor cAMP response element binding (CREB) in the hippocampus of mice. Taken together, these findings suggest that 6,7,4'-THIF improves cognitive dysfunction induced by scopolamine and enhances learning and memory by activation of the cholinergic system and the p-CREB/BDNF signaling pathway in mice. Copyright © 2018 Elsevier B.V. All rights reserved.

Role of Ocimum basilicum L. in prevention of ischemia and reperfusion-induced cerebral damage, and motor dysfunctions in mice brain.

PubMed

Bora, Kundan Singh; Arora, Shruti; Shri, Richa

2011-10-11

The genus Ocimum (Lamiaceae) has a long history of use as culinary and medicinal herbs. Many species are used for their antioxidant and neuroprotective activity in various parts of the world. Ocimum basilicum Linn. has been used traditionally for the treatment of anxiety, diabetes, cardiovascular diseases, headaches, nerve pain, as anticonvulsant and anti-inflammatory, and used in a variety of neurodegenerative disorders. The present study is designed to investigate the effect of ethyl acetate extract of Ocimum basilicum leaves on ischemia and reperfusion-induced cerebral damage, and motor dysfunctions in mice. Global cerebral ischemia was induced by bilateral carotid artery occlusion for 15 min followed by reperfusion for 24h. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. The concentration of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content was determined by colorimetric assay. Short-term memory was evaluated using elevated plus-maze. Inclined beam walking was employed to assess motor coordination. Bilateral carotid artery occlusion followed by reperfusion produced significant increase in cerebral infarct size and lipid peroxidation (TBARS), and reduced GSH content, and impaired short-term memory and motor coordination. Pre-treatment with standardized ethyl acetate extract of Ocimum basilicum (100 and 200mg/kg, p.o.) markedly reduced cerebral infarct size and lipid peroxidation, restored GSH content, and attenuated impairment in short-term memory and motor coordination. The results of the study suggest that Ocimum basilicum could be useful clinically in the prevention of stroke. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model

PubMed Central

Back, Adam; Tupper, Kelsey Y.; Bai, Tao; Chiranand, Paulpoj; Goldenberg, Fernando D.; Frank, Jeffrey I.; Brorson, James R.

2013-01-01

Objectives Acute liver failure produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in acute liver failure is incompletely understood. In vitro models of the cerebral effects of acute liver failure have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long-term culture model incorporating both neural and glial elements in a three-dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in acute liver failure. Methods We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices. Results Ammonia exposure at 1–10 mM produced swelling of immunochemically-identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half. Discussion Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an in vitro model of cerebral effects of conditions relevant to acute liver failure, applicable to pathophysiological investigations. PMID:22196764

Psychological stress-induced cerebrovascular dysfunction: the role of metabolic syndrome and exercise.

PubMed

Brooks, Steven; Brnayan, Kayla W; DeVallance, Evan; Skinner, Roy; Lemaster, Kent; Sheets, J Whitney; Pitzer, Christopher R; Asano, Shinichi; Bryner, Randall W; Olfert, I Mark; Frisbee, Jefferson C; Chantler, Paul D

2018-05-01

What is the central question of this study? How does chronic stress impact cerebrovascular function and does metabolic syndrome accelerate the cerebrovascular adaptations to stress? What role does exercise training have in preventing cerebrovascular changes to stress and metabolic syndrome? What is the main finding and its importance? Stressful conditions lead to pathological adaptations of the cerebrovasculature via an oxidative nitric oxide pathway, and the presence of metabolic syndrome produces a greater susceptibility to stress-induced cerebrovascular dysfunction. The results also provide insight into the mechanisms that may contribute to the influence of stress and the role of exercise in preventing the negative actions of stress on cerebrovascular function and structure. Chronic unresolvable stress leads to the development of depression and cardiovascular disease. There is a high prevalence of depression with the metabolic syndrome (MetS), but to what extent the MetS concurrent with psychological stress affects cerebrovascular function is unknown. We investigated the differential effect of MetS on cerebrovascular structure/function in rats (16-17 weeks old) following 8 weeks of unpredictable chronic mild stress (UCMS) and whether exercise training could limit any cerebrovascular dysfunction. In healthy lean Zucker rats (LZR), UCMS decreased (28%, P < 0.05) ex vivo middle cerebral artery (MCA) endothelium-dependent dilatation (EDD), but changes in MCA remodelling and stiffness were not evident, though cerebral microvessel density (MVD) decreased (30%, P < 0.05). The presence of UCMS and MetS (obese Zucker rats; OZR) decreased MCA EDD (35%, P < 0.05) and dilatation to sodium nitroprusside (20%, P < 0.05), while MCA stiffness increased and cerebral MVD decreased (31%, P < 0.05), which were linked to reduced nitric oxide and increased oxidative levels. Aerobic exercise prevented UCMS impairments in MCA function and MVD in LZR, and partly restored MCA function, stiffness and MVD in OZR. Our data suggest that the benefits of exercise with UCMS were due to a reduction in oxidative stress and increased production of nitric oxide in the cerebral vessels. In conclusion, UCMS significantly impaired MCA structure and function, but the effects of UCMS were more substantial in OZR vs. LZR. Importantly, aerobic exercise when combined with UCMS prevented the MCA dysfunction through subtle shifts in nitric oxide and oxidative stress in the cerebral microvasculature. © 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.

Neurotransmitter-based strategies for the treatment of cognitive dysfunction in Down syndrome.

PubMed

Das, Devsmita; Phillips, Cristy; Hsieh, Wayne; Sumanth, Krithika; Dang, Van; Salehi, Ahmad

2014-10-03

Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimer's disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important roles in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration. Published by Elsevier Inc.

Olfactory identification and Stroop interference converge in schizophrenia.

PubMed Central

Purdon, S E

1998-01-01

OBJECTIVE: To test the discriminant validity of a model predicting a dissociation between measures of right and left frontal lobe function in people with schizophrenia. PARTICIPANTS: Twenty-one clinically stable outpatients with schizophrenia. INTERVENTIONS: Patients were administered the University of Pennsylvania Smell Identification Test (UPSIT), the Stroop Color-Word Test (Stroop), and the Positive and Negative Syndrome Scale (PANSS). OUTCOME MEASURES: Scores on these tests and relation among scores. RESULTS: There was a convergence of UPSII and Stroop interference scores consistent with a common cerebral basis for limitations in olfactory identification and inhibition of distraction. There was also a divergence of UPSIT and Stroop reading scores suggesting that the olfactory identification limitation is distinct from a general limitation of attention or a dysfunction of the left dorsolateral prefrontal cortex. Most notable was the 81% classification convergence between the UPSIT and Stroop incongruous colour naming scores compared with the near-random 57% classification convergence of the UPSIT and Stroop reading scores. CONCLUSIONS: These data are consistent with a right orbitofrontal dysfunction in a subgroup of patients with schizophrenia, although the involvement of mesial temporal structures in both tasks must be ruled out with further study. A multifactorial model depicting contributions from diverse cerebral structures is required to describe the pathophysiology of schizophrenia. Valid behavioural methods for classifying suspected subgroups of patients with particular cerebral dysfunction would be of value in the construction of this model. PMID:9595890

Vertigo and nystagmus in orthostatic hypotension.

PubMed

Choi, J-H; Seo, J-D; Kim, M-J; Choi, B-Y; Choi, Y R; Cho, B M; Kim, J S; Choi, K-D

2015-04-01

Generalized cerebral ischaemia from cardiovascular dysfunction usually leads to presyncopal dizziness, but several studies reported a higher frequency of rotatory vertigo in cardiovascular patients. Whether generalized cerebral ischaemia due to cardiovascular disorders may produce objective vestibular dysfunction was investigated. Thirty-three patients with orthostatic dizziness/vertigo due to profound orthostatic hypotension and 30 controls were recruited. All participants underwent recording of eye movements during two orthostatic challenging tests: the Schellong and the squatting-standing tests. Most patients had neuroimaging, and patients with abnormal eye movements were subjected to follow-up evaluations. Symptoms associated with orthostatic dizziness/vertigo included blurred vision, fainting and tinnitus. Ten (30%) of 33 patients developed rotatory vertigo and nystagmus during the Schellong (n = 5) or squatting-standing test (n = 5). Four of them showed pure downbeat nystagmus whilst five had downbeat and horizontal nystagmus with or without torsional component. Patients with orthostatic nystagmus had shorter duration of orthostatic intolerance than those without nystagmus (1.0 ± 1.6 vs. 11.0 ± 9.7 months, P < 0.001). In two patients, orthostatic nystagmus disappeared during follow-up despite the persistence of profound orthostatic hypotension. Generalized cerebral ischaemia caused by orthostatic hypotension induces rotatory vertigo due to objective vestibular dysfunction. The presence of orthostatic vertigo and nystagmus has an association with the duration of orthostatic intolerance. © 2014 EAN.

Possible role of pannexin 1/P2x7 purinoceptor in neuroprotective mechanism of ischemic postconditioning in mice.

PubMed

Mahi, Namarta; Kumar, Amit; Jaggi, Amteshwar S; Singh, Nirmal; Dhawan, Ravi

2015-06-01

Previous studies have suggested a significant role of pannexin 1 (Panx1)/P2X7 receptor complex in cardioprotective mechanism of ischemic preconditioning and postconditioning (IPC). The present study has been undertaken to investigate whether Panx1/P2X7 purinoceptors are also involved in the neuroprotective mechanism of IPC in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was used to produce ischemia-reperfusion-induced cerebral injury in Swiss albino mice. For IPC immediately after BCAO of 12 min, three cycles of 10-s ischemia and reperfusion each were given and then prolonged reperfusion of 24 h was used. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using a Morris water maze test. Rotarod test, inclined beam walking test, and neurologic severity score (NSS) were used to assess motor dysfunction. Acetylcholine esterase levels, brain thiobarbituric acid reactive species, and glutathione level were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, NSS along with impairment of memory and motor dysfunction. It also increased brain acetylcholine esterase, thiobarbituric acid reactive species levels, and decreased the glutathione level. IPC produced a significant decrease in the cerebral infarct size and NSS along with reversal of ischemia-reperfusion-induced impairment of memory, motor dysfunction, and altered biochemical levels in the brain. IPC-induced neuroprotective effects were significantly abolished by pretreatment of mefloquine (15.0 mg/kg orally; 30.0 mg/kg orally), blocker of Panx1/P2X7 purinoceptor. Therefore, activation of Panx1/P2X7 purinoceptors appears to play a significant role in the neuroprotective mechanism of IPC. Copyright © 2015 Elsevier Inc. All rights reserved.

Catechin treatment improves cerebrovascular flow-mediated dilation and learning abilities in atherosclerotic mice

PubMed Central

Drouin, Annick; Bolduc, Virginie; Thorin-Trescases, Nathalie; Bélanger, Élisabeth; Fernandes, Priscilla; Baraghis, Edward; Lesage, Frédéric; Gillis, Marc-Antoine; Villeneuve, Louis; Hamel, Edith; Ferland, Guylaine; Thorin, Eric

2013-01-01

Severe dyslipidemia and the associated oxidative stress could accelerate the age-related decline in cerebrovascular endothelial function and cerebral blood flow (CBF), leading to neuronal loss and impaired learning abilities. We hypothesized that a chronic treatment with the polyphenol catechin would prevent endothelial dysfunction, maintain CBF responses, and protect learning abilities in atherosclerotic (ATX) mice. We treated ATX (C57Bl/6-LDLR−/− hApoB+/+; 3 mo old) mice with catechin (30 mg·kg−1·day−1) for 3 mo, and C57Bl/6 [wild type (WT), 3 and 6 mo old] mice were used as controls. ACh- and flow-mediated dilations (FMD) were recorded in pressurized cerebral arteries. Basal CBF and increases in CBF induced by whisker stimulation were measured by optical coherence tomography and Doppler, respectively. Learning capacities were evaluated with the Morris water maze test. Compared with 6-mo-old WT mice, cerebral arteries from 6-mo-old ATX mice displayed a higher myogenic tone, lower responses to ACh and FMD, and were insensitive to NOS inhibition (P < 0.05), suggesting endothelial dysfunction. Basal and increases in CBF were lower in 6-mo-old ATX than WT mice (P < 0.05). A decline in the learning capabilities was also observed in ATX mice (P < 0.05). Catechin 1) reduced cerebral superoxide staining (P < 0.05) in ATX mice, 2) restored endothelial function by reducing myogenic tone, improving ACh- and FMD and restoring the sensitivity to nitric oxide synthase inhibition (P < 0.05), 3) increased the changes in CBF during stimulation but not basal CBF, and 4) prevented the decline in learning abilities (P < 0.05). In conclusion, catechin treatment of ATX mice prevents cerebrovascular dysfunctions and the associated decline in learning capacities. PMID:21186270

Application of wavelet analysis to detect dysfunction in cerebral blood flow autoregulation during experimental hyperhomocysteinaemia.

PubMed

Aleksandrin, Valery V; Ivanov, Alexander V; Virus, Edward D; Bulgakova, Polina O; Kubatiev, Aslan A

2018-04-03

The purpose of the present study was to investigate the use of laser Doppler flowmetry (LDF) signals coupled with spectral wavelet analysis to detect endothelial link dysfunction in the autoregulation of cerebral blood flow in the setting of hyperhomocysteinaemia (HHcy). Fifty-one rats were assigned to three groups (intact, control, and HHcy) according to the results of biochemical assays of homocysteine level in blood plasma. LDF signals on the rat brain were recorded by LAKK-02 device to measure the microcirculatory blood flow. The laser operating wavelength and output power density were1064 nm and 0.051 W/mm 2 , respectively. A Morlet mother wavelet transform was applied to the measured 8-min LDF signals, and periodic oscillations with five frequency intervals were identified (0.01-0.04 Hz, 0.04-0.15 Hz, 0.15-0.4 Hz, 0.4-2 Hz, and 2-5 Hz) corresponding to endothelial, neurogenic, myogenic, respiratory, and cardiac origins, respectively. In initial state, the amplitude of the oscillations decreased by 38% (P < 0.05) in the endothelial range in HHcy rats than in control rats. Cerebral autoregulation was challenged by hemorrhagic hypotension. The lower limit of autoregulation raised in a rat model of chronic HHcy (71.5 ± 0.7 mmHg in HHcy vs. 62.3 ± 0.5 mmHg in control). The data obtained indicate that the laser Doppler method and wavelet analysis may be successfully applied to detect the dysfunction of the endothelial link in cerebral vessel tone and to reveal the pathological shift of lower limit of autoregulation.

Cerebral toxoplasmosis in Acquired Immunodeficiency Syndrome (AIDS) patients also provides unifying pathophysiologic hypotheses for Holmes tremor.

PubMed

Lekoubou, Alain; Njouoguep, Rodrigue; Kuate, Callixte; Kengne, André Pascal

2010-06-03

Holmes tremor is a rare symptomatic movement disorder. Currently suggested pathophysiological mechanisms of the disease are mostly derived from stroke cases. Although rare, cerebral toxoplasmosis may strengthen the pathophysiologic mechanism of disease. A case of Holmes tremor secondary to cerebral toxoplasmosis in an AIDS patient is presented. A relevant literature search was performed, using pubmed and several entries for Holmes tremor as labelled in the literature. The unifying feature of our case and those of the literature is the involvement of either the cerebello-thalamo-cortical and/or the dentato-rubro-olivary pathways. The abscess or the extension of surrounding edema beyond these two circuits may account for the superimposed dysfunction of the nigrostriatal system in some but not all cases. The short delay observed in our observation and the dramatic response to treatment may indirectly support the secondary neuronal degeneration theory in the mechanism of Holmes tremor. Cases of cerebral toxoplasmosis in AIDS patients also provide arguments for the role of the thalamo-cortical and/or the dentato-rubro-olivary pathways dysfunction in the pathogenesis of Holmes tremor. Involvement of the nigro-striatal pathway may not be crucial in the development of this syndrome. Our case also brings additional indirect arguments for the role of secondary neuronal degeneration in the mechanism of Holmes tremor.

Clinical study on the treatment of vertigo by ant vertigo

NASA Astrophysics Data System (ADS)

Liu, Xiaobin; Li, Chongxian; Hao, Shaojun; Lian, Linlin; Chen, Weiliang; Wang, Hongyu; Guan, Zhijiang; Zhang, Zhengchen

2018-04-01

To observe the clinical curative effect of antiglare granule in the treatment of hypertension, cerebral arteriosclerosis, vertebrobasilar artery insufficiency, Meniere's disease, autonomic dysfunction caused by vertigo etc, the patients with vertigo were randomly divided into 300 cases of cerebral arteriosclerosis, vertebral basilar artery insufficiency, Meniere's disease into three groups, treatment group: control group 1, 2 groups of. 3 times a day, 30 days for a course of treatment, once a two treatment, observation and treatment effect. Control group: conventional doses of Yangxue Qingnao Granule, enteric coated aspirin treatment ibid. After 2 courses of treatment were observed and recorded the key concept of vertigo degree change number. Compare the outcome of TCM symptom medication after February, the total effective rate of treatment group was 96%, 1 in the control group the total efficiency of 69.7%, 2 in the control group the total efficiency of 71.7%, the treatment group curative effect on the treatment of hypertension, cerebral arteriosclerosis, vertebral basilar artery insufficiency vertigo, Meniere's disease, head weight light, walking foot stable curative effect is better than that of Yangxue Qingnao Granule, enteric coated aspirin effect. Aanti glare granule in the treatment of hypertension, cerebral arteriosclerosis and vertebral basilar artery insufficiency, Meniere's disease, autonomic dysfunction caused by vertigo has good clinical curative effect.

Factitious buccal lesion secondary to bruxism in a child with cerebral palsy

PubMed Central

Harris, D

2006-01-01

Children with cerebral palsy are at greater risk of a whole range of oral conditions than their peers. These include bruxism (tooth grinding), oral skill dysfunction, gross malocclusion due to effects of the abnormal orofacial muscle tone on tooth eruption, drooling of saliva, and poor oral hygiene.1 A challenging case of a painful buccal lesion in a 2 year old girl with cerebral palsy (CP) that did not respond to antifungal, antiviral or antibiotic treatment is presented as a factitious lesion. The recognition and significance of self‐injurious behaviour and factitious lesions in children are discussed. PMID:16373789

Factitious buccal lesion secondary to bruxism in a child with cerebral palsy.

PubMed

Harris, D

2006-01-01

Children with cerebral palsy are at greater risk of a whole range of oral conditions than their peers. These include bruxism (tooth grinding), oral skill dysfunction, gross malocclusion due to effects of the abnormal orofacial muscle tone on tooth eruption, drooling of saliva, and poor oral hygiene. A challenging case of a painful buccal lesion in a 2 year old girl with cerebral palsy (CP) that did not respond to antifungal, antiviral or antibiotic treatment is presented as a factitious lesion. The recognition and significance of self-injurious behaviour and factitious lesions in children are discussed.

Local cerebral glucose metabolism in patients with long-term behavioral and cognitive deficits following mild traumatic brain injury.

PubMed

Gross, H; Kling, A; Henry, G; Herndon, C; Lavretsky, H

1996-01-01

A retrospective study of 20 patients with mild traumatic brain injury (MTBI) examined brain regions of interest by comparing [18F]-2-deoxyglucose PET, neuropsychological test results, and continuing behavioral dysfunction. Abnormal local cerebral metabolic rates (rLCMs) were most prominent in midtemporal, anterior cingulate, precuneus, anterior temporal, frontal white, and corpus callosum brain regions. Abnormal rLCMs were significantly correlated statistically with 1) overall clinical complaints, most specifically with inconsistent attention/concentration and 2) overall neuropsychological test results. The authors conclude that 1) even mild TBI may result in continuing brain behavioral deficits; 2) PET can help elucidate dysfunctional brain circuitry in neurobehavioral disorders; and 3) specific brain areas may correlate with deficits in daily neurobehavioral functioning and neuropsychological test findings.

Mulberry Fruit Extract Protects against Memory Impairment and Hippocampal Damage in Animal Model of Vascular Dementia

PubMed Central

Kaewkaen, Pratchaya; Tong-un, Terdthai; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Kaewrueng, Wiroje; Wongcharoenwanakit, Sathaporn

2012-01-01

Nowadays, the preventive strategy of vascular dementia, one of the challenge problems of elderly, has received attention due to the limitation of therapeutic efficacy. In this study, we aimed to determine the protective effect and possible mechanism of action of mulberry fruit extract on memory impairment and brain damage in animal model of vascular dementia. Male Wistar rats, weighing 300–350 g, were orally given mulberry extract at doses of 2, 10 and 50 mg/kg at a period of 7 days before and 21 days after the occlusion of right middle cerebral artery (Rt.MCAO). It was found that rats subjected to mulberry fruits plus Rt.MCAO showed the enhanced memory, the increased densities of neuron, cholinergic neuron, Bcl-2-immunopositive neuron together with the decreased oxidative stress in hippocampus. Taken all data together, the cognitive enhancing effect of mulberry fruit extract observed in this study might be partly associated with the increased cholinergic function and its neuroprotective effect in turn occurs partly via the decreased oxidative stress and apoptosis. Therefore, mulberry fruit is the potential natural cognitive enhancer and neuroprotectant. However, further researches are essential to elucidate the possible active ingredient. PMID:22952555

Cerebral versus Ocular Visual Impairment: The Impact on Developmental Neuroplasticity.

PubMed

Martín, Maria B C; Santos-Lozano, Alejandro; Martín-Hernández, Juan; López-Miguel, Alberto; Maldonado, Miguel; Baladrón, Carlos; Bauer, Corinna M; Merabet, Lotfi B

2016-01-01

Cortical/cerebral visual impairment (CVI) is clinically defined as significant visual dysfunction caused by injury to visual pathways and structures occurring during early perinatal development. Depending on the location and extent of damage, children with CVI often present with a myriad of visual deficits including decreased visual acuity and impaired visual field function. Most striking, however, are impairments in visual processing and attention which have a significant impact on learning, development, and independence. Within the educational arena, current evidence suggests that strategies designed for individuals with ocular visual impairment are not effective in the case of CVI. We propose that this variance may be related to differences in compensatory neuroplasticity related to the type of visual impairment, as well as underlying alterations in brain structural connectivity. We discuss the etiology and nature of visual impairments related to CVI, and how advanced neuroimaging techniques (i.e., diffusion-based imaging) may help uncover differences between ocular and cerebral causes of visual dysfunction. Revealing these differences may help in developing future strategies for the education and rehabilitation of individuals living with visual impairment.

Cerebral versus Ocular Visual Impairment: The Impact on Developmental Neuroplasticity

PubMed Central

Martín, Maria B. C.; Santos-Lozano, Alejandro; Martín-Hernández, Juan; López-Miguel, Alberto; Maldonado, Miguel; Baladrón, Carlos; Bauer, Corinna M.; Merabet, Lotfi B.

2016-01-01

Cortical/cerebral visual impairment (CVI) is clinically defined as significant visual dysfunction caused by injury to visual pathways and structures occurring during early perinatal development. Depending on the location and extent of damage, children with CVI often present with a myriad of visual deficits including decreased visual acuity and impaired visual field function. Most striking, however, are impairments in visual processing and attention which have a significant impact on learning, development, and independence. Within the educational arena, current evidence suggests that strategies designed for individuals with ocular visual impairment are not effective in the case of CVI. We propose that this variance may be related to differences in compensatory neuroplasticity related to the type of visual impairment, as well as underlying alterations in brain structural connectivity. We discuss the etiology and nature of visual impairments related to CVI, and how advanced neuroimaging techniques (i.e., diffusion-based imaging) may help uncover differences between ocular and cerebral causes of visual dysfunction. Revealing these differences may help in developing future strategies for the education and rehabilitation of individuals living with visual impairment. PMID:28082927

Effective treatment of dyssynergic defecation using sacral neuromodulation in a patient with cerebral palsy.

PubMed

Chan, Daniel K; Barker, Matthew A

2015-01-01

Dyssynergic defecation is a complex bowel problem that leads to chronic constipation and abdominal pain. Management is often challenging owing to the incoordination of multiple pelvic floor muscles involved in normal defecation. We report a case of dyssynergic defecatory dysfunction in a patient with cerebral palsy treated with sacral neuromodulation. At presentation, Sitz marker study and magnetic resonance defecography showed evidence of chronic functional constipation. Anorectal manometry, rectal anal inhibitory reflex, and rectal sensation study showed intact reflex and decreased first sensation of lower canal at 50 mL. After stage 2 of InterStim implant placement, bowel habits improved to once- to twice-daily soft solid bowel movements from no regular solid bowel movements. Fecal incontinence improved from daily liquid and small solid loss to no stool leakage. In patients with systemic medical problems contributing to defecatory dysfunction and bowel incontinence, such as cerebral palsy, sacral neuromodulation was found to provide significant relief of bowel symptoms in addition to associated abdominal pain. As a result of intervention, the patient reported significant improvement in quality of life and less limitations due to dyssynergic defecation.

Platelet adhesion via glycoprotein IIb integrin is critical for atheroprogression and focal cerebral ischemia: an in vivo study in mice lacking glycoprotein IIb.

PubMed

Massberg, Steffen; Schürzinger, Katrin; Lorenz, Michael; Konrad, Ildiko; Schulz, Christian; Plesnila, Nikolaus; Kennerknecht, Elisabeth; Rudelius, Martina; Sauer, Susanne; Braun, Siegmund; Kremmer, Elisabeth; Emambokus, Nikla R; Frampton, Jon; Gawaz, Meinrad

2005-08-23

The platelet glycoprotein (GP) IIb/IIIa integrin binds to fibrinogen and thereby mediates platelet aggregation. Here, we addressed the role of GP IIb for platelet adhesion and determined the relevance of platelet GP IIb for the processes of atherosclerosis and cerebral ischemia-reperfusion (I/R) injury. GP IIb(-/-) mice were generated and bred with ApoE(-/-) animals to create GP IIb(-/-)ApoE(-/-) mice. Platelet adhesion to the mechanically injured or atherosclerotic vessel wall was monitored by in vivo video fluorescence microscopy. In the presence of GP IIb, vascular injury and early atherosclerosis induced platelet adhesion in the carotid artery (CA). In contrast, platelet adhesion was significantly reduced in the absence of GP IIb integrin (P<0.05). To address the contribution of platelet GP IIb to atheroprogression, we determined atherosclerotic lesion formation in the CA and aortic arch (AA) of GP IIb(+/+)ApoE(-/-) or GP IIb(-/-)ApoE(-/-) mice. Interestingly, the absence of GP IIb attenuated lesion formation in CA and AA, indicating that platelets, via GP IIb, contribute substantially to atherosclerosis. Next, we assessed the implication of GP IIb for cerebral I/R injury. We observed that after occlusion of the middle cerebral artery, the cerebral infarct size was drastically reduced in mice lacking GP IIb compared with wild-types. These findings show for the first time in vivo that GP IIb not only mediates platelet aggregation but also triggers platelet adhesion to exposed extracellular matrices and dysfunctional endothelial cells. In a process strictly involving GP IIb, platelets, which are among the first blood cells to arrive at the scene of endothelial dysfunction, contribute essentially to atherosclerosis and cerebral I/R injury.

Evaluation of physical growth in cerebral palsied children and its possible relationship with gross motor development.

PubMed

Ibrahim, Alaa I; Hawamdeh, Ziad M

2007-03-01

The object of this study was to detect any possible relation between the current gross motor function score for cerebral palsy children and their physical growth parameters. We measured 71 children with spastic cerebral palsy (35 diplegic, 25 quadriplegic and 11 hemiplegic) and a control group of 80 normal children. Measures taken for cerebral palsy and normal children included stature, weight, head circumference and mid upper-arm circumference, and, additionally for the cerebral palsied children, duration of the disease, birth weight, presence or absence of orofacial dysfunction, distribution of paralysis and degree of spasticity. Motor abilities were measured using the Gross Motor Function Measure. Results showed a significant decrease in the stature, current weight, head circumference and mid upper-arm circumference of both sexes of the quadriplegic children, and significant decreases in the current weight of the diplegic girls and the head circumference of the hemiplegic girls. There were also significant decreases in all scores of the quadriplegic children compared to the diplegic and hemiplegic children. Diplegic children had significantly decreased standing, walking and running, and total scores, compared to the hemiplegic children. Total score at age of testing was independently predicted by the duration of the disease, distribution of paralysis, presence or absence of orofacial dysfunction, spasticity index and the current body weight. Our findings indicate that in spastic cerebral palsy the physical growth parameters were markedly decreased in the quadriplegic form compared to other forms. Only current body weight, from the growth parameters, in addition to other relevant clinical data, can be considered predictors of the current gross motor abilities of those children.

Chronic kidney disease and poor outcomes in ischemic stroke: is impaired cerebral autoregulation the missing link?

PubMed

Castro, Pedro; Azevedo, Elsa; Rocha, Isabel; Sorond, Farzaneh; Serrador, Jorge M

2018-03-02

Chronic kidney disease increases stroke incidence and severity but the mechanisms behind this cerebro-renal interaction are mostly unexplored. Since both vascular beds share similar features, microvascular dysfunction could be the possible missing link. Therefore, we examined the relationship between renal function and cerebral autoregulation in the early hours post ischemia and its impact on outcome. We enrolled 46 ischemic strokes (middle cerebral artery). Dynamic cerebral autoregulation was assessed by transfer function (coherence, phase and gain) of spontaneous blood pressure oscillations to blood flow velocity within 6 h from symptom-onset. Estimated glomerular filtration rate (eGFR) was calculated. Hemorrhagic transformation (HT) and white matter lesions (WML) were collected from computed tomography performed at presentation and 24 h. Outcome was evaluated with modified Rankin Scale at 3 months. High gain (less effective autoregulation) was correlated with lower eGFR irrespective of infarct side (p < 0.05). Both lower eGFR and higher gain correlated with WML grade (p < 0.05). Lower eGFR and increased gain, alone and in combination, progressively reduced the odds of a good functional outcome [ipsilateral OR = 4.39 (CI95% 3.15-25.6), p = 0.019; contralateral OR = 8.15 (CI95% 4.15-15.6), p = 0.002] and increased risk of HT [ipsilateral OR = 3.48 (CI95% 0.60-24.0), p = 0.132; contralateral OR = 6.43 (CI95% 1.40-32.1), p = 0.034]. Lower renal function correlates with less effective dynamic cerebral autoregulation in acute ischemic stroke, both predicting a bad outcome. The evaluation of serum biomarkers of renal dysfunction could have interest in the future for assessing cerebral microvascular risk and relationship with stroke complications.

Mitochondrial dysfunction precedes depression of AMPK/AKT signaling in insulin resistance induced by high glucose in primary cortical neurons.

PubMed

Peng, Yunhua; Liu, Jing; Shi, Le; Tang, Ying; Gao, Dan; Long, Jiangang; Liu, Jiankang

2016-06-01

Recent studies have demonstrated brain insulin signaling impairment and mitochondrial dysfunction in diabetes. Hyperinsulinemia and hyperlipidemia arising from diabetes have been linked to neuronal insulin resistance, and hyperglycemia induces peripheral sensory neuronal impairment and mitochondrial dysfunction. However, how brain glucose at diabetic conditions elicits cortical neuronal insulin signaling impairment and mitochondrial dysfunction remains unknown. In the present study, we cultured primary cortical neurons with high glucose levels and investigated the neuronal mitochondrial function and insulin response. We found that mitochondrial function was declined in presence of 10 mmol/L glucose, prior to the depression of AKT signaling in primary cortical neurons. We further demonstrated that the cerebral cortex of db/db mice exhibited both insulin resistance and loss of mitochondrial complex components. Moreover, we found that adenosine monophosphate-activated protein kinase (AMPK) inactivation is involved in high glucose-induced mitochondrial dysfunction and insulin resistance in primary cortical neurons and neuroblastoma cells, as well as in cerebral cortex of db/db mice, and all these impairments can be rescued by mitochondrial activator, resveratrol. Taken together, our results extend the finding that high glucose (≥10 mmol/L) comparable to diabetic brain extracellular glucose level leads to neuronal mitochondrial dysfunction and resultant insulin resistance, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. We found that high glucose (≥10 mmol/L), comparable to diabetic brain extracellular glucose level, leads to neuronal mitochondrial dysfunction and resultant insulin resistance in an AMPK-dependent manner, and targeting mitochondria-AMPK signaling might be a promising strategy to protect against diabetes-related neuronal impairment in central nerves system. © 2016 International Society for Neurochemistry.

Huperzine A, but not tacrine, stimulates S100B secretion in astrocyte cultures.

PubMed

Lunardi, Paula; Nardin, Patrícia; Guerra, Maria Cristina; Abib, Renata; Leite, Marina Concli; Gonçalves, Carlos-Alberto

2013-04-09

The loss of cholinergic function in the central nervous system contributes significantly to the cognitive decline associated with advanced age and dementias. Huperzine A (HupA) is a selective inhibitor of acetylcholinesterase (AChE) and has been shown to significantly reduce cognitive impairment in animal models of dementia. Based on the importance of astrocytes in physiological and pathological brain activities, we investigated the effect of HupA and tacrine on S100B secretion in primary astrocyte cultures. S100B is an astrocyte-derived protein that has been proposed to be a marker of brain injury. Primary astrocyte cultures were exposed to HupA, tacrine, cholinergic agonists, and S100B secretion was measured by enzyme-linked immunosorbent assay (ELISA) at 1 and 24h. HupA, but not tacrine, at 100μM significantly increased S100B secretion in astrocyte cultures. Nicotine (at 100 and 1000μM) was able to stimulate S100B secretion in astrocyte cultures. Our data reinforce the idea that AChE inhibitors, particularly HupA, do not act exclusively on the acetylcholine balance. This effect of HupA could contribute to improve the cognitive deficit observed in patients, which are attributed to cholinergic dysfunction. In addition, for the first time, to our knowledge, these data indicate that S100B secretion can be modulated by nicotinic receptors, in addition to glutamate, dopamine and serotonin receptors. Copyright © 2013 Elsevier Inc. All rights reserved.

Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease

PubMed Central

Hadjihambi, Anna; De Chiara, Francesco; Hosford, Patrick S.; Habtetion, Abeba; Karagiannis, Anastassios; Davies, Nathan

2017-01-01

The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte‐neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia‐lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia‐induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. Conclusion: The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel‐mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (Hepatology 2017;65:1306‐1318) PMID:28066916

Global Cerebral Ischemia: Synaptic and Cognitive Dysfunction

PubMed Central

Neumann, Jake T.; Cohan, Charles H.; Dave, Kunjan R.; Wright, Clinton B.; Perez-Pinzon, Miguel A.

2018-01-01

Cardiopulmonary arrest is one of the leading causes of death and disability, primarily occurring in the aged population. Numerous global cerebral ischemia animal models induce neuronal damage similar to cardiac arrest. These global cerebral ischemia models range from vessel occlusion to total cessation of cardiac function, both of which have allowed for the investigation of this multifaceted disease and detection of numerous agents that are neuroprotective. Synapses endure a variety of alterations after global cerebral ischemia from the resulting excitotoxicity and have been a major target for neuroprotection; however, neuroprotective agents have proven unsuccessful in clinical trials, as neurological outcomes have not displayed significant improvements in patients. A majority of these neuroprotective agents have specific neuronal targets, where the success of future neuroprotective agents may depend on non-specific targets and numerous cognitive improvements. This review focuses on the different models of global cerebral ischemia, neuronal synaptic alterations, synaptic neuroprotection and behavioral tests that can be used to determine deficits in cognitive function after global cerebral ischemia. PMID:23170794

Effect of magnolol on cerebral injury and blood brain barrier dysfunction induced by ischemia-reperfusion in vivo and in vitro.

PubMed

Liu, Xiaoyan; Chen, Xiaoling; Zhu, Yuanjun; Wang, Kewei; Wang, Yinye

2017-08-01

Magnolol, a neolignan compound isolated from traditional Chinese medicine Magnolia officinalis, has a potentially therapeutic influence on ischemic stroke. Previous studies have demonstrated that cerebral ischemia-reperfusion (I-R) and blood-brain barrier (BBB) are involved in the pathogeneses of stroke. Therefore, in vivo and in vitro studies were designed to investigate the effects of magnolol on I-R-induced neural injury and BBB dysfunction. In cerebral I-R model of mice, cerebral infarct volumes, brain water content, and the exudation of Evans blue were significantly reduced by intravenous injection with magnolol at the doses of 1.4, 7.0, and 35.0 μg/kg. When primary cultured microglial cells were treated with 1 μg/ml lipopolysaccharide (LPS) plus increasing concentrations of magnolol, ranging from 0.01 to 10 μmol/L, magnolol could statistically inhibit LPS-induced NO release, TNF-α secretion, and expression of p65 subunit of NF-κB in the nucleus of microglial cells. In the media of brain microvascular endothelial cells (BMECs), oxygen and glucose deprivation-reperfusion (OGD-R) could remarkably lead to the elevation of TNF-α and IL-1β levels, while magnolol evidently reversed these effects. In BBB model in vitro, magnolol dose- and time-dependently declined BBB hyperpermeability induced by oxygen and glucose deprivation (OGD), OGD-R, and ephrin-A1 treatment. More importantly, magnolol could obviously inhibit phosphorylation of EphA2 (p-EphA2) not only in ephrin-A1-treated BMECs but also in cerebral I-R model of mice. In contrast to p-EphA2, magnolol significantly increased ZO-1 and occludin levels in BMECs subjected to OGD. Taken together, magnolol can protect neural damage from cerebral ischemia- and OGD-reperfusion, which may be associated with suppressing cerebral inflammation and improving BBB function.

Cerebral activation of mitogen-activated protein kinases after circulatory arrest and low flow cardiopulmonary bypass.

PubMed

Aharon, Alon S; Mulloy, Matthew R; Drinkwater, Davis C; Lao, Oliver B; Johnson, Mahlon D; Thunder, Megan; Yu, Chang; Chang, Paul

2004-11-01

Mitogen-activated protein kinases (MAPK) are important intermediates in the signal transduction pathways involved in neuronal dysfunction following cerebral ischemia-reperfusion injury. One subfamily, extracellular regulated kinase 1/2, has been heavily implicated in the pathogenesis of post-ischemic neuronal damage. However, the contribution of extracellular regulated kinase 1/2 to neuronal damage following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass is unknown. We attempted to correlate the extent of neuronal damage present following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass with phosphorylated extracellular regulated kinase 1/2 expression in the cerebral vascular endothelium. Piglets underwent normal flow cardiopulmonary bypass (n=4) deep hypothermic circulatory arrest (n=6) and low flow cardiopulmonary bypass (n=5). Brains were harvested following 24 h of post-cardiopulmonary bypass recovery. Cerebral cortical watershed zones, hippocampus, basal ganglia, thalamus, cerebellum, mesencephalon, pons and medulla were evaluated using hematoxylin and eosin staining. A section of ischemic cortex was evaluated by immunohistochemistry with rabbit polyclonal antibodies against phosphorylated extracellular regulated kinase 1/2. Compared to cardiopulmonary bypass controls, the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass piglets exhibited diffuse ischemic changes with overlapping severity and distribution. Significant neuronal damage occurred in the frontal watershed zones and basal ganglia of the deep hypothermic circulatory arrest group (P<0.05). No detectable phosphorylated extracellular regulated kinase 1/2 immunoreactivity was found in the cardiopulmonary bypass controls; however, ERK 1/2 immunoreactivity was present in the cerebral vascular endothelium of the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass groups. Our results indicate that phosphorylated extracellular regulated kinase 1/2 may play a prominent role in early cerebral ischemia-reperfusion injury and endothelial dysfunction. The pharmacologic inhibition of extracellular regulated kinase 1/2 represents a new and exciting opportunity for the modulation of cerebral tolerance to low flow cardiopulmonary bypass and deep hypothermic circulatory arrest.

Cholinergic Dysfunction in Fragile X Syndrome and Potential Intervention

PubMed Central

Kesler, Shelli R; Lightbody, Amy A; Reiss, Allan L

2009-01-01

Males with fragile X syndrome are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X syndrome and 9 age-matched typically developing controls using 1H magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls. In controls, both left and right choline was significantly positively correlated with intelligence and age was significantly negatively correlated with left choline. There were no correlations in the fragile X group. Subjects with fragile X syndrome participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function. Studies utilizing biochemical neuroimaging techniques such as these have the potential to significantly impact the design of treatment strategies for fragile X syndrome and other genetic disorders by helping identify neurochemical targets for intervention as well as serving as metrics for treatment efficacy. PMID:19215057

Acupuncture Stimulation Alleviates Corticosterone-Induced Impairments of Spatial Memory and Cholinergic Neurons in Rats

PubMed Central

Lee, Bombi; Sur, Bong-Jun; Kwon, Sunoh; Jung, Euntaek; Shim, Insop; Lee, Hyejung; Hahm, Dae-Hyun

2012-01-01

The purpose of this study was to examine whether acupuncture improves spatial cognitive impairment induced by repeated corticosterone (CORT) administration in rats. The effect of acupuncture on the acetylcholinergic system was also investigated in the hippocampus. Male rats were subcutaneously injected with CORT (5 mg/kg) once daily for 21 days. Acupuncture stimulation was performed at the HT7 (Sinmun) acupoint for 5 min before CORT injection. HT7 acupoint is located at the end of transverse crease of ulnar wrist of forepaw. In CORT-treated rats, reduced spatial cognitive function was associated with significant increases in plasma CORT level (+36%) and hippocampal CORT level (+204%) compared with saline-treated rats. Acupuncture stimulation improved the escape latency for finding the platform in the Morris water maze. Consistently, the acupuncture significantly alleviated memory-associated decreases in cholinergic immunoreactivity and mRNA expression of BDNF and CREB in the hippocampus. These findings demonstrate that stimulation of HT7 acupoint produced significant neuroprotective activity against the neuronal impairment and memory dysfunction. PMID:22216057

Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care

PubMed Central

Hulse, Elspeth J.; Davies, James O. J.; Simpson, A. John; Sciuto, Alfred M.

2014-01-01

Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities. PMID:25419614

Effects of Incretin-Based Therapies on Neuro-Cardiovascular Dynamic Changes Induced by High Fat Diet in Rats.

PubMed

Marques-Neto, Silvio Rodrigues; Castiglione, Raquel Carvalho; Pontes, Aiza; Oliveira, Dahienne Ferreira; Ferraz, Emanuelle Baptista; Nascimento, José Hamilton Matheus; Bouskela, Eliete

2016-01-01

Obesity promotes cardiac and cerebral microcirculatory dysfunction that could be improved by incretin-based therapies. However, the effects of this class of compounds on neuro-cardiovascular system damage induced by high fat diet remain unclear. The aim of this study was to investigate the effects of incretin-based therapies on neuro-cardiovascular dysfunction induced by high fat diet in Wistar rats. We have evaluated fasting glucose levels and insulin resistance, heart rate variability quantified on time and frequency domains, cerebral microcirculation by intravital microscopy, mean arterial blood pressure, ventricular function and mitochondrial swelling. High fat diet worsened biometric and metabolic parameters and promoted deleterious effects on autonomic, myocardial and haemodynamic parameters, decreased capillary diameters and increased functional capillary density in the brain. Biometric and metabolic parameters were better improved by glucagon like peptide-1 (GLP-1) compared with dipeptdyl peptidase-4 (DPP-4) inhibitor. On the other hand, both GLP-1 agonist and DPP-4 inhibitor reversed the deleterious effects of high fat diet on autonomic, myocardial, haemodynamic and cerebral microvascular parameters. GLP-1 agonist and DPP-4 inhibitor therapy also increased mitochondrial permeability transition pore resistance in brain and heart tissues of rats subjected to high fat diet. Incretin-based therapies improve deleterious cardiovascular effects induced by high fat diet and may have important contributions on the interplay between neuro-cardiovascular dynamic controls through mitochondrial dysfunction associated to metabolic disorders.

Presynaptic Neuronal Nicotinic Receptors Differentially Shape Select Inputs to Auditory Thalamus and Are Negatively Impacted by Aging.

PubMed

Sottile, Sarah Y; Hackett, Troy A; Cai, Rui; Ling, Lynne; Llano, Daniel A; Caspary, Donald M

2017-11-22

Acetylcholine (ACh) is a potent neuromodulator capable of modifying patterns of acoustic information flow. In auditory cortex, cholinergic systems have been shown to increase salience/gain while suppressing extraneous information. However, the mechanism by which cholinergic circuits shape signal processing in the auditory thalamus (medial geniculate body, MGB) is poorly understood. The present study, in male Fischer Brown Norway rats, seeks to determine the location and function of presynaptic neuronal nicotinic ACh receptors (nAChRs) at the major inputs to MGB and characterize how nAChRs change during aging. In vitro electrophysiological/optogenetic methods were used to examine responses of MGB neurons after activation of nAChRs during a paired-pulse paradigm. Presynaptic nAChR activation increased responses evoked by stimulation of excitatory corticothalamic and inhibitory tectothalamic terminals. Conversely, nAChR activation appeared to have little effect on evoked responses from inhibitory thalamic reticular nucleus and excitatory tectothalamic terminals. In situ hybridization data showed nAChR subunit transcripts in GABAergic inferior colliculus neurons and glutamatergic auditory cortical neurons supporting the present slice findings. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were diminished by aging. These findings suggest that cholinergic input to the MGB increases the strength of tectothalamic inhibitory projections, potentially improving the signal-to-noise ratio and signal detection while increasing corticothalamic gain, which may facilitate top-down identification of stimulus identity. These mechanisms appear to be affected negatively by aging, potentially diminishing speech perception in noisy environments. Cholinergic inputs to the MGB appear to maximize sensory processing by adjusting both top-down and bottom-up mechanisms in conditions of attention and arousal. SIGNIFICANCE STATEMENT The pedunculopontine tegmental nucleus is the source of cholinergic innervation for sensory thalamus and is a critical part of an ascending arousal system that controls the firing mode of thalamic cells based on attentional demand. The present study describes the location and impact of aging on presynaptic neuronal nicotinic acetylcholine receptors (nAChRs) within the circuitry of the auditory thalamus (medial geniculate body, MGB). We show that nAChRs are located on ascending inhibitory and descending excitatory presynaptic inputs onto MGB neurons, likely increasing gain selectively and improving temporal clarity. In addition, we show that aging has a deleterious effect on nAChR efficacy. Cholinergic dysfunction at the level of MGB may affect speech understanding negatively in the elderly population. Copyright © 2017 the authors 0270-6474/17/3711378-13$15.00/0.

Presynaptic Neuronal Nicotinic Receptors Differentially Shape Select Inputs to Auditory Thalamus and Are Negatively Impacted by Aging

PubMed Central

Sottile, Sarah Y.; Hackett, Troy A.

2017-01-01

Acetylcholine (ACh) is a potent neuromodulator capable of modifying patterns of acoustic information flow. In auditory cortex, cholinergic systems have been shown to increase salience/gain while suppressing extraneous information. However, the mechanism by which cholinergic circuits shape signal processing in the auditory thalamus (medial geniculate body, MGB) is poorly understood. The present study, in male Fischer Brown Norway rats, seeks to determine the location and function of presynaptic neuronal nicotinic ACh receptors (nAChRs) at the major inputs to MGB and characterize how nAChRs change during aging. In vitro electrophysiological/optogenetic methods were used to examine responses of MGB neurons after activation of nAChRs during a paired-pulse paradigm. Presynaptic nAChR activation increased responses evoked by stimulation of excitatory corticothalamic and inhibitory tectothalamic terminals. Conversely, nAChR activation appeared to have little effect on evoked responses from inhibitory thalamic reticular nucleus and excitatory tectothalamic terminals. In situ hybridization data showed nAChR subunit transcripts in GABAergic inferior colliculus neurons and glutamatergic auditory cortical neurons supporting the present slice findings. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were diminished by aging. These findings suggest that cholinergic input to the MGB increases the strength of tectothalamic inhibitory projections, potentially improving the signal-to-noise ratio and signal detection while increasing corticothalamic gain, which may facilitate top-down identification of stimulus identity. These mechanisms appear to be affected negatively by aging, potentially diminishing speech perception in noisy environments. Cholinergic inputs to the MGB appear to maximize sensory processing by adjusting both top-down and bottom-up mechanisms in conditions of attention and arousal. SIGNIFICANCE STATEMENT The pedunculopontine tegmental nucleus is the source of cholinergic innervation for sensory thalamus and is a critical part of an ascending arousal system that controls the firing mode of thalamic cells based on attentional demand. The present study describes the location and impact of aging on presynaptic neuronal nicotinic acetylcholine receptors (nAChRs) within the circuitry of the auditory thalamus (medial geniculate body, MGB). We show that nAChRs are located on ascending inhibitory and descending excitatory presynaptic inputs onto MGB neurons, likely increasing gain selectively and improving temporal clarity. In addition, we show that aging has a deleterious effect on nAChR efficacy. Cholinergic dysfunction at the level of MGB may affect speech understanding negatively in the elderly population. PMID:29061702

Pure misallocation of "0" in number transcoding: a new symptom of right cerebral dysfunction.

PubMed

Furumoto, Hideharu

2006-03-01

To account for the mechanism of number transcoding, many authors have proposed various models, for example, semantic-abstract model, lexical-semantic model, triple-code model, and so on. However, almost all of them are based on the symptoms of patients with left cerebral damage. Previously, I reported two Japanese patients with right posterior cerebral infarction showing pure misallocation of "0" (omission: "40,265"-->"4,265," addition: "107"-->"1,007," transposition: "4,072"-->"4,702") both in writing and oral reading of Arabic numerals. To examine whether the pure misallocation of "0" is commonly observed in patients with right cerebral damage, I investigated writing and oral reading of Arabic numerals in 18 patients with right cerebral damage and 16 healthy controls. All patients with right cerebral damage showed pure misallocation of "0" both in writing and reading. The pure misallocation of "0" due to right cerebral damage cannot be explained by current models. It may be more useful to explain the phenomenon by regarding an Arabic numeral as graph on a two-dimensional plane composed of two axes (place-holding values and digits).

Motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment: a diffusion tensor imaging study

PubMed Central

Kim, Jin Hyun; Kwon, Yong Min; Son, Su Min

2015-01-01

Previous diffusion tensor imaging (DTI) studies regarding pediatric patients with motor dysfunction have confirmed the correlation between DTI parameters of the injured corticospinal tract and the severity of motor dysfunction. There is also evidence that DTI parameters can help predict the prognosis of motor function of patients with cerebral palsy. But few studies are reported on the DTI parameters that can reflect the motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment. In the present study, 36 pediatric patients with hemiplegic cerebral palsy were included. Before and after rehabilitation treatment, DTI was used to measure the fiber number (FN), fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of bilateral corticospinal tracts. Functional Level of Hemiplegia scale (FxL) was used to assess the therapeutic effect of rehabilitative therapy on clinical hemiplegia. Correlation analysis was performed to assess the statistical interrelationship between the change amount of DTI parameters and FxL. DTI findings obtained at the initial and follow-up evaluations demonstrated that more affected corticospinal tract yielded significantly decreased FN and FA values and significantly increased ADC value compared to the less affected corticospinal tract. Correlation analysis results showed that the change amount of FxL was positively correlated to FN and FA values, and the correlation to FN was stronger than the correlation to FA. The results suggest that FN and FA values can be used to evaluate the motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment and FN is of more significance for evaluation. PMID:26170825

Berberine alleviates the cerebrovascular contractility in streptozotocin-induced diabetic rats through modulation of intracellular Ca²⁺ handling in smooth muscle cells.

PubMed

Ma, Yu-Guang; Zhang, Yin-Bin; Bai, Yun-Gang; Dai, Zhi-Jun; Liang, Liang; Liu, Mei; Xie, Man-Jiang; Guan, Hai-Tao

2016-04-12

Vascular dysfunction is a distinctive phenotype in diabetes mellitus. Current treatments mostly focus on the tight glycemic control and few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. As a classical natural medicine, berberine has been explored as a possible therapy for DM. In addition, it is reported that berberine has an extra-protective effect in diabetic vascular dysfunction. However, little is known whether the berberine treatment could ameliorate the smooth muscle contractility independent of a functional endothelium under hyperglycemia. Furthermore, it remains unknown whether berberine affects the arterial contractility by regulating the intracellular Ca(2+) handling in vascular smooth cells (VSMCs) under hyperglycemia. Sprague-Dawley rats were used to establish the diabetic model with a high-fat diet plus injections of streptozotocin (STZ). Berberine (50, 100, and 200 mg/kg/day) were intragastrically administered to control and diabetic rats for 8 weeks since the injection of STZ. The intracellular Ca(2+) handling of isolated cerebral VSMCs was investigated by recording the whole-cell L-type Ca(2+) channel (CaL) currents, assessing the protein expressions of CaL channel, and measuring the intracellular Ca(2+) in response to caffeine. Our results showed that chronic administration of 100 mg/kg/day berberine not only reduced glucose levels, but also inhibited the augmented contractile function of cerebral artery to KCl and 5-hydroxytryptamine (5-HT) in diabetic rats. Furthermore, chronic administration of 100 mg/kg/day berberine significantly inhibited the CaL channel current densities, reduced the α1C-subunit expressions of CaL channel, decreased the resting intracellular Ca(2+) ([Ca(2+)]i) level, and suppressed the Ca(2+) releases from RyRs in cerebral VSMCs isolated from diabetic rats. Correspondingly, acute application of 10 μM berberine could directly inhibit the hyperglycemia-induced CaL currents and suppress the hyperglycemia-induced Ca(2+) releases from RyRs in cerebral VSMCs isolated from normal control rats. Our study indicated that berberine alleviated the cerebral arterial contractility in the rat model of streptozotocin-induced diabetes via regulating the intracellular Ca(2+) handling of smooth muscle cells.

Activation of the cholinergic anti-inflammatory pathway by GTS-21 attenuates cisplatin-induced acute kidney injury in mice

PubMed Central

Chatterjee, Prodyot K.; Yeboah, Michael M.; Solanki, Malvika H.; Kumar, Gopal; Xue, Xiangying; Pavlov, Valentin A.; Al-Abed, Yousef

2017-01-01

Acute kidney injury (AKI) is the most common side effect of cisplatin, a widely used chemotherapy drug. Although AKI occurs in up to one third of cancer patients receiving cisplatin, effective renal protective strategies are lacking. Cisplatin targets renal proximal tubular epithelial cells leading to inflammation, reactive oxygen species, tubular cell injury, and eventually cell death. The cholinergic anti-inflammatory pathway is a vagus nerve-mediated reflex that suppresses inflammation via α7 nicotinic acetylcholine receptors (α7nAChRs). Our previous studies demonstrated the renoprotective and anti-inflammatory effects of cholinergic agonists, including GTS-21. Therefore, we examined the effect of GTS-21 on cisplatin-induced AKI. Male C57BL/6 mice received either saline or GTS-21 (4mg/kg, i.p.) twice daily for 4 days before cisplatin and treatment continued through euthanasia; 3 days post-cisplatin mice were euthanized and analyzed for markers of renal injury. GTS-21 significantly reduced cisplatin-induced renal dysfunction and injury (p<0.05). GTS-21 significantly attenuated renal Ptgs2/COX-2 mRNA and IL-6, IL-1β, and CXCL1 protein expression, as well as neutrophil infiltration after cisplatin. GTS-21 blunted cisplatin-induced renal ERK1/2 activation, as well as renal ATP depletion and apoptosis (p<0.05). GTS-21 suppressed the expression of CTR1, a cisplatin influx transporter and enhanced the expression of cisplatin efflux transporters MRP2, MRP4, and MRP6 (p<0.05). Using breast, colon, and lung cancer cell lines we showed that GTS-21 did not inhibit cisplatin’s tumor cell killing activity. GTS-21 protects against cisplatin-AKI by attenuating renal inflammation, ATP depletion and apoptosis, as well as by decreasing renal cisplatin influx and increasing efflux, without impairing cisplatin-mediated tumor cell killing. Our results support further exploring the cholinergic anti-inflammatory pathway for preventing cisplatin-induced AKI. PMID:29190774

Neuroprotective role of quercetin in locomotor activities and cholinergic neurotransmission in rats experimentally demyelinated with ethidium bromide.

PubMed

Beckmann, Diego V; Carvalho, Fabiano B; Mazzanti, Cinthia M; Dos Santos, Rosmarini P; Andrades, Amanda O; Aiello, Graciane; Rippilinger, Angel; Graça, Dominguita L; Abdalla, Fátima H; Oliveira, Lizielle S; Gutierres, Jessié M; Schetinger, Maria Rosa C; Mazzanti, Alexandre

2014-05-17

The purpose of this study was to investigate whether the flavonoid quercetin can prevent alterations in the behavioral tests and of cholinergic neurotransmission in rats submitted to the ethidium bromide (EB) experimental demyelination model during events of demyelination and remyelination. Wistar rats were randomly distributed into four groups (20 animals per group): Control (pontine saline injection and treatment with ethanol), Querc (pontine saline injection and treatment with quercetin), EB (pontine 0.1% EB injection and treatment with ethanol), and EB+Querc (pontine 0.1% EB injection and treatment with quercetin). The groups Querc and Querc+EB were treated once daily with quercetin (50mg/kg) diluted in 25% ethanol solution (1ml/kg) and the animals of the control and EB groups were treated once daily with 25% ethanol solution (1ml/kg). Two stages were observed: phase of demyelination (peak on day 7) and phase of remyelination (peak on day 21 post-injection). Behavioral tests (beam walking, foot fault and inclined plane test), acetylcholinesterase (AChE) activity and lipid peroxidation in pons, cerebellum, hippocampus, hypothalamus, striatum and cerebral cortex were measured. The quercetin promoted earlier locomotor recovery, suggesting that there was demyelination prevention or further remyelination velocity as well as it was able to prevent the inhibition of AChE activity and the increase of lipidic peroxidation, suggesting that this compound can protect cholinergic neurotransmission. These results may contribute to a better understanding of the neuroprotective role of quercetin and the importance of an antioxidant diet in humans to provide benefits in neurodegenerative diseases such as MS. Copyright © 2014. Published by Elsevier Inc.

Maternal Fructose Exposure Programs Metabolic Syndrome-Associated Bladder Overactivity in Young Adult Offspring

PubMed Central

Lee, Wei-Chia; Tain, You-Lin; Wu, Kay L. H.; Leu, Steve; Chan, Julie Y. H.

2016-01-01

Maternal fructose exposure (MFE) programs the development of metabolic syndrome (MetS) in young adult offspring. Epidemiological data indicate that MetS may increase the risks of overactive bladder (OAB) symptoms. However, it remains unknown whether MFE programs MetS-associated bladder dysfunction in adult offspring. Using Sprague-Dawley rats, we investigated the effects of MFE during pregnancy and lactation on developmental programming of MetS-associated bladder dysfunction. In addition, next generation sequencing technology was used to identify potential transcripts involved in the programmed bladder dysfunction in adult male offspring to MFE. We found that MFE programmed the MetS-associated OAB symptoms (i.e., an increase in micturition frequency and a shortened mean inter-contractile interval) in young adult male offspring, alongside significant alterations in bladder transcripts, including Chrm2, Chrm3, P2rx1, Trpv4, and Vipr2 gene expression. At protein level, the expressions of M2-, M3-muscarinic and P2X1 receptor proteins were upregulated in the MFE bladder. Functionally, the carbachol-induced detrusor contractility was reduced in the MFE offspring. These data suggest that alterations in the bladder transcripts and impairment of the bladder cholinergic pathways may underlie the pathophysiology of programmed bladder dysfunction in adult offspring to MFE. PMID:27703194

Maternal Fructose Exposure Programs Metabolic Syndrome-Associated Bladder Overactivity in Young Adult Offspring.

PubMed

Lee, Wei-Chia; Tain, You-Lin; Wu, Kay L H; Leu, Steve; Chan, Julie Y H

2016-10-05

Maternal fructose exposure (MFE) programs the development of metabolic syndrome (MetS) in young adult offspring. Epidemiological data indicate that MetS may increase the risks of overactive bladder (OAB) symptoms. However, it remains unknown whether MFE programs MetS-associated bladder dysfunction in adult offspring. Using Sprague-Dawley rats, we investigated the effects of MFE during pregnancy and lactation on developmental programming of MetS-associated bladder dysfunction. In addition, next generation sequencing technology was used to identify potential transcripts involved in the programmed bladder dysfunction in adult male offspring to MFE. We found that MFE programmed the MetS-associated OAB symptoms (i.e., an increase in micturition frequency and a shortened mean inter-contractile interval) in young adult male offspring, alongside significant alterations in bladder transcripts, including Chrm2, Chrm3, P2rx1, Trpv4, and Vipr2 gene expression. At protein level, the expressions of M 2 -, M 3 -muscarinic and P2X 1 receptor proteins were upregulated in the MFE bladder. Functionally, the carbachol-induced detrusor contractility was reduced in the MFE offspring. These data suggest that alterations in the bladder transcripts and impairment of the bladder cholinergic pathways may underlie the pathophysiology of programmed bladder dysfunction in adult offspring to MFE.

Axon-glial disruption: the link between vascular disease and Alzheimer's disease?

PubMed

Horsburgh, Karen; Reimer, Michell M; Holland, Philip; Chen, Guiquan; Scullion, Gillian; Fowler, Jill H

2011-08-01

Vascular risk factors play a critical role in the development of cognitive decline and AD (Alzheimer's disease), during aging, and often result in chronic cerebral hypoperfusion. The neurobiological link between hypoperfusion and cognitive decline is not yet defined, but is proposed to involve damage to the brain's white matter. In a newly developed mouse model, hypoperfusion, in isolation, produces a slowly developing and diffuse damage to myelinated axons, which is widespread in the brain, and is associated with a selective impairment in working memory. Cerebral hypoperfusion, an early event in AD, has also been shown to be associated with white matter damage and notably an accumulation of amyloid. The present review highlights some of the published data linking white matter disruption to aging and AD as a result of vascular dysfunction. A model is proposed by which chronic cerebral hypoperfusion, as a result of vascular factors, results in both the generation and accumulation of amyloid and injury to white matter integrity, resulting in cognitive impairment. The generation of amyloid and accumulation in the vasculature may act to perpetuate further vascular dysfunction and accelerate white matter pathology, and as a consequence grey matter pathology and cognitive decline.

Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers.

PubMed

London, Edythe D; Berman, Steven M; Voytek, Bradley; Simon, Sara L; Mandelkern, Mark A; Monterosso, John; Thompson, Paul M; Brody, Arthur L; Geaga, Jennifer A; Hong, Michael S; Hayashi, Kiralee M; Rawson, Richard A; Ling, Walter

2005-11-15

Methamphetamine (MA) abusers have cognitive deficits, abnormal metabolic activity and structural deficits in limbic and paralimbic cortices, and reduced hippocampal volume. The links between cognitive impairment and these cerebral abnormalities are not established. We assessed cerebral glucose metabolism with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Regional brain radioactivity served as a marker for relative glucose metabolism. Error rates on the task were related to regional radioactivity and hippocampal morphology. Methamphetamine users had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects.

Usefulness of Deep Hypothermic Circulatory Arrest and Regional Cerebral Perfusion in Children

PubMed Central

Guo, Zheng; Hu, Ren-Jie; Zhu, De-Ming; Zhu, Zhong-Qun; Zhang, Hai-Bo

2013-01-01

To compare the safety and usefulness of deep hypothermic circulatory arrest (DHCA) and regional cerebral perfusion (RCP) during pediatric open heart surgery. Between January 1, 2004 and September 30, 2012, 1250 children with congenital cardiac defect underwent corrective operation with the DHCA or RCP technique in the Shanghai Children's Medical Center. Of them, 947 cases underwent the operation with the aid of DHCA (DHCA group), and 303 cases with RCP (RCP group). The mean DHCA time was 30.64±15.81 (7–63) minutes and mean RCP time was 36.18±12.86 (10–82) minutes. The mortality rate was 7.18% (68/947) and 6.60% (20/30) in two groups, respectively. The postoperative incidences of temporary and permanent neurological dysfunction were 6.23% (59/947) in the DHCA group and 2.64% (8/303) in the RCP group (p<0.01). The incidence of other complications such as low cardiac output, renal dysfunction, and lung issues are similar in both groups. RCP is a reliable technique for cerebral protection and it facilitates time-consuming corrected procedures for complex congenital cardiac defect repair procedures. PMID:24066266

[Osmotic demyelination syndrome in Addison crisis and severe hyponatremia].

PubMed

Andersen, Signe Elisabeth Bødker; Stausbøl-Grøn, Brian; Rasmussen, Torsten Bloch

2008-12-08

Acute adrenal insufficiency is a life threatening disease with dehydration, hypotension, cerebral dysfunction and gastrointestinal symptoms accompanied by low plasma sodium and high plasma potassium. Osmotic demyelination syndrome (ODS) can occur rarely following correction of plasma sodium. We describe a case with extremely low plasma sodium and subsequent development of ODS. Correction which is too slow may lead to cerebral oedema, brain stem herniation and low sodium encephalopathy. Correction which is too fast may cause ODS. The dilemma is accentuated by concomitant Addison crisis.

Neural Vascular Mechanism for the Cerebral Blood Flow Autoregulation after Hemorrhagic Stroke.

PubMed

Xiao, Ming; Li, Qiang; Feng, Hua; Zhang, Le; Chen, Yujie

2017-01-01

During the initial stages of hemorrhagic stroke, including intracerebral hemorrhage and subarachnoid hemorrhage, the reflex mechanisms are activated to protect cerebral perfusion, but secondary dysfunction of cerebral flow autoregulation will eventually reduce global cerebral blood flow and the delivery of metabolic substrates, leading to generalized cerebral ischemia, hypoxia, and ultimately, neuronal cell death. Cerebral blood flow is controlled by various regulatory mechanisms, including prevailing arterial pressure, intracranial pressure, arterial blood gases, neural activity, and metabolic demand. Evoked by the concept of vascular neural network, the unveiled neural vascular mechanism gains more and more attentions. Astrocyte, neuron, pericyte, endothelium, and so forth are formed as a communicate network to regulate with each other as well as the cerebral blood flow. However, the signaling molecules responsible for this communication between these new players and blood vessels are yet to be definitively confirmed. Recent evidence suggested the pivotal role of transcriptional mechanism, including but not limited to miRNA, lncRNA, exosome, and so forth, for the cerebral blood flow autoregulation. In the present review, we sought to summarize the hemodynamic changes and underline neural vascular mechanism for cerebral blood flow autoregulation in stroke-prone state and after hemorrhagic stroke and hopefully provide more systematic and innovative research interests for the pathophysiology and therapeutic strategies of hemorrhagic stroke.

Volumetric Magnetic Resonance Imaging Study of Brain and Cerebellum in Children with Cerebral Palsy

PubMed Central

Maciorkowska, Elżbieta; Gościk, Elżbieta

2016-01-01

Introduction. Quantitative magnetic resonance imaging (MRI) studies are rarely used in the diagnosis of patients with cerebral palsy. The aim of present study was to assess the relationships between the volumetric MRI and clinical findings in children with cerebral palsy compared to control subjects. Materials and Methods. Eighty-two children with cerebral palsy and 90 age- and sex-matched healthy controls were collected. Results. The dominant changes identified on MRI scans in children with cerebral palsy were periventricular leukomalacia (42%) and posthemorrhagic hydrocephalus (21%). The total brain and cerebellum volumes in children with cerebral palsy were significantly reduced in comparison to controls. Significant grey matter volume reduction was found in the total brain in children with cerebral palsy compared with the control subjects. Positive correlations between the age of the children of both groups and the grey matter volumes in the total brain were found. Negative relationship between width of third ventricle and speech development was found in the patients. Positive correlations were noted between the ventricles enlargement and motor dysfunction and mental retardation in children with cerebral palsy. Conclusions. By using the voxel-based morphometry, the total brain, cerebellum, and grey matter volumes were significantly reduced in children with cerebral palsy. PMID:27579318

Volumetric Magnetic Resonance Imaging Study of Brain and Cerebellum in Children with Cerebral Palsy.

PubMed

Kułak, Piotr; Maciorkowska, Elżbieta; Gościk, Elżbieta

2016-01-01

Introduction. Quantitative magnetic resonance imaging (MRI) studies are rarely used in the diagnosis of patients with cerebral palsy. The aim of present study was to assess the relationships between the volumetric MRI and clinical findings in children with cerebral palsy compared to control subjects. Materials and Methods. Eighty-two children with cerebral palsy and 90 age- and sex-matched healthy controls were collected. Results. The dominant changes identified on MRI scans in children with cerebral palsy were periventricular leukomalacia (42%) and posthemorrhagic hydrocephalus (21%). The total brain and cerebellum volumes in children with cerebral palsy were significantly reduced in comparison to controls. Significant grey matter volume reduction was found in the total brain in children with cerebral palsy compared with the control subjects. Positive correlations between the age of the children of both groups and the grey matter volumes in the total brain were found. Negative relationship between width of third ventricle and speech development was found in the patients. Positive correlations were noted between the ventricles enlargement and motor dysfunction and mental retardation in children with cerebral palsy. Conclusions. By using the voxel-based morphometry, the total brain, cerebellum, and grey matter volumes were significantly reduced in children with cerebral palsy.

Pediatric Cerebral Palsy in Botswana: Etiology, Outcomes, and Comorbidities

PubMed Central

Bearden, David R.; Monokwane, Baphaleng; Khurana, Esha; Baier, James; Baranov, Esther; Westmoreland, Kate; Mazhani, Loeto; Steenhoff, Andrew P.

2016-01-01

BACKGROUND Cerebral palsy is the most common cause of motor dysfunction in children worldwide and is often accompanied by multiple comorbidities. Although cerebral palsy has been studied extensively in high-resource settings, there are few published studies on cerebral palsy etiology, outcomes and comorbidities in low-resource settings. METHODS Children with cerebral palsy were prospectively enrolled from inpatient and outpatient settings at a referral center in Gaborone, Botswana, in a cross-sectional study conducted from 2013 to 2014. Cerebral palsy etiology, outcomes, and comorbidities were determined through caregiver interviews, review of medical records, and direct physical examination. RESULTS Sixty-eight children with cerebral palsy were enrolled. Subjects were 41% male, with a median age of 4 years (interquartile range = 2 to 7). The most common etiologies for cerebral palsy in our cohort were intrapartum hypoxic events (18%), postnatal infections (15%), prematurity (15%), focal ischemic strokes (10%), and prenatal infections (10%). Severe motor impairment was common, with the most severe category present in 41%. The predominant comorbidities were cognitive impairment (84%), epilepsy (77%), and visual impairment (46%). CONCLUSIONS Cerebral palsy in Botswana has different etiologies and is associated with poorer outcomes and higher prevalence of comorbidities than what has been reported in high-resource settings. Further studies are necessary to determine optimal preventative and treatment strategies in this population. PMID:27114082

Recurrent Fat Embolic Strokes in a Patient With Duchenne Muscular Dystrophy With Long Bone Fractures and a Patent Foramen Ovale.

PubMed

Bugnitz, Christopher J; Cripe, Linda H; Lo, Warren D; Flanigan, Kevin M

2016-10-01

Individuals with Duchenne muscular dystrophy have an increased risk of long bone fractures. Such fractures are sometimes associated with brain dysfunction due to fat embolism syndrome, although this syndrome has seldom been documented in muscular dystrophy patients. We describe a child with Duchenne muscular dystrophy who developed fat embolism syndrome with neurological dysfunction following multiple long bone fractures. He experienced recurrent cerebral infarctions that probably resulted from embolization through a patent foramen ovale. The patent foramen ovale was closed by an occluder device in the cardiac catheterization laboratory, and he did not experience further infarctions. Fat embolism with ischemic cerebral infarction can occur in individuals with Duchenne muscular dystrophy following long bone fractures. In this setting it is important to identify and close atrial level shunts in order to prevent additional infarctions. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of sildenafil citrate (Viagra) on cerebral blood flow in patients with cerebrovascular risk factors.

PubMed

Lorberboym, M; Mena, I; Wainstein, J; Boaz, M; Lampl, Y

2010-06-01

Sildenafil citrate is widely used for erectile dysfunction. The present study examined the short-term effects of sildenafil administration in individuals with cerebrovascular risk factors, including patients with a history of stroke. Twenty-five consecutive male patients with erectile dysfunction and vascular risk factors were included in the study. A perfusion brain SPECT study was performed at baseline and 1 h after the oral administration of sildenafil. Associations between any of the risk factors and the perfusion scores were not detected, with the exception of stroke. Stroke patients showed significantly more areas with diminished perfusion after sildenafil administration compared to baseline. In patients with diabetes or hypertension, a dose of 50 mg sildenafil does not appear to produce detrimental effects on cerebral blood flow. However, patients with a history of stroke may be at increased risk of hemodynamic impairment after the use of sildenafil.

TRPM2 Channel Aggravates CNS Inflammation and Cognitive Impairment via Activation of Microglia in Chronic Cerebral Hypoperfusion.

PubMed

Miyanohara, Jun; Kakae, Masashi; Nagayasu, Kazuki; Nakagawa, Takayuki; Mori, Yasuo; Arai, Ken; Shirakawa, Hisashi; Kaneko, Shuji

2018-04-04

Chronic cerebral hypoperfusion is a characteristic seen in widespread CNS diseases, including neurodegenerative and mental disorders, and is commonly accompanied by cognitive impairment. Recently, several studies demonstrated that chronic cerebral hypoperfusion can induce the excessive inflammatory responses that precede neuronal dysfunction; however, the precise mechanism of cognitive impairment due to chronic cerebral hypoperfusion remains unknown. Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+ -permeable channel that is abundantly expressed in immune cells and is involved in aggravation of inflammatory responses. Therefore, we investigated the pathophysiological role of TRPM2 in a mouse chronic cerebral hypoperfusion model with bilateral common carotid artery stenosis (BCAS). When male mice were subjected to BCAS, cognitive dysfunction and white matter injury at day 28 were significantly improved in TRPM2 knock-out (TRPM2-KO) mice compared with wild-type (WT) mice, whereas hippocampal damage was not observed. There were no differences in blood-brain barrier breakdown and H 2 O 2 production between the two genotypes at 14 and 28 d after BCAS. Cytokine production was significantly suppressed in BCAS-operated TRPM2-KO mice compared with WT mice at day 28. In addition, the number of Iba1-positive cells gradually decreased from day 14. Moreover, daily treatment with minocycline significantly improved cognitive perturbation. Surgical techniques using bone marrow chimeric mice revealed that activated Iba1-positive cells in white matter could be brain-resident microglia, not peripheral macrophages. Together, these findings suggest that microglia contribute to the aggravation of cognitive impairment by chronic cerebral hypoperfusion, and that TRPM2 may be a potential target for chronic cerebral hypoperfusion-related disorders. SIGNIFICANCE STATEMENT Chronic cerebral hypoperfusion is manifested in a wide variety of CNS diseases, including neurodegenerative and mental disorders that are accompanied by cognitive impairment; however, the underlying mechanisms require clarification. Here, we used a chronic cerebral hypoperfusion mouse model to investigate whether TRPM2, a Ca 2+ -permeable cation channel highly expressed in immune cells, plays a destructive role in the development of chronic cerebral hypoperfusion-induced cognitive impairment, and propose a new hypothesis in which TRPM2-mediated activation of microglia, not macrophages, specifically contributes to the pathology through the aggravation of inflammatory responses. These findings shed light on the understanding of the mechanisms of chronic cerebral hypoperfusion-related inflammation, and are expected to provide a novel therapeutic molecule for cognitive impairment in CNS diseases. Copyright © 2018 the authors 0270-6474/18/383521-14$15.00/0.

Nuclear 82-kDa choline acetyltransferase decreases amyloidogenic APP metabolism in neurons from APP/PS1 transgenic mice.

PubMed

Albers, Shawn; Inthathirath, Fatima; Gill, Sandeep K; Winick-Ng, Warren; Jaworski, Ewa; Wong, Daisy Y L; Gros, Robert; Rylett, R Jane

2014-09-01

Alzheimer disease (AD) is associated with increased amyloidogenic processing of amyloid precursor protein (APP) to β-amyloid peptides (Aβ), cholinergic neuron loss with decreased choline acetyltransferase (ChAT) activity, and cognitive dysfunction. Both 69-kDa ChAT and 82-kDa ChAT are expressed in cholinergic neurons in human brain and spinal cord with 82-kDa ChAT localized predominantly to neuronal nuclei, suggesting potential alternative functional roles for the enzyme. By gene microarray analysis, we found that 82-kDa ChAT-expressing IMR32 neural cells have altered expression of genes involved in diverse cellular functions. Importantly, genes for several proteins that regulate APP processing along amyloidogenic and non-amyloidogenic pathways are differentially expressed in 82-kDa ChAT-containing cells. The predicted net effect based on observed changes in expression patterns of these genes would be decreased amyloidogenic APP processing with decreased Aβ production. This functional outcome was verified experimentally as a significant decrease in BACE1 protein levels and activity and a concomitant reduction in the release of endogenous Aβ1-42 from neurons cultured from brains of AD-model APP/PS1 transgenic mice. The expression of 82-kDa ChAT in neurons increased levels of GGA3, which is involved in trafficking BACE1 to lysosomes for degradation. shRNA-induced decreases in GGA3 protein levels attenuated the 82-kDa ChAT-mediated decreases in BACE1 protein and activity and Aβ1-42 release. Evidence that 82-kDa ChAT can enhance GGA3 gene expression is shown by enhanced GGA3 gene promoter activity in SN56 neural cells expressing this ChAT protein. These studies indicate a novel relationship between cholinergic neurons and APP processing, with 82-kDa ChAT acting as a negative regulator of Aβ production. This decreased formation of Aβ could result in protection for cholinergic neurons, as well as protection of other cells in the vicinity that are sensitive to increased levels of Aβ. Decreasing levels of 82-kDa ChAT due to increasing age or neurodegeneration could alter the balance towards increasing Aβ production, with this potentiating the decline in function of cholinergic neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment.

PubMed

Jahrling, Jordan B; Lin, Ai-Ling; DeRosa, Nicholas; Hussong, Stacy A; Van Skike, Candice E; Girotti, Milena; Javors, Martin; Zhao, Qingwei; Maslin, Leigh Ann; Asmis, Reto; Galvan, Veronica

2018-01-01

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR -/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

Selective Cognitive Dysfunction Is Related to a Specific Pattern of Cerebral Damage in Persons With Severe Traumatic Brain Injury.

PubMed

Di Paola, Margherita; Phillips, Owen; Costa, Alberto; Ciurli, Paola; Bivona, Umberto; Catani, Sheila; Formisano, Rita; Caltagirone, Carlo; Carlesimo, Giovanni Augusto

2015-01-01

Cognitive dysfunction is a common sequela of traumatic brain injury (TBI); indeed, patients show a heterogeneous pattern of cognitive deficits. This study was aimed at investigating whether patients who show selective cognitive dysfunction after TBI present a selective pattern of cerebral damage. Post-Coma Unit, IRCCS Santa Lucia Foundation, Rome, Italy. We collected data from 8 TBI patients with episodic memory disorder and without executive deficits, 7 patients with executive function impairment and preserved episodic memory capacities, and 16 healthy controls. We used 2 complementary analyses: (1) an exploratory and qualitative approach in which we investigated the distribution of lesions in the TBI groups, and (2) a hypothesis-driven and quantitative approach in which we calculated the volume of hippocampi of individuals in the TBI and control groups. Neuropsychological scores and hippocampal volumes. We found that patients with TBI and executive functions impairment presented focal lesions involving the frontal lobes, whereas patients with TBI and episodic memory disorders showed atrophic changes of the mesial temporal structure (hippocampus). The complexity of TBI is due to several heterogeneous factors. Indeed, studying patients with TBI and selective cognitive dysfunction should lead to a better understanding of correlations with specific brain impairment and damage, better follow-up of long-term outcome scenarios, and better planning of selective and focused rehabilitation programs.

Ligands for SPECT and PET imaging of muscarinic-cholinergic receptors of the heart and brain

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

Knapp, F.F. Jr.; McPherson, D.W.; Luo, H.

1995-06-01

Interest in the potential use of cerebral SPECT and PET imaging for determination of the density and activity of muscarinic-cholinergic receptors (mAChR) has been stimulated by the changes in these receptors which occur in many neurological diseases. In addition, the important involvement of mAChR in modulating negative inotropic cardiac activity suggests that such receptor ligands may have important applications in evaluation of changes which may occur in cardiac disease. In this paper, the properties of several key muscarinic receptor ligands being developed or which have been used for clinical SPECT and PET are discussed. In addition, the ORNL development ofmore » the new iodinated IQNP ligand based on QNB and the results of in vivo biodistribution studies in rats, in vitro competitive binding studies and ex vivo autoradiographic experiments are described. The use of radioiodinated IQNP may offer several advantages in comparison to IQNB because of its easy and high yield preparation and high brain uptake and the potential usefulness of the {open_quotes}partial{close_quotes} subtype selective IONP isomers. We also describe the development of new IQNP-type analogues which offer the opportunity for radiolabeling with positron-emitting radioisotopes (carbon-11, fluorine-18 and bromine-76) for potential use with PET.« less

Catecholamines alter the intrinsic variability of cortical population activity and perception

PubMed Central

Avramiea, Arthur-Ervin; Nolte, Guido; Engel, Andreas K.; Linkenkaer-Hansen, Klaus; Donner, Tobias H.

2018-01-01

The ascending modulatory systems of the brain stem are powerful regulators of global brain state. Disturbances of these systems are implicated in several major neuropsychiatric disorders. Yet, how these systems interact with specific neural computations in the cerebral cortex to shape perception, cognition, and behavior remains poorly understood. Here, we probed into the effect of two such systems, the catecholaminergic (dopaminergic and noradrenergic) and cholinergic systems, on an important aspect of cortical computation: its intrinsic variability. To this end, we combined placebo-controlled pharmacological intervention in humans, recordings of cortical population activity using magnetoencephalography (MEG), and psychophysical measurements of the perception of ambiguous visual input. A low-dose catecholaminergic, but not cholinergic, manipulation altered the rate of spontaneous perceptual fluctuations as well as the temporal structure of “scale-free” population activity of large swaths of the visual and parietal cortices. Computational analyses indicate that both effects were consistent with an increase in excitatory relative to inhibitory activity in the cortical areas underlying visual perceptual inference. We propose that catecholamines regulate the variability of perception and cognition through dynamically changing the cortical excitation–inhibition ratio. The combined readout of fluctuations in perception and cortical activity we established here may prove useful as an efficient and easily accessible marker of altered cortical computation in neuropsychiatric disorders. PMID:29420565

Cerebral asymmetry and behavioral lateralization in rats chronically lacking n-3 polyunsaturated fatty acids.

PubMed

Vancassel, Sylvie; Aïd, Sabah; Pifferi, Fabien; Morice, Elise; Nosten-Bertrand, Marika; Chalon, Sylvie; Lavialle, Monique

2005-11-15

Anatomic and functional brain lateralization underlies hemisphere specialization for cognitive and motor control, and deviations from the normal patterns of asymmetry appear to be related to behavioral deficits. Studies on n-3 polyunsaturated fatty acid (PUFA) deficiency and behavioral impairments led us to postulate that a chronic lack of n-3 PUFA can lead to changes in lateralized behavior by affecting structural or neurochemical patterns of asymmetry in motor-related brain structures. We compared the effects of a chronic n-3 PUFA deficient diet with a balanced diet on membrane phospholipid fatty acids composition and immunolabeling of choline acetyltransferase (ChAt), as a marker of cholinergic neurons, in left and right striatum of rats. Lateral motor behavior was assessed by rotation and paw preference. Control rats had an asymmetric PUFA distribution with a right behavioral preference, whereas ChAt density was symmetrical. In deficient rats, the cholinergic neuron density was 30% lower on the right side, associated with a loss of PUFA asymmetry and behavior laterality. They present higher rotation behavior, and significantly more of them failed the handedness test. These results indicate that a lack of n-3 PUFA is linked with a lateral behavior deficit, possibly leading to cognitive disturbances.

Endothelial dysfunction in rat mesenteric resistance artery after transient middle cerebral artery occlusion.

PubMed

Martinez-Revelles, Sonia; Jiménez-Altayó, Francesc; Caracuel, Laura; Pérez-Asensio, Fernando J; Planas, Anna M; Vila, Elisabet

2008-05-01

Stroke triggers a local and systemic inflammatory response leading to the production of cytokines that can influence blood vessel reactivity. In this study, we aimed to assess whether cerebral ischemia/reperfusion could affect vasoconstriction and vasodilatation on mesenteric resistance arteries (MRA) from Wistar Kyoto rats. The right middle cerebral artery was occluded (90 min) and reperfused (24 h). Sham-operated animals were used as controls. Plasma levels of interleukin (IL)-6 and IL-1beta were measured at 24 h. Vasoconstrictor and vasodilator responses were recorded in a wire myograph. Protein expression was determined by Western blot and immunofluorescence, and superoxide anion (O(2)(.)) production was evaluated by ethidium fluorescence. In MRA, ischemia/reperfusion increased plasma levels of IL-6, O2. production, protein expression of cyclooxygenase-2, and protein tyrosine nitrosylation, but it impaired acetylcholine (ACh) vasodilatation without modifying the vasodilatations to sodium nitroprusside or the contractions to phenylephrine and KCl. Superoxide dismutase (SOD) and indomethacin reversed the impairment of ACh relaxation induced by ischemia/reperfusion. However, N(omega)-nitro-l-arginine methyl ester affected similarly ACh-induced vasodilatations in MRA of ischemic and sham-operated rats. Protein expression of endothelial and inducible nitric-oxide synthase, copper/zinc SOD, manganese SOD, and extracellular SOD was similar in both groups of rats. Our results show MRA endothelial dysfunction 24 h after brain ischemia/reperfusion. Excessive production of O2. in MRA mediates endothelial dysfunction, and the increase in plasma cytokine levels after brain ischemia/reperfusion might be involved in this effect.

Targeted overexpression of endothelial nitric oxide synthase in endothelial cells improves cerebrovascular reactivity in Ins2Akita-type-1 diabetic mice.

PubMed

Chandra, Saurav B; Mohan, Sumathy; Ford, Bridget M; Huang, Lei; Janardhanan, Preethi; Deo, Kaiwalya S; Cong, Linlin; Muir, Eric R; Duong, Timothy Q

2016-06-01

Reduced bioavailability of nitric oxide due to impaired endothelial nitric oxide synthase (eNOS) activity is a leading cause of endothelial dysfunction in diabetes. Enhancing eNOS activity in diabetes is a potential therapeutic target. This study investigated basal cerebral blood flow and cerebrovascular reactivity in wild-type mice, diabetic mice (Ins2(Akita+/-)), nondiabetic eNOS-overexpressing mice (TgeNOS), and the cross of two transgenic mice (TgeNOS-Ins2(Akita+/-)) at six months of age. The cross was aimed at improving eNOS expression in diabetic mice. The major findings were: (i) Body weights of Ins2(Akita+/-) and TgeNOS-Ins2(Akita+/-) were significantly different from wild-type and TgeNOS mice. Blood pressure of TgeNOS mice was lower than wild-type. (ii) Basal cerebral blood flow of the TgeNOS group was significantly higher than cerebral blood flow of the other three groups. (iii) The cerebrovascular reactivity in the Ins2(Akita+/-) mice was significantly lower compared with wild-type, whereas that in the TgeNOS-Ins2(Akita+/-) was significantly higher compared with the Ins2(Akita+/-) and TgeNOS groups. Overexpression of eNOS rescued cerebrovascular dysfunction in diabetic animals, resulting in improved cerebrovascular reactivity. These results underscore the possible role of eNOS in vascular dysfunction in the brain of diabetic mice and support the notion that enhancing eNOS activity in diabetes is a potential therapeutic target. © The Author(s) 2015.

Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

PubMed Central

Jerlhag, Elisabet; Janson, Anna Carin; Waters, Susanna; Engel, Jörgen A.

2012-01-01

Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating. PMID:23166710

Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects.

PubMed

Wezenberg, E; Verkes, R J; Sabbe, B G C; Ruigt, G S F; Hulstijn, W

2005-09-01

The central cholinergic system is implicated in cognitive functioning. The dysfunction of this system is expressed in many diseases like Alzheimer's disease, dementia of Lewy body, Parkinson's disease and vascular dementia. In recent animal studies, it was found that selective cholinergic modulation affects visuospatial processes even more than memory function. In the current study, we tried to replicate those findings. In order to investigate the acute effects of cholinergic drugs on memory and visuospatial functions, a selective anticholinergic drug, biperiden, was compared to a selective acetylcholinesterase-inhibiting drug, rivastigmine, in healthy elderly subjects. A double-blind, placebo-controlled, randomised, cross-over study was performed in 16 healthy, elderly volunteers (eight men, eight women; mean age 66.1, SD 4.46 years). All subjects received biperiden (2 mg), rivastigmine (3 mg) and placebo with an interval of 7 days between them. Testing took place 1 h after drug intake (which was around Tmax for both drugs). Subjects were presented with tests for episodic memory (wordlist and picture memory), working memory tasks (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Visuospatial abilities were assessed by tests with high visual scanning components (tangled lines and Symbol Digit Substitution Test). Episodic memory was impaired by biperiden. Rivastigmine impaired recognition parts of the episodic memory performance. Working memory was non-significantly impaired by biperiden and not affected by rivastigmine. Motor learning as well as visuospatial processes were impaired by biperiden and improved by rivastigmine. These results implicate acetylcholine as a modulator not only of memory but also of visuospatial abilities.

Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway.

PubMed

Mesquita, Thássio R R; de Jesus, Itamar C G; Dos Santos, Jucilene F; de Almeida, Grace K M; de Vasconcelos, Carla M L; Guatimosim, Silvia; Macedo, Fabrício N; Dos Santos, Robervan V; de Menezes-Filho, José E R; Miguel-Dos-Santos, Rodrigo; Matos, Paulo T D; Scalzo, Sérgio; Santana-Filho, Valter J; Albuquerque-Júnior, Ricardo L C; Pereira-Filho, Rose N; Lauton-Santos, Sandra

2017-01-01

Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba -mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M 2 ) and downregulation of β 1 -AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo , we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M 2 /NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba .

Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway

PubMed Central

Mesquita, Thássio R. R.; de Jesus, Itamar C. G.; dos Santos, Jucilene F.; de Almeida, Grace K. M.; de Vasconcelos, Carla M. L.; Guatimosim, Silvia; Macedo, Fabrício N.; dos Santos, Robervan V.; de Menezes-Filho, José E. R.; Miguel-dos-Santos, Rodrigo; Matos, Paulo T. D.; Scalzo, Sérgio; Santana-Filho, Valter J.; Albuquerque-Júnior, Ricardo L. C.; Pereira-Filho, Rose N.; Lauton-Santos, Sandra

2017-01-01

Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of β1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba. PMID:28553225

Involvement of decreased muscarinic receptor function in prepulse inhibition deficits in mice reared in social isolation

PubMed Central

Koda, K; Ago, Y; Yano, K; Nishimura, M; Kobayashi, H; Fukada, A; Takuma, K; Matsuda, T

2011-01-01

BACKGROUND AND PURPOSE We have previously reported that galantamine, a weak acetylcholinesterase inhibitor, improves prepulse inhibition (PPI) deficits in mice reared in social isolation. ACh receptors are involved in the underlying mechanism of PPI, but whether rearing in social isolation causes dysfunction of the cholinergic system is unknown. In this study, we examined the involvement of muscarinic receptors in the improvement of PPI deficits induced by galantamine, and whether the cholinergic system is altered in mice reared in isolation. EXPERIMENTAL APPROACH Three-week-old male ddY mice were housed in isolated cages for 6 weeks before the initiation of experiments to create PPI deficits. Cholinergic functions were determined by measuring the behavioural and neurochemical responses to nicotinic and muscarinic receptor agonists. KEY RESULTS The improvement by galantamine of social isolation-induced PPI deficits was blocked by scopolamine, a non-selective muscarinic antagonist, and telenzepine, a preferential M1 receptor antagonist. Activation of M1 receptors improved social isolation-induced PPI deficits. Social isolation did not affect choline acetyltransferase and acetylcholinesterase activities in the prefrontal cortex and hippocampus, but it reduced the locomotor-suppressive response to muscarinic agonist oxotremorine, but not to nicotine. The isolation also attenuated the M1 receptor agonist N-desmethylclozapine-induced increase in prefrontal dopamine release. CONCLUSIONS AND IMPLICATIONS Galantamine improves PPI deficits of mice reared in social isolation via activation of M1 receptors. Social isolation reduces the muscarinic, especially M1, receptor function and this is involved in PPI deficits. PMID:20958289

Specific multi-nutrient enriched diet enhances hippocampal cholinergic transmission in aged rats.

PubMed

Cansev, Mehmet; van Wijk, Nick; Turkyilmaz, Mesut; Orhan, Fulya; Sijben, John W C; Broersen, Laus M

2015-01-01

Fortasyn Connect (FC) is a specific nutrient combination designed to target synaptic dysfunction in Alzheimer's disease by providing neuronal membrane precursors and other supportive nutrients. The aim of the present study was to investigate the effects of FC on hippocampal cholinergic neurotransmission in association with its effects on synaptic membrane formation in aged rats. Eighteen-month-old male Wistar rats were randomized to receive a control diet for 4 weeks or an FC-enriched diet for 4 or 6 weeks. At the end of the dietary treatments, acetylcholine (ACh) release was investigated by in vivo microdialysis in the right hippocampi. On completion of microdialysis studies, the rats were sacrificed, and the left hippocampi were obtained to determine the levels of choline, ACh, membrane phospholipids, synaptic proteins, and choline acetyltransferase. Our results revealed that supplementation with FC diet for 4 or 6 weeks, significantly enhanced basal and stimulated hippocampal ACh release and ACh tissue levels, along with levels of phospholipids. Feeding rats the FC diet for 6 weeks significantly increased the levels of choline acetyltransferase, the presynaptic marker Synapsin-1, and the postsynaptic marker PSD-95, but decreased levels of Nogo-A, a neurite outgrowth inhibitor. These data show that the FC diet enhances hippocampal cholinergic neurotransmission in aged rats and suggest that this effect is mediated by enhanced synaptic membrane formation. These data provide further insight into cellular and molecular mechanisms by which FC may support memory processes in Alzheimer's disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2014-07-15

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

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

PubMed Central

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

2014-01-01

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

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke.

PubMed

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms.

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke

PubMed Central

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms. PMID:28217291

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy.

PubMed

Srour, Myriam; Shimokawa, Noriaki; Hamdan, Fadi F; Nassif, Christina; Poulin, Chantal; Al Gazali, Lihadh; Rosenfeld, Jill A; Koibuchi, Noriyuki; Rouleau, Guy A; Al Shamsi, Aisha; Michaud, Jacques L

2017-05-04

Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Effects of different frequencies of repetitive transcranial magnetic stimulation on the recovery of upper limb motor dysfunction in patients with subacute cerebral infarction.

PubMed

Li, Jiang; Meng, Xiang-Min; Li, Ru-Yi; Zhang, Ru; Zhang, Zheng; Du, Yi-Feng

2016-10-01

Studies have confirmed that low-frequency repetitive transcranial magnetic stimulation can decrease the activity of cortical neurons, and high-frequency repetitive transcranial magnetic stimulation can increase the excitability of cortical neurons. However, there are few studies concerning the use of different frequencies of repetitive transcranial magnetic stimulation on the recovery of upper-limb motor function after cerebral infarction. We hypothesized that different frequencies of repetitive transcranial magnetic stimulation in patients with cerebral infarction would produce different effects on the recovery of upper-limb motor function. This study enrolled 127 patients with upper-limb dysfunction during the subacute phase of cerebral infarction. These patients were randomly assigned to three groups. The low-frequency group comprised 42 patients who were treated with 1 Hz repetitive transcranial magnetic stimulation on the contralateral hemisphere primary motor cortex (M1). The high-frequency group comprised 43 patients who were treated with 10 Hz repetitive transcranial magnetic stimulation on ipsilateral M1. Finally, the sham group comprised 42 patients who were treated with 10 Hz of false stimulation on ipsilateral M1. A total of 135 seconds of stimulation was applied in the sham group and high-frequency group. At 2 weeks after treatment, cortical latency of motor-evoked potentials and central motor conduction time were significantly lower compared with before treatment. Moreover, motor function scores were significantly improved. The above indices for the low- and high-frequency groups were significantly different compared with the sham group. However, there was no significant difference between the low- and high-frequency groups. The results show that low- and high-frequency repetitive transcranial magnetic stimulation can similarly improve upper-limb motor function in patients with cerebral infarction.

Desensitizing Mitochondrial Permeability Transition by ERK-Cyclophilin D Axis Contributes to the Neuroprotective Effect of Gallic Acid against Cerebral Ischemia/Reperfusion Injury

PubMed Central

Sun, Jing; Ren, Da-Dui; Wan, Jin-Yi; Chen, Chen; Chen, Dong; Yang, Huan; Feng, Chun-Lai; Gao, Jing

2017-01-01

Ischemic stroke is a devastating disease with complex pathophysiology. Much evidence confirms that opening of the mitochondrial permeability transition pore (MPTP) is related with mitochondrial dysfunction to apoptosis in ischemic stroke, thus elucidating its signaling mechanism and screening novel MPTP inhibitor is therefore of paramount importance. Our earlier studies identified that gallic acid (GA), a naturally occurring plant phenol, endows with effect on inhibition of mitochondrial dysfunction, which has significant neuroprotective effect in cerebral ischemia/reperfusion injury. However, its molecular mechanisms regulating mitochondrial dysfunction remain elusive. Here, we uncover a role of GA in protecting mitochondria via MPTP inhibition. In addition to inhibit CypD binding to adenine nucleotide translocator, GA potentiates extracellular signal-regulated kinases (ERK) phosphorylation, leading to a decrease in cyclophilin D (CypD) expression, resulting in a desensitization to induction of MPTP, thus inhibiting caspase activation and ultimately giving rise to cellular survival. Our study firstly identifies ERK-CypD axis is one of the cornerstones of the cell death pathways following ischemic stroke, and confirms GA is a novel inhibitor of MPTP, which inhibits apoptosis depending on regulating the ERK-CypD axis. PMID:28428752

Acute high-altitude hypoxic brain injury: Identification of ten differential proteins

PubMed Central

Li, Jianyu; Qi, Yuting; Liu, Hui; Cui, Ying; Zhang, Li; Gong, Haiying; Li, Yaxiao; Li, Lingzhi; Zhang, Yongliang

2013-01-01

Hypobaric hypoxia can cause severe brain damage and mitochondrial dysfunction, and is involved in hypoxic brain injury. However, little is currently known about the mechanisms responsible for mitochondrial dysfunction in hypobaric hypoxic brain damage. In this study, a rat model of hypobaric hypoxic brain injury was established to investigate the molecular mechanisms associated with mitochondrial dysfunction. As revealed by two-dimensional electrophoresis analysis, 16, 21, and 36 differential protein spots in cerebral mitochondria were observed at 6, 12, and 24 hours post-hypobaric hypoxia, respectively. Furthermore, ten protein spots selected from each hypobaric hypoxia subgroup were similarly regulated and were identified by mass spectrometry. These detected proteins included dihydropyrimidinase-related protein 2, creatine kinase B-type, isovaleryl-CoA dehydrogenase, elongation factor Ts, ATP synthase beta-subunit, 3-mercaptopyruvate sulfurtransferase, electron transfer flavoprotein alpha-subunit, Chain A of 2-enoyl-CoA hydratase, NADH dehydrogenase iron-sulfur protein 8 and tropomyosin beta chain. These ten proteins are all involved in the electron transport chain and the function of ATP synthase. Our findings indicate that hypobaric hypoxia can induce the differential expression of several cerebral mitochondrial proteins, which are involved in the regulation of mitochondrial energy production. PMID:25206614

[Effect of Tongluo Xingnao effervescent tablets on learning and memory dysfunction in rats with chronic cerebral ischemia].

PubMed

Hu, Yong; Ju, Shao-Hua; Zhang, Yin-Jie; Xiong, Min; Xu, Shi-Jun; Ma, Yun-Tong; Zhong, Zhen-Dong

2014-05-01

To study the effect of Tongluo Xingnao effervescent tablets on learning and memory capacity and expression of Na(+)-K(+)-ATPase in hippocampus of rats with chronic cerebral ischemia-induced learning and memory dysfunction model. The 2-VO method was used to establish sd rat model learning and memory dysfunction induced by chronic cerebral ischemia. The 50 rats in the successfully established model were randomly divided into the model control group, the Dihydroergotoxine Mesylate tablets group (0.7 mg x kg(-1), Tongluo Xingnao effervescent tablets high dose (7.56 g x kg(-1)), middle dose (3.78 g x kg(-1)) and low dose (1.59 g x kg(-1)) groups and the sham operation group (n = 10) as the control group. The groups were orally given 10 ml x kg(-1) x d(-1) drugs for consecutively 90 days. On the 86th day, Morris water maze was adopted for them. On the 90th day, a leaning and memory capacity test was held. The brain tissues were fixed with 10% formaldehyde and observed for pathomorphism after routine slide preparation and staining. The expression of hippocampal Na(+)-K(+)-ATPase was detected with immunohistochemistry and image quantitative analysis. Compared with the model group, all of Tongluo Xingnao effervescent tablets groups showed significant decrease in the escape latency at the 5th day in the Morris water maze, and notable increase in the frequency of the first quadrant dwell, the frequency passing the escape platform and the frequency entering effective area (p < 0.05). According to the pathomorphological detection, the control group showed a significantly higher pathological score than the sham operation group (p < 0.01), the middle dose group showed a significantly lower pathological score than the model group (p < 0.05). According to the immunohistochemistical detection, the model control group showed a remarkably lower mean OD value of Na(+)-K(+)-ATPase than the sham operation group (p < 0.05), high and middle dose groups showed a significantly higher mean od value than the model control group (p < 0.01). Tongluo Xingnao effervescent tablets can improve the learning and memory capacity, reduce pathological changes of hippocampal tissues of rats with chronic cerebral ischemia-induced learning and memory dysfunction model, and promote the expression of Na(+)-K(+)-ATPase in hippocampus.

High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature.

PubMed

Li, Wei; Maloney, Ronald E; Aw, Tak Yee

2015-08-01

We previously demonstrated that in normal glucose (5mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG-occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG-occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature

PubMed Central

Li, Wei; Maloney, Ronald E.; Aw, Tak Yee

2015-01-01

We previously demonstrated that in normal glucose (5 mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6 h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG–occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG–occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. PMID:25867911

Feeding and gastrointestinal problems in children with cerebral palsy.

PubMed

Erkin, Gulten; Culha, Canan; Ozel, Sumru; Kirbiyik, Eylem Gulsen

2010-09-01

The aim of our study was to identify feeding and gastrointestinal system (GIS) problems in children with cerebral palsy (CP), and to evaluate the relationship between these problems and the severity of CP. A total of 120 children with CP were enrolled consecutively into the study (67 males, 53 females; mean age: 6.0±2.4 years; range: 2-12 years). The children were classified according to the Swedish classification as diplegic, hemiplegic, or quadriplegic. Severity of CP was classified based on the Gross Motor Function Classification System. The amount of time that the caregiver allocated to mealtimes, modifications of the food, as well as feeding and GIS problems was evaluated. Feeding dysfunction was classified as mild, moderate, or severe. Comparisons of GIS and feeding disorders and the severity of CP were carried out using χ test. The results indicated lack of appetite in 46 of the 120 children (38.3%), sialorrhea in 37 (30.8%), constipation in 30 (25%), difficulty in swallowing in 23 (19.2%), and feeding dysfunction in 26 (21.7%). On the basis of the Gross Motor Function Classification System (GMFCS), the incidence of GIS problems and feeding dysfunction was found to be significantly higher in the children classified in the severe group. The time taken to consume meals was significantly longer among children with feeding dysfunction. Feeding and GIS problems are frequent in children with CP, and more marked in those with severe CP. Approximately one fourth of children with CP suffer from feeding dysfunction, and more time has to be allocated to consume meals.

A prospective, longitudinal study of growth, nutrition and sedentary behaviour in young children with cerebral palsy.

PubMed

Bell, Kristie L; Boyd, Roslyn N; Tweedy, Sean M; Weir, Kelly A; Stevenson, Richard D; Davies, Peter S W

2010-04-06

Cerebral palsy is the most common cause of physical disability in childhood, occurring in one in 500 children. It is caused by a static brain lesion in the neonatal period leading to a range of activity limitations. Oral motor and swallowing dysfunction, poor nutritional status and poor growth are reported frequently in young children with cerebral palsy and may impact detrimentally on physical and cognitive development, health care utilisation, participation and quality of life in later childhood. The impact of modifiable factors (dietary intake and physical activity) on growth, nutritional status, and body composition (taking into account motor severity) in this population is poorly understood. This study aims to investigate the relationship between a range of factors - linear growth, body composition, oral motor and feeding dysfunction, dietary intake, and time spent sedentary (adjusting for motor severity) - and health outcomes, health care utilisation, participation and quality of life in young children with cerebral palsy (from corrected age of 18 months to 5 years). This prospective, longitudinal, population-based study aims to recruit a total of 240 young children with cerebral palsy born in Queensland, Australia between 1st September 2006 and 31st December 2009 (80 from each birth year). Data collection will occur at three time points for each child: 17 - 25 months corrected age, 36 +/- 1 months and 60 +/- 1 months. Outcomes to be assessed include linear growth, body weight, body composition, dietary intake, oral motor function and feeding ability, time spent sedentary, participation, medical resource use and quality of life. This protocol describes a study that will provide the first longitudinal description of the relationship between functional attainment and modifiable lifestyle factors (dietary intake and habitual time spent sedentary) and their impact on the growth, body composition and nutritional status of young children with cerebral palsy across all levels of functional ability.

Smooth muscle‐generated methylglyoxal impairs endothelial cell‐mediated vasodilatation of cerebral microvessels in type 1 diabetic rats

PubMed Central

Alomar, Fadhel; Singh, Jaipaul; Jang, Hee‐Seong; Rozanzki, George J; Shao, Chun Hong; Padanilam, Babu J; Mayhan, William G

2016-01-01

Background and Purpose Endothelial cell‐mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia‐reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs). Experimental Approach Endothelial cell‐mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia‐reperfusion injury were assessed in brains of male Sprague‐Dawley rats with streptozotocin‐induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal‐degrading enzyme glyoxalase‐I (Glo‐I) in cSMCs. Key Results After 7–8 weeks of T1D, endothelial cell‐mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF‐κB activity and TNF‐α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid‐cerebral artery exacerbated ischaemia‐reperfusion injury. In cSMCs, Glo‐I protein was decreased, and the methylglyoxal‐synthesizing enzyme, vascular adhesion protein 1 (VAP‐1) and methylglyoxal were increased. Restoring Glo‐I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP‐1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia‐reperfusion injury and increased microvessel perfusion. Conclusions and Implications Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia‐reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D. PMID:27611446

Similar cerebral protective effectiveness of antegrade and retrograde cerebral perfusion during deep hypothermic circulatory arrest in aortic surgery: a meta-analysis of 7023 patients.

PubMed

Guo, Shasha; Sun, Yanhua; Ji, Bingyang; Liu, Jinping; Wang, Guyan; Zheng, Zhe

2015-04-01

In aortic arch surgery, deep hypothermic circulatory arrest (DHCA) combined with cerebral perfusion is employed worldwide as a routine practice. Even though antegrade cerebral perfusion (ACP) is more widely used than retrograde cerebral perfusion (RCP), the difference in benefit and risk between ACP and RCP during DHCA is uncertain. The purpose of this meta-analysis is to compare neurologic outcomes and early mortality between ACP and RCP in patients who underwent aortic surgery during DHCA. PubMed, EMBASE, and the Cochrane Library were searched using the key words "antegrade," "retrograde," "cerebral perfusion," "cardiopulmonary bypass," "extracorporeal circulation," and "cardiac surgery" for studies reporting on clinical endpoints including early mortality, stroke, temporary neurologic dysfunction (TND), and permanent neurologic dysfunction (PND) in aortic surgery requiring DHCA with ACP or RCP. Heterogeneity was analyzed with the Cochrane Q statistic and I(2) statistic. Publication bias was tested with Begg's funnel plot and Egger's test. Thirty-four studies were included in this meta-analysis, with 4262 patients undergoing DHCA + ACP and 2761 undergoing DHCA + RCP. The overall pooled relative risk for TND was 0.722 (95% CI = [0.579, 0.900]), and the z-score for overall effect was 2.9 (P = 0.004). There was low heterogeneity (I(2) = 18.7%). The analysis showed that patients undergoing DHCA + ACP had better outcomes than those undergoing DHCA + RCP in terms of TND, while there were no significant differences between groups in terms of PND, stroke, and early mortality. This meta-analysis indicates that DHCA + ACP has an advantage over DHCA + RCP in terms of TND, while the two methods show similar results in terms of PND, early mortality, and stroke. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

A prospective, longitudinal study of growth, nutrition and sedentary behaviour in young children with cerebral palsy

PubMed Central

2010-01-01

Background Cerebral palsy is the most common cause of physical disability in childhood, occurring in one in 500 children. It is caused by a static brain lesion in the neonatal period leading to a range of activity limitations. Oral motor and swallowing dysfunction, poor nutritional status and poor growth are reported frequently in young children with cerebral palsy and may impact detrimentally on physical and cognitive development, health care utilisation, participation and quality of life in later childhood. The impact of modifiable factors (dietary intake and physical activity) on growth, nutritional status, and body composition (taking into account motor severity) in this population is poorly understood. This study aims to investigate the relationship between a range of factors - linear growth, body composition, oral motor and feeding dysfunction, dietary intake, and time spent sedentary (adjusting for motor severity) - and health outcomes, health care utilisation, participation and quality of life in young children with cerebral palsy (from corrected age of 18 months to 5 years). Design/Methods This prospective, longitudinal, population-based study aims to recruit a total of 240 young children with cerebral palsy born in Queensland, Australia between 1st September 2006 and 31st December 2009 (80 from each birth year). Data collection will occur at three time points for each child: 17 - 25 months corrected age, 36 ± 1 months and 60 ± 1 months. Outcomes to be assessed include linear growth, body weight, body composition, dietary intake, oral motor function and feeding ability, time spent sedentary, participation, medical resource use and quality of life. Discussion This protocol describes a study that will provide the first longitudinal description of the relationship between functional attainment and modifiable lifestyle factors (dietary intake and habitual time spent sedentary) and their impact on the growth, body composition and nutritional status of young children with cerebral palsy across all levels of functional ability. PMID:20370929

Brain 18F-FDG PET Metabolic Abnormalities in Patients with Long-Lasting Macrophagic Myofascitis.

PubMed

Van Der Gucht, Axel; Aoun Sebaiti, Mehdi; Guedj, Eric; Aouizerate, Jessie; Yara, Sabrina; Gherardi, Romain K; Evangelista, Eva; Chalaye, Julia; Cottereau, Anne-Ségolène; Verger, Antoine; Bachoud-Levi, Anne-Catherine; Abulizi, Mukedaisi; Itti, Emmanuel; Authier, François-Jérôme

2017-03-01

The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with 18 F-FDG. Methods: 18 F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean ± SD], 45.9 ± 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all 18 F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 ± 16 y; P = 0.87) and sex (73% women; P = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment ( n = 42), those with frontal subcortical (FSC) dysfunction ( n = 29), those with Papez circuit dysfunction ( n = 22), and those with callosal disconnection ( n = 7). Results: In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism ( P < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Conclusion: Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Increasing proportions of tyrosine hydroxylase-immunoreactive interneurons colocalize with choline acetyltransferase or vasoactive intestinal peptide in the developing rat cerebral cortex

PubMed Central

Asmus, Stephen E.; Cocanougher, Benjamin T.; Allen, Donald L.; Boone, John B.; Brooks, Elizabeth A.; Hawkins, Sarah M.; Hench, Laura A.; Ijaz, Talha; Mayfield, Meredith N.

2011-01-01

Cortical interneurons are critical for information processing, and their dysfunction has been implicated in neurological disorders. One subset of this diverse cell population expresses tyrosine hydroxylase (TH) during postnatal rat development. Cortical TH-immunoreactive neurons appear at postnatal day (P) 16. The number of TH cells sharply increases between P16 and P20 and subsequently decreases to adult values. The absence of apoptotic markers in these cells suggests that the reduction in cell number is not due to cell death but is due to a decline in TH production. Cortical TH cells lack all additional catecholaminergic enzymes, and many coexpress GABA and calretinin, but little else is known about their phenotype or function. Because interneurons containing choline acetyltransferase (ChAT) or vasoactive intestinal peptide (VIP) share characteristics with cortical TH neurons, the coexpression of TH with ChAT or VIP was examined throughout the neocortex at P16, P20, and P30. The proportions of TH cell profiles double-labeled for ChAT or VIP significantly increased between P16 and P30. Based on their proximity to blood vessels, intrinsic cholinergic and VIPergic cells have been hypothesized to regulate cortical microcirculation. Labeling with the gliovascular marker aquaporin-4 revealed that at least half of the TH cells were apposed to microvessels at these ages, and many of these cells contained ChAT or VIP. Cortical TH neurons did not coproduce nitric oxide synthase. These results suggest that increasing proportions of cortical TH neurons express ChAT or VIP developmentally and that a subset of these TH neurons may regulate local blood flow. PMID:21295554

Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy

PubMed Central

Reijmer, Yael D.; Fotiadis, Panagiotis; Martinez-Ramirez, Sergi; Salat, David H.; Schultz, Aaron; Shoamanesh, Ashkan; Ayres, Alison M.; Vashkevich, Anastasia; Rosas, Diana; Schwab, Kristin; Leemans, Alexander; Biessels, Geert-Jan; Rosand, Jonathan; Johnson, Keith A.; Viswanathan, Anand; Gurol, M. Edip

2015-01-01

Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = −0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression. PMID:25367025

Hepatic encephalopathy in acute-on-chronic liver failure.

PubMed

Lee, Guan-Huei

2015-10-01

The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.

Cerebral vasomotor reactivity in neurodegenerative diseases.

PubMed

Smoliński, Łukasz; Członkowska, Anna

Small-caliber cerebral vessels change their diameters in response to alterations of key metabolite concentrations such as carbon dioxide or oxygen. This phenomenon, termed the cerebral vasomotor reactivity (CVMR), is the basis for blood flow regulation in the brain in accordance with its metabolic status. Typically, CVMR is determined as the amount of change in cerebral blood flow in response to a vasodilating stimulus, which can be measured by various neuroimaging methods or by transcranial Doppler. It has been shown that CVMR is impaired in cerebrovascular diseases, but there is also evidence of a similar dysfunction in neurodegenerative disorders. Here, we review studies that have investigated CVMR in the common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. Moreover, we discuss potential neurodegenerative mechanisms responsible for the impairment of CVMR. Copyright © 2016 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Biological substrates of schizophrenia.

PubMed

Kovelman, J A; Scheibel, A B

1986-01-01

Schizophrenia is increasingly believed to represent a group of organic disorders which primarily, although not exclusively, affect the central nervous system. Our purpose is to review a representative sample of twentieth-century literature which speaks to the biological substrates of the syndrome. Subjects reviewed include genetic and environmental contributions to the onset of illness, early and recent findings of gross structural anomalies, and apparent histopathological alterations in cerebral cortex, cerebellar vermis, limbic system, and brain stem, as well as problems of cerebral asymmetry. Data from a diverse group of electrophysiological studies reveal several promising correlates of these areas of investigation. Despite the inconsistent nature of the findings to date, several themes have begun to emerge, including patterns of hypofrontal/hyperparietal regional cerebral flow and glucose utilization, left hemispheric dysfunction, and deficits of interhemispheric information processing. The interpretation and significance of these emerging patterns remains unclear and must await more profound insights into the nature of normal and abnormal cerebral function.

Preterm Birth: Transition to Adulthood

ERIC Educational Resources Information Center

Allen, Marilee C.; Cristofalo, Elizabeth; Kim, Christina

2010-01-01

Preterm birth is associated with greater difficulty with transitions from childhood to adolescence to adulthood. Adolescents and young adults born preterm have higher rates of cerebral palsy, intellectual disability, cognitive impairment, learning disability, executive dysfunction, attention deficit disorder, and social-emotional difficulties than…

Learning Disabilities

ERIC Educational Resources Information Center

Myklebust, Helmer R.

1976-01-01

Minimal cerebral dysfunctions are noted as primary cause for learning disability in children. Although children have normal capacities for learning, it is stated that their cognitive processes have been altered and special instructional techniques and procedures are needed. The various types of learning disabilities are discussed. (EB)

Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular, Histopathological, and Behavioral Outcomes in Rats

PubMed Central

Zeng, Yaping; Deyo, Donald; Parsley, Margaret A.; Hawkins, Bridget E.; Prough, Donald S.; DeWitt, Douglas S.

2018-01-01

Abstract To determine the effects of mild blast-induced traumatic brain injury (bTBI), several groups of rats were subjected to blast injury or sham injury in a compressed air-driven shock tube. The effects of bTBI on relative cerebral perfusion (laser Doppler flowmetry [LDF]), and mean arterial blood pressure (MAP) cerebral vascular resistance were measured for 2 h post-bTBI. Dilator responses to reduced intravascular pressure were measured in isolated middle cerebral arterial (MCA) segments, ex vivo, 30 and 60 min post-bTBI. Neuronal injury was assessed (Fluoro-Jade C [FJC]) 24 and 48 h post-bTBI. Neurological outcomes (beam balance and walking tests) and working memory (Morris water maze [MWM]) were assessed 2 weeks post-bTBI. Because impact TBI (i.e., non-blast TBI) is often associated with reduced cerebral perfusion and impaired cerebrovascular function in part because of the generation of reactive oxygen and nitrogen species such as peroxynitrite (ONOO−), the effects of the administration of the ONOO− scavenger, penicillamine methyl ester (PenME), on cerebral perfusion and cerebral vascular resistance were measured for 2 h post-bTBI. Mild bTBI resulted in reduced relative cerebral perfusion and MCA dilator responses to reduced intravascular pressure, increases in cerebral vascular resistance and in the numbers of FJC-positive cells in the brain, and significantly impaired working memory. PenME administration resulted in significant reductions in cerebral vascular resistance and a trend toward increased cerebral perfusion, suggesting that ONOO− may contribute to blast-induced cerebral vascular dysfunction. PMID:29160141

Neuroprotection of Osthole against Cerebral Ischemia/Reperfusion Injury through an Anti-apoptotic Pathway in Rats.

PubMed

Li, Kang; Ding, Dun; Zhang, Ming

2016-01-01

Cerebral ischemia/reperfusion (I/R) injury is a major cause of acute brain injury. The pathogenetic mechanisms underlying I/R injury involve apoptosis, inflammation and oxidative stress. Osthole-a plant coumarin compound-has been reported to protect against focal cerebral I/R-induced injury in rats. However, the mechanism remains unknown. Here we hypothesize that osthole acts through inhibition of apoptosis during focal cerebral I/R injury in rats. We induced cerebral I/R injury by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. We randomly assigned 60 rats to three groups (20 rats per group): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intraperitoneally with osthole (40 mg/kg) or vehicle 30 min before cerebral ischemia. We harvested the brains for infarct volume, brain water content, histological changes and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining as well as cleaved caspase-3, bax, and bcl-2 levels 24 h after reperfusion. Osthole treatment significantly attenuated cerebral dysfunction and histologic damage induced by I/R injury. Moreover, osthole-treated rats had a dramatic decrease in apoptotic neuronal cells along with a decrease in bax and cleaved caspase-3. The bcl-2 levels increased. Osthole treatment protects the brain from cerebral I/R injury by suppressing cell apoptosis. Thus, osthole may represent a novel practical strategy to prevent cerebral I/R injury.

Klotho upregulation contributes to the neuroprotection of ligustilide against cerebral ischemic injury in mice.

PubMed

Long, Fang-Yi; Shi, Meng-Qi; Zhou, Hong-Jing; Liu, Dong-Ling; Sang, Na; Du, Jun-Rong

2018-02-05

Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor. Our previous studies showed that ligustilide minimizes the cognitive dysfunction and brain damage induced by cerebral ischemia; however, the underlying mechanisms remain unclear. This study aims to investigate whether klotho is involved in the protective effects of ligustilide against cerebral ischemic injury in mice. Cerebral ischemia was induced by bilateral common carotid arterial occlusion. Neurobehavioral tests as well as Nissl and Fluoro-Jade B staining were used to evaluate the protective effects of ligustilide in cerebral ischemia, and Western blotting and ELISA approaches were used to investigate the underlying mechanisms. Administration of ligustilide prevented the development of neurological deficits and reduced neuronal loss in the hippocampal CA1 region and the caudate putamen after cerebral ischemia. The protective effects were associated with inhibition of the RIG-I/NF-κB p65 and Akt/FoxO1 pathways and with prevention of inflammation and oxidative stress in the brain. Further, downregulation of klotho could attenuate the neuroprotection of ligustilide against cerebral ischemic injury. Ligustilide exerted neuroprotective effects in mice after cerebral ischemia by regulating anti-inflammatory and anti-oxidant signaling pathways. Furthermore, klotho upregulation contributes to the neuroprotection of LIG against cerebral ischemic injury. These results indicated that ligustilide may be a promising therapeutic agent for the treatment of cerebral ischemia. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells.

PubMed

Kokubu, Yasuhiro; Yamaguchi, Tomoko; Kawabata, Kenji

2017-04-29

Brain-derived microvascular endothelial cells (BMECs), which play a central role in blood brain barrier (BBB), can be used for the evaluation of drug transport into the brain. Although human BMEC cell lines have already been reported, they lack original properties such as barrier integrity. Pluripotent stem cells (PSCs) can be used for various applications such as regenerative therapy, drug screening, and pathological study. In the recent study, an induction method of BMECs from PSCs has been established, making it possible to more precisely study the in vitro human BBB function. Here, using induced pluripotent stem (iPS) cell-derived BMECs, we examined the effects of oxygen-glucose deprivation (OGD) and OGD/reoxygenation (OGD/R) on BBB permeability. OGD disrupted the barrier function, and the dysfunction was rapidly restored by re-supply of the oxygen and glucose. Interestingly, TNF-α, which is known to be secreted from astrocytes and microglia in the cerebral ischemia, prevented the restoration of OGD-induced barrier dysfunction in an apoptosis-independent manner. Thus, we could establish the in vitro BBB disease model that mimics the cerebral ischemia by using iPS cell-derived BMECs. Copyright © 2017 Elsevier Inc. All rights reserved.

Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein.

PubMed

Yang, Rui-Xin; Lei, Jie; Wang, Bo-Dong; Feng, Da-Yun; Huang, Lu; Li, Yu-Qian; Li, Tao; Zhu, Gang; Li, Chen; Lu, Fang-Fang; Nie, Tie-Jian; Gao, Guo-Dong; Gao, Li

2017-01-01

Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro . SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein

PubMed Central

Yang, Rui-Xin; Lei, Jie; Wang, Bo-Dong; Feng, Da-Yun; Huang, Lu; Li, Yu-Qian; Li, Tao; Zhu, Gang; Li, Chen; Lu, Fang-Fang; Nie, Tie-Jian; Gao, Guo-Dong; Gao, Li

2017-01-01

Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro. SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke. PMID:28649223

Melatonin Ameliorates Injury and Specific Responses of Ischemic Striatal Neurons in Rats

PubMed Central

Ma, Yuxin; Feng, Qiqi; Ma, Jing; Feng, Zhibo; Zhan, Mali; OuYang, Lisi; Mu, Shuhua; Liu, Bingbing; Jiang, Zhuyi; Jia, Yu; Li, Youlan

2013-01-01

Studies have confirmed that middle cerebral artery occlusion (MCAO) causes striatal injury in which oxidative stress is involved in the pathological mechanism. Increasing evidence suggests that melatonin may have a neuroprotective effect on cerebral ischemic damage. This study aimed to examine the morphological changes of different striatal neuron types and the effect of melatonin on striatal injury by MCAO. The results showed that MCAO induced striatum-related dysfunctions of locomotion, coordination, and cognition, which were remarkably relieved with melatonin treatment. MCAO induced severe striatal neuronal apoptosis and loss, which was significantly decreased with melatonin treatment. Within the outer zone of the infarct, the number of Darpp-32+ projection neurons and the densities of dopamine-receptor-1 (D1)+ and dopamine-receptor-2 (D2)+ fibers were reduced; however, both parvalbumin (Parv)+ and choline acetyltransferase (ChAT)+ interneurons were not significantly decreased in number, and neuropeptide Y (NPY)+ and calretinin (Cr)+ interneurons were even increased. With melatonin treatment, the loss of projection neurons and characteristic responses of interneurons were notably attenuated. The present study demonstrates that the projection neurons are rather vulnerable to ischemic damage, whereas the interneurons display resistance and even hyperplasia against injury. In addition, melatonin alleviates striatal dysfunction, neuronal loss, and morphological transformation of interneurons resulting from cerebral ischemia. PMID:23686363

Intranasal insulin treatment of an experimental model of moderate traumatic brain injury.

PubMed

Brabazon, Fiona; Wilson, Colin M; Jaiswal, Shalini; Reed, John; Frey, William H; Byrnes, Kimberly R

2017-09-01

Traumatic brain injury (TBI) results in learning and memory dysfunction. Cognitive deficits result from cellular and metabolic dysfunction after injury, including decreased cerebral glucose uptake and inflammation. This study assessed the ability of intranasal insulin to increase cerebral glucose uptake after injury, reduce lesion volume, improve memory and learning function and reduce inflammation. Adult male rats received a controlled cortical impact (CCI) injury followed by intranasal insulin or saline treatment daily for 14 days. PET imaging of [18F]-FDG uptake was performed at baseline and at 48 h and 10 days post-injury and MRI on days three and nine post injury. Motor function was tested with the beam walking test. Memory function was assessed with Morris water maze. Intranasal insulin after CCI significantly improved several outcomes compared to saline. Insulin-treated animals performed better on beam walk and demonstrated significantly improved memory. A significant increase in [18F]-FDG uptake was observed in the hippocampus. Intranasal insulin also resulted in a significant decrease in hippocampus lesion volume and significantly less microglial immunolabeling in the hippocampus. These data show that intranasal insulin improves memory, increases cerebral glucose uptake and decreases neuroinflammation and hippocampal lesion volume, and may therefore be a viable therapy for TBI.

Gastrointestinal Disorders in Children with Neurodevelopmental Disabilities

ERIC Educational Resources Information Center

Sullivan, Peter B.

2008-01-01

Children with neurodevelopmental disabilities such as cerebral palsy (CP), spina bifida, or inborn errors of metabolism frequently have associated gastrointestinal problems. These include oral motor dysfunction leading to feeding difficulties, risk of aspiration, prolonged feeding times, and malnutrition with its attendant physical compromise.…

Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders.

PubMed

Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E

2017-03-01

Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer's disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of neurovascular function. Published by Elsevier B.V.

Electrophysiology and functional MRI in post-acute mild traumatic brain injury.

PubMed

Gosselin, Nadia; Bottari, Carolina; Chen, Jen-Kai; Petrides, Michael; Tinawi, Simon; de Guise, Elaine; Ptito, Alain

2011-03-01

Symptoms persisting beyond the acute phase (>2 months) after a mild traumatic brain injury (MTBI) are often reported, but their origin remains controversial. Some investigators evoke dysfunctional cerebral mechanisms, while others ascribe them to the psychological consequences of the injury. We address this controversy by exploring possible cerebral dysfunction with functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) in a group of patients during the post-acute phase. Fourteen MTBI symptomatic patients (5.7±2.9 months post-injury) were tested with fMRI and ERP using a visual externally ordered working memory task, and were compared with 23 control subjects. Attenuated blood oxygen level dependent (BOLD) signal changes in the left and right mid-dorsolateral prefrontal cortex (mid-DLPFC), the putamen, the body of the caudate nucleus, and the right thalamus were found in the MTBI group compared with the control group. Moreover, symptom severity and BOLD signal changes were correlated: patients with more severe symptoms had lower BOLD signal changes in the right mid-DLPFC. For ERP, a group×task interaction was observed for N350 amplitude. A larger amplitude for the working memory task than for the control task was found in control subjects, but not in MTBI subjects, who had weak amplitudes for both tasks. This study confirms that persistent symptoms after MTBI cannot be uniquely explained by psychological factors, such as depression and/or malingering, and indicates that they can be associated with cerebral dysfunction. ERP reveals decreased amplitude of the N350 component, while fMRI demonstrates that the more severe the symptoms, the lower the BOLD signal changes in the mid-DLPFC.

TREATMENT OF THE SPASTICITY IN CHILDREN WITH CEREBRAL PALSY

PubMed Central

Meholjić-Fetahović, Ajša

2007-01-01

Botulinum toxin is a natural purified protein and one of the strongest biological poisons - neurotoxin. It is produced by the bacterium Clostridium botulinum. Its medical usage started in USA in 1981 and in Europe in 1992. There are seven different immune types of the toxin: A, B, C1, D, E, F and G. Toxin types A and B are used to decrease muscular spasticity. Botulinum toxin prevents the formation of acetylcholine from cholinergic nerve tissues in muscles, which in the end irreversibly destroys neuromuscular synapses. It is called temporary local chemodenervation. It does not affect the synthesis of acetylcholine. As it affects neuromuscular bond it also affects one of the symptoms of cerebral palsy - spasticity Decreasing the spasticity of children with cerebral palsy leads to the improvement of conscious movements, muscles are less toned, passive mobility is improved, orthosis tolerance is also improved, and the child is enabled to perform easier and better motor functions such as crawling, standing and walking. Since the action of Botulinum toxin is limited to 2-6 months, new neural collaterals are formed and neuromuscular conductivity is reestablished which in the end once again develops a muscular spasm. This leads to a conclusion that botulinum toxin should again be applied into spastic muscles. It is very important for good effect of Botulinum toxin to set the goals of the therapy in advance. The goals include improvement of a function, prevention of contractions and deformities, ease of care and decrease of pain for children with cerebral palsy. After application of botulinum toxin, it is necessary to perform adequate and intensive physical treatment with regular monitoring of effects. This work shows a case of a boy with spastic form of cerebral palsy. After being habilitated using Vojta therapy and Bobath concept and the conduct of certain physical procedures, botulinum toxin is administered into his lower limbs’ muscles and kinezitherapy intensified. After the administration of botulinum toxin significant functional improvement is noted. PMID:18039197

Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging

PubMed Central

Bentley, Paul; Driver, Jon; Dolan, Raymond J.

2011-01-01

Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing ‘effort’-associated activations in prefrontal regions; and deactivation of a ‘resting-state network’ in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an ‘inverted-U shaped’ pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications. PMID:21708219

Chronic treatment of DA-8159, a new phosphodiesterase type V inhibitor, attenuates endothelial dysfunction in stroke-prone spontaneously hypertensive rat.

PubMed

Choi, Seul Min; Kim, Jee Eun; Kang, Kyung Koo

2006-02-09

This study examined the effects of chronic treatment of a new phosphodiesterase type 5 inhibitor, DA-8159, on endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHR-SP). Six-week-old male SHR-SP were divided into 4 groups; vehicle control, DA-8159 1, 3, and 10 mg/kg/day. During a 32-week experimental period, the animals were administered DA-8159 orally and fed a 4% NaCl-loaded diet. The systolic blood pressure was measured every two weeks throughout the experimental period using the tail-cuff method. At the end of experiments, the vascular function (acetylcholine-induced vasodilation) in the endothelium-intact aortic rings was investigated. In addition, the mortality, the left ventricular hypertrophy index, the plasma parameters and the incidence of a cerebral infarction were assessed. In the DA-8159 treated-rats, the vascular reactivity improved significantly in a dose-dependent manner. Although DA-8159 did not alter the elevation of the systolic blood pressure directly, the 3 and 10 mg/kg/day DA-8159 treatment delayed the early death caused by stroke. DA-8159 significantly reduced the left ventricular heart weight/body weight ratio compared with the vehicle control group. Furthermore, the DA-8159 treatment significantly increased the plasma nitric oxide, cGMP, and the total antioxidative status. The DA-8159 treatment also reduced the occurrence of stroke-associated cerebral damage. These results indicate that DA-8159 can ameliorate an endothelial dysfunction-related vascular injury. Therefore, pharmacological intervention aimed at attenuating an endothelial dysfunction is important and might be useful in both preventing and treating endothelial dysfunction-related complications.

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice.

PubMed

Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra; Liu, Jiahui; Pike, Christian J; Smith, Conor; LaDu, Mary Jo; Sullivan, Patrick M; Morgan, Todd E; Dolzhenko, Egor; Charidimou, Andreas; Wahlund, Lars-Olof; Wiberg, Maria Kristofferson; Shams, Sara; Chiang, Gloria Chia-Yi; Finch, Caleb E

2016-01-01

The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition. Copyright © 2016 Elsevier Inc. All rights reserved.

Cerebral Vascular Injury in Traumatic Brain Injury.

PubMed

Kenney, Kimbra; Amyot, Franck; Haber, Margalit; Pronger, Angela; Bogoslovsky, Tanya; Moore, Carol; Diaz-Arrastia, Ramon

2016-01-01

Traumatic cerebral vascular injury (TCVI) is a very frequent, if not universal, feature after traumatic brain injury (TBI). It is likely responsible, at least in part, for functional deficits and TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive cerebral microvascular injury in humans and experimental animal, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI, and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences (MRI-ASL), Transcranial Doppler (TCD), and Near InfraRed Spectroscopy (NIRS). Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for the development of novel therapies for TBI. Published by Elsevier Inc.

Brain endothelial dysfunction in cerebral adrenoleukodystrophy.

PubMed

Musolino, Patricia L; Gong, Yi; Snyder, Juliet M T; Jimenez, Sandra; Lok, Josephine; Lo, Eng H; Moser, Ann B; Grabowski, Eric F; Frosch, Matthew P; Eichler, Florian S

2015-11-01

See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

Li, Qiang; Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011; Zhang, Ting

Highlights: • Rapamycin enhances mitophagy via increasing p62 translocation to the mitochondria. • Rapamycin attenuates brain ischemic damage and improves mitochondrial function. • The protection of rapamycin to mitochondrial is linked to enhanced mitophagy. - Abstract: Rapamycin has been demonstrated to exhibit neuroprotective functions via the activation of autophagy in a cerebral ischemia model. However, the involvement of mitophagy in this process and its contribution to the protection of mitochondrial function remains unknown. The present study explored the characteristics of mitophagy after cerebral ischemia and the effect of rapamycin on mitochondrial function. Male Sprague–Dawley rats underwent transient middle cerebral arterymore » occlusion (tMCAO). Neurological deficits scores; infarct volumes; mitophagy morphology; and the levels of malondialdehyde (MDA), adenosine triphosphate (ATP) and mitochondrial membrane potentials (Δψm) were examined. The expression of LC3, Beclin-1 and p62 in the mitochondrial fraction combined with transmission electronic microscopy were used to explore mitophagic activity after ischemia. We also blocked autophagosome formation using 3-methyladenine (3-MA) to check the linkage between the mitochondrial protective effect of rapamycin and enhanced mitophagy. We observed that rapamycin significantly enhanced mitophagy, as evidenced by the increase in LC3-II and Beclin-1 expression in the mitochondria and p62 translocation to the mitochondria. Rapamycin reduced infarct volume, improved neurological outcomes and inhibited mitochondrial dysfunction compared with the control animals (p < 0.05). However, these protective effects were reversed by 3-methyladenine treatment after rapamycin. The present study indicates that rapamycin treatment attenuates mitochondrial dysfunction following cerebral ischemia, which is linked to enhanced mitophagy.« less

Neuropsychological Disorders in Children: Effects of Medication on Learning and Behavior in Hyperactivity.

ERIC Educational Resources Information Center

Hartlage, Lawrence C.; Telzrow, Cathy Fultz

1982-01-01

Hyperactivity is defined, and the relationships among minimal brain dysfunction, cerebral stimulants, and student characteristics such as activity level, attention and learning, and behavior are discussed. Hyperactive children's responses to the use of Ritalin and methylphenidate are reported. (CJ)

A SELECTIVE BIBLIOGRAPHY ON BRAIN-DAMAGED CHILDREN.

ERIC Educational Resources Information Center

Woods School for Exceptional Children, Langhorne, PA.

THIS SELECTIVE BIBLIOGRAPHY INCLUDES 317 ANNOTATED REFERENCES DEALING DIRECTLY WITH THE BEHAVIORAL CHARCTERISTICS OF CHILDREN WITH CEREBRAL DYSFUNCTION. REFERENCES HAVE APPEARED IN JOURNALS OR OTHER SOURCES AVAILABLE IN UNIVERSITY LIBRARIES. THE BIBLIOGRAPHY IS CLASSIFIED INTO SIX MAJOR DIVISIONS--(1) THE ENTITY AND ITS DESCRIPTION, (2) CLINICAL…

Manic Depressive Disorder in Mental Handicap.

ERIC Educational Resources Information Center

Berney, T. P.; Jones, P. M.

1988-01-01

Eight cases of early onset bipolar affective disorder in adolescents with mental impairment are described, focusing on age of onset; common characteristics such as rapid cycling, mixed affective states, and lithium resistance; and the likelihood that cerebral dysfunction might cause a secondary form of bipolar disorder. (JDD)

In vivo optical activation of astrocytes as a potential therapeutic strategy for neurodegenerative diseases

NASA Astrophysics Data System (ADS)

Chen, Yuanxin; Mancuso, James; Zhao, Zhen; Li, Xuping; Xue, Zhong; Wong, Stephen T. C.

2013-03-01

Neurovascular dysfunction in many neurodegenerative diseases, such as Alzheimer's disease (AD), reduces blood flow to affected brain areas and causes neuronal dysfunction and loss. A new optical imaging technique is developed to activate astrocytes in live animal models in order to investigate the increase of local cerebral blood flow as a potential therapeutic strategy for AD. The technique uses fluorescent labeling of vasculature and astrocytes coupled with intravital 2-photon microscopy to visualize the astrocyte-vasculature interactions in live animals. Using femtosecond laser stimulation, calcium uncaging is applied to specifically target and activate astrocytes in vivo with high spatial and temporal resolutions. Intravital 2-photon microscopy imaging was employed to demonstrate that single endfoot optical activation around an arteriole induced a 25% increase in arteriole diameter, which in turn increased cerebral local blood flow in down-stream capillaries. This quantitative result indicates the potential of using optical activation of astrocytes in afflicted brain areas of neurodegeneration to restore normal neurovascular functions.

Magnetic Resonance Spectroscopy: An In Vivo Molecular Imaging Biomarker for Parkinson's Disease?

PubMed Central

Ciurleo, Rosella; Di Lorenzo, Giuseppe; Marino, Silvia

2014-01-01

Parkinson's disease (PD) is a neurodegenerative disorder caused by selective loss of dopaminergic neurons in the substantia nigra pars compacta which leads to dysfunction of cerebral pathways critical for the control of movements. The diagnosis of PD is based on motor symptoms, such as bradykinesia, akinesia, muscular rigidity, postural instability, and resting tremor, which are evident only after the degeneration of a significant number of dopaminergic neurons. Currently, a marker for early diagnosis of PD is still not available. Consequently, also the development of disease-modifying therapies is a challenge. Magnetic resonance spectroscopy is a quantitative imaging technique that allows in vivo measurement of certain neurometabolites and may produce biomarkers that reflect metabolic dysfunctions and irreversible neuronal damage. This review summarizes the abnormalities of cerebral metabolites found in MRS studies performed in patients with PD and other forms of parkinsonism. In addition, we discuss the potential role of MRS as in vivo molecular imaging biomarker for early diagnosis of PD and for monitoring the efficacy of therapeutic interventions. PMID:25302300

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats

PubMed Central

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Kallás, Esper Georges; Irigoyen, Maria Cláudia

2016-01-01

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg−1·day−1) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups—denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups—were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3+ cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4+CD25+FOXP3+), and a less extreme decrease in conventional T cells (CD25+FOXP3−) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. PMID:26791829

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats.

PubMed

Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Lacchini, Silvia; Kallás, Esper Georges; Irigoyen, Maria Cláudia; Consolim-Colombo, Fernanda M

2016-04-15

We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. Copyright © 2016 the American Physiological Society.

Cholinergic dysfunctions and enhanced oxidative stress in the neurobehavioral toxicity of lambda-cyhalothrin in developing rats.

PubMed

Ansari, Reyaz W; Shukla, Rajendra K; Yadav, Rajesh S; Seth, Kavita; Pant, Aditya B; Singh, Dhirendra; Agrawal, Ashok K; Islam, Fakhrul; Khanna, Vinay K

2012-11-01

This study is focused on understanding the mechanism of neurobehavioral toxicity of lambda-cyhalothrin, a new generation type II synthetic pyrethroid in developing rats following their exposure from post-lactational day (PLD)22 to PLD49 and investigate whether neurobehavioral alterations are transient or persistent. Post-lactational exposure to lambda-cyhalothrin (1.0 or 3.0 mg/kg body weight, p.o.) affected grip strength and learning activity in rats on PLD50 and the persistent impairment of grip strength and learning was observed at 15 days after withdrawal of exposure on PLD65. A decrease in the binding of muscarinic-cholinergic receptors in frontocortical, hippocampal, and cerebellar membranes associated with decreased expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in hippocampus was observed following exposure to lambda-cyhalothrin on PLD50 and PLD65. Exposure to lambda-cyhalothrin was also found to increase the expression of growth-associated protein-43 in hippocampus of rats on PLD50 and PLD65 as compared to controls. A significant increase in lipid peroxidation and protein carbonyl levels and decreased levels of reduced glutathione and activity of superoxide dismutase, catalase, and glutathione peroxidase in brain regions of lambda-cyhalothrin exposed rats were distinctly observed indicating increased oxidative stress. Inhibition of ChAT and AChE activity may cause down-regulation of muscarinic-cholinergic receptors consequently impairing learning activity in developing rats exposed to lambda-cyhalothrin. The data further indicate that long-term exposure to lambda-cyhalothrin at low doses may be detrimental and changes in selected behavioral and neurochemical end points may persist if exposure to lambda-cyhalothrin continues.

Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: possible involvement of glutamatergic and cholinergic systems.

PubMed

Le, Xoan Thi; Pham, Hang Thi Nguyet; Do, Phuong Thi; Fujiwara, Hironori; Tanaka, Ken; Li, Feng; Van Nguyen, Tai; Nguyen, Khoi Minh; Matsumoto, Kinzo

2013-10-01

This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.

Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment.

PubMed

Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe; Bastlund, Jesper Frank

2014-01-01

P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

Role of sensory C fibers in hypoxia/ reoxygenation-impaired myogenic constriction of cerebral arteries

PubMed Central

Xie, Hui; Ray, Patricio E.; Short, Billie Lou

2009-01-01

Objective Hypoxia/reoxygenation (H/R) associated with extracorporeal membrane oxygenation disrupts cerebral autoregulation. However, the underlying mechanisms remain poorly understood. The present study was designed to investigate the role of sensory C-fibers in myogenic responsiveness of cerebral arteries. Methods Arterial diameter and intraluminal pressure were simultaneously measured in vitro on rat posterior cerebral arteries. Results Cerebral arteries constricted in response to graded increase in intraluminal pressure (20–100 mmHg, in 20 mmHg increments). In vitro C-fiber desensitization with capsaicin (1 μmol/l, 20 minutes) significantly suppressed myogenic constriction by over 50%, but did not affect 5-hydroxytryptamine (0.01–10 μmol/l) and KCl (120 mmol/l)-induced constriction. Capsazepine (5 μmol/l, 30 minutes), a selective blocker of neuronal vanilloid receptor TRPV1, had similar inhibitory effect on cerebral myogenic constriction to elevated pressure. Cerebral myogenic constriction was significantly attenuated by H/R; the impairment by H/R was further enhanced after C-fiber desensitization (except at a pressure level of 100 mmHg). Discussion These findings indicate that C-fiber activity contributes to myogenic constriction of cerebral arteries under normal and H/R conditions. H/R-impaired myogenic responsiveness is exaggerated by C-fiber dysfunction. These results raise the possibility that therapeutic strategies directed toward preserving C-fiber nerve endings or supplying its constituent neuropeptides could be developed. PMID:19570322

Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.

PubMed

Sabri, Osama; Meyer, Philipp M; Gräf, Susanne; Hesse, Swen; Wilke, Stephan; Becker, Georg-Alexander; Rullmann, Michael; Patt, Marianne; Luthardt, Julia; Wagenknecht, Gudrun; Hoepping, Alexander; Smits, Rene; Franke, Annegret; Sattler, Bernhard; Tiepolt, Solveig; Fischer, Steffen; Deuther-Conrad, Winnie; Hegerl, Ulrich; Barthel, Henryk; Schönknecht, Peter; Brust, Peter

2018-06-01

In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (-)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4β2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (-)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (-)-18F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (-)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.

Application and validation of the barrow neurological institute screen for higher cerebral functions in a control population and in patient groups commonly seen in neurorehabilitation.

PubMed

Hofgren, Caisa; Esbjörnsson, Eva; Aniansson, Hans; Sunnerhagen, Katharina Stibrant

2007-09-01

To determine whether the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) can differentiate brain-dysfunctional patients from controls. A case-control study. A total of 92 controls and 120 patients from a neuro-rehabilitation clinic with a diagnosis of: right and left hemisphere stroke, traumatic brain injury, Parkinson's disease or anoxic brain damage. The BNIS has a maximum total score of 50 points, < 47 indicates cognitive dysfunction. Group comparisons and exploration of variables influencing the BNIS total score were made. A significant difference was found between the control group and the total patient group for the BNIS total score and for the subscales (p < 0.0005). Sensitivity was 88% and specificity 78%. Presence of disease and educational level had the greatest influence on the results of the BNIS. Patients with Parkinson's disease were shown to be the least cognitively affected and those with anoxic brain damage the most affected. The BNIS has potential value as a screening instrument for cognitive functions and is sufficiently sensitive to differentiate brain-dysfunctional patients from a control population. It appears to be applicable in a neurological rehabilitation setting, and can be used early in the process, giving a baseline cognitive functional level.

Evaluation of cerebral vasomotor reactivity in Parkinson's disease: is there any association with orthostatic hypotension?

PubMed

Zamani, Babak; Mehrabani, Mehrnoush; Fereshtehnejad, Seyed-Mohammad; Rohani, Mohammad

2011-06-01

Our aim was to look for a probable relationship between cerebral vasomotor reactivity (VMR) and orthostatic hypotension (OH) in Parkinson's disease (PD). This study was conducted on 44 patients with PD. Assessment of cerebral VMR was performed by means of transcranial Doppler (TCD) of middle cerebral artery (MCA) before and after a vasodilatory stimulus, carbon dioxide test. Moreover, orthostatic hypotension was evaluated. OH was presented in 12 (27.3%) Parkinson's patients. The average resting blood flow velocity (BFV) in the MCA was 30.20 (SD=9.58)cms(-1) which significantly increased to 46.25 (SD=16.23)cms(-1) after carbon dioxide test (P<0.001). Impaired VMR was observed in 15 (34.1%) of the subjects, while it was not associated with the presence of OH (P=0.770). Evaluation of VMR in patients affected by PD, could assist in early diagnosis of cerebral autonomic dysfunction and prevent its serious consequences prior and more valid to OH. Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.

Inhibitory effect of ebselen on cerebral acetylcholinesterase activity in vitro: kinetics and reversibility of inhibition.

PubMed

Martini, Franciele; Bruning, César Augusto; Soares, Suelen Mendonca; Nogueira, Cristina Wayne; Zeni, Gilson

2015-01-01

Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti-inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 µM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis.

Phospho-eIF2α level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice.

PubMed

Devi, Latha; Ohno, Masuo

2010-09-23

β-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) generation and thus represents a prime therapeutic target in treating Alzheimer's disease (AD). Notably, increasing evidence indicates that BACE1 levels become elevated in AD brains as disease progresses; however, it remains unclear how the BACE1 upregulation may affect efficacies of therapeutic interventions including BACE1-inhibiting approaches. Here, we crossed heterozygous BACE1 knockout mice with AD transgenic mice (5XFAD model) and compared the abilities of partial BACE1 reduction to rescue AD-like phenotypes at earlier (6-month-old) and advanced (15-18-month-old) stages of disease, which expressed normal (∼100%) and elevated (∼200%) levels of BACE1, respectively. BACE1(+/-) deletion rescued memory deficits as tested by the spontaneous alternation Y-maze task in 5XFAD mice at the earlier stage and prevented their septohippocampal cholinergic deficits associated with significant neuronal loss. Importantly, BACE1(+/-) deletion was no longer able to rescue memory deficits or cholinergic neurodegeneration in 5XFAD mice at the advanced stage. Moreover, BACE1(+/-) deletion significantly reduced levels of Aβ42 and the β-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic β-cleavage products dramatically elevated with age and were not affected by BACE1(+/-) deletion in 15-18-month-old 5XFAD brains. Interestingly, although BACE1(+/-) deletion lowered BACE1 expression by ∼50% in 5XFAD mice irrespective of age in concordance with the reduction in gene copy number, BACE1 equivalent to wild-type controls remained in BACE1(+/-)·5XFAD mice at the advanced age. In accord, phosphorylation of the translation initiation factor eIF2α, an important mediator of BACE1 elevation, was dramatically increased (∼9-fold) in 15-18-month-old 5XFAD mice and remained highly upregulated (∼6-fold) in age-matched BACE1(+/-)·5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.

Organ procurement and successful transplantation after malathion poisoning.

PubMed

Dribben, W H; Kirk, M A

2001-01-01

One of the major limitations to organ procurement and donation is the lack of suitable donors. As the demand for suitable organs exceeds the supply, identification of potential donors continues to evolve. Due to perceived risks of transmittable toxins and insufficient understanding of toxicological fate, poisoned patients are often overlooked as organ donors. A 17-year-old white male was found by his mother having a seizure in bed. A strong odor of pesticides was noted and an empty container of malathion was found. He was transported to an outlying hospital and underwent prolonged cardiopulmonary resuscitation. The patient exhibited symptoms consistent with cholinergic poisoning and received a total of 12 mg of atropine and a pralidoxime bolus of 1 g followed by an infusion at 500 mg/h. Initial plasma cholinesterase was 1433 IU/L (normal 7500-14,600). The patient developed aspiration pneumonia and remained comatose. No further treatment for cholinergic toxicity was needed 5 days after admission and a cerebral blood flow scan confirmed brain death. After review of the available literature on the disposition andfate of malathion in human tissues, the patient's liver and kidneys were harvested for transplantation. The recipients were all doing well 1 year posttransplantation. This case of successful transplantation after organophosphate exposure underscores the fact that poisoned patients should not be overlooked as transplant candidates. Decisions should be based on the clinical presentation and knowledge of the properties of the toxin.

Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

PubMed

Lecrux, C; Hamel, E

2016-10-05

Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. © 2016 The Author(s).

Advances in the mechanisms and early warning indicators of the postoperative cognitive dysfunction after the extracorporeal circulation.

PubMed

Liu, Chao; Han, Jian-ge

2015-02-01

The high incidence of postoperative cognitive dysfunction (POCD) after extracorporeal circulation has seriously affected the prognosis and quality of life. Its mechanism may involve the inflammatory response and oxidative stress,the excessive phosphorylation of tau protein, the decreased blood volume and oxygen in the cerebral cortex. Appropriate early warning indicators of POCD after the extracorporeal circulation should be chosen to facilitate the cross validation of the results obtained different technical approaches and thus promote the early diagnosis and treatment of POCD.

Clinical image: MRI during migraine with aura

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

McNeal, A.C.

1996-03-01

Migraine refers to severe headaches that are usually unilateral, throbbing, and associated with nausea, vomiting, photophobia, and phonophobia. Migraine with aura (formerly called {open_quotes}classic migraine{close_quotes}) consists of the headache preceded or accompanied by neurological dysfunction. This dysfunction (aura) usually involves visual and sensory symptoms. The patient described herein experienced migraine with aura. MRI during and after the attack showed a reversible abnormality of the right posterior cerebral artery, with no parenchymal lesions. This appears to be the first report of abnormal MR vascular imaging during migraine with aura. 10 refs., 2 figs.

Cholinergic Inputs from Basal Forebrain Add an Excitatory Bias to Odor Coding in the Olfactory Bulb

PubMed Central

Rothermel, Markus; Carey, Ryan M.; Puche, Adam; Shipley, Michael T.

2014-01-01

Cholinergic modulation of central circuits is associated with active sensation, attention, and learning, yet the neural circuits and temporal dynamics underlying cholinergic effects on sensory processing remain unclear. Understanding the effects of cholinergic modulation on particular circuits is complicated by the widespread projections of cholinergic neurons to telencephalic structures that themselves are highly interconnected. Here we examined how cholinergic projections from basal forebrain to the olfactory bulb (OB) modulate output from the first stage of sensory processing in the mouse olfactory system. By optogenetically activating their axons directly in the OB, we found that cholinergic projections from basal forebrain regulate OB output by increasing the spike output of presumptive mitral/tufted cells. Cholinergic stimulation increased mitral/tufted cell spiking in the absence of inhalation-driven sensory input and further increased spiking responses to inhalation of odorless air and to odorants. This modulation was rapid and transient, was dependent on local cholinergic signaling in the OB, and differed from modulation by optogenetic activation of cholinergic neurons in basal forebrain, which led to a mixture of mitral/tufted cell excitation and suppression. Finally, bulbar cholinergic enhancement of mitral/tufted cell odorant responses was robust and occurred independent of the strength or even polarity of the odorant-evoked response, indicating that cholinergic modulation adds an excitatory bias to mitral/tufted cells as opposed to increasing response gain or sharpening response spectra. These results are consistent with a role for the basal forebrain cholinergic system in dynamically regulating the sensitivity to or salience of odors during active sensing of the olfactory environment. PMID:24672011

2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-Glucoside Attenuates Ischemia/Reperfusion-Induced Brain Injury in Rats by Promoting Angiogenesis.

PubMed

Mu, Ying; Xu, Zhaohui; Zhou, Xuanxuan; Zhang, Huinan; Yang, Qian; Zhang, Yunlong; Xie, Yanhua; Kang, Juan; Li, Feng; Wang, Siwang

2017-05-01

Cerebral ischemia can cause brain infarcts, which are difficult to recover due to poor angiogenesis. 2,3,5,4'-Tetrahydroxystilbene-2-O- β -D-glucoside is a natural polyphenol, has antioxidant and anti-inflammatory activity, and can protect from ischemic neuronal injury. However, little is known about the effect of 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside on brain microcirculation after stroke. This study aimed at investigating the influence of 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside on brain lesions and angiogenesis after stroke. Sprague-Dawley rats were subjected to right middle cerebral artery occlusion and treated with vehicle, nimodipine, or different doses of 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside daily beginning at 6 h post-middle cerebral artery occlusion for 14 days. The volume of cerebral infarcts, degree of neurological dysfunction, and level of microvessel density were determined longitudinally. The levels of vascular endothelial growth factor, angiopoietin 1, and angiopoietin receptor-2 expression in the brain lesions were characterized by immunohistochemistry and Western blot assays at 14 days post-middle cerebral artery occlusion. We found that 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside significantly promoted postoperative recovery in rats by minimizing the volume of cerebral infarcts and improving neurological dysfunction in a dose- and time-dependent manner. Additionally, 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside significantly increased the microvessel density in the brain and upregulated CD31 expression in ischemic penumbra, relative to that in the control. Finally, treatment with 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside significantly upregulated the relative levels of vascular endothelial growth factor, angiopoietin 1, and angiopoietin receptor-2 expression in the brain lesions of rats. Therefore, these data indicated that 2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside treatment promoted angiogenesis and recovery from ischemia/reperfusion-induced brain injury in rats. Georg Thieme Verlag KG Stuttgart · New York.

The effects of therapeutic taping on gross motor function in children with cerebral palsy.

PubMed

Footer, Cheryl Burditt

2006-01-01

Therapeutic taping to address dysfunctional sitting control in children with cerebral palsy (CP) was investigated in this study. Eighteen children with quadriplegic CP, Gross Motor Function Classification System for Cerebral Palsy levels IV (n = 9) and V (n = 9) participated in the 12-week program. Subjects were assigned randomly to one of two groups: therapeutic taping + physical therapy or physical therapy only. Therapeutic taping was applied for periods of up to 72 hours over the paraspinal region. The effects were assessed with the Gross Motor Function Measure (GMFM-88) at baseline, six weeks, and 12 weeks. A factorial analysis of variance was used to examine group differences over time. No significant differences were found for the GMFM-88 scores between groups over time. Therapeutic taping does not evoke a positive functional change in the seated postural control of children with quadriplegic cerebral palsy. Subjective observation, however, suggested that one child with athetosis benefited from therapeutic taping over the paraspinal region.

Cerebral blood flow and oxygenation in infants after birth asphyxia. Clinically useful information?

PubMed

Greisen, Gorm

2014-10-01

The term 'luxury perfusion' was coined nearly 50 years ago after observation of bright-red blood in the cerebral veins of adults with various brain pathologies. The bright-red blood represents decreased oxygen extraction and hence the perfusion is 'luxurious' compared to oxygen needs. Gradual loss of cellular energy charge during the hours following severe birth asphyxia was observed twenty years later by sequential cranial magnetic resonance spectroscopy. This led to the concept of delayed energy failure that is linked to mitochondrial dysfunction and apoptotic cell death. Abnormally increased perfusion and lack of normal cerebral blood flow regulation are also typically present, but whether the perfusion abnormalities at this secondary stage are detrimental, beneficial, or a mere epiphenomenon remains elusive. In contrast, incomplete reoxygenation of the brain during and following resuscitation is likely to compromise outcome. The clinical value of cerebral oximetry in this context can only be examined in a randomised clinical trial. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neuroimmunological Blood Brain Barrier Opening in Experimental Cerebral Malaria

PubMed Central

Baer, Kerstin; Mikolajczak, Sebastian A.; Kappe, Stefan H. I.; Frevert, Ute

2012-01-01

Plasmodium falciparum malaria is responsible for nearly one million annual deaths worldwide. Because of the difficulty in monitoring the pathogenesis of cerebral malaria in humans, we conducted a study in various mouse models to better understand disease progression in experimental cerebral malaria (ECM). We compared the effect on the integrity of the blood brain barrier (BBB) and the histopathology of the brain of P. berghei ANKA, a known ECM model, P. berghei NK65, generally thought not to induce ECM, P. yoelii 17XL, originally reported to induce human cerebral malaria-like histopathology, and P. yoelii YM. As expected, P. berghei ANKA infection caused neurological signs, cerebral hemorrhages, and BBB dysfunction in CBA/CaJ and Swiss Webster mice, while Balb/c and A/J mice were resistant. Surprisingly, PbNK induced ECM in CBA/CaJ mice, while all other mice were resistant. P. yoelii 17XL and P. yoelii YM caused lethal hyperparasitemia in all mouse strains; histopathological alterations, BBB dysfunction, or neurological signs were not observed. Intravital imaging revealed that infected erythrocytes containing mature parasites passed slowly through capillaries making intimate contact with the endothelium, but did not arrest. Except for relatively rare microhemorrhages, mice with ECM presented no obvious histopathological alterations that would explain the widespread disruption of the BBB. Intravital imaging did reveal, however, that postcapillary venules, but not capillaries or arterioles, from mice with ECM, but not hyperparasitemia, exhibit platelet marginalization, extravascular fibrin deposition, CD14 expression, and extensive vascular leakage. Blockage of LFA-1 mediated cellular interactions prevented leukocyte adhesion, vascular leakage, neurological signs, and death from ECM. The endothelial barrier-stabilizing mediators imatinib and FTY720 inhibited vascular leakage and neurological signs and prolonged survival to ECM. Thus, it appears that neurological signs and coma in ECM are due to regulated opening of paracellular-junctional and transcellular-vesicular fluid transport pathways at the neuroimmunological BBB. PMID:23133375

Effect of type 1 diabetes on the production and vasoactivity of hydrogen sulfide in rat middle cerebral arteries

PubMed Central

Streeter, Elosie Y; Badoer, Emilio; Woodman, Owen L; Hart, Joanne L

2013-01-01

Hydrogen sulfide (H2S) is produced endogenously in vascular tissue and has both vasoregulation and antioxidant effects. This study examines the effect of diabetes-induced oxidative stress on H2S production and function in rat middle cerebral arteries. Diabetes was induced in rats with streptozotocin (50 mg/kg, i.v.). Middle cerebral artery function was examined using a small vessel myograph and superoxide anion generation measured using nicotinamide adenine dinucleotide phosphate (NADPH)-dependent lucigenin-enhanced chemiluminescence. Cystathionine-γ-lyase (CSE) mRNA expression was measured via RT-PCR. Diabetic rats had elevated blood glucose and significantly reduced cerebral artery endothelial function. Maximum vasorelaxation to the H2S donor NaHS was unaffected in diabetic cerebral arteries and was elicited via a combination of K+, Cl−, and Ca2+ channel modulation, although the contribution of Cl− channels was significantly less in the diabetic cerebral arteries. Vasorelaxation to the H2S precursor l-cysteine and CSE mRNA were significantly increased in diabetic cerebral arteries. Cerebral artery superoxide production was significantly increased in diabetes, but this increase was attenuated ex vivo by incubation with the H2S donor NaHS. These data confirm that cerebral artery endothelial dysfunction and oxidative stress occurs in diabetes. Endogenous H2S production and activity is upregulated in cerebral arteries in this model of diabetes. Vasorelaxation responses to exogenous H2S are preserved and exogenous H2S attenuates the enhanced cerebral artery generated superoxide observed in the diabetic group. These data suggest that upregulation of endogenous H2S in diabetes may play an antioxidant and vasoprotective role. PMID:24303182

Central-Approach Surgical Repair of Coarctation of the Aorta with a Back-up Left Ventricular Assist Device for an Infant Presenting with Severe Left Ventricular Dysfunction.

PubMed

Kim, Tae Hoon; Shin, Yu Rim; Kim, Young Sam; Kim, Do Jung; Kim, Hyohyun; Shin, Hong Ju; Htut, Aung Thein; Park, Han Ki

2015-12-01

A two-month-old infant presented with coarctation of the aorta, severe left ventricular dysfunction, and moderate to severe mitral regurgitation. Through median sternotomy, the aortic arch was repaired under cardiopulmonary bypass and regional cerebral perfusion. The patient was postoperatively supported with a left ventricular assist device for five days. Left ventricular function gradually improved, eventually recovering with the concomitant regression of mitral regurgitation. Prompt surgical repair of coarctation of the aorta is indicated for patients with severe left ventricular dysfunction. A central approach for surgical repair with a back-up left ventricular assist device is a safe and effective treatment strategy for these patients.

Medical Surveillance Monthly Report (MSMR). Volume 18, Number 03, March 2011

DTIC Science & Technology

2011-03-01

nervous system dysfunction; the diagnosis was also applicable to patients with laboratory evidence of injury to the liver , muscles, or kidneys. Th e...decrease cerebral blood fl ow and disrupt brain function (e.g., hypotonic encephalopathy , seizures, coma). Without rapid and defi nitive treatment to

Ischemia-induced endothelial cell swelling and mitochondrial dysfunction are attenuated by dietary polyphenols in vitro

USDA-ARS?s Scientific Manuscript database

Polyphenols possess anti-oxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular uni...

Historical Roots of the Field of Learning Disabilities: Some Nineteenth-Century German Contributions.

ERIC Educational Resources Information Center

Opp, Gunther

1994-01-01

This article highlights the scientific contributions of nineteenth-century German researchers in describing neuropsychologic dysfunction and in conceptualizing and cerebrally localizing clinical syndromes associated with learning disabilities. Noted are contributions of Pierre Paul Broca, Carl Wernicke, Ludwig Lichtheim, Hugo Karl Liepmann, B.…

Tolerance to Central Hypovolemia: The Influence of Oscillations in Arterial Pressure and Cerebral Blood Velocity

DTIC Science & Technology

2011-10-01

specific details about whether they were taking oral contraceptive medications, both of which can impact cardiovascular responses to hypovo- lemia (4, 20...Gerontology 49: 279–286, 2003. 59. Stewart JM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and

Prefrontal Dysfunction in Attention-Deficit/Hyperactivity Disorder as Measured by Near-Infrared Spectroscopy

ERIC Educational Resources Information Center

Negoro, Hideki; Sawada, Masayuki; Iida, Junzo; Ota, Toyosaku; Tanaka, Shohei; Kishimoto, Toshifumi

2010-01-01

Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders with measurement of hemoglobin concentrations as cerebral blood volume. Twenty medication-naive children with attention-deficit/hyperactivity disorder (ADHD) and 20 age- and sex-matched healthy control…

Obstructive Sleep Apnea is Linked to Depression and Cognitive Impairment: Evidence and Potential Mechanisms

PubMed Central

Kerner, Nancy A.; Roose, Steven P.

2017-01-01

Obstructive sleep apnea (OSA) is highly prevalent but very frequently undiagnosed. OSA is an independent risk factor for depression and cognitive impairment/dementia. Herein the authors review studies in the literature pertinent to the effects of OSA on the cerebral microvascular and neurovascular systems and present a model to describe the key pathophysiologic mechanisms that may underlie the associations, including hypoperfusion, endothelial dysfunction, and neuroinflammation. Intermittent hypoxia plays a critical role in initiating and amplifying these pathologic processes. Hypoperfusion and impaired cerebral vasomotor reactivity lead to the development or progression of cerebral small vessel disease (C-SVD). Hypoxemia exacerbates these processes, resulting in white matter lesions, white matter integrity abnormalities, and gray matter loss. Blood–brain barrier (BBB) hyperpermeability and neuroinflammation lead to altered synaptic plasticity, neuronal damage, and worsening C-SVD. Thus, OSA may initiate or amplify the pathologic processes of C-SVD and BBB dysfunction, resulting in the development or exacerbation of depressive symptoms and cognitive deficits. Given the evidence that adequate treatment of OSA with continuous positive airway pressure improves depression and neurocognitive functions, it is important to identify OSA when assessing patients with depression or cognitive impairment. Whether treatment of OSA changes the deteriorating trajectory of elderly patients with already-diagnosed vascular depression and cognitive impairment/dementia remains to be determined in randomized controlled trials. PMID:27139243

Brain imaging and cognitive dysfunctions in Huntington's disease

PubMed Central

Montoya, Alonso; Price, Bruce H.; Menear, Matthew; Lepage, Martin

2006-01-01

Recent decades have seen tremendous growth in our understanding of the cognitive dysfunctions observed in Huntington's disease (HD). Advances in neuroimaging have contributed greatly to this growth. We reviewed the role that structural and functional neuroimaging techniques have played in elucidating the cerebral bases of the cognitive deficits associated with HD. We conducted a computer-based search using PubMed and PsycINFO databases to retrieve studies of patients with HD published between 1965 and December 2004 that reported measures on cognitive tasks and used neuroimaging techniques. Structural neuroimaging has provided important evidence of morphological brain changes in HD. Striatal and cortical atrophy are the most common findings, and they correlate with cognitive deficits in attention, working memory and executive functions. Functional studies have also demonstrated correlations between striatal dysfunction and cognitive performance. Striatal hypoperfusion and decreased glucose utilization correlate with executive dysfunction. Hypometabolism also occurs throughout the cerebral cortex and correlates with performance on recognition memory, language and perceptual tests. Measures of presynaptic and postsynaptic dopamine biochemistry have also correlated with measurements of episodic memory, speed of processing and executive functioning. Aided by the results of numerous neuroimaging studies, it is becoming increasingly clear that cognitive deficits in HD involve abnormal connectivity between the basal ganglia and cortical areas. In the future, neuroimaging techniques may shed the most light on the pathophysiology of HD by defining neurodegenerative disease phenotypes as a valuable tool for knowing when patients become “symptomatic,” having been in a gene-positive presymptomatic state, and as a biomarker in following the disease, thereby providing a prospect for improved patient care. PMID:16496032

Indian Ginseng (Withania somnifera) supplementation ameliorates oxidative stress and mitochondrial dysfunctions in experimental model of stroke.

PubMed

Sood, Abhilasha; Mehrotra, Arpit; Dhawan, Devinder K; Sandhir, Rajat

2018-04-18

Stroke is an increasingly prevalent clinical condition and second leading cause of death globally. The present study evaluated the therapeutic potential of Indian Ginseng, also known as Withania somnifera (WS), supplementation on middle cerebral artery occlusion (MCAO) induced mitochondrial dysfunctions in experimental model of ischemic stroke. Stroke was induced in animals by occluding the middle cerebral artery, followed by reperfusion injury. Ischemia reperfusion injury resulted in increased oxidative stress indicated by increased reactive oxygen species and protein carbonyl levels; compromised antioxidant system; in terms of reduced superoxide dismutase and catalase activity, along with reduction in GSH levels and the redox ratio, impaired mitochondrial functions and enhanced expression of apoptosis markers. Ischemia reperfusion injury induced mitochondrial dysfunctions in terms of (i) reduced activity of the mitochondrial respiratory chain enzymes, (ii) reduced histochemical staining of complex-II and IV, (iii) reduced in-gel activity of mitochondrial complex-I to V, (iv) mitochondrial structural changes in terms of increased mitochondrial swelling, reduced mitochondrial membrane potential and ultrastructural changes. Additionally, an increase in the activity of caspase-3 and caspase-9 was also observed, along with altered expression of apoptotic proteins Bcl-2 and Bax in MCAO animals. MCAO animals also showed significant impairment in cognitive functions assessed using Y maze test. WS pre-supplementation, on the other hand ameliorated MCAO induced oxidative stress, mitochondrial dysfunctions, apoptosis and cognitive impairments. The results show protective effect of WS pre-supplementation in ischemic stroke and are suggestive of its potential application in stroke management.

Cholinergic mechanisms in spinal locomotion—potential target for rehabilitation approaches

PubMed Central

Jordan, Larry M.; McVagh, J. R.; Noga, B. R.; Cabaj, A. M.; Majczyński, H.; Sławińska, Urszula; Provencher, J.; Leblond, H.; Rossignol, Serge

2014-01-01

Previous experiments implicate cholinergic brainstem and spinal systems in the control of locomotion. Our results demonstrate that the endogenous cholinergic propriospinal system, acting via M2 and M3 muscarinic receptors, is capable of consistently producing well-coordinated locomotor activity in the in vitro neonatal preparation, placing it in a position to contribute to normal locomotion and to provide a basis for recovery of locomotor capability in the absence of descending pathways. Tests of these suggestions, however, reveal that the spinal cholinergic system plays little if any role in the induction of locomotion, because MLR-evoked locomotion in decerebrate cats is not prevented by cholinergic antagonists. Furthermore, it is not required for the development of stepping movements after spinal cord injury, because cholinergic agonists do not facilitate the appearance of locomotion after spinal cord injury, unlike the dramatic locomotion-promoting effects of clonidine, a noradrenergic α-2 agonist. Furthermore, cholinergic antagonists actually improve locomotor activity after spinal cord injury, suggesting that plastic changes in the spinal cholinergic system interfere with locomotion rather than facilitating it. Changes that have been observed in the cholinergic innervation of motoneurons after spinal cord injury do not decrease motoneuron excitability, as expected. Instead, the development of a “hyper-cholinergic” state after spinal cord injury appears to enhance motoneuron output and suppress locomotion. A cholinergic suppression of afferent input from the limb after spinal cord injury is also evident from our data, and this may contribute to the ability of cholinergic antagonists to improve locomotion. Not only is a role for the spinal cholinergic system in suppressing locomotion after SCI suggested by our results, but an obligatory contribution of a brainstem cholinergic relay to reticulospinal locomotor command systems is not confirmed by our experiments. PMID:25414645

Variable expression of GFP in different populations of peripheral cholinergic neurons of ChATBAC-eGFP transgenic mice.

PubMed

Brown, T Christopher; Bond, Cherie E; Hoover, Donald B

2018-03-01

Immunohistochemistry is used widely to identify cholinergic neurons, but this approach has some limitations. To address these problems, investigators developed transgenic mice that express enhanced green fluorescent protein (GFP) directed by the promoter for choline acetyltransferase (ChAT), the acetylcholine synthetic enzyme. Although, it was reported that these mice express GFP in all cholinergic neurons and non-neuronal cholinergic cells, we could not detect GFP in cardiac cholinergic nerves in preliminary experiments. Our goals for this study were to confirm our initial observation and perform a qualitative screen of other representative autonomic structures for the presences of GFP in cholinergic innervation of effector tissues. We evaluated GFP fluorescence of intact, unfixed tissues and the cellular localization of GFP and vesicular acetylcholine transporter (VAChT), a specific cholinergic marker, in tissue sections and intestinal whole mounts. Our experiments identified two major tissues where cholinergic neurons and/or nerve fibers lacked GFP: 1) most cholinergic neurons of the intrinsic cardiac ganglia and all cholinergic nerve fibers in the heart and 2) most cholinergic nerve fibers innervating airway smooth muscle. Most cholinergic neurons in airway ganglia stained for GFP. Cholinergic systems in the bladder and intestines were fully delineated by GFP staining. GFP labeling of input to ganglia with long preganglionic projections (vagal) was sparse or weak, while that to ganglia with short preganglionic projections (spinal) was strong. Total absence of GFP might be due to splicing out of the GFP gene. Lack of GFP in nerve projections from GFP-positive cell bodies might reflect a transport deficiency. Copyright © 2017 Elsevier B.V. All rights reserved.

Sympathetic sprouting drives hippocampal cholinergic reinnervation that prevents loss of a muscarinic receptor-dependent long-term depression at CA3-CA1 synapses.

PubMed

Scheiderer, Cary L; McCutchen, Eve; Thacker, Erin E; Kolasa, Krystyna; Ward, Matthew K; Parsons, Dee; Harrell, Lindy E; Dobrunz, Lynn E; McMahon, Lori L

2006-04-05

Degeneration of septohippocampal cholinergic neurons results in memory deficits attributable to loss of cholinergic modulation of hippocampal synaptic circuits. A remarkable consequence of cholinergic degeneration is the sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. The functional impact of sympathetic ingrowth on synaptic physiology has never been investigated. Here, we report that, at CA3-CA1 synapses, a Hebbian form of long-term depression (LTD) induced by muscarinic M1 receptor activation (mLTD) is lost after medial septal lesion. Unexpectedly, expression of mLTD is rescued by sympathetic sprouting. These effects are specific because LTP and other forms of LTD are unaffected. The rescue of mLTD expression is coupled temporally with the reappearance of cholinergic fibers in hippocampus, as assessed by the immunostaining of fibers for VAChT (vesicular acetylcholine transporter). Both the cholinergic reinnervation and mLTD rescue are prevented by bilateral superior cervical ganglionectomy, which also prevents the noradrenergic sympathetic sprouting. The new cholinergic fibers likely originate from the superior cervical ganglia because unilateral ganglionectomy, performed when cholinergic reinnervation is well established, removes the reinnervation on the ipsilateral side. Thus, the temporal coupling of the cholinergic reinnervation with mLTD rescue, together with the absence of reinnervation and mLTD expression after ganglionectomy, demonstrate that the autonomic-driven cholinergic reinnervation is essential for maintaining mLTD after central cholinergic cell death. We have discovered a novel phenomenon whereby the autonomic and central nervous systems experience structural rearrangement to replace lost cholinergic innervation in hippocampus, with the consequence of preserving a form of LTD that would otherwise be lost as a result of cholinergic degeneration.

Emergency management of fat embolism syndrome

PubMed Central

Shaikh, Nissar

2009-01-01

Fat emboli occur in all patients with long-bone fractures, but only few patients develop systemic dysfunction, particularly the triad of skin, brain, and lung dysfunction known as the fat embolism syndrome (FES). Here we review the FES literature under different subheadings. The incidence of FES varies from 1–29%. The etiology may be traumatic or, rarely, nontraumatic. Various factors increase the incidence of FES. Mechanical and biochemical theories have been proposed for the pathophysiology of FES. The clinical manifestations include respiratory and cerebral dysfunction and a petechial rash. Diagnosis of FES is difficult. The other causes for the above-mentioned organ dysfunction have to be excluded. The clinical criteria along with imaging studies help in diagnosis. FES can be detected early by continuous pulse oximetry in high-risk patients. Treatment of FES is essentially supportive. Medications, including steroids, heparin, alcohol, and dextran, have been found to be ineffective. PMID:19561953

Thyroid function, Alzheimer's disease and postoperative cognitive dysfunction: a tale of dangerous liaisons?

PubMed

Mafrica, Federica; Fodale, Vincenzo

2008-05-01

Hypothyroidism and hyperthyroidism are commonly present conditions in adults, leading to neurological symptoms, affecting the central and peripheral nervous system, and to neurocognitive impairment. Several studies investigated a possible association between Alzheimer's disease (AD) and thyroid dysfunctions. Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in AD. Moreover, thyroid hormones negatively regulate expression of the amyloid-beta protein precursor (AbetaPP), which plays a key role in the development of AD. A condition, the so called euthyroid sick syndrome (ESS), characterized by reduced serum T_{3} and T_{4} concentrations without increased serum thyroid stimulation hormone secretion, occurs within hours after major surgery. After surgery, elderly patients often exhibit a transient, reversible state of cognitive alterations. Delirium occurs in 10-26% of general medical patients over 65, and it is associated with a significant increase in morbidity and mortality. Modifications in thyroid hormone functioning may take place as a consequence of psycho-physical stress caused by surgery, and probably as a consequence of reduced conversion of T4 into T3 by the liver engaged in metabolizing anesthetic drugs. Therefore, modifications of thyroid hormones post-surgery, might play a role in the pathogenesis of postoperative cognitive dysfunction.

Neural Mechanisms Underlying Lower Urinary Tract Dysfunction

PubMed Central

Ogawa, Teruyuki; Miyazato, Minoru; Kitta, Takeya; Furuta, Akira; Chancellor, Michael B.; Tyagi, Pradeep

2014-01-01

This article summarizes anatomical, neurophysiological, and pharmacological studies in humans and animals to provide insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract and alterations in these mechanisms in lower urinary tract dysfunction. The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Therefore, injury or diseases of the nervous system, as well as disorders of the peripheral organs, can produce lower urinary tract dysfunction, leading to lower urinary tract symptoms, including both storage and voiding symptoms, and pelvic pain. Neuroplasticity underlying pathological changes in lower urinary tract function is discussed. PMID:24578802

Longitudinal imaging of the availability of dopamine transporter and D2 receptor in rat striatum following mild ischemia.

PubMed

Momosaki, Sotaro; Ito, Miwa; Yamato, Hiroko; Iimori, Hitoshi; Sumiyoshi, Hirokazu; Morimoto, Kenji; Imamoto, Natsumi; Watabe, Tadashi; Shimosegawa, Eku; Hatazawa, Jun; Abe, Kohji

2017-02-01

The changes in the availability of striatal dopamine transporter and dopamine D2 receptor after mild focal ischemia in rats were measured using a small animal positron emission tomography system. Mild focal ischemia was induced by 20-minute middle cerebral artery occlusion. [ 11 C]PE2I binding to dopamine transporter was transiently increased on the ipsilateral side of the striatum at 2 days after middle cerebral artery occlusion. On day 7 and 14 after middle cerebral artery occlusion, [ 11 C]PE2I binding levels were decreased. In contrast, [ 11 C]raclopride binding to dopamine D2 receptor in the ipsilateral striatum had not changed at 2 days after middle cerebral artery occlusion. [ 11 C]Raclopride binding was significantly decreased on the ischemic side of the striatum at 7 and 14 days after middle cerebral artery occlusion. Moreover, on day 1 and 2 after middle cerebral artery occlusion, significant circling behavior to the contralateral direction was induced by amphetamine challenge. This behavior disappeared at 7 days after middle cerebral artery occlusion. At 14 days, circling behavior to the ipsilateral direction (middle cerebral artery occlusion side) was significantly increased, and that to the contralateral direction also appeared again. The present study suggested that amphetamine-induced circling behavior indicated striatal dopaminergic alterations and that dopamine transporter and dopamine D2 receptor binding could be key markers for predicting motor dysfunction after mild focal ischemia.

Cholinergic Mesopontine Signals Govern Locomotion and Reward Through Dissociable Midbrain Pathways

PubMed Central

Xiao, Cheng; Cho, Jounhong Ryan; Zhou, Chunyi; Treweek, Jennifer B.; Chan, Ken; McKinney, Sheri L.; Yang, Bin; Gradinaru, Viviana

2016-01-01

The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons, however although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders. PMID:27100197

Schizophrenia and the alpha7 nicotinic acetylcholine receptor.

PubMed

Martin, Laura F; Freedman, Robert

2007-01-01

In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills. Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic-mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The alpha7 nicotinic agonist 3-(2,4 dimethoxy)benzylidene-anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia.

Recovery of diminished mealtime-associated anticipatory behavior by aniracetam in aged rats.

PubMed

Tanaka, Y; Kurasawa, M; Nakamura, K

2000-08-01

Disease- or age-related neuropsychiatric symptoms and cognitive and chronobiological impairments greatly aggravate the activities of daily living (ADL) in patients. The present study evaluates the effects of aniracetam on a decline in mealtime-associated anticipatory behavior in aged rats, as an animal model of temporally regulated behaviors or habitual daily activities. Aged rats showed a lower but typical nocturnal motor activity rhythm than young rats when the animals were fed ad lib. Mealtime-associated anticipatory behavior emerged in young rats when the rats were fed at a fixed time for 6 days, but the activity in aged rats was diminished. Repeated administration of aniracetam (100 mg/kg PO) or physostigmine (0.1 mg/kg SC) for 7 days ameliorated the impaired anticipatory behavior in aged rats. Nefiracetam (10 mg/kg PO) was ineffective. All compounds tested had no effect on appetite or motor ability. These results indicate that aging disturbs the timing or temporal regulation of anticipatory behavior, probably resulting from dysfunction in a food-entrainable oscillator linked to central cholinergic systems. The restoration of the time-keeping ability by aniracetam may be mediated by the facilitation of reticulothalamic cholinergic neurotransmission, and the action may lead to the improvement of declined ADL in stroke patients.

Inhibition of choline acetyltransferase by excitatory amino acids as a possible mechanism for cholinergic dysfunction in the central nervous system.

PubMed

Loureiro-Dos-Santos, N E; Reis, R A; Kubrusly, R C; de Almeida, O M; Gardino, P F; de Mello, M C; de Mello, F G

2001-05-01

Choline acetyltransferase (ChAT) activity was reduced by more than 85% in cultured retina cells after 16 h treatment with 150 microM kainate (T(1/2) : 3.5 h). Glutamate, AMPA and quisqualate also inhibited the enzyme in equivalent proportion. Cell lesion measured by lactate dehydrogenase (LDH) release, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide - thiazolyl blue (MTT) reduction and microscopic observation was not detected even after 48 h with kainate. Other retina neurochemical markers were not affected by kainate and full recovery of the enzyme was achieved 9 days after kainate removal. Moreover, hemicolinium-3 sensitive choline uptake and hemicolinium-3 binding sites were maintained intact after kainate treatment. The immunoblot and immunohistochemical analysis of the enzyme revealed that ChAT molecules were maintained in cholinergic neurons. The use of antagonists showed that ionotropic and group 1 metabotropic receptors mediated the effect of glutamate on ChAT inhibition, in a calcium dependent manner. The quisqualate mediated ChAT inhibition and part of the kainate effect (30%) was prevented by 5 mM N(G)-nitro-L-arginine methyl ester (L-NAME). Veratridine (3 microM) also reduced ChAT by a Ca(2+) dependent, but glutamate independent mechanism and was prevented by 1 microM tetrodotoxin.

[Efferent innervation of the arteries of human leptomeninx in arterial hypertension].

PubMed

Chertok, V M; Kotsiuba, A E; Babich, E V

2009-01-01

Structure of the efferent nerve plexuses (adrenergic, acetylcholinestherase- and cholinacetyltranspherase-positive, NO-dependent), was studied in the arteries of human leptomeninx with different diameters. Material was obtained from the corpses of the healthy people and of the patients with initial stages of arterial hypertension (AH). It was shown that the concentrations of cholinergic and adrenergic nerve fibers and varicosities in axon terminal part, innervating the arteries with the diameters ranging from 450 till 100 microm, were not significantly different. In these arteries, NO-ergic plexuses were also detected. In patients with AH, regardless the arterial diameters, the significant increase (up to 15-20%) of adrenergic nerve fiber and varicosity concentrations was found. The changes in cholinergic nerve fiber concentration were found to depend on the vessel diameter: the significant decrease of these parameter was observed only in arteries with the diameter of 100-200 microm. No significant changes in nerve plexus concentration was noticed in the arteries with greater or smaller diameter. In NO-ergic neural conductors, the enzyme activity decreased only in the large arteries, and remained almost unchanged in the small vascular branches. The changes in the vasomotor innervation described in AH, are interpreted as a vasomotor innervation dysfunction of the leptomeninx arteries that may result in the hemodynamic disturbances.

[Neurologic manifestations associated with antiphospholipid antibodies. Or what remains of neurolupus?].

PubMed

Hachulla, E; Leys, D; Deleume, J F; Pruvo, J P; Devulder, B

1995-01-01

Antiphospholipid antibody is associated with a clinical syndrome of vascular thrombosis, thrombocytopenia, recurrent fetal loss and livedo reticularis, whether or not a clinical diagnosis of systemic lupus erythematosus (SLE) coexists. Central nervous system involvement in SLE is multifactorial, thrombotic events, antineuronal antibodies, hypertension, infection, side effects of drugs etc. Antiphospholipid antibodies may play a role in focal neurological manifestations in SLE. In the absence of SLE, different neurological symptoms are well associated with antiphospholipid antibodies including stroke, seizures, dementia, migraine, ocular ischemia, chorea, transverse myelopathy, cerebral phlebitis. Other association are more controversal like Guillain Barré syndrome, motor neuron disease, communicating hydrocephalus. In all patients with antiphospholipid antibodies with neurological involvement, cerebral MRI may be performed with an echocardiographic study because a possible association with Libman and Sacks endocarditis, valve dysfunction or cardiac thrombus source of cerebral ischemia.

Brain Circulation during Panic Attack: A Transcranial Doppler Study with Clomipramine Challenge.

PubMed

Rotella, Francesco; Marinoni, Marinella; Lejeune, Francesca; Alari, Fabiana; Depinesi, Daniela; Cosci, Fiammetta; Faravelli, Carlo

2014-01-01

Introduction. Cerebral blood flow has been well studied in patients with panic disorder, but only few studies analyzed the mechanisms underlying the onset of a panic attack. The aim of the present study was to monitor the cerebral hemodynamics modifications during a panic attack. Materials and Methods. 10 panic disorder patients with recent onset, fully drug naïve, were compared to 13 patients with panic disorder with a previous history of treatment and to 14 controls. A continuous bilateral monitoring of mean flow velocities in right and left middle cerebral arteries was performed by transcranial Doppler. Clomipramine was chosen as challenge. Results. Eight out of 10 patients drug naïve and 6 control subjects out of 13 had a full blown panic attack during the test, whereas none of the patients with a history of treatment panicked. The occurrence of a panic attack was accompanied by a rapid decrease of flow velocities in both right and left middle cerebral arteries. Discussion. The bilateral acute decrease of mean flow velocity during a panic attack suggests the vasoconstriction of the microcirculation of deep brain structures perfused by middle cerebral arteries and involved in the so-called "fear circuitry," thus suggesting that cerebral homeostatic dysfunctions seem to have a key role in the onset of a panic attack.

Olfaction in Parkinson's disease and related disorders

PubMed Central

Doty, Richard L.

2012-01-01

Olfactory dysfunction is an early ‘pre-clinical’ sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclein- and tau-related pathology,or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances. PMID:22192366

Structural and functional cardiac cholinergic deficits in adult neurturin knockout mice.

PubMed

Mabe, Abigail M; Hoover, Donald B

2009-04-01

Previous work provided indirect evidence that the neurotrophic factor neurturin (NRTN) is required for normal cholinergic innervation of the heart. This study used nrtn knockout (KO) and wild-type (WT) mice to determine the effect of nrtn deletion on cardiac cholinergic innervation and function in the adult heart. Immunohistochemistry, confocal microscopy, and quantitative image analysis were used to directly evaluate intrinsic cardiac neuronal development. Atrial acetylcholine (ACh) levels were determined as an indirect index of cholinergic innervation. Cholinergic function was evaluated by measuring negative chronotropic responses to right vagal nerve stimulation in anaesthetized mice and responses of isolated atria to muscarinic agonists. KO hearts contained only 35% the normal number of cholinergic neurons, and the residual cholinergic neurons were 15% smaller than in WT. Cholinergic nerve density at the sinoatrial node was reduced by 87% in KOs, but noradrenergic nerve density was unaffected. Atrial ACh levels were substantially lower in KO mice (0.013 +/- 0.004 vs. 0.050 +/- 0.011 pmol/microg protein; P < 0.02) as expected from cholinergic neuron and nerve fibre deficits. Maximum bradycardia evoked by vagal stimulation was reduced in KO mice (38 +/- 6% vs. 69 +/- 3% decrease at 20 Hz; P < 0.001), and chronotropic responses took longer to develop and fade. In contrast to these deficits, isolated atria from KO mice had normal post-junctional sensitivity to carbachol and bethanechol. These findings demonstrate that NRTN is essential for normal cardiac cholinergic innervation and cholinergic control of heart rate. The presence of residual cardiac cholinergic neurons and vagal bradycardia in KO mice suggests that additional neurotrophic factors may influence this system.

Localization of cholinergic innervation and neurturin receptors in adult mouse heart and expression of the neurturin gene.

PubMed

Mabe, Abigail M; Hoard, Jennifer L; Duffourc, Michelle M; Hoover, Donald B

2006-10-01

Neurturin (NRTN) is a neurotrophic factor required during development for normal cholinergic innervation of the heart, but whether NRTN continues to function in the adult heart is unknown. We have therefore evaluated NRTN expression in adult mouse heart and the association of NRTN receptors with intracardiac cholinergic neurons and nerve fibers. Mapping the regional distribution and density of cholinergic nerves in mouse heart was an integral part of this goal. Analysis of RNA from adult C57BL/6 mouse hearts demonstrated NRTN expression in atrial and ventricular tissue. Virtually all neurons in the cardiac parasympathetic ganglia exhibited the cholinergic phenotype, and over 90% of these cells contained both components of the NRTN receptor, Ret tyrosine kinase and GDNF family receptor alpha2 (GFRalpha2). Cholinergic nerve fibers, identified by labeling for the high affinity choline transporter, were abundant in the sinus and atrioventricular nodes, ventricular conducting system, interatrial septum, and much of the right atrium, but less abundant in the left atrium. The right ventricular myocardium contained a low density of cholinergic nerves, which were sparse in other regions of the working ventricular myocardium. Some cholinergic nerves were also associated with coronary vessels. GFRalpha2 was present in most cholinergic nerve fibers and in Schwann cells and their processes throughout the heart. Some cholinergic nerve fibers, such as those in the sinus node, also exhibited Ret immunoreactivity. These findings provide the first detailed mapping of cholinergic nerves in mouse heart and suggest that the neurotrophic influence of NRTN on cardiac cholinergic innervation continues in mature animals.

The role of 5-HT(1A) receptors in learning and memory.

PubMed

Ogren, Sven Ove; Eriksson, Therese M; Elvander-Tottie, Elin; D'Addario, Claudio; Ekström, Joanna C; Svenningsson, Per; Meister, Björn; Kehr, Jan; Stiedl, Oliver

2008-12-16

The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT(1A) receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT(1A) receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.

Neuropharmacology of cognition and memory: a unifying theory of neuromodulator imbalance in psychiatry and amnesia.

PubMed

Vakalopoulos, Costa

2006-01-01

The case of HM, a man with intractable epilepsy who became amnesic following bilateral medial temporal lobe surgery nearly half a century ago has instigated ongoing research and theoretical speculation on the nature of memory and the role of the hippocampus. Neuropsychological testing showed that although HM had extensive anterograde memory loss he could still acquire motor and cognitive skills implicitly, but could not remember the context of this learning. This has lead to declarative and procedural descriptions of the memory process. Cholinergic and monoaminergic neurotransmitter systems have also been implicated in the memory process and anticholinergic drugs traditionally have been associated with impairment of declarative memory. The cholinergic hypothesis of Alzheimer's disease is a classic example of an application of these neuropharmacological findings. In schizophrenia, preattentive deficits have been amply demonstrated by unconscious priming studies. Memory processes are also impaired in these patients. Dopamine, glutamate and even cholinergic dysfunction has been implicated in the clinical picture of schizophrenia. The present paper will attempt to bring together both the anatomical and pharmacological data from these disparate fields of research under a cohesive theory of cognition and memory. A hypothesis is presented for an inverse relationship between monoaminergic and cholinergic systems in the modulation of implicit (unconscious) and explicit (conscious) cognitive processes. It is postulated that muscarinic cholinergic receptors and monoaminergic systems facilitate unconscious and conscious processes, respectively, and they disfacilitate conscious and unconscious processes, respectively (the purported inverse relationship). In fact, the muscarinic and monoaminergic modulations of a neural network are proposed to be finely balanced such that, if, the activity of one receptor system is modified then this by necessity has effects on the other system. It takes into account receptor subtypes and their effects mediated through excitatory and inhibitory G-protein complexes. For example, m1/D2 and D1/m4 paired receptor subtypes, colocalized on separate neurons would have opposing functional effects. A theory is then presented that the critical underlying pathophysiology of schizophrenia involves a hypofunctional muscarinic cholinergic system, which induces abnormal facilitation of monoaminergic subsystems such as dopamine (e.g., a decrease in m1R function would potentiate D2R function). This extends the idea of an inverted U function for optimal monoaminergic concentrations. Not only would this impair unconscious preattentive processes, but according to the hypothesis, explicit cognition as well including memory deficits and would underlie the mechanism of psychosis. Contrary to current thinking a different view is also presented for the role of the hippocampus in the memory process. It is postulated that long-term explicit memory traces in the neocortex are laid down by phasic coactivation of forebrain projecting monoaminergic systems above some basal firing rate, such as the rostral serotonergic raphe, which projects diffusely to the cortex and according to a modified Hebbian principle. This is the proposed principal function of the hippocampal theta rhythm. The phasic activation of the cholinergic basal forebrain is mediated by projections from a separate cortical structure, possibly the lateral prefrontal cortex. Phasic muscarinic receptor activation is proposed to strengthen implicit memory traces (at a synaptic level) in the neocortex. Thus, the latter are spared by medial temporal surgery explaining the dissociation of explicit from implicit memory.

Simple retrograde cerebral perfusion is as good as complex antegrade cerebral perfusion for hemiarch replacement.

PubMed

Tanaka, Akiko; Estrera, Anthony L

2018-01-01

Cerebral complication is a major concern after aortic arch surgery, which may lead to death. Thus, cerebral protection strategy plays the key role to obtain respectable results in aortic arch repair. Deep hypothermic circulatory arrest was introduced in 1970s to decrease the ischemic insults to the brain. However, safe duration of circulatory arrest time was limited to 30 minutes. The 1990s was the decade of evolution for cerebral protection, in which two adjuncts for deep hypothermic circulatory arrest were introduced: retrograde and antegrade cerebral perfusion (ACP) techniques. These two cerebral perfusion techniques significantly decreased incidence of postoperative neurological dysfunction and mortality after aortic arch surgery. Although there are no large prospective studies that demonstrate which perfusion technique provide better outcomes, multiple retrospective studies implicate that ACP may decrease cerebral complications compared to retrograde cerebral perfusion (RCP) when a long circulatory arrest time is required during aortic arch reconstructions. To date, many surgeons favor ACP over RCP during a complex aortic arch repair, such as total arch replacement and hybrid arch replacement. However, the question is whether the use of ACP is necessary during a short, limited circulatory arrest time, such as hemiarch replacement? There is a paucity of data that proves the advantages of a complex ACP over a simple RCP for a short circulatory arrest time. RCP with deep hypothermic circulatory arrest is the simple, efficient cerebral protection technique with minimal interference to the surgical field-and it potentially allows to flush atheromatous debris out from the arch vessels. Thus, it is the preferred adjunct to deep hypothermic circulatory arrest during hemiarch replacement in our institution.

Simple retrograde cerebral perfusion is as good as complex antegrade cerebral perfusion for hemiarch replacement

PubMed Central

Tanaka, Akiko

2018-01-01

Cerebral complication is a major concern after aortic arch surgery, which may lead to death. Thus, cerebral protection strategy plays the key role to obtain respectable results in aortic arch repair. Deep hypothermic circulatory arrest was introduced in 1970s to decrease the ischemic insults to the brain. However, safe duration of circulatory arrest time was limited to 30 minutes. The 1990s was the decade of evolution for cerebral protection, in which two adjuncts for deep hypothermic circulatory arrest were introduced: retrograde and antegrade cerebral perfusion (ACP) techniques. These two cerebral perfusion techniques significantly decreased incidence of postoperative neurological dysfunction and mortality after aortic arch surgery. Although there are no large prospective studies that demonstrate which perfusion technique provide better outcomes, multiple retrospective studies implicate that ACP may decrease cerebral complications compared to retrograde cerebral perfusion (RCP) when a long circulatory arrest time is required during aortic arch reconstructions. To date, many surgeons favor ACP over RCP during a complex aortic arch repair, such as total arch replacement and hybrid arch replacement. However, the question is whether the use of ACP is necessary during a short, limited circulatory arrest time, such as hemiarch replacement? There is a paucity of data that proves the advantages of a complex ACP over a simple RCP for a short circulatory arrest time. RCP with deep hypothermic circulatory arrest is the simple, efficient cerebral protection technique with minimal interference to the surgical field—and it potentially allows to flush atheromatous debris out from the arch vessels. Thus, it is the preferred adjunct to deep hypothermic circulatory arrest during hemiarch replacement in our institution. PMID:29682460

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s Disease of humans and mice

PubMed Central

Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra; Liu, Jiahui; Pike, Christian J.; Sullivan, Patrick M.; Morgan, Todd E.; Dolzhenko, Egor; Charidimou, Andreas; Wahlund, Lars-Olaf; Wiberg, Maria Kristofferson; Shams, Sara; Chiang, Gloria Chia-Yi; Finch, Caleb E.

2015-01-01

The APOE4 allele confers greater risk of Alzheimer’s Disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment (MCI) and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in two clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes. At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy (CAA), plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and CAA increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds vs the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition. PMID:26686669

Estrogen-Cholinergic Interactions: Implications for Cognitive Aging

PubMed Central

Newhouse, Paul; Dumas, Julie

2015-01-01

While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. PMID:26187712

[Minimal emotional dysfunction and first impression formation in personality disorders].

PubMed

Linden, M; Vilain, M

2011-01-01

"Minimal cerebral dysfunctions" are isolated impairments of basic mental functions, which are elements of complex functions like speech. The best described are cognitive dysfunctions such as reading and writing problems, dyscalculia, attention deficits, but also motor dysfunctions such as problems with articulation, hyperactivity or impulsivity. Personality disorders can be characterized by isolated emotional dysfunctions in relation to emotional adequacy, intensity and responsivity. For example, paranoid personality disorders can be characterized by continuous and inadequate distrust, as a disorder of emotional adequacy. Schizoid personality disorders can be characterized by low expressive emotionality, as a disorder of effect intensity, or dissocial personality disorders can be characterized by emotional non-responsivity. Minimal emotional dysfunctions cause interactional misunderstandings because of the psychology of "first impression formation". Studies have shown that in 100 ms persons build up complex and lasting emotional judgements about other persons. Therefore, minimal emotional dysfunctions result in interactional problems and adjustment disorders and in corresponding cognitive schemata.From the concept of minimal emotional dysfunctions specific psychotherapeutic interventions in respect to the patient-therapist relationship, the diagnostic process, the clarification of emotions and reality testing, and especially an understanding of personality disorders as impairment and "selection, optimization, and compensation" as a way of coping can be derived.

Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammatory Pathway.

PubMed

Zhai, Qian; Lai, Dengming; Cui, Ping; Zhou, Rui; Chen, Qixing; Hou, Jinchao; Su, Yunting; Pan, Libiao; Ye, Hui; Zhao, Jing-Wei; Fang, Xiangming

2017-10-01

Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored. Animal research. University research laboratory. Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice. The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used. Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation. These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis.

Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors tropomyosin-related kinase A and p75.

PubMed

Hoard, J L; Hoover, D B; Mabe, A M; Blakely, R D; Feng, N; Paolocci, N

2008-09-22

Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart expresses enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e. synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine beta-hydroxylase (DBH) and norepinephrine transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac neurons (ICNs), like those of humans, have a complex neurochemical phenotype that goes beyond the classical view of cardiac parasympathetic neurons. They also suggest that neurotrophins and local NE synthesis might have important effects on neurons of the mouse ICG.

Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors TrkA and p75

PubMed Central

Hoard, Jennifer L.; Hoover, Donald B.; Mabe, Abigail M.; Blakely, Randy D.; Feng, Ning; Paolocci, Nazareno

2008-01-01

Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart express enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e., synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine β-hydroxylase (DBH) and NE transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac neurons (ICNs), like those of humans, have a complex neurochemical phenotype that goes beyond the classical view of cardiac parasympathetic neurons. They also suggest that neurotrophins and local NE synthesis might have important effects on neurons of the mouse ICG. PMID:18674600

Cognitive Ameliorating Effect of Acanthopanax koreanum Against Scopolamine-Induced Memory Impairment in Mice.

PubMed

Lee, Sunhee; Park, Ho Jae; Jeon, Se Jin; Kim, Eunji; Lee, Hyung Eun; Kim, Haneul; Kwon, Yubeen; Zhang, Jiabao; Jung, In Ho; Ryu, Jong Hoon

2017-03-01

Acanthopanax koreanum Nakai (Araliaceae) is one of the most widely cultivated medicinal plants in Jeju Island, Korea, and the roots and stem bark of A. koreanum have been traditionally used as a tonic agent for general weakness. However, the use of A. koreanum for general weakness observed in the elderly, including those with declined cognitive function, has not been intensively investigated. This study was performed to investigate the effect of the ethanol extract of A. koreanum (EEAK) on cholinergic blockade-induced memory impairment in mice. To evaluate the ameliorating effects of EEAK against scopolamine-induced memory impairment, mice were orally administered EEAK (25, 50, 100, or 200 mg/kg), and several behavioral tasks, including a passive avoidance task, the Y-maze, and a novel object recognition task, were employed. Besides, western blot analysis was conducted to examine whether EEAK affected memory-associated signaling molecules, such as protein kinase B (Akt), Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), and cAMP response element-binding protein (CREB). The administration of EEAK (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in the passive avoidance task, the Y-maze, and the novel object recognition task. The phosphorylation levels of both Akt and CaMKII were significantly increased by approximately two-fold compared with the control group because of the administration of EEAK (100 or 200 mg/kg) (p < 0.05). Moreover, the phosphorylation level of CREB was also significantly increased compared with the control group by the administration of EEAK (200 mg/kg) (p < 0.05). The present study suggests that EEAK ameliorates the cognitive dysfunction induced by the cholinergic blockade, in part, via several memory-associated signaling molecules and may hold therapeutic potential against cognitive dysfunction, such as that presented in neurodegenerative diseases, for example, Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Cholinergic signaling controls conditioned-fear behaviors and enhances plasticity of cortical-amygdala circuits

PubMed Central

Jiang, Li; Kundu, Srikanya; Lederman, James D.; López-Hernández, Gretchen Y.; Ballinger, Elizabeth C.; Wang, Shaohua; Talmage, David A.; Role, Lorna W.

2016-01-01

Summary We examined the contribution of endogenous cholinergic signaling to the acquisition and extinction of fear- related memory by optogenetic regulation of cholinergic input to the basal lateral amygdala (BLA). Stimulation of cholinergic terminal fields within the BLA in awake-behaving mice during training in a cued fear-conditioning paradigm slowed the extinction of learned fear as assayed by multi-day retention of extinction learning. Inhibition of cholinergic activity during training reduced the acquisition of learned fear behaviors. Circuit mechanisms underlying the behavioral effects of cholinergic signaling in the BLA were assessed by in vivo and ex vivo electrophysiological recording. Photo-stimulation of endogenous cholinergic input: (1) enhances firing of putative BLA principal neurons through activation of acetylcholine receptors (AChRs); (2) enhances glutamatergic synaptic transmission in the BLA and (3) induces LTP of cortical-amygdala circuits. These studies support an essential role of cholinergic modulation of BLA circuits in the inscription and retention of fear memories. PMID:27161525

Biotechnology Predictors of Physical Security Personnel Performance: Cerebral Potential Measures Related to Stress.

DTIC Science & Technology

1984-02-01

often characterizes those who develop duodenal ulcers (Alexander, 1950), while the latter often seems to be the case in those who possess hysterical...vulnerable body organ-system, whose dysfunction most severely reflects the effects of the stressor. For example, patients are referred to as " ulcer -prone

Investigation of Abnormal Left Temporal Functioning in Dyslexia through rCBF, Auditory Evoked Potentials, and Positron Emission Tomography.

ERIC Educational Resources Information Center

Wood, Frank; And Others

1991-01-01

Investigates the proposed left hemisphere dysfunction in dyslexia by reviewing four studies using regional cerebral blood flow (RCBF) and combined auditory evoked responses with positron emission tomography. Emphasizes methodological issues. Finds that dyslexics showed a positive correlation between Heschl's gyrus activation and phonemic…

Effect of polyphenols on oxidative stress and mitochondrial dysfunction in neuronal death, brain edema, and cell swelling in cerebral ischemia

USDA-ARS?s Scientific Manuscript database

Polyphenols are natural substances with variable phenolic structures and are elevated in vegetables, fruits, grains, bark, roots, tea, and wine. while there are over 8000 polyphenolic structures identified in plants, edible plants contain only several hundred polyphenolic structures. In addition t...

Fronto-limbic dysfunction in borderline personality disorder: a 18F-FDG positron emission tomography study.

PubMed

Salavert, José; Gasol, Miquel; Vieta, Eduard; Cervantes, Ana; Trampal, Carlos; Gispert, Juan Domingo

2011-06-01

Several functional neuroimaging studies have demonstrated abnormalities in fronto-limbic pathways when comparing borderline personality disorder (BPD) patients with controls. The present study aimed to evaluate regional cerebral metabolism in euthymic BPD patients with similar measured impulsivity levels by means of 18F-FDG PET during resting state and to compare them against a control group. The present study evaluates regional cerebral metabolism in 8 euthymic BPD patients with 18F-FDG PET during resting state as compared to 8 controls with similar socio-geographic characteristics. BPD patients presented a marked hypo-metabolism in frontal lobe and showed hyper-metabolism in motor cortex (paracentral lobules and post-central cortex), medial and anterior cingulus, occipital lobe, temporal pole, left superior parietal gyrus and right superior frontal gyrus. No significant differences appeared in basal ganglia or thalamus. Results reveal a dysfunction in patients' frontolimbic network during rest and provide further evidence for the importance of these regions in relation to BPD symptomatology. Copyright © 2011 Elsevier B.V. All rights reserved.

Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline

PubMed Central

Engedal, Thorbjørn S; Moreton, Fiona; Hansen, Mikkel B; Wardlaw, Joanna M; Dalkara, Turgay; Markus, Hugh S; Muir, Keith W

2015-01-01

Cerebral small vessel disease (SVD) gives rise to one in five strokes worldwide and constitutes a major source of cognitive decline in the elderly. SVD is known to occur in relation to hypertension, diabetes, smoking, radiation therapy and in a range of inherited and genetic disorders, autoimmune disorders, connective tissue disorders, and infections. Until recently, changes in capillary patency and blood viscosity have received little attention in the aetiopathogenesis of SVD and the high risk of subsequent stroke and cognitive decline. Capillary flow patterns were, however, recently shown to limit the extraction efficacy of oxygen in tissue and capillary dysfunction therefore proposed as a source of stroke-like symptoms and neurodegeneration, even in the absence of physical flow-limiting vascular pathology. In this review, we examine whether capillary flow disturbances may be a shared feature of conditions that represent risk factors for SVD. We then discuss aspects of capillary dysfunction that could be prevented or alleviated and therefore might be of general benefit to patients at risk of SVD, stroke or cognitive decline. PMID:26661176

Panax ginseng extract attenuates neuronal injury and cognitive deficits in rats with vascular dementia induced by chronic cerebral hypoperfusion.

PubMed

Zhu, Jun-De; Wang, Jun-Jie; Zhang, Xian-Hu; Yu, Yan; Kang, Zhao-Sheng

2018-04-01

Panax ginseng is a slow-growing perennial plant. Panax ginseng extract has numerous biological activities, including antitumor, anti-inflammatory and antistress activities. Panax ginseng extract also has a cognition-enhancing effect in rats with alcohol-induced memory impairment. In this study, we partially occluded the bilateral carotid arteries in the rat to induce chronic cerebral hypoperfusion, a well-known model of vascular dementia. The rats were then intragastrically administered 50 or 100 mg/kg Panax ginseng extract. Morris water maze and balance beam tests were used to evaluate memory deficits and motor function, respectively. Protein quantity was used to evaluate cholinergic neurons. Immunofluorescence staining was used to assess the number of glial fibrillary acidic protein-positive cells. Western blot assay was used to evaluate protein levels of vascular endothelial growth factor, basic fibroblast growth factor, Bcl-2 and Bax. Treatment with Panax ginseng extract for 8 weeks significantly improved behavioral function and increased neuronal density and VEGF and bFGF protein expression in the hippocampal CA3 area. Furthermore, Panax ginseng extract reduced the number of glial fibrillary acidic protein-immunoreactive cells, and it decreased apoptosis by upregulating Bcl-2 and downregulating Bax protein expression. The effect of Panax ginseng extract was dose-dependent and similar to that of nimodipine, a commonly used drug for the treatment of vascular dementia. These findings suggest that Panax ginseng extract is neuroprotective against vascular dementia induced by chronic cerebral hypoperfusion, and therefore might have therapeutic potential for preventing and treating the disease.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex.

PubMed

Jeong, Da Un; Oh, Jin Hwan; Lee, Ji Eun; Lee, Jihyeon; Cho, Zang Hee; Chang, Jin Woo; Chang, Won Seok

2016-01-01

Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by ¹⁸F-2-fluoro-2-deoxyglucose positron emission tomography. During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

Cholinergic regulation of fear learning and extinction.

PubMed

Wilson, Marlene A; Fadel, Jim R

2017-03-01

Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study.

PubMed

Zant, Janneke C; Kim, Tae; Prokai, Laszlo; Szarka, Szabolcs; McNally, James; McKenna, James T; Shukla, Charu; Yang, Chun; Kalinchuk, Anna V; McCarley, Robert W; Brown, Ritchie E; Basheer, Radhika

2016-02-10

Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that "selective" stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of "selective" optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons. Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel "opto-dialysis" probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of "opto-dialysis" for dissecting the complex brain circuitry underlying behavior. Copyright © 2016 the authors 0270-6474/16/362058-11$15.00/0.

Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study

PubMed Central

Zant, Janneke C.; Kim, Tae; Prokai, Laszlo; Szarka, Szabolcs; McNally, James; McKenna, James T.; Shukla, Charu; Yang, Chun; Kalinchuk, Anna V.; McCarley, Robert W.; Brown, Ritchie E.

2016-01-01

Understanding the control of sleep–wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep–wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that “selective” stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of “selective” optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons. SIGNIFICANCE STATEMENT Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel “opto-dialysis” probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of “opto-dialysis” for dissecting the complex brain circuitry underlying behavior. PMID:26865627

Cholinergic modulation of hippocampal network function

PubMed Central

Teles-Grilo Ruivo, Leonor M.; Mellor, Jack R.

2013-01-01

Cholinergic septohippocampal projections from the medial septal area to the hippocampus are proposed to have important roles in cognition by modulating properties of the hippocampal network. However, the precise spatial and temporal profile of acetylcholine release in the hippocampus remains unclear making it difficult to define specific roles for cholinergic transmission in hippocampal dependent behaviors. This is partly due to a lack of tools enabling specific intervention in, and recording of, cholinergic transmission. Here, we review the organization of septohippocampal cholinergic projections and hippocampal acetylcholine receptors as well as the role of cholinergic transmission in modulating cellular excitability, synaptic plasticity, and rhythmic network oscillations. We point to a number of open questions that remain unanswered and discuss the potential for recently developed techniques to provide a radical reappraisal of the function of cholinergic inputs to the hippocampus. PMID:23908628

Parkinson's: a syndrome rather than a disease?

PubMed

Titova, Nataliya; Padmakumar, C; Lewis, Simon J G; Chaudhuri, K Ray

2017-08-01

Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson's disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson's to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently. Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson's is a multi-organ disorder. The Parkinson's phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease.

Estrogen-cholinergic interactions: Implications for cognitive aging.

PubMed

Newhouse, Paul; Dumas, Julie

2015-08-01

This article is part of a Special Issue "Estradiol and Cognition". While many studies in humans have investigated the effects of estrogen and hormone therapy on cognition, potential neurobiological correlates of these effects have been less well studied. An important site of action for estrogen in the brain is the cholinergic system. Several decades of research support the critical role of CNS cholinergic systems in cognition in humans, particularly in learning and memory formation and attention. In humans, the cholinergic system has been implicated in many aspects of cognition including the partitioning of attentional resources, working memory, inhibition of irrelevant information, and improved performance on effort-demanding tasks. Studies support the hypothesis that estradiol helps to maintain aspects of attention and verbal and visual memory. Such cognitive domains are exactly those modulated by cholinergic systems and extensive basic and preclinical work over the past several decades has clearly shown that basal forebrain cholinergic systems are dependent on estradiol support for adequate functioning. This paper will review recent human studies from our laboratories and others that have extended preclinical research examining estrogen-cholinergic interactions to humans. Studies examined include estradiol and cholinergic antagonist reversal studies in normal older women, examinations of the neural representations of estrogen-cholinergic interactions using functional brain imaging, and studies of the ability of selective estrogen receptor modulators such as tamoxifen to interact with cholinergic-mediated cognitive performance. We also discuss the implications of these studies for the underlying hypotheses of cholinergic-estrogen interactions and cognitive aging, and indications for prophylactic and therapeutic potential that may exploit these effects. Published by Elsevier Inc.

Quantification of amyloid deposits and oxygen extraction fraction in the brain with multispectral optoacoustic imaging in arcAβ mouse model of Alzheimer's disease

NASA Astrophysics Data System (ADS)

Ni, Ruiqing; Vaas, Markus; Rudin, Markus; Klohs, Jan

2018-02-01

Beta-amyloid (Aβ) deposition and vascular dysfunction are important contributors to the pathogenesis in Alzheimer's disease (AD). However, the spatio-temporal relationship between an altered oxygen metabolism and Aβ deposition in the brain remains elusive. Here we provide novel in-vivo estimates of brain Aβ load with Aβ-binding probe CRANAD-2 and measures of brain oxygen saturation by using multi-spectral optoacoustic imaging (MSOT) and perfusion imaging with magnetic resonance imaging (MRI) in arcAβ mouse models of AD. We demonstrated a decreased cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in the cortical region of the arcAβ mice compared to wildtype littermates at 24 months. In addition, we showed proof-of-concept for the detection of cerebral Aβ deposits in brain from arcAβ mice compared to wild-type littermates.

In silico development of new acetylcholinesterase inhibitors.

PubMed

Pascoini, A L; Federico, L B; Arêas, A L F; Verde, B A; Freitas, P G; Camps, I

2018-04-19

In this work, we made use of fragment-based drug design (FBDD) and de novo design to obtain more powerful acetylcholinesterase (AChE) inhibitors. AChE is associated with Alzheimer's disease (AD). It was found that the cholinergic pathways in the cerebral cortex are compromised in AD and the accompanying cholinergic deficiency contributes to the cognitive deterioration of AD patients. In the FBDD approach, fragments are docked into the active site of the protein. As fragments are molecular groups with a low number of atoms, it is possible to study their interaction with localized amino acids. Once the interactions are measured, the fragments are organized by affinity and then linked together to form new molecules with a high degree of interaction with the active site. In the other approach, we used the de novo design technique starting from reference drugs used in the AD treatment. These drugs were broken into fragments (seeds). In the growing strategy, fragments were added to each seed, growing new molecules. In the linking strategy, two or more separated seeds were linked with different fragments. Both strategies combined produced a library of more than 2 million compounds. This library was filtered using absorption, distribution, metabolism, and excretion properties. The resulting library with around six thousand compounds was filtered again. In this case, structures with Tanimoto coefficients >.85 were discarded. The final library with 1500 compounds was submitted to docking studies. As a result, 10 compounds with better interaction energy than the reference drugs were obtained.

Retrograde and antegrade cerebral perfusion: results in short elective arch reconstructive times.

PubMed

Milewski, Rita Karianna; Pacini, Davide; Moser, G William; Moeller, Patrick; Cowie, Doreen; Szeto, Wilson Y; Woo, Y Joseph; Desai, Nimesh; Di Marco, Luca; Pochettino, Alberto; Di Bartolomeo, Roberto; Bavaria, Joseph E

2010-05-01

Debate remains regarding optimal cerebral circulatory management during relatively noncomplex, short arch reconstructive times. Both retrograde cerebral perfusion with deep hypothermic circulatory arrest (RCP/DHCA) and antegrade cerebral perfusion with moderate hypothermic circulatory arrest (ACP/MHCA) have emerged as established techniques. The aim of the study was to evaluate perioperative outcomes between antegrade and retrograde cerebral perfusion techniques for elective arch reconstruction times less than 45 minutes. Between 1997 and September 2008, 776 cases from two institutions were reviewed to compare RCP/DHCA and ACP/MHCA perfusion techniques. At the University of Pennsylvania, 682 were treated utilizing RCP/DHCA cerebral protection. At the University of Bologna, 94 were treated with ACP/MHCA and bilateral cerebral perfusion. Mean cerebral ischemic time and visceral ischemic time differed between RCP/DHCA and ACP/MHCA (p < 0.001). Multivariate analysis showed age more than 65 years, atherosclerotic aneurysm, and cross-clamp time as predictors of the composite endpoint of mortality, neurologic event, and acute myocardial infarction. There was no significant difference in permanent neurologic deficit, temporary neurologic dysfunction, or renal failure, between RCP/DHCA and ACP/MHCA. Mortality was comparable across both techniques. Both RCP/DHCA and ACP/MHCA have emerged as effective techniques for selected aortic arch operations with low morbidity and mortality. Univariate analysis revealed no statistically significant differences in primary or secondary outcomes between techniques for aortic reconstruction times less than 45 minutes. Data from this study demonstrate that selective use of either RCP/DHCA or ACP/MHCA provides excellent cerebral and visceral outcomes for elective open aortic surgery with short arch reconstructive times. Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

ASPREE-NEURO study protocol: A randomized controlled trial to determine the effect of low-dose aspirin on cerebral microbleeds, white matter hyperintensities, cognition, and stroke in the healthy elderly.

PubMed

Ward, Stephanie A; Raniga, Parnesh; Ferris, Nicholas J; Woods, Robyn L; Storey, Elsdon; Bailey, Michael J; Brodtmann, Amy; Yates, Paul A; Donnan, Geoffrey A; Trevaks, Ruth E; Wolfe, Rory; Egan, Gary F; McNeil, John J

2017-01-01

Rationale Cerebral microbleeds seen on brain magnetic resonance imaging are markers of small vessel disease, linked to cognitive dysfunction and increased ischemic and hemorrhagic stroke risk. Observational studies suggest that aspirin use may induce cerebral microbleeds, and associated overt intracranial hemorrhage, but this has not been definitively resolved. Aims ASPREE-NEURO will determine the effect of aspirin on cerebral microbleed development over three years in healthy adults aged 70 years and over, participating in the larger 'ASPirin in Reducing Events in the Elderly (ASPREE)' primary prevention study of aspirin. Sample size Five hundred and fifty-nine participants provide 75% power (two-sided p value of 0.05) to determine an average difference of 0.5 cerebral microbleed per person after three years. Methods and design A multi-center, randomized placebo-controlled trial of 100 mg daily aspirin in participants who have brain magnetic resonance imaging at study entry, one and three years after randomization and who undergo cognitive testing at the same time points. Study outcomes The primary outcome is the number of new cerebral microbleeds on magnetic resonance imaging after three years. Secondary outcomes are the number of new cerebral microbleeds after one year, change in volume of white matter hyperintensity, cognitive function, and stroke. Discussion ASPREE-NEURO will resolve whether aspirin affects the presence and number of cerebral microbleeds, their relationship with cognitive performance, and indicate whether consideration of cerebral microbleeds alters the risk-benefit profile of aspirin in primary prevention for older people. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001313729.

Cerebral blood flow regulation during cognitive tasks

PubMed Central

Sorond, Farzaneh A.; Schnyer, D.M.; Serrador, J.M.; Milberg, W.P.; Lipsitz, L.A.

2008-01-01

Aging is associated with frontal subcortical microangiopathy and executive cognitive dysfunction, suggesting that elderly individuals may have impaired metabolic activation of cerebral blood flow to the frontal lobes. We used transcranial Doppler (TCD) ultrasound to examine the cerebral blood flow response to executive control and visual tasks in the anterior and posterior cerebral circulations and to determine the effects of healthy aging on cerebral blood flow regulation during cognitive tasks. Continuous simultaneous anterior cerebral artery (ACA) and posterior cerebral artery (PCA) blood flow velocities (BFVs) and mean arterial pressure (MAP) were measured in response to word stem completion (WSC) and a visual search (VS) task in 29 healthy subjects (14 young, 30 ± 1.5 years; 15 old, 74 ± 1.4 years). We found that: (1) ACA and PCA blood flow velocities are both significantly increased during WSC and VS cognitive tasks, (2) ACA and PCA activations were task specific in our young volunteers, with ACA > PCA BFV during the WSC task and PCA > ACA BFV during the VS task, (3) while healthy elderly subjects also had PCA > ACA BFV during the VS task, they did not have ACA > PCA activation during the WSC task, and (4) healthy elderly subjects tend to have overall greater increases in BFV during both cognitive tasks. We conclude that TCD can be used to monitor cerebrovascular hemodynamics during the performance of cognitive tasks. Our data suggest that there is differential blood flow increase in the ACA and PCA in young versus elderly subjects during cognitive tasks. PMID:18387547

Slow pupillary light responses in infants at high risk of cerebral palsy were associated with periventricular leukomalacia and neurological outcome.

PubMed

Hamer, Elisa G; Vermeulen, R Jeroen; Dijkstra, Linze J; Hielkema, Tjitske; Kos, Claire; Bos, Arend F; Hadders-Algra, Mijna

2016-12-01

Having observed slow pupillary light responses (PLRs) in infants at high risk of cerebral palsy, we retrospectively evaluated whether these were associated with specific brain lesions or unfavourable outcomes. We carried out neurological examinations on 30 infants at very high risk of cerebral palsy five times until the corrected age of 21 months, classifying each PLR assessment as normal or slow. The predominant reaction during development was determined for each infant. Neonatal brain scans were classified based on the type of brain lesion. Developmental outcome was evaluated at 21 months of corrected age with a neurological examination, the Bayley Scales of Infant Development Second Edition and the Infant Motor Profile. Of the 30 infants, 16 developed cerebral palsy. Predominantly slow PLRs were observed in eight infants and were associated with periventricular leukomalacia (p = 0.007), cerebral palsy (p = 0.039), bilateral cerebral palsy (p = 0.001), poorer quality of motor behaviour (p < 0.0005) and poorer cognitive outcome (p = 0.045). This explorative study suggested that predominantly slow PLR in infants at high risk of cerebral palsy were associated with periventricular leukomalacia and poorer developmental outcome. Slow PLR might be an expression of white matter damage, resulting in dysfunction of the complex cortico-subcortical circuitries. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

A new hypothesis on the manifestation of cerebral malaria: the secret is in the liver.

PubMed

Martins, Yuri Chaves; Daniel-Ribeiro, Cláudio Tadeu

2013-11-01

Despite the abundance of information on cerebral malaria (CM), the pathogenesis of this disease is not completely understood. At present, two nonexclusive dominant hypotheses exist to explain how the neurological syndrome manifests: the sequestration (or mechanical) hypothesis and the inflammatory hypothesis. The sequestration hypothesis states that sequestration of Plasmodium falciparum-parasitized red blood cells (pRBCs) to brain capillary endothelia causes obstruction of capillary blood flow followed by brain tissue anoxia and coma. The inflammatory hypothesis postulates that P. falciparum infection releases toxic molecules in the circulation, inducing an imbalanced systemic inflammatory response that leads to coagulopathy, brain endothelial cell dysfunction, accumulation of leukocytes in the brain microcirculation, blood brain barrier (BBB) leakage, cerebral vasoconstriction, edema, and coma. However, both hypotheses, even when considered together, are not sufficient to fully explain the pathogenesis of CM. Here, we propose that the development of acute liver failure (ALF) together with BBB breakdown are the necessary and sufficient conditions for the genesis of CM. ALF is characterized by coagulopathy and hepatic encephalopathy (HE) in a patient without pre-existing liver disease. Signs of hepatic dysfunction have been shown to occur in 2.5-40% of CM patients. In addition, recent studies with murine models demonstrated that mice presenting experimental cerebral malaria (ECM) had hepatic damage and brain metabolic changes characteristic of HE. However, the occurrence of CM in patients with mild or without apparent hepatocellular liver damage and the presence of liver damage in non-CM murine models indicate that the development of ALF during malaria infection is not the single factor responsible for neuropathology. To solve this problem, we also propose that BBB breakdown contributes to the pathogenesis of CM and synergizes with hepatic failure to cause neurological signs and symptoms. BBB dysfunction would thus occur in CM by a mechanism similar to the one occurring in sepsis and is in agreement with the inflammatory hypothesis. Nevertheless, differently from in the inflammatory hypothesis, BBB leakage would facilitate the penetration of ammonia and other toxins into the brain parenchyma, but would not be sufficient to cause CM when occurring alone. We believe our hypothesis better explains the pathogenesis of CM, does not have problems to deal with the exception data not explained by the previous hypotheses, and reveals new targets for adjunctive therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mechanisms of cholinergic dysfunction in rabbits following recurrent aspiration of cow's milk.

PubMed

Larsen, G L; Loader, J; Nguyen, D D; Colasurdo, G N

2001-12-01

Recurrent aspiration of cow's milk has been shown to alter neural control of airways in young rabbits (Gelfand et al., 1997). The purpose of this study was to define the mechanisms responsible for in vitro cholinergic hyperresponsiveness in this model. Beginning at 1 week of age, rabbits received either 0.5 mL/kg whole cow's milk or sterile saline intranasally while under light anesthesia. This was repeated each weekday for 2 weeks. At 8 weeks of age, rabbits were sacrificed. Portions of lungs underwent lavage with sterile saline. Tracheal smooth muscle (TSM) segments were also removed. Segments were assessed for acetylcholine (ACh) release by high-performance liquid chromatography ( HPLC) with electrochemical detection or acetylcholinesterase (AChE) kinetic activity by spectrophotometry. Substance P (SP), a neuropeptide that can increase ACh release from nerves, was also assessed using an enzyme immunoassay to define the content in lavage and TSM segments. Immunohistochemistry for SP within airways was also assessed. We found that recurrent aspiration of milk led to statistically significant alterations in many parameters. Acetylcholine release was significantly greater in segments of airways from rabbits that had aspirated cow's milk (27.5 +/- 1.7 vs. 20.1 +/- 1.6 pmol/min/g tissue) than saline. At the same time, AChE activity was less in the group that aspirated milk (8.7 +/- 0.4 vs. 10.2 +/- 0.5 nmol/min/mg protein) compared to saline. The amount of SP within both lavage as well as tissue homogenates was greater in the group that had aspirated the foreign protein (159.1 +/- 28.9 vs. 41.9 +/- 5.2 pmol/mg protein in lavage; 158.7 +/- 31.9 vs. 80.5 +/- 7.8 pmol/mg protein in tissues) than saline controls. While total cholinergic nerve density as assessed by choline acetyltransferase was not significantly different between groups, SP-positive immunoreactive nerves were easily identified in the group that aspirated cow's milk. This study suggests that cholinergic hyperresponsiveness caused by repeated aspiration of milk is due to several abnormalities, including prejunctional (increase in ACh release) as well as junctional (decrease in AChE) mechanisms within the airways. In addition, an upregulation of SP within airways is part of this process. Copyright 2001 Wiley-Liss, Inc.

Lesions of cholinergic pedunculopontine tegmental nucleus neurons fail to affect cocaine or heroin self-administration or conditioned place preference in rats.

PubMed

Steidl, Stephan; Wang, Huiling; Wise, Roy A

2014-01-01

Cholinergic input to the ventral tegmental area (VTA) is known to contribute to reward. Although it is known that the pedunculopontine tegmental nucleus (PPTg) provides an important source of excitatory input to the dopamine system, the specific role of PPTg cholinergic input to the VTA in cocaine reward has not been previously determined. We used a diphtheria toxin conjugated to urotensin-II (Dtx::UII), the endogenous ligand for urotensin-II receptors expressed by PPTg cholinergic but not glutamatergic or GABAergic cells, to lesion cholinergic PPTg neurons. Dtx::UII toxin infusion resulted in the loss of 95.78 (±0.65)% of PPTg cholinergic cells but did not significantly alter either cocaine or heroin self-administration or the development of cocaine or heroin conditioned place preferences. Thus, cholinergic cells originating in PPTg do not appear to be critical for the rewarding effects of cocaine or of heroin.

Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

PubMed

Dautan, Daniel; Souza, Albert S; Huerta-Ocampo, Icnelia; Valencia, Miguel; Assous, Maxime; Witten, Ilana B; Deisseroth, Karl; Tepper, James M; Bolam, J Paul; Gerdjikov, Todor V; Mena-Segovia, Juan

2016-08-01

Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

Functional magnetic resonance imaging in primary writing tremor and writer’s cramp: A pilot study

PubMed Central

Sahni, Hirdesh; Jayakumar, Peruvumba N.; Pal, Pramod Kumar

2010-01-01

Objectives: The precise pathophysiology of primary writing tremor (PWT) and writer’s cramp (WC) is not known. The aim of this study is to compare the cerebral activation patterns in patients of PWT, WC and healthy controls, during a task of signing on paper, using functional magnetic resonance imaging (fMRI). Materials and Methods: Six subjects with PWT, three with WC and six healthy volunteers were examined using a 1.5-Tesla scanner. The paradigm consisted of three times repetition of a set of period of rest and activity. Each set consisted of 10 blood oxygen level dependent (BOLD) echo-planar imaging (EPI) acquisitions at rest followed by 10 BOLD EPI acquisitions while signing their names on paper using the dominant right hand. Entire brain was covered. SPM99 analysis was done. Results: In comparison to the healthy controls, the following differences in cerebral activation were noted in the patients: (a) primary and supplementary motor areas showed overactivation in patients of PWT and underactivation in patients of WC, (b) the cingulate motor area showed underactivation in patients of PWT and overactivation in patients of WC and (c) the cerebellar activity was reduced in both WC and PWT. Conclusion: Our preliminary findings suggest that the cerebral and cerebellar activation patterns in PWT and WC during signing on paper are distinct from each other and from healthy controls. There may be cerebellar dysfunction in addition to motor dysfunctions in the pathogenesis of these disorders. PMID:21085530

Signal transducers and activators of transcription: STATs-mediated mitochondrial neuroprotection.

PubMed

Lin, Hung Wen; Thompson, John W; Morris, Kahlilia C; Perez-Pinzon, Miguel A

2011-05-15

Cerebral ischemia is defined as little or no blood flow in cerebral circulation, characterized by low tissue oxygen and glucose levels, which promotes neuronal mitochondria dysfunction leading to cell death. A strategy to counteract cerebral ischemia-induced neuronal cell death is ischemic preconditioning (IPC). IPC results in neuroprotection, which is conferred by a mild ischemic challenge prior to a normally lethal ischemic insult. Although many IPC-induced mechanisms have been described, many cellular and subcellular mechanisms remain undefined. Some reports have suggested key signal transduction pathways of IPC, such as activation of protein kinase C epsilon, mitogen-activated protein kinase, and hypoxia-inducible factors, that are likely involved in IPC-induced mitochondria mediated-neuroprotection. Moreover, recent findings suggest that signal transducers and activators of transcription (STATs), a family of transcription factors involved in many cellular activities, may be intimately involved in IPC-induced ischemic tolerance. In this review, we explore current signal transduction pathways involved in IPC-induced mitochondria mediated-neuroprotection, STAT activation in the mitochondria as it relates to IPC, and functional significance of STATs in cerebral ischemia.

Signal Transducers and Activators of Transcription: STATs-Mediated Mitochondrial Neuroprotection

PubMed Central

Lin, Hung Wen; Thompson, John W.; Morris, Kahlilia C.

2011-01-01

Abstract Cerebral ischemia is defined as little or no blood flow in cerebral circulation, characterized by low tissue oxygen and glucose levels, which promotes neuronal mitochondria dysfunction leading to cell death. A strategy to counteract cerebral ischemia-induced neuronal cell death is ischemic preconditioning (IPC). IPC results in neuroprotection, which is conferred by a mild ischemic challenge prior to a normally lethal ischemic insult. Although many IPC-induced mechanisms have been described, many cellular and subcellular mechanisms remain undefined. Some reports have suggested key signal transduction pathways of IPC, such as activation of protein kinase C epsilon, mitogen-activated protein kinase, and hypoxia-inducible factors, that are likely involved in IPC-induced mitochondria mediated-neuroprotection. Moreover, recent findings suggest that signal transducers and activators of transcription (STATs), a family of transcription factors involved in many cellular activities, may be intimately involved in IPC-induced ischemic tolerance. In this review, we explore current signal transduction pathways involved in IPC-induced mitochondria mediated-neuroprotection, STAT activation in the mitochondria as it relates to IPC, and functional significance of STATs in cerebral ischemia. Antioxid. Redox Signal. 14, 1853–1861. PMID:20712401

Gender and rapid alterations of hemispheric dominance during planning.

PubMed

Schuepbach, Daniel; Skotchko, Tatjana; Duschek, Stefan; Theodoridou, Anastasia; Grimm, Simone; Boeker, Heinz; Seifritz, Erich

2012-01-01

Mental planning and carrying out a plan provoke specific cerebral hemodynamic responses. Gender aspects of hemispheric laterality using rapid cerebral hemodynamics have not been reported. Here, we applied functional transcranial Doppler sonography to examine lateralization of cerebral hemodynamics of the middle cerebral arteries of 28 subjects (14 women and 14 men) performing a standard planning task. There were easy and difficult problems, and mental planning without motor activity was separated from movement execution. Difficult mental planning elicited lateralization to the right hemisphere after 2 or more seconds, a feature that was not observed during movement execution. In females, there was a dominance to the left hemisphere during movement execution. Optimized problem solving yielded an increased laterality change to the right during mental planning. Gender-related hemispheric dominance appears to be condition-dependent, and change of laterality to the right may play a role in optimized performance. Results are of relevance when considering laterality from a perspective of performance enhancement of higher cognitive functions, and also of psychiatric disorders with cognitive dysfunctions and abnormal lateralization patterns such as schizophrenia. Copyright © 2012 S. Karger AG, Basel.

A Virtual Environment to Improve the Detection of Oral-Facial Malfunction in Children with Cerebral Palsy.

PubMed

Martín-Ruiz, María-Luisa; Máximo-Bocanegra, Nuria; Luna-Oliva, Laura

2016-03-26

The importance of an early rehabilitation process in children with cerebral palsy (CP) is widely recognized. On the one hand, new and useful treatment tools such as rehabilitation systems based on interactive technologies have appeared for rehabilitation of gross motor movements. On the other hand, from the therapeutic point of view, performing rehabilitation exercises with the facial muscles can improve the swallowing process, the facial expression through the management of muscles in the face, and even the speech of children with cerebral palsy. However, it is difficult to find interactive games to improve the detection and evaluation of oral-facial musculature dysfunctions in children with CP. This paper describes a framework based on strategies developed for interactive serious games that is created both for typically developed children and children with disabilities. Four interactive games are the core of a Virtual Environment called SONRIE. This paper demonstrates the benefits of SONRIE to monitor children's oral-facial difficulties. The next steps will focus on the validation of SONRIE to carry out the rehabilitation process of oral-facial musculature in children with cerebral palsy.

Cortical cholinergic signaling controls the detection of cues

PubMed Central

Gritton, Howard J.; Howe, William M.; Mallory, Caitlin S.; Hetrick, Vaughn L.; Berke, Joshua D.; Sarter, Martin

2016-01-01

The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses. PMID:26787867

Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline.

PubMed

Kucinski, Aaron; Sarter, Martin

2015-04-01

In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson's disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice

PubMed Central

Devi, Latha; Ohno, Masuo

2010-01-01

β-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) generation and thus represents a prime therapeutic target in treating Alzheimer's disease (AD). Notably, increasing evidence indicates that BACE1 levels become elevated in AD brains as disease progresses; however, it remains unclear how the BACE1 upregulation may affect efficacies of therapeutic interventions including BACE1-inhibiting approaches. Here, we crossed heterozygous BACE1 knockout mice with AD transgenic mice (5XFAD model) and compared the abilities of partial BACE1 reduction to rescue AD-like phenotypes at earlier (6-month-old) and advanced (15–18-month-old) stages of disease, which expressed normal (∼100%) and elevated (∼200%) levels of BACE1, respectively. BACE1+/− deletion rescued memory deficits as tested by the spontaneous alternation Y-maze task in 5XFAD mice at the earlier stage and prevented their septohippocampal cholinergic deficits associated with significant neuronal loss. Importantly, BACE1+/− deletion was no longer able to rescue memory deficits or cholinergic neurodegeneration in 5XFAD mice at the advanced stage. Moreover, BACE1+/− deletion significantly reduced levels of Aβ42 and the β-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic β-cleavage products dramatically elevated with age and were not affected by BACE1+/− deletion in 15–18-month-old 5XFAD brains. Interestingly, although BACE1+/− deletion lowered BACE1 expression by ∼50% in 5XFAD mice irrespective of age in concordance with the reduction in gene copy number, BACE1 equivalent to wild-type controls remained in BACE1+/−·5XFAD mice at the advanced age. In accord, phosphorylation of the translation initiation factor eIF2α, an important mediator of BACE1 elevation, was dramatically increased (∼9-fold) in 15–18-month-old 5XFAD mice and remained highly upregulated (∼6-fold) in age-matched BACE1+/−·5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration. PMID:20886088

Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain.

PubMed

Schliebs, R; Liebmann, A; Bhattacharya, S K; Kumar, A; Ghosal, S; Bigl, V

1997-02-01

Although some promising results have been achieved by acetylcholinesterase inhibitors, an effective therapeutic intervention in Alzheimer's disease still remains an important goal. Sitoindosides VII-X, and withaferin-A, isolated from aqueous methanol extract from the roots of cultivated varieties of Withania somnifera (known as Indian Ginseng), as well as Shilajit, a pale-brown to blackish brown exudation from steep rocks of the Himalaya mountain, are used in Indian medicine to attenuate cerebral functional deficits, including amnesia, in geriatric patients. The present investigation was conducted to assess whether the memory-enhancing effects of plant extracts from Withania somnifera and Shilajit are owing to neurochemical alterations of specific transmitter systems. Therefore, histochemistry to analyse acetylcholinesterase activity as well as receptor autoradiography to detect cholinergic, glutamatergic and GABAergic receptor subtypes were performed in brain slices from adult male Wistar rats, injected intraperitoneally daily with an equimolar mixture of sitoindosides VII-X and withaferin-A (prepared from Withania somnifera) or with Shilajit, at doses of 40 mg/kg of body weight for 7 days. Administration of Shilajit led to reduced acetylcholinesterase staining, restricted to the basal forebrain nuclei including medial septum and the vertical limb of the diagonal band. Systemic application of the defined extract from Withania somnifera, however, led to differential effects on AChE activity in basal forebrain nuclei: slightly enhanced AChE activity was found in the lateral septum and globus pallidus, whereas in the vertical diagonal band AChE activity was reduced following treatment with sitoindosides VII-X and withaferin-A. These changes were accompanied by enhanced M1-muscarinic cholinergic receptor binding in lateral and medial septum as well as in frontal cortices, whereas the M2-muscarinic receptor binding sites were increased in a number of cortical regions including cingulate, frontal, piriform, parietal and retrosplenial cortex. Treatment with Shilajit or the defined extract from Withania somnifera affected neither GABAA and benzodiazepine receptor binding nor NMDA and AMPA glutamate receptor subtypes in any of the cortical or subcortical regions studied. The data suggest that Shilajit and the defined extract from Withania somnifera affect preferentially events in the cortical and basal forebrain cholinergic signal transduction cascade. The drug-induced increase in cortical muscarinic acetylcholine receptor capacity might partly explain the cognition-enhancing and memory-improving effects of extracts from Withania somnifera observed in animals and humans.

Remodeling of cardiac cholinergic innervation and control of heart rate in mice with streptozotocin-induced diabetes.

PubMed

Mabe, Abigail M; Hoover, Donald B

2011-07-05

Cardiac autonomic neuropathy is a frequent complication of diabetes and often presents as impaired cholinergic regulation of heart rate. Some have assumed that diabetics have degeneration of cardiac cholinergic nerves, but basic knowledge on this topic is lacking. Accordingly, our goal was to evaluate the structure and function of cardiac cholinergic neurons and nerves in C57BL/6 mice with streptozotocin-induced diabetes. Electrocardiograms were obtained weekly from conscious control and diabetic mice for 16 weeks. Resting heart rate decreased in diabetic mice, but intrinsic heart rate was unchanged. Power spectral analysis of electrocardiograms revealed decreased high frequency and increased low frequency power in diabetic mice, suggesting a relative reduction of parasympathetic tone. Negative chronotropic responses to right vagal nerve stimulation were blunted in 16-week diabetic mice, but postjunctional sensitivity of isolated atria to muscarinic agonists was unchanged. Immunohistochemical analysis of hearts from diabetic and control mice showed no difference in abundance of cholinergic neurons, but cholinergic nerve density was increased at the sinoatrial node of diabetic mice (16 weeks: 14.9±1.2% area for diabetics versus 8.9±0.8% area for control, P<0.01). We conclude that disruption of cholinergic function in diabetic mice cannot be attributed to a loss of cardiac cholinergic neurons and nerve fibers or altered cholinergic sensitivity of the atria. Instead, decreased responses to vagal stimulation might be caused by a defect of preganglionic cholinergic neurons and/or ganglionic neurotransmission. The increased density of cholinergic nerves observed at the sinoatrial node of diabetic mice might be a compensatory response. Copyright © 2011 Elsevier B.V. All rights reserved.

Modulation of cholinergic functions by serotonin and possible implications in memory: general data and focus on 5-HT(1A) receptors of the medial septum.

PubMed

Jeltsch-David, Hélène; Koenig, Julie; Cassel, Jean-Christophe

2008-12-16

Cholinergic systems were linked to cognitive processes like attention and memory. Other neurotransmitter systems having minor influence on cognitive functions - as shown by the weakness of the effects of their selective lesions - modulate cholinergic functions. The serotonergic system is such a system. Conjoined functional changes in cholinergic and serotonergic systems may have marked cognitive consequences [Cassel JC, Jeltsch H. Serotoninergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 1995;69(1):1-41; Steckler T, Sahgal A. The role of serotoninergic-cholinergic interactions in the mediation of cognitive behaviour. Behav Brain Res 1995;67:165-99]. A crucial issue in that concern is the identification of the neuroanatomical and neuropharmacological substrates where functional effects of serotonergic/cholinergic interactions originate. Approaches relying on lesions and intracerebral cell grafting, on systemic drug-cocktail injections, or even on intracerebral drug infusions represent the main avenues on which our knowledge about the role of serotonergic/cholinergic interactions has progressed. The present review will visit some of these avenues and discuss their contribution to what is currently known on the potential or established implication(s) into memory functions of serotonergic/cholinergic interactions. It will then focus on a brain region and a neuropharmacological substrate that have been poorly studied as regards serotonergic modulation of memory functions, namely the medial septum and its 5-HT(1A) receptors. Based on recent findings of our laboratory, we suggest that these receptors, located on both cholinergic and GABAergic septal neurons, take part in a mechanism that controls encoding, to some extent consolidation, but not retrieval, of hippocampal-dependent memories. This control, however, does not occur by the way of an exclusive action of serotonin on cholinergic neurons.

Heterogeneity in Kv7 channel function in the cerebral and coronary circulation.

PubMed

Lee, Sewon; Yang, Yan; Tanner, Miles A; Li, Min; Hill, Michael A

2015-02-01

Kv7 channels are considered important regulators of vascular smooth muscle contractility. The present study aimed to examine the hypotheses that (i) Kv7 channels are present in mouse cerebral and coronary arteries and regulate vascular reactivity and (ii) regional differences exist in the activity of these channels. PCR confirmed that basilar, Circle of Willis and LAD arteries express predominantly Kv7.1 and 7.4. Western blot analysis, however, showed greater Kv7.4 protein levels in the cerebral vessels. Relaxation to the Kv7 channel activator, retigabine (1-50 μM) was significantly greater in the basilar artery compared to the LAD artery. Similarly, the Kv7 channel inhibitor, linopirdine (10 μM) caused a stronger contraction of the basilar artery. Furthermore, pre-incubation with linopirdine reduced forskolin (cAMP activator)-induced vasorelaxation in basilar while not altering forskolin-induced vasorelaxation of the LAD, suggesting that Kv7 channels play a more prominent role in the cerebral than in the coronary circulation. Consistent with the vessel data, whole cell Kv7 currents in cerebral VSMCs were potentiated by retigabine and inhibited by linopirdine, while these responses were blunted in coronary VSMCs. This study provides evidence that mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. Such heterogeneity has important implications for developing novel therapeutics for cardiovascular dysfunction. © 2014 John Wiley & Sons Ltd.

Heterogeneity in Kv7 channel function in the Cerebral and Coronary Circulation

PubMed Central

Tanner, Miles A.; Li, Min; Hill, Michael A.

2014-01-01

Kv7 channels are considered important regulators of vascular smooth muscle contractility. The present study examined the hypotheses that 1. Kv7 channels are present in mouse cerebral and coronary arteries and regulate vascular reactivity, and 2. regional differences exist in the activity of these channels. PCR confirmed that basilar, Circle of Willis and left anterior descending (LAD) arteries express predominantly Kv7.1 and 7.4. Western blot analysis, however, showed greater Kv7.4 protein levels in the cerebral vessels. Relaxation to the Kv7 channel activator, retigabine (1-50μM) was significantly greater in basilar compared to LAD. Similarly, the Kv7 channel inhibitor, linopirdine (10μM) caused stronger contraction of the basilar artery. Furthermore, pre-incubation with linopirdine reduced forskolin (cAMP activator)-induced vasorelaxation in basilar while not altering forskolin-induced vasorelaxation of the LAD, suggesting that Kv7 channels play a more prominent role in the cerebral than coronary circulation. Consistent with the vessel data, whole cell Kv7 currents in cerebral VSMCs were potentiated by retigabine and inhibited by linopirdine, while these responses were blunted in coronary VSMCs. This study provides evidence that mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. Such heterogeneity has important implications for developing novel therapeutics for cardiovascular dysfunction. PMID:25476662

Curcumin and Apigenin – novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease

PubMed Central

Venigalla, Madhuri; Gyengesi, Erika; Münch, Gerald

2015-01-01

Alzheimer's disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer's disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer's disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer's disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer's disease or slow down its progression, and they should enter clinical trials as soon as possible. PMID:26487830

Cerebral Oedema, Blood-Brain Barrier Breakdown and the Decrease in Na(+),K(+)-ATPase Activity in the Cerebral Cortex and Hippocampus are Prevented by Dexamethasone in an Animal Model of Maple Syrup Urine Disease.

PubMed

Rosa, Luciana; Galant, Leticia S; Dall'Igna, Dhébora M; Kolling, Janaina; Siebert, Cassiana; Schuck, Patrícia F; Ferreira, Gustavo C; Wyse, Angela T S; Dal-Pizzol, Felipe; Scaini, Giselli; Streck, Emilio L

2016-08-01

Maple syrup urine disease (MSUD) is a rare metabolic disorder associated with acute and chronic brain dysfunction. This condition has been shown to lead to macroscopic cerebral alterations that are visible on imaging studies. Cerebral oedema is widely considered to be detrimental for MSUD patients; however, the mechanisms involved are still poorly understood. Therefore, we investigated whether acute administration of branched-chain amino acids (BCAA) causes cerebral oedema, modifies the Na(+),K(+)-ATPase activity, affects the permeability of the blood-brain barrier (BBB) and alters the levels of cytokines in the hippocampus and cerebral cortex of 10-day-old rats. Additionally, we investigated the influence of concomitant administration of dexamethasone on the alterations caused by BCAA. Our results showed that the animals submitted to the model of MSUD exhibited an increase in the brain water content, both in the cerebral cortex and in the hippocampus. By investigating the mechanism of cerebral oedema, we discovered an association between H-BCAA and the Na(+),K(+)-ATPase activity and the permeability of the BBB to small molecules. Moreover, the H-BCAA administration increases Il-1β, IL-6 and TNF-α levels in the hippocampus and cerebral cortex, whereas IL-10 levels were decreased in the hippocampus. Interestingly, we showed that the administration of dexamethasone successfully reduced cerebral oedema, preventing the inhibition of Na(+),K(+)-ATPase activity, BBB breakdown and the increase in the cytokines levels. In conclusion, these findings suggest that dexamethasone can improve the acute cerebral oedema and brain injury associated with high levels of BCAA, either through a direct effect on brain capillary Na(+),K(+)-ATPase or through a generalized effect on the permeability of the BBB to all compounds.

Legacy Clinical Data from the Epo TBI Trial

DTIC Science & Technology

2016-06-01

investigators through the Federal Interagency Traumatic Brain Injury (FITBIR) Informatics System. This trial was funded by National Institute of Neurological...Effects of Erythropoietin (Epo) on Cerebral Vascular Dysfunction and Anemia in Traumatic Brain Injury (TBI)” which we will share with other...the format required by FITBIR. 2. KEYWORDS: Traumatic brain injury Erythropoietin Anemia Transfusion threshold 3. ACCOMPLISHMENTS: What

Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

PubMed Central

Musicki, Biljana; Hannan, Johanna L.; Lagoda, Gwen; Bivalacqua, Trinity J.; Burnett, Arthur L.

2016-01-01

Men with type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED) have greater risk of cardiovascular events than T2DM men without ED, suggesting ED as a predictor of cardiovascular events in diabetic men. However, molecular mechanisms underlying endothelial dysfunction in the diabetic penis explaining these clinical observations are not known. We evaluated whether the temporal relationship between ED and endothelial dysfunction in the systemic vasculature in T2DM involves earlier redox imbalance and endothelial nitric oxidase synthase (eNOS) dysfunction in the penis than in the systemic vasculature, such as the carotid artery. Rats were rendered T2DM by high-fat diet for 2 weeks, followed by an injection with low-dose streptozotocin. After 3 weeks, erectile function (intracavernosal pressure) was measured and penes and carotid arteries were collected for molecular analyses of eNOS uncoupling, protein S-glutathionylation, oxidative stress (4-hydroxy-2-nonenal, 4-HNE), protein expression of NADPH oxidase subunit gp91phox, endothelium-dependent vasodilation in the carotid artery, and non-andrenergic, non-cholinergic (NANC) mediated cavernosal relaxation. Erectile response to electrical stimulation of the cavernous nerve and NANC mediated cavernosal relaxation were decreased (p<0.05), while relaxation of the carotid artery to acetylcholine was not impaired in T2DM rats. eNOS monomerization, protein expressions of 4-HNE and gp91phox, and protein S-glutathionylation, were increased (p<0.05) in the penis, but not in the carotid artery, of T2DM compared to nondiabetic rats. In conclusion, redox imbalance, increased oxidative stress by NADPH oxidase, and eNOS uncoupling, occur early in T2DM in the penis, but not in the carotid artery. These molecular changes contribute to T2DM ED, while vascular function in the systemic vasculature remains preserved. PMID:27153512

Olfaction in Parkinson's disease and related disorders.

PubMed

Doty, Richard L

2012-06-01

Olfactory dysfunction is an early 'pre-clinical' sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclein- and tau-related pathology, or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances. Copyright © 2011 Elsevier Inc. All rights reserved.

Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET.

PubMed

Gjerløff, Trine; Fedorova, Tatyana; Knudsen, Karoline; Munk, Ole L; Nahimi, Adjmal; Jacobsen, Steen; Danielsen, Erik H; Terkelsen, Astrid J; Hansen, John; Pavese, Nicola; Brooks, David J; Borghammer, Per

2015-03-01

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Rescue of Amyloid-Beta-Induced Inhibition of Nicotinic Acetylcholine Receptors by a Peptide Homologous to the Nicotine Binding Domain of the Alpha 7 Subtype

PubMed Central

Trujillo, Cleber A.; Sathler, Luciana B.; Juliano, Maria A.; Juliano, Luiz; Ulrich, Henning; Ferreira, Sergio T.

2013-01-01

Alzheimer's disease (AD) is characterized by brain accumulation of the neurotoxic amyloid-β peptide (Aβ) and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs). Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD. PMID:23894286

Learning history and cholinergic modulation in the dorsal hippocampus are necessary for rats to infer the status of a hidden event.

PubMed

Fast, Cynthia D; Flesher, M Melissa; Nocera, Nathanial A; Fanselow, Michael S; Blaisdell, Aaron P

2016-06-01

Identifying statistical patterns between environmental stimuli enables organisms to respond adaptively when cues are later observed. However, stimuli are often obscured from detection, necessitating behavior under conditions of ambiguity. Considerable evidence indicates decisions under ambiguity rely on inference processes that draw on past experiences to generate predictions under novel conditions. Despite the high demand for this process and the observation that it deteriorates disproportionately with age, the underlying mechanisms remain unknown. We developed a rodent model of decision-making during ambiguity to examine features of experience that contribute to inference. Rats learned either a simple (positive patterning) or complex (negative patterning) instrumental discrimination between the illumination of one or two lights. During test, only one light was lit while the other relevant light was blocked from physical detection (covered by an opaque shield, rendering its status ambiguous). We found experience with the complex negative patterning discrimination was necessary for rats to behave sensitively to the ambiguous test situation. These rats behaved as if they inferred the presence of the hidden light, responding differently than when the light was explicitly absent (uncovered and unlit). Differential expression profiles of the immediate early gene cFos indicated hippocampal involvement in the inference process while localized microinfusions of the muscarinic antagonist, scopolamine, into the dorsal hippocampus caused rats to behave as if only one light was present. That is, blocking cholinergic modulation prevented the rat from inferring the presence of the hidden light. Collectively, these results suggest cholinergic modulation mediates recruitment of hippocampal processes related to past experiences and transfer of these processes to make decisions during ambiguous situations. Our results correspond with correlations observed between human brain function and inference abilities, suggesting our experiments may inform interventions to alleviate or prevent cognitive dysfunction. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Comparative clinical study between retrograde cerebral perfusion and selective cerebral perfusion in surgery for acute type A aortic dissection.

PubMed

Usui, A; Yasuura, K; Watanabe, T; Maseki, T

1999-05-01

Selection of a brain protection method is a primary concern for aortic arch surgery. We performed a retrospective study to compare the respective advantages and disadvantages of retrograde cerebral perfusion (RCP) and selective cerebral perfusion (SCP) in patients who underwent surgery for acute type A aortic dissection. The study reviewed 166 patients who underwent surgery at Nagoya University or its eight branch hospitals between January 1990 and August 1996. There were 91 patients who received SCP and 75 patients who underwent RCP. Results for these two groups were compared. There were no significant differences in age, gender, Marfan syndrome rate, DeBakey classification, or emergency operation rate. Rates of various preoperative complications were similar except for aortic valve regurgitation. Arch replacement was performed more often in SCP than in RCP patients (49% vs. 27%, P = 0.0028). There were no significant differences between groups in cardiac ischemic time or visceral organ ischemic time. However, RCP group showed shorter cardio-pulmonary bypass time (297+/-99 vs. 269+/-112 min, P = 0.013) and lower the lowest core temperature (21.6+/-3.1 degrees C vs. 18.7+/-2.1 degrees C, P = 0.0001). SCP duration was longer than RCP duration (103+/-56 vs. 54+/-24 min, P < 0.0001). Despite these differences, RCP patients were not significantly different from SCP patients with regard to any postoperative complication, neurological dysfunction (16 vs. 19%), or operative mortality (all deaths within the hospitalization; 24 vs. 21%). Regarding neurologic dysfunction, there were six cases of coma, six of motor paralysis, two of paraplegia and one of visual loss among SCP patients, and eight cases of coma, three of motor paralysis, and three of convulsion in the RCP group. The incidence of motor paralysis was higher in the SCP group, while the incidence of coma was higher in the RCP group. RCP can be performed without clamping or cannulation of the cervical arteries, which is an advantage in reducing the chances of arterial injury or cerebral embolization. RCP is comparable to SCP in terms of clinical outcome.

The Role Of Basal Forebrain Cholinergic Neurons In Fear and Extinction Memory

PubMed Central

Knox, Dayan

2016-01-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. PMID:27264248

Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac.

PubMed

Paz, Rodrigo Manuel; Tubert, Cecilia; Stahl, Agostina; Díaz, Analía López; Etchenique, Roberto; Murer, Mario Gustavo; Rela, Lorena

2018-05-11

Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs. We found that autonomous firing of striatal cholinergic interneurons is not regulated by Kv7 channels. In contrast, Kv7 channels limit the summation of excitatory postsynaptic potentials in cholinergic interneurons through a postsynaptic mechanism. Striatal cholinergic interneurons have a high reserve of Kv7 channels, as their opening using pharmacological tools completely silenced the tonic firing and markedly reduced their intrinsic excitability. A strong inhibition of striatal cholinergic interneurons was also observed in response to the anti-inflammatory drugs diclofenac and meclofenamic acid, however, this effect was independent of Kv7 channels. These data bring attention to new potential molecular targets and pharmacological tools to control striatal cholinergic interneuron activity in pathological conditions where they are believed to be hyperactive, including Parkinson's disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cerebral fat embolism and the "starfield" pattern: a case report.

PubMed

Aravapalli, Amit; Fox, James; Lazaridis, Christos

2009-11-19

Nearly all long-bone fractures are accompanied by some form of fat embolism. The rare complication of clinically significant fat embolism syndrome, however, occurs in only 0.9-2.2% of cases. The clinical triad of fat embolism syndrome consists of respiratory distress, altered mental status, and petechial rash. Cerebral fat embolism causes the neurologic involvement seen in fat embolism syndrome. A 19-year-old African-American male was admitted with gunshot wounds to his right hand and right knee. He had diffuse hyperactive deep tendon reflexes, bilateral ankle clonus and decerebrate posturing with a Glasgow Coma Scale (GCS) score of 4T. Subsequent MRI of the brain showed innumerable punctate areas of restricted diffusion consistent with "starfield" pattern. On a 10-week follow up he has a normal neurological examination and he is discharged home. Despite the severity of the neurologic insult upon initial presentation, the majority of case reports on cerebral fat embolism illustrate that cerebral dysfunction associated with cerebral fat embolism is reversible. When neurologic deterioration occurs in the non-head trauma patient, then a systemic cause such as fat emboli should be considered. We describe a patient with non-head trauma who demonstrated the classic "starfield" pattern on diffusion-weighted MRI imaging.

Biaxial Response of Passive Human Cerebral Arteries

PubMed Central

Monson, Kenneth L.; Barbaro, Nicholas M.; Manley, Geoffrey T.

2008-01-01

The cerebral circulation is fundamental to the health and maintenance of brain tissue, but injury and disease may result in dysfunction of the vessels. Characterization of cerebral vessel mechanical response is an important step toward a more complete understanding of injury mechanisms and disease development in these vessels, paving the way for improved prevention and treatment. We recently reported a large series of uniaxial tests on fresh human cerebral vessels, but the multi-axial behavior of these vessels has not been previously described. Twelve arteries were obtained from the surface of the temporal lobe of patients undergoing surgery and were subjected to various combinations of axial stretch and pressure around typical physiological conditions before being stretched to failure. Axial and circumferential responses were compared, and measured data were fit to a four parameter, Fung-type hyperelastic constitutive model. Artery behavior was nonlinear and anisotropic, with considerably greater resistance to deformation in the axial direction than around the circumference. Results from axial failure tests of pressurized vessels resulted in a small shift in stress-stretch response compared to previously reported data from unpressurized specimens. These results further define the biaxial response of the cerebral arteries and provide data required for more rigorous study of head injury mechanisms and development of cerebrovascular disease. PMID:18855141

Contralateral cerebello-thalamo-cortical pathways with prominent involvement of associative areas in humans in vivo.

PubMed

Palesi, Fulvia; Tournier, Jacques-Donald; Calamante, Fernando; Muhlert, Nils; Castellazzi, Gloria; Chard, Declan; D'Angelo, Egidio; Wheeler-Kingshott, Claudia A M

2015-11-01

In addition to motor functions, it has become clear that in humans the cerebellum plays a significant role in cognition too, through connections with associative areas in the cerebral cortex. Classical anatomy indicates that neo-cerebellar regions are connected with the contralateral cerebral cortex through the dentate nucleus, superior cerebellar peduncle, red nucleus and ventrolateral anterior nucleus of the thalamus. The anatomical existence of these connections has been demonstrated using virus retrograde transport techniques in monkeys and rats ex vivo. In this study, using advanced diffusion MRI tractography we show that it is possible to calculate streamlines to reconstruct the pathway connecting the cerebellar cortex with contralateral cerebral cortex in humans in vivo. Corresponding areas of the cerebellar and cerebral cortex encompassed similar proportion (about 80%) of the tract, suggesting that the majority of streamlines passing through the superior cerebellar peduncle connect the cerebellar hemispheres through the ventrolateral thalamus with contralateral associative areas. This result demonstrates that this kind of tractography is a useful tool to map connections between the cerebellum and the cerebral cortex and moreover could be used to support specific theories about the abnormal communication along these pathways in cognitive dysfunctions in pathologies ranging from dyslexia to autism.

Patterns of postictal cerebral perfusion in idiopathic generalized epilepsy: a multi-delay multi-parametric arterial spin labelling perfusion MRI study.

PubMed

Chen, Guangxiang; Lei, Du; Ren, Jiechuan; Zuo, Panli; Suo, Xueling; Wang, Danny J J; Wang, Meiyun; Zhou, Dong; Gong, Qiyong

2016-07-04

The cerebral haemodynamic status of idiopathic generalized epilepsy (IGE) is a very complicated process. Little attention has been paid to cerebral blood flow (CBF) alterations in IGE detected by arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI). However, the selection of an optimal delay time is difficult for single-delay ASL. Multi-delay multi-parametric ASL perfusion MRI overcomes the limitations of single-delay ASL. We applied multi-delay multi-parametric ASL perfusion MRI to investigate the patterns of postictal cerebral perfusion in IGE patients with absence seizures. A total of 21 IGE patients with absence seizures and 24 healthy control subjects were enrolled. IGE patients exhibited prolonged arterial transit time (ATT) in the left superior temporal gyrus. The mean CBF of IGE patients was significantly increased in the left middle temporal gyrus, left parahippocampal gyrus and left fusiform gyrus. Prolonged ATT in the left superior temporal gyrus was negatively correlated with the age at onset in IGE patients. This study demonstrated that cortical dysfunction in the temporal lobe and fusiform gyrus may be related to epileptic activity in IGE patients with absence seizures. This information can play an important role in elucidating the pathophysiological mechanism of IGE from a cerebral haemodynamic perspective.

Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people.

PubMed

Bridges, Leslie R; Andoh, Joycelyn; Lawrence, Andrew J; Khoong, Cheryl H L; Poon, Wayne; Esiri, Margaret M; Markus, Hugh S; Hainsworth, Atticus H

2014-11-01

The blood-brain barrier protects brain tissue from potentially harmful plasma components. Small vessel disease (SVD; also termed arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis, and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and immunoglobulin G, which are assumed to reflect blood-brain barrier dysfunction, in deep gray matter (DGM; anterior caudate-putamen) and deep subcortical white matter (DWM) in the brains of a well-characterized cohort of donated brains with minimal Alzheimer disease pathology (Braak Stages 0-II) (n = 84; aged 65 years or older). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and immunoglobulin G was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that, in aged brains, plasma extravasation and hence local blood-brain barrier dysfunction are common but do not support an association with SVD.

[Retinal vasculopathy with cerebral leukoencephalopathy carrying TREX1 mutation diagnosed by the intracranial calcification: a case report].

PubMed

Komaki, Ryouhei; Ueda, Takehiro; Tsuji, Yukio; Miyawaki, Toko; Kusuhara, Sentaro; Hara, Shigeo; Toda, Tatsushi

2018-02-28

A 40-year-old woman with renal dysfunction for 2 years was admitted to our hospital suffering from a headache. Family history revealed that her mother had a headache, renal dysfunction, and brain infarction in younger age. She had a retinal hemorrhage, a retinal atrophy, pitting edema in her lower extremities. Her neurological findings were unremarkable. Brain imaging showed multiple white matter lesions accompanied with calcifications and slightly enhancement. Kidney biopsy showed the thrombotic microangiopathy, Gene analysis demonstrated a causative mutation in three-prime repair exonuclease-1 (TREX1) gene, c.703_704insG (p.Val235GlyfsX6), thereby we diagnosed her as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). RVCL is an autosomal dominant condition caused by C-terminal frame-shift mutation in TREX1. TREX1 protein is a major 3' to 5' DNA exonuclease, which are important in DNA repair. While TREX1 mutations identified in Aicardi-Goutieres syndrome patients lead to a reduction of enzyme activity, it is suggested that mutations in RVCL alter an intracellular location of TREX1 protein. There are no treatments based evidences in RVCL. We administered cilostazol to protect endothelial function, and her brain lesions and renal function have not become worse for 10 months after. It is necessary to consider RVCL associated with TREX1 mutation if a patient has retinal lesions, white matter lesions accompanied with calcifications, and multiple organ dysfunction.

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

PubMed Central

Bartolini, Alessandro; Cesare Mannelli, Lorenzo Di; Ghelardini, Carla

2011-01-01

The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M1 subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N1) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed. PMID:21585331

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

PubMed Central

Smith, Darrell R.; Frizzi, Katie; Sabbir, Mohammad Golam; Chowdhury, Subir K. Roy; Mixcoatl-Zecuatl, Teresa; Saleh, Ali; Muttalib, Nabeel; Van der Ploeg, Randy; Ochoa, Joseline; Gopaul, Allison; Tessler, Lori; Wess, Jürgen; Jolivalt, Corinne G.

2017-01-01

Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor–dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible. PMID:28094765

Novel channel-mediated choline transport in cholinergic neurons of the mouse retina.

PubMed

Ishii, Toshiyuki; Homma, Kohei; Mano, Asuka; Akagi, Takumi; Shigematsu, Yasuhide; Shimoda, Yukio; Inoue, Hiroyoshi; Kakinuma, Yoshihiko; Kaneda, Makoto

2017-10-01

Choline uptake into the presynaptic terminal of cholinergic neurons is mediated by the high-affinity choline transporter and is essential for acetylcholine synthesis. In a previous study, we reported that P2X 2 purinoceptors are selectively expressed in OFF-cholinergic amacrine cells of the mouse retina. Under specific conditions, P2X 2 purinoceptors acquire permeability to large cations, such as N -methyl-d-glucamine, and therefore potentially could act as a noncanonical pathway for choline entry into neurons. We tested this hypothesis in OFF-cholinergic amacrine cells of the mouse retina. ATP-induced choline currents were observed in OFF-cholinergic amacrine cells, but not in ON-cholinergic amacrine cells, in mouse retinal slice preparations. High-affinity choline transporters are expressed at higher levels in ON-cholinergic amacrine cells than in OFF-cholinergic amacrine cells. In dissociated preparations of cholinergic amacrine cells, ATP-activated cation currents arose from permeation of extracellular choline. We also examined the pharmacological properties of choline currents. Pharmacologically, α,β-methylene ATP did not produce a cation current, whereas ATPγS and benzoyl-benzoyl-ATP (BzATP) activated choline currents. However, the amplitude of the choline current activated by BzATP was very small. The choline current activated by ATP was strongly inhibited by pyridoxalphosphate-6-azophenyl-2',4'-sulfonic acid. Accordingly, P2X 2 purinoceptors expressed in HEK-293T cells were permeable to choline and similarly functioned as a choline uptake pathway. Our physiological and pharmacological findings support the hypothesis that P2 purinoceptors, including P2X 2 purinoceptors, function as a novel choline transport pathway and may provide a new regulatory mechanism for cholinergic signaling transmission at synapses in OFF-cholinergic amacrine cells of the mouse retina. NEW & NOTEWORTHY Choline transport across the membrane is exerted by both the high-affinity and low-affinity choline transporters. We found that choline can permeate P2 purinergic receptors, including P2X 2 purinoceptors, in cholinergic neurons of the retina. Our findings show the presence of a novel choline transport pathway in cholinergic neurons. Our findings also indicate that the permeability of P2X 2 purinergic receptors to choline observed in the heterologous expression system may have a physiological relevance in vivo. Copyright © 2017 the American Physiological Society.

Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity

PubMed Central

Harsono, Mimily; Pourcyrous, Massroor; Jolly, Elliott J.; de Jongh Curry, Amy; Fedinec, Alexander L.; Liu, Jianxiong; Basuroy, Shyamali; Zhuang, Daming; Leffler, Charles W.

2016-01-01

Epileptic seizures in neonates cause cerebrovascular injury and impairment of cerebral blood flow (CBF) regulation. In the bicuculline model of seizures in newborn pigs, we tested the hypothesis that selective head cooling prevents deleterious effects of seizures on cerebral vascular functions. Preventive or therapeutic ictal head cooling was achieved by placing two head ice packs during the preictal and/or ictal states, respectively, for the ∼2-h period of seizures. Head cooling lowered the brain and core temperatures to 25.6 ± 0.3 and 33.5 ± 0.1°C, respectively. Head cooling had no anticonvulsant effects, as it did not affect the bicuculline-evoked electroencephalogram parameters, including amplitude, duration, spectral power, and spike frequency distribution. Acute and long-term cerebral vascular effects of seizures in the normothermic and head-cooled groups were tested during the immediate (2–4 h) and delayed (48 h) postictal periods. Seizure-induced cerebral vascular injury during the immediate postictal period was detected as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive staining of cerebral arterioles and a surge of brain-derived circulating endothelial cells in peripheral blood in the normothermic group, but not in the head-cooled groups. During the delayed postictal period, endothelium-dependent cerebral vasodilator responses were greatly reduced in the normothermic group, indicating impaired CBF regulation. Preventive or therapeutic ictal head cooling mitigated the endothelial injury and greatly reduced loss of postictal cerebral vasodilator functions. Overall, head cooling during seizures is a clinically relevant approach to protecting the neonatal brain by preventing cerebrovascular injury and the loss of the endothelium-dependent control of CBF without reducing epileptiform activity. PMID:27591217

Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment.

PubMed

Tan, Xing-Lin; Xue, Yue-Qiang; Ma, Tao; Wang, Xiaofang; Li, Jing Jing; Lan, Lubin; Malik, Kafait U; McDonald, Michael P; Dopico, Alejandro M; Liao, Francesca-Fang

2015-06-24

Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer's disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS(+/-) mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels. Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS(+/-) mice as early as 3-6 months of age but not in eNOS(+/+) mice at any age. Remarkably, vascular occlusions in eNOS(+/-) mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS(+/-) mice. These data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS(+/-) mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD.

Sympathetic sprouting in visual cortex stimulated by cholinergic denervation rescues expression of two forms of long-term depression at layer 2/3 synapses.

PubMed

McCoy, P A; McMahon, L L

2010-07-14

Cholinergic innervation of hippocampus and cortex is required for some forms of learning and memory. Several reports have shown that activation of muscarinic m1 receptors induces a long-term depression (mLTD) at glutamate synapses in hippocampus and in several areas of cortex, including perirhinal and visual cortices. This plasticity likely contributes to cognitive function dependent upon the cholinergic system. In rodent models, degeneration of hippocampal cholinergic innervation following lesion of the medial septum stimulates sprouting of adrenergic sympathetic axons, originating from the superior cervical ganglia (SCG), into denervated hippocampal subfields. We previously reported that this adrenergic sympathetic sprouting occurs simultaneously with a reappearance of cholinergic fibers in hippocampus and rescue of mLTD at CA3-CA1 synapses. Because cholinergic neurons throughout basal forebrain degenerate in aging and Alzheimer's disease, it is critical to determine if this compensatory sprouting occurs in other regions impacted by cholinergic cell loss. To this end, we investigated whether lesion of the nucleus basalis magnocellularis (NbM) to cholinergically denervate cortex stimulates adrenergic sympathetic sprouting and the accompanying increase in cholinergic innervation. Further, we assessed whether the presence of sprouting positively correlates with the ability of glutamate synapses in acute visual cortex slices to express mLTD and low frequency stimulation induced LTD (LFS LTD), another cholinergic dependent form of plasticity in visual cortex. We found that both mLTD and LFS LTD are absent in animals when NbM lesion is combined with bilateral removal of the SCG to prevent possible compensatory sprouting. In contrast, when the SCG remain intact to permit sprouting in animals with NbM lesion, cholinergic fiber density is increased concurrently with adrenergic sympathetic sprouting, and mLTD and LFS LTD are preserved. Our findings suggest that autonomic compensation for central cholinergic degeneration is not specific to hippocampus, but is a general repair mechanism occurring in other brain regions important for normal cognitive function. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Distribution and co-localization of choline acetyltransferase and p75 neurotrophin receptors in the sheep basal forebrain: implications for the use of a specific cholinergic immunotoxin.

PubMed

Ferreira, G; Meurisse, M; Tillet, Y; Lévy, F

2001-01-01

The basal forebrain cholinergic system is involved in different forms of memory. To study its role in social memory in sheep, an immunotoxin, ME20.4 immunoglobulin G (IgG)-saporin, was developed that is specific to basal forebrain cholinergic neurons bearing the p75 neurotrophin receptor. The distribution of sheep cholinergic neurons was mapped with an antibody against choline acetyltransferase. To assess the localization of the p75 receptor on basal forebrain cholinergic neurons, the distribution of p75 receptor-immunoreactive neurons with ME20.4 IgG was examined, and a double-labeling study with antibodies against choline acetyltransferase and p75 receptor was undertaken. The loss of basal forebrain cholinergic neurons and acetylcholinesterase fibers in basal forebrain projection areas was assessed in ewes that had received intracerebroventricular injections of the immunotoxin (50, 100 or 150 microg) alone, as well as, in some of the ewes treated with the highest dose, with bilateral immunotoxin injections in the nucleus basalis (11 microg/side). Results indicated that choline acetyltransferase- and p75 receptor-immunoreactive cells had similar distributions in the medial septum, the vertical and horizontal limbs of the band of Broca, and the nucleus basalis. The double-labeling procedure revealed that 100% of the cholinergic neurons are also p75 receptor positive in the medial septum and in the vertical and horizontal limbs of the band of Broca, and 82% in the nucleus basalis. Moreover, 100% of the p75 receptor-immunoreactive cells of these four nuclei were cholinergic. Combined immunotoxin injections into ventricles and the nucleus basalis produced a near complete loss (80-95%) of basal forebrain cholinergic neurons and acetylcholinesterase-positive fibers in the hippocampus, olfactory bulb and entorhinal cortex. This study provides the first anatomical data concerning the basal forebrain cholinergic system in ungulates. The availability of a selective cholinergic immunotoxin effective in sheep provides a new tool to probe the involvement of basal forebrain cholinergic neurons in cognitive processes in this species.

[The neurochemistry and neuropharmacology of frontotemporal dementia].

PubMed

Alonso-Navarro, H; Jabbour-Wadih, T; Ayuso-Peralta, L; Jiménez-Jiménez, F J

To review the neurochemical features and therapeutic options for frontotemporal dementia (FTD). The main neurochemical alterations in FTD are the serotoninergic and dopamine depletion. In contrast with Alzheimer's and diffuse Lewy bodies disease, there are not significant alterations of the cholinergic system. Cerebral perfusion and glucose metabolism studies usually show hypoperfusion or hypometabolism, with predominant involvement of temporal and frontal cortices. There have been described some alterations related with oxidative stress and apoptosis, although its pathogenetic role in FTD is not well known. Treatment of FTD is not well established, because there are only a few studies with some drugs. The most studied drugs are serotonin reuptake inhibitors, however, despite the well-known serotoninergic deficiency described in FTD, the results are not conclusive. The main neurochemical alterations of FTD are serotoninergic and dopaminergic deficiencies. The treatment is not well established, although it should be theoretically ideal to use drugs which modulate these neurotransmitter systems.

Neurological signs and morphological cerebral changes in schizophrenia: An analysis of NSS subscales in patients with first episode psychosis.

PubMed

Heuser, Mark; Thomann, Philipp A; Essig, Marco; Bachmann, Silke; Schröder, Johannes

2011-05-31

Neurological soft signs (NSS) comprise a broad range of minor motor and sensory deficits which are frequently found in schizophrenia. However, the cerebral changes underlying NSS are only partly understood. We therefore investigated the cerebral correlates of NSS by using magnetic resonance imaging (MRI) in 102 patients with first episode schizophrenia. NSS were assessed after remission of acute psychotic symptoms using the Heidelberg scale (HS), which consists of five NSS subscales ("motor coordination", "complex motor tasks", "orientation", "integrative functions", and "hard signs"). Correlations between NSS scores and cerebral changes were established by optimized voxel-based morphometry. NSS total scores were significantly associated with reduced gray matter densities in the precentral and postcentral gyri, the inferior parietal lobule and the inferior occipital gyrus. Both of the NSS subscales "motor coordination" and "complex motor tasks", referred to motor strip changes but showed differential correlations with parietal, insular, cerebellar or frontal sites, respectively. The NSS subscales "orientation" and "integrative functions" were associated with left frontal, parietal, and occipital changes or bihemispheric frontal changes, respectively. The NSS subscale "hard signs" was associated with deficits in the right cerebellum and right parastriate cortex. Repeated analyses for white matter changes revealed similar results. These findings confirm the associations between NSS and cerebral changes in areas important for motor and sensory functioning. This variety of cerebral sites corresponds to the heterogeneity of NSS and are consistent with the hypothesis that NSS reflect both a rather generalized cerebral dysfunction and localized deficits specific for particular signs. 2010 Elsevier Ireland Ltd. All rights reserved.

Effectiveness of sugammadex for cerebral ischemia/reperfusion injury.

PubMed

Ozbilgin, Sule; Yılmaz, Osman; Ergur, Bekir Ugur; Hancı, Volkan; Ozbal, Seda; Yurtlu, Serhan; Gunenc, Sakize Ferim; Kuvaki, Bahar; Kucuk, Burcu Ataseven; Sisman, Ali Rıza

2016-06-01

Cerebral ischemia may cause permanent brain damage and behavioral dysfunction. The efficacy and mechanisms of pharmacological treatments administered immediately after cerebral damage are not fully known. Sugammadex is a licensed medication. As other cyclodextrins have not passed the necessary phase tests, trade preparations are not available, whereas sugammadex is frequently used in clinical anesthetic practice. Previous studies have not clearly described the effects of the cyclodextrin family on cerebral ischemia/reperfusion (I/R) damage. The aim of this study was to determine whether sugammadex had a neuroprotective effect against transient global cerebral ischemia. Animals were assigned to control, sham-operated, S 16 and S 100 groups. Transient global cerebral ischemia was induced by 10-minute occlusion of the bilateral common carotid artery, followed by 24-hour reperfusion. At the end of the experiment, neurological behavior scoring was performed on the rats, followed by evaluation of histomorphological and biochemical measurements. Sugammadex 16 mg/kg and 100 mg/kg improved neurological outcome, which was associated with reductions in both histological and neurological scores. The hippocampus TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase results in the S 16 and S 100 treatment groups were significantly lower than those of the I/R group. Neurological scores in the treated groups were significantly higher than those of the I/R group. The study showed that treatment with 16 mg/kg and 100 mg/kg sugammadex had a neuroprotective effect in a transient global cerebral I/R rat model. However, 100 mg/kg sugammadex was more neuroprotective in rats. Copyright © 2016. Published by Elsevier Taiwan.

Chronic Stress Modulates Regional Cerebral Glucose Transporter Expression in an Age-Specific and Sexually-Dimorphic Manner

PubMed Central

Kelly, Sean D.; Harrell, Constance S.; Neigh, Gretchen N.

2014-01-01

Facilitative glucose transporters (GLUT) mediate glucose uptake across the blood-brain-barrier into neurons and glia. Deficits in specific cerebral GLUT isoforms are linked to developmental and neurological dysfunction, but less is known about the range of variation in cerebral GLUT expression in normal conditions and the effects of environmental influences on cerebral GLUT expression. Knowing that puberty is a time of increased cerebral plasticity, metabolic demand, and shifts in hormonal balance for males and females, we first assessed gene expression of five GLUT subtypes in four brain regions in male and female adolescent and adult Wistar rats. The data indicated that sex differences in GLUT expression were most profound in the hypothalamus, and the transition from adolescence to adulthood had the most profound effect on GLUT expression in the hippocampus. Next, given the substantial energetic demands during adolescence and prior demonstrations of the adverse effects of adolescent stress, we determined the extent to which chronic stress altered GLUT expression in males and females in both adolescence and adulthood. Chronic stress significantly altered cerebral GLUT expression in males and females throughout both developmental stages but in a sexually dimorphic and brain region-specific manner. Collectively, our data demonstrate that cerebral GLUTs are expressed differentially based on brain region, sex, age, and stress exposure. These results suggest that developmental and environmental factors influence GLUT expression in multiple brain regions. Given the importance of appropriate metabolic balance within the brain, further assessment of the functional implications of life stage and environmentally-induced changes in GLUTs are warranted. PMID:24382486

Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

PubMed

Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

2017-09-01

A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p < 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

Disruption of medial septum and diagonal bands of Broca cholinergic projections to the ventral hippocampus disrupt auditory fear memory.

PubMed

Staib, Jennifer M; Della Valle, Rebecca; Knox, Dayan K

2018-07-01

In classical fear conditioning, a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US), which leads to a fear memory. If the CS is repeatedly presented without the US after fear conditioning, the formation of an extinction memory occurs, which inhibits fear memory expression. A previous study has demonstrated that selective cholinergic lesions in the medial septum and vertical limb of the diagonal bands of Broca (MS/vDBB) prior to fear and extinction learning disrupt contextual fear memory discrimination and acquisition of extinction memory. MS/vDBB cholinergic neurons project to a number of substrates that are critical for fear and extinction memory. However, it is currently unknown which of these efferent projections are critical for contextual fear memory discrimination and extinction memory. To address this, we induced cholinergic lesions in efferent targets of MS/vDBB cholinergic neurons. These included the dorsal hippocampus (dHipp), ventral hippocampus (vHipp), medial prefrontal cortex (mPFC), and in the mPFC and dHipp combined. None of these lesion groups exhibited deficits in contextual fear memory discrimination or extinction memory. However, vHipp cholinergic lesions disrupted auditory fear memory. Because MS/vDBB cholinergic neurons are the sole source of acetylcholine in the vHipp, these results suggest that MS/vDBB cholinergic input to the vHipp is critical for auditory fear memory. Taken together with previous findings, the results of this study suggest that MS/vDBB cholinergic neurons are critical for fear and extinction memory, though further research is needed to elucidate the role of MS/vDBB cholinergic neurons in these types of emotional memory. Copyright © 2018 Elsevier Inc. All rights reserved.

The role of basal forebrain cholinergic neurons in fear and extinction memory.

PubMed

Knox, Dayan

2016-09-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Cholinergic left-right asymmetry in the habenulo-interpeduncular pathway.

PubMed

Hong, Elim; Santhakumar, Kirankumar; Akitake, Courtney A; Ahn, Sang Jung; Thisse, Christine; Thisse, Bernard; Wyart, Claire; Mangin, Jean-Marie; Halpern, Marnie E

2013-12-24

The habenulo-interpeduncular pathway, a highly conserved cholinergic system, has emerged as a valuable model to study left-right asymmetry in the brain. In larval zebrafish, the bilaterally paired dorsal habenular nuclei (dHb) exhibit prominent left-right differences in their organization, gene expression, and connectivity, but their cholinergic nature was unclear. Through the discovery of a duplicated cholinergic gene locus, we now show that choline acetyltransferase and vesicular acetylcholine transporter homologs are preferentially expressed in the right dHb of larval zebrafish. Genes encoding the nicotinic acetylcholine receptor subunits α2 and β4 are transcribed in the target interpeduncular nucleus (IPN), suggesting that the asymmetrical cholinergic pathway is functional. To confirm this, we activated channelrhodopsin-2 specifically in the larval dHb and performed whole-cell patch-clamp recording of IPN neurons. The response to optogenetic or electrical stimulation of the right dHb consisted of an initial fast glutamatergic excitatory postsynaptic current followed by a slow-rising cholinergic current. In adult zebrafish, the dHb are divided into discrete cholinergic and peptidergic subnuclei that differ in size between the left and right sides of the brain. After exposing adults to nicotine, fos expression was activated in subregions of the IPN enriched for specific nicotinic acetylcholine receptor subunits. Our studies of the newly identified cholinergic gene locus resolve the neurotransmitter identity of the zebrafish habenular nuclei and reveal functional asymmetry in a major cholinergic neuromodulatory pathway of the vertebrate brain.

Role of interstitial cells of Cajal in the generation and modulation of motor activity induced by cholinergic neurotransmission in the stomach.

PubMed

Zhang, R-X; Wang, X-Y; Chen, D; Huizinga, J D

2011-09-01

Interstitial cells of Cajal (ICC) are intimately linked to the enteric nervous system and a better understanding of the interactions between the two systems is going to advance our understanding of gut motor control. The objective of the present study was to investigate the role of ICC in the generation of gastric motor activity induced by cholinergic neurotransmission. Gastric motor activity was evoked through activation of intrinsic cholinergic neural activity, in in vitro muscle strips by electrical field stimulation, in the in vitro whole stomach by distension and in vivo by fluoroscopy after gavaging the stomach with barium sulfate. The cholinergic activity was assessed as that component of the effect of the stimulus that was sensitive to atropine. These experiments were carried out in wild-type and Ws/Ws rats that have few intramuscular ICC (ICC-IM) in the stomach. Under all three experimental conditions, cholinergic activity was prominent in both wild-type and W mutant rats providing evidence against the hypothesis that cholinergic neurotransmission to smooth muscle is primarily mediated by ICC-IM. Strong cholinergic activity in Ws/Ws rats was not due to upregulation of muscarinic receptors in ICC but possibly in smooth muscle of the antrum. Pacemaker ICC play a prominent role in the expression of motor activity induced by cholinergic activity and our data suggest that cholinergic neurotransmission to ICC affects the pacemaker frequency. © 2011 Blackwell Publishing Ltd.

Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer's disease

PubMed Central

Kar, Satyabrata; Slowikowski, Stephen P.M.; Westaway, David; Mount, Howard T.J.

2004-01-01

Alzheimer's disease is an age-related neurodegenerative disorder that is characterized by a progressive loss of memory and deterioration of higher cognitive functions. The brain of an individual with Alzheimer's disease exhibits extracellular plaques of aggregated β-amyloid protein (Aβ), intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Aβ accumulation may trigger or contribute to the process of neurodegeneration. However, the mechanisms whereby Aβ induces basal forebrain cholinergic cell loss and cognitive impairment remain obscure. Physiologically relevant concentrations of Aβ-related peptides have acute, negative effects on multiple aspects of acetylcholine (ACh) synthesis and release, without inducing toxicity. These data suggest a neuromodulatory influence of the peptides on central cholinergic functions. Long-term exposure to micromolar Aβ induces cholinergic cell toxicity, possibly via hyperphosphorylation of tau protein. Conversely, activation of selected cholinergic receptors has been shown to alter the processing of the amyloid precursor protein as well as phosphorylation of tau protein. A direct interaction between Aβ and nicotinic ACh receptors has also been demonstrated. This review addresses the role of Aβ-related peptides in regulating the function and survival of central cholinergic neurons and the relevance of these effects to cholinergic deficits in Alzheimer's disease. Understanding the functional interrelations between Aβ peptides, cholinergic neurons and tau phosphorylation will unravel the biologic events that precede neurodegeneration and may lead to the development of more effective pharmacotherapies for Alzheimer's disease. PMID:15644984

Neural Correlates of Motor Dysfunction in Children with Traumatic Brain Injury: Exploration of Compensatory Recruitment Patterns

ERIC Educational Resources Information Center

Caeyenberghs, K.; Wenderoth, N.; Smits-Engelsman, B. C. M.; Sunaert, S.; Swinnen, S. P.

2009-01-01

Traumatic brain injury (TBI) is a common form of disability in children. Persistent deficits in motor control have been documented following TBI but there has been less emphasis on changes in functional cerebral activity. In the present study, children with moderate to severe TBI (n = 9) and controls (n = 17) were scanned while performing cyclical…

Linear and Nonlinear Analysis of Brain Dynamics in Children with Cerebral Palsy

ERIC Educational Resources Information Center

Sajedi, Firoozeh; Ahmadlou, Mehran; Vameghi, Roshanak; Gharib, Masoud; Hemmati, Sahel

2013-01-01

This study was carried out to determine linear and nonlinear changes of brain dynamics and their relationships with the motor dysfunctions in CP children. For this purpose power of EEG frequency bands (as a linear analysis) and EEG fractality (as a nonlinear analysis) were computed in eyes-closed resting state and statistically compared between 26…

The Effect of tDCS on Cognition and Neurologic Recovery of Rats with Alzheimer's Disease.

PubMed

Yu, Seong Hun; Park, Seong Doo; Sim, Ki Chel

2014-02-01

[Purpose] This study examined the effect of the application of transcranial direct current stimulation (tDCS) on neurologic recovery and cognitive function of rats with Alzheimer-like dementia induced by scopolamine injections. [Subjects] To create a cognition dysfunction model, intraperitoneal injection of scopolamine was given to Sprague-Dawley rats that subsequently received tDCS for 4 weeks. [Methods] Changes in motor behavior were evaluated by conducting an open field test. Acetylcholine content in the cerebral cortex and hippocampus was examined for a biochemical assessment. [Results] With respect to changes in motor behavior, group II showed the most meaningful difference after scopolamine injection, followed by group III. In the biochemical assessment, the results of the examination of acetylcholine content in the tissue of the cerebral cortex and the hippocampus on the 14th and 28th days, respectively, showed the most significant increase in group II, followed by group III. [Conclusion] The above findings confirm that tDCS application after the onset of cognitive dysfunction caused by Alzheimer's disease leads to a positive effect on motor behavior and biochemical changes, and this effect is maintained over a specific period of time.

Molecular mechanisms and cell signaling of 20-hydroxyeicosatetraenoic acid in vascular pathophysiology

PubMed Central

Fan, Fan; Ge, Ying; Lv, Wenshan; Elliott, Matthew R.; Muroya, Yoshikazu; Hirata, Takashi; Booz, George W.; Roman, Richard J.

2016-01-01

Cytochrome P450s enzymes catalyze the metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid and hydroxyeicosatetraeonic acid (HETEs). 20-HETE is a vasoconstrictor that depolarizes vascular smooth muscle cells by blocking K+ channels. EETs serve as endothelial derived hyperpolarizing factors. Inhibition of the formation of 20-HETE impairs the myogenic response and autoregulation of renal and cerebral blood flow. Changes in the formation of EETs and 20-HETE have been reported in hypertension and drugs that target these pathways alter blood pressure in animal models. Sequence variants in CYP4A11 and CYP4F2 that produce 20-HETE, UDP-glucuronosyl transferase involved in the biotransformation of 20-HETE and soluble epoxide hydrolase that inactivates EETs are associated with hypertension in human studies. 20-HETE contributes to the regulation of vascular hypertrophy, restenosis, angiogenesis and inflammation. It also promotes endothelial dysfunction and contributes to cerebral vasospasm and ischemia-reperfusion injury in the brain, kidney and heart. This review will focus on the role of 20-HETE in vascular dysfunction, inflammation, ischemic and hemorrhagic stroke and cardiac and renal ischemia reperfusion injury. PMID:27100515

[Immunocytochemical study of cholinergic innervation in the neurosensory epithelia of human vestibule].

PubMed

Kong, W; Hussl, B; Schrott-Fischer, A

1998-02-01

To investigate the cholinergic innervation of the neurosensory epithelia of human vestibule. A modified preembedding immunostaining technique for immunoelectronmicroscopy was applied to this study. A polyclonal antibody to choline acetyltransferase (ChAT) was used as the marker of cholinergic fibers. ChAT-immunoreactive products were restricted to the nerve fibers and terminals which were rich in synaptic vesicles. The ChAT-immunoreactive fibers synaps with afferent chalice as well as with type II sensory hair cells. This study demonstrates that cholinergic fibers innervate the neurosensory epithelia of human vestible. The cholinergic fibers of human vestibular sensory epithelia belong to the vestibular efferent system.

The effects of caffeine on the cholinergic system.

PubMed

Pohanka, Miroslav

2014-01-01

Caffeine is a secondary metabolite of tea and coffee plants. It is the active psychostimulant ingredient of widely consumed beverages, chocolate and some drugs as well. The major pathways for caffeine including interaction with adenosine receptors have been identified but caffeine has several minor pathways as well that remain poorly understood including the cholinergic system. Given the role of caffeine in the cholinergic system, some molecular targets have been tracked and a mechanism of its action has been proposed in research studies. However, the biological effect of caffeine on the cholinergic system is not completely understood. The present review focuses on the role of caffeine in the cholinergic system.

Endothelin-1-induced focal cerebral ischemia in the growth hormone/IGF-1 deficient Lewis Dwarf rat.

PubMed

Yan, Han; Mitschelen, Matthew; Toth, Peter; Ashpole, Nicole M; Farley, Julie A; Hodges, Erik L; Warrington, Junie P; Han, Song; Fung, Kar-Ming; Csiszar, Anna; Ungvari, Zoltan; Sonntag, William E

2014-11-01

Aging is a major risk factor for cerebrovascular disease. Growth hormone (GH) and its anabolic mediator, insulin-like growth factor (IGF)-1, decrease with advancing age and this decline has been shown to promote vascular dysfunction. In addition, lower GH/IGF-1 levels are associated with higher stroke mortality in humans. These results suggest that decreased GH/IGF-1 level is an important factor in increased risk of cerebrovascular diseases. This study was designed to assess whether GH/IGF-1-deficiency influences the outcome of cerebral ischemia. We found that endothelin-1-induced middle cerebral artery occlusion resulted in a modest but nonsignificant decrease in cerebral infarct size in GH/IGF-1 deficient dw/dw rats compared with control heterozygous littermates and dw/dw rats with early-life GH treatment. Expression of endothelin receptors and endothelin-1-induced constriction of the middle cerebral arteries were similar in the three experimental groups. Interestingly, dw/dw rats exhibited reduced brain edema and less astrocytic infiltration compared with their heterozygous littermates and this effect was reversed by GH-treatment. Because reactive astrocytes are critical for the regulation of poststroke inflammatory processes, maintenance of the blood-brain barrier and neural repair, further studies are warranted to determine the long-term functional consequences of decreased astrocytic activation in GH/IGF-1 deficient animals after cerebral ischemia. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

PubMed Central

Pavlov, Valentin A.; Ochani, Mahendar; Gallowitsch-Puerta, Margot; Ochani, Kanta; Huston, Jared M.; Czura, Christopher J.; Al-Abed, Yousef; Tracey, Kevin J.

2006-01-01

TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this “cholinergic antiinflammatory pathway” inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents. PMID:16549778

Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation

PubMed Central

Grace, Kevin P.; Horner, Richard L.

2015-01-01

Rapid eye movement (REM) sleep – characterized by vivid dreaming, motor paralysis, and heightened neural activity – is one of the fundamental states of the mammalian central nervous system. Initial theories of REM sleep generation posited that induction of the state required activation of the “pontine REM sleep generator” by cholinergic inputs. Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation. We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail. PMID:26388832

Glycine Administration Alters MAPK Signaling Pathways and Causes Neuronal Damage in Rat Brain: Putative Mechanisms Involved in the Neurological Dysfunction in Nonketotic Hyperglycinemia.

PubMed

Moura, Alana Pimentel; Parmeggiani, Belisa; Gasparotto, Juciano; Grings, Mateus; Fernandez Cardoso, Gabriela Miranda; Seminotti, Bianca; Moreira, José Cláudio Fonseca; Gelain, Daniel Pens; Wajner, Moacir; Leipnitz, Guilhian

2018-01-01

High glycine (GLY) levels have been suggested to induce neurotoxic effects in the central nervous system of patients with nonketotic hyperglycinemia (NKH). Since the mechanisms involved in the neuropathophysiology of NKH are not totally established, we evaluated the effect of a single intracerebroventricular administration of GLY on the content of proteins involved in neuronal damage and inflammatory response, as well as on the phosphorylation of the MAPK p38, ERK1/2, and JNK in rat striatum and cerebral cortex. We also examined glial fibrillary acidic protein (GFAP) staining, a marker of glial reactivity. The parameters were analyzed 30 min or 24 h after GLY administration. GLY decreased Tau phosphorylation in striatum and cerebral cortex 30 min and 24 h after its administration. On the other hand, synaptophysin levels were decreased in striatum at 30 min and in cerebral cortex at 24 h after GLY injection. GLY also decreased the phosphorylation of p38, ERK1/2, and JNK 30 min after its administration in both brain structures. Moreover, GLY-induced decrease of p38 phosphorylation in striatum was attenuated by N-methyl-D-aspartate receptor antagonist MK-801. In contrast, synuclein, NF-κB, iκB, inducible nitric oxide synthase and nitrotyrosine content, and GFAP immunostaining were not altered by GLY infusion. It may be presumed that the decreased phosphorylation of MAPK associated with alterations of markers of neuronal injury induced by GLY may contribute to the neurological dysfunction observed in NKH.

Executive dysfunction, brain aging, and political leadership.

PubMed

Fisher, Mark; Franklin, David L; Post, Jerrold M

2014-01-01

Decision-making is an essential component of executive function, and a critical skill of political leadership. Neuroanatomic localization studies have established the prefrontal cortex as the critical brain site for executive function. In addition to the prefrontal cortex, white matter tracts as well as subcortical brain structures are crucial for optimal executive function. Executive function shows a significant decline beginning at age 60, and this is associated with age-related atrophy of prefrontal cortex, cerebral white matter disease, and cerebral microbleeds. Notably, age-related decline in executive function appears to be a relatively selective cognitive deterioration, generally sparing language and memory function. While an individual may appear to be functioning normally with regard to relatively obvious cognitive functions such as language and memory, that same individual may lack the capacity to integrate these cognitive functions to achieve normal decision-making. From a historical perspective, global decline in cognitive function of political leaders has been alternatively described as a catastrophic event, a slowly progressive deterioration, or a relatively episodic phenomenon. Selective loss of executive function in political leaders is less appreciated, but increased utilization of highly sensitive brain imaging techniques will likely bring greater appreciation to this phenomenon. Former Israeli Prime Minister Ariel Sharon was an example of a political leader with a well-described neurodegenerative condition (cerebral amyloid angiopathy) that creates a neuropathological substrate for executive dysfunction. Based on the known neuroanatomical and neuropathological changes that occur with aging, we should probably assume that a significant proportion of political leaders over the age of 65 have impairment of executive function.

Perfusion status of the stroke-like lesion at the hyperacute stage in MELAS.

PubMed

Yeh, Hsu-Ling; Chen, Yen-Kung; Chen, Wei-Hung; Wang, Han-Cheng; Chiu, Hou-Chang; Lien, Li-Ming; Wei, Yau-Huei

2013-02-01

Hypoperfusion on single-photon emission computed tomography (SPECT) of the stroke-like lesion (SLL) at the hyperacute stage of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is considered to be a supportive evidence of the mitochondrial angiopathy theory. Our objectives were to examine whether other neuroimages, especially transcranial color-coded sonography (TCCS), done at the hyperacute stage of stroke-like episode (SLE) is consistent with hypoperfusion of the SLL. We reviewed the magnetic resonance imaging (MRI), SPECT, cerebral angiography, and TCCS of a patient with MELAS syndrome, all of which were performed at the hyperacute stage of one SLE. MRI on the 1st day post SLE showed right temporoparietal lesion with vasogenic edema. SPECT on the 2nd day showed focal decreased uptake of technetium-99m hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) in the same region, but cerebral angiography and TCCS on the 3rd day showed increased regional cerebral blood flow (rCBF) and distal arteriole dilation in the same region. TCCS can delineate increased rCBF of the SLL at the hyperacute stage of SLE. We propose that the discrepancy between the decreased (99m)Tc-HMPAO uptake and increased rCBF might be caused by mitochondrial dysfunction. The phenomenon of "hypoperfusion" on SPECT might be caused by cell dysfunction but not decreased rCBF. We suggest that SPECT can be complemented by angiography and TCCS in future studies to delineate the perfusion status of SLLs. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Coma reversal with cerebral dysfunction recovery after repetitive hyperbaric oxygen therapy for severe carbon monoxide poisoning.

PubMed

Dean, B S; Verdile, V P; Krenzelok, E P

1993-11-01

The accepted beneficial effects of hyperbaric oxygen (HBO) include a greatly diminished carboxyhemoglobin (COHgb) half-life, enhanced tissue clearance of residual carbon monoxide (CO), reduced cerebral edema, and reversal of cytochrome oxidase inhibition, and prevention of central nervous system lipid peroxidation. Debate regarding the criteria for selection of HBO versus 100% normobaric oxygen therapy continues, and frequently is based solely on the level of COHgb saturation. Patients who manifest signs of serious CO intoxication (unconsciousness, neuropsychiatric symptoms, cardiac or hemodynamic instability) warrant immediate HBO therapy. An unresponsive 33-year-old woman was found in a closed garage, inside her automobile with the ignition on. Her husband admitted to seeing her 6 hours before discovery. 100% normobaric oxygen was administered in the prehospital and emergency department settings. The patient had an initial COHgb saturation of 46.7%, a Glasgow coma score of 3, and was transferred for HBO therapy. Before HBO therapy, the patient remained unresponsive and demonstrated decerebrate posturing and a positive doll's eyes (negative oculocephalic reflex). The electroencephalogram pattern suggested bilateral cerebral dysfunction consistent with a toxic metabolic or hypoxic encephalopathy. The patient underwent HBO therapy at 2.4 ATA for 90 minutes twice a day for 3 consecutive days. On day 7, the patient began to awaken, was weaned from ventilatory support, and was not soon verbalizing appropriately. A Folstein mental status examination showed a score of 26 of 30. Neurological examination demonstrated mild residual left upper extremity weakness and a normal gait. There was no evidence of significant neurological sequelae at 1 month follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Robotic Quantification of Position Sense in Children With Perinatal Stroke.

PubMed

Kuczynski, Andrea M; Dukelow, Sean P; Semrau, Jennifer A; Kirton, Adam

2016-09-01

Background Perinatal stroke is the leading cause of hemiparetic cerebral palsy. Motor deficits and their treatment are commonly emphasized in the literature. Sensory dysfunction may be an important contributor to disability, but it is difficult to measure accurately clinically. Objective Use robotics to quantify position sense deficits in hemiparetic children with perinatal stroke and determine their association with common clinical measures. Methods Case-control study. Participants were children aged 6 to 19 years with magnetic resonance imaging-confirmed unilateral perinatal arterial ischemic stroke or periventricular venous infarction and symptomatic hemiparetic cerebral palsy. Participants completed a position matching task using an exoskeleton robotic device (KINARM). Position matching variability, shift, and expansion/contraction area were measured with and without vision. Robotic outcomes were compared across stroke groups and controls and to clinical measures of disability (Assisting Hand Assessment) and sensory function. Results Forty stroke participants (22 arterial, 18 venous, median age 12 years, 43% female) were compared with 60 healthy controls. Position sense variability was impaired in arterial (6.01 ± 1.8 cm) and venous (5.42 ± 1.8 cm) stroke compared to controls (3.54 ± 0.9 cm, P < .001) with vision occluded. Impairment remained when vision was restored. Robotic measures correlated with functional disability. Sensitivity and specificity of clinical sensory tests were modest. Conclusions Robotic assessment of position sense is feasible in children with perinatal stroke. Impairment is common and worse in arterial lesions. Limited correction with vision suggests cortical sensory network dysfunction. Disordered position sense may represent a therapeutic target in hemiparetic cerebral palsy. © The Author(s) 2016.

 Rapid identification system of frontal dysfunction in subclinical hepatic encephalopathy.

PubMed

Moretti, Rita; Gazzin, Silvia; Crocè, Lory Saveria; Baso, Beatrice; Masutti, Flora; Bedogni, Giorgio; Tiribelli, Claudio

2016-01-01

 Introduction and aim. Liver disease is associated with cognitive dysfunction also at early stages, and minimal hepatic encephalopathy, affecting 20-70% of patients, is frequently under-recognized. The main purpose of this work was to demonstrate that a substantial number of patients, enrolled due to an acute confusional state in absence of a diagnosis of liver disease, suffers of hepatic encephalopathy. Before a diagnosis of a well-compensated liver diseases was performed, 410 patients with an acute confusional state were enrolled in this study. Even in the presence of minimal alterations of hepatic function, the psychometric tests applied demonstrated early signs of cerebral frontal alteration. The alteration was associated with the severity of liver disease, paralleling the progression of the patient to minimal hepatic failure or chronic liver disease. These psychometric tests are essential to detect early and subclinical frontal failure. Frontal dysfunction may be a useful tool in the follow-up of these patients.

A cellular and regulatory map of the cholinergic nervous system of C. elegans

PubMed Central

Pereira, Laura; Kratsios, Paschalis; Serrano-Saiz, Esther; Sheftel, Hila; Mayo, Avi E; Hall, David H; White, John G; LeBoeuf, Brigitte; Garcia, L Rene; Alon, Uri; Hobert, Oliver

2015-01-01

Nervous system maps are of critical importance for understanding how nervous systems develop and function. We systematically map here all cholinergic neuron types in the male and hermaphrodite C. elegans nervous system. We find that acetylcholine (ACh) is the most broadly used neurotransmitter and we analyze its usage relative to other neurotransmitters within the context of the entire connectome and within specific network motifs embedded in the connectome. We reveal several dynamic aspects of cholinergic neurotransmitter identity, including a sexually dimorphic glutamatergic to cholinergic neurotransmitter switch in a sex-shared interneuron. An expression pattern analysis of ACh-gated anion channels furthermore suggests that ACh may also operate very broadly as an inhibitory neurotransmitter. As a first application of this comprehensive neurotransmitter map, we identify transcriptional regulatory mechanisms that control cholinergic neurotransmitter identity and cholinergic circuit assembly. DOI: http://dx.doi.org/10.7554/eLife.12432.001 PMID:26705699

Cognitive dysfunction in multiple sclerosis: a review of recent developments.

PubMed

Bobholz, Julie A; Rao, Stephen M

2003-06-01

Nearly half of all patients diagnosed with multiple sclerosis will develop cognitive dysfunction, a symptom associated with significant decline in activities of daily living. The purpose of this review is to discuss recent literature investigating issues related to cognitive dysfunction in multiple sclerosis. Recent studies, examined in this review, have provided increased understanding regarding specific cognitive processes affected in multiple sclerosis, as well as a characterization of its natural history. Studies have also continued to emphasize the extent to which cognitive deficits in the condition are associated with decline in daily living skills. Recent concerns regarding driving performance have been documented among cognitively impaired individuals. Studies have also examined correlates of cognitive dysfunction, with particular emphasis on neuroimaging techniques reflecting disease activity or lesion burden. With increased understanding of neurobiological correlates of cognitive deficits, investigators have begun to examine potential treatments for managing cognitive dysfunction. This area of research has suggested that disease modifying medications can have an impact on magnetic resonance imaging disease activity by altering the cerebral demyelinating process resulting in a slower decline in cognitive functions over time and improved activities of daily living for patients with multiple sclerosis.

Age-related changes in endothelial function and blood flow regulation.

PubMed

Toda, Noboru

2012-02-01

Vascular endothelial dysfunction is regarded as a primary phenotypic expression of normal human aging. This senescence-induced disorder is the likely culprit underlying the increased cardiovascular and metabolic disease risks associated with aging. The rate of this age-dependent deterioration is largely influenced by the poor-quality lifestyle choice, such as smoking, sedentary daily life, chronic alcohol ingestion, high salt intake, unbalanced diet, and mental stress; and it is accelerated by cardiovascular and metabolic diseases. Although minimizing these detrimental factors is the best course of action, nonetheless chronological age steadily impairs endothelial function through reduced endothelial nitric oxide synthase (eNOS) expression/action, accelerated nitric oxide (NO) degradation, increased phosphodiesterase activity, inhibition of NOS activity by endogenous NOS inhibitors, increased production of reactive oxygen species, inflammatory reactions, decreased endothelial progenitor cell number and function, and impaired telomerase activity or telomere shortening. Endothelial dysfunction in regional vasculatures results in cerebral hypoperfusion triggering cognitive dysfunction and Alzheimer's disease, coronary artery insufficiency, penile erectile dysfunction, and circulatory failures in other organs and tissues. Possible prophylactic measures to minimize age-related endothelial dysfunction are also summarized in this review. Copyright © 2011 Elsevier Inc. All rights reserved.

Cell-type Specific Optogenetic Mice for Dissecting Neural Circuitry Function

PubMed Central

Zhao, Shengli; Ting, Jonathan T.; Atallah, Hisham E.; Qiu, Li; Tan, Jie; Gloss, Bernd; Augustine, George J.; Deisseroth, Karl; Luo, Minmin; Graybiel, Ann M.; Feng, Guoping

2011-01-01

Optogenetic methods have emerged as powerful tools for dissecting neural circuit connectivity, function, and dysfunction. We used a Bacterial Artificial Chromosome (BAC) transgenic strategy to express Channelrhodopsin2 (ChR2) under the control of cell-type specific promoter elements. We provide a detailed functional characterization of the newly established VGAT-ChR2-EYFP, ChAT-ChR2-EYFP, TPH2-ChR2-EYFP and Pvalb-ChR2-EYFP BAC transgenic mouse lines and demonstrate the utility of these lines for precisely controlling action potential firing of GABAergic, cholinergic, serotonergic, and parvalbumin+ neuron subsets using blue light. This resource of cell type-specific ChR2 mouse lines will facilitate the precise mapping of neuronal connectivity and the dissection of the neural basis of behavior. PMID:21985008

Milrinone, a phosphodiesterase III inhibitor, prevents reduction of jugular bulb saturation during rewarming from hypothermic cardiopulmonary bypass.

PubMed

Iritakenishi, T; Hayashi, Y; Yamanaka, H; Kamibayashi, T; Ueda, K; Mashimo, T

2012-01-01

Inadequate cerebral oxygen balance during cardiopulmonary bypass may cause neuropsychological dysfunction. Milrinone, a phosphodiesterase III inhibitor, augments cerebral blood flow by direct vasodilatation. We conducted a prospective, randomized study in patients undergoing cardiac surgery with cardiopulmonary bypass to clarify the clinical efficacy of milrinone in the imbalance of cerebral oxygen supply and demand during the rewarming period of cardiopulmonary bypass. This is a prospective, randomized and placebo-controlled study. After anesthesia, a 5.5 F fiberoptic oximeter catheter was inserted into the right jugular bulb retrogradely for monitoring the jugular venous oxyhemoglobin saturation (SjO(2)). Patients were randomly assigned to two groups, one receiving a continuous infusion of milrinone, 0.5 µg/kg/min during hypothermic cardiopulmonary bypass, and the other receiving saline as control. Milrinone significantly prevented the reduction of the jugular venous oxyhemoglobin saturation at 10 minutes from the start of rewarming compared with the control group, but did not do so from 10 to 20 minutes after rewarming. Milrinone suppresses the reduction of SjO(2) and improves the balance of cerebral oxygen supply and demand during the early rewarming period of hypothermic cardiopulmonary bypass.

Role of phosphoinositide 3-kinase in ischemic postconditioning-induced attenuation of cerebral ischemia-evoked behavioral deficits in mice.

PubMed

Rehni, Ashish K; Singh, Nirmal

2007-01-01

The present study has been designed to pharmacologically investigate the role of phosphoinositide 3-kinase in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion-induced behavioral dysfunction in mice. Bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h was employed in the present study to produce ischemia and reperfusion-induced cerebral injury in mice. Short-term memory was evaluated using the elevated plus maze test. The inclined beam walking test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced impaired short-term memory, motor co-ordination and lateral push response. Three episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia-reperfusion-induced behavioral deficit measured in terms of loss of short-term memory, motor coordination and lateral push response. Wortmannin (2 mg/kg, iv), a phosphoinositide 3-kinase inhibitor given 10 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that beneficial effects of ischemic postconditioning on global cerebral ischemia and reperfusion-induced behavioral deficits may involve activation of phosphoinositide 3-kinase-linked pathway.

A Virtual Environment to Improve the Detection of Oral-Facial Malfunction in Children with Cerebral Palsy

PubMed Central

Martín-Ruiz, María-Luisa; Máximo-Bocanegra, Nuria; Luna-Oliva, Laura

2016-01-01

The importance of an early rehabilitation process in children with cerebral palsy (CP) is widely recognized. On the one hand, new and useful treatment tools such as rehabilitation systems based on interactive technologies have appeared for rehabilitation of gross motor movements. On the other hand, from the therapeutic point of view, performing rehabilitation exercises with the facial muscles can improve the swallowing process, the facial expression through the management of muscles in the face, and even the speech of children with cerebral palsy. However, it is difficult to find interactive games to improve the detection and evaluation of oral-facial musculature dysfunctions in children with CP. This paper describes a framework based on strategies developed for interactive serious games that is created both for typically developed children and children with disabilities. Four interactive games are the core of a Virtual Environment called SONRIE. This paper demonstrates the benefits of SONRIE to monitor children’s oral-facial difficulties. The next steps will focus on the validation of SONRIE to carry out the rehabilitation process of oral-facial musculature in children with cerebral palsy. PMID:27023561

Cerebral blood flow is reduced in patients with sepsis syndrome

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

Bowton, D.L.; Bertels, N.H.; Prough, D.S.

The relationship between sepsis-induced CNS dysfunction and changes in brain blood flow remains unknown, and animal studies examining the influence of sepsis on cerebral blood flow (CBF) do not satisfactorily address that relationship. We measured CBF and cerebrovascular reactivity to CO/sub 2/ in nine patients with sepsis syndrome using the /sup 133/Xe clearance technique. Mean CBF was 29.6 +/- 15.8 (SD) ml/100 g.min, significantly lower than the normal age-matched value in this laboratory of 44.9 +/- 6.2 ml/100 g.min (p less than .02). This depression did not correlate with changes in mean arterial pressure. Despite the reduction in CBF, themore » specific reactivity of the cerebral vasculature to changes in CO/sub 2/ was normal, 1.3 +/- 0.9 ml/100 g.min/mm Hg. Brain blood flow is reduced in septic humans; the contribution of this reduction to the metabolic and functional changes observed in sepsis requires further study.« less

Blood-brain barrier dysfunction and amyloid precursor protein accumulation in microvascular compartment following ischemia-reperfusion brain injury with 1-year survival.

PubMed

Pluta, R

2003-01-01

This study examined the late microvascular consequences of brain ischemia due to cardiac arrest in rats. In reacted vibratome sections scattered foci of extravasated horseradish peroxidase were noted throughout the brain and did not appear to be restricted to any specific area of brain. Ultrastructural investigation of leaky sites frequently presented platelets adhering to the endothelium of venules and capillaries. Endothelial cells demonstrated pathological changes with evidence of perivascular astrocytic swelling. At the same time, we noted C-terminal of amyloid precursor protein/beta-amyloid peptide (CAPP/betaA) deposits in cerebral blood vessels, with a halo of CAPP/betaA immunoreactivity in the surrounding parenchyma suggested diffusion of CAPP/betaA out of the vascular compartment. Changes predominated in the hippocampus, cerebral and entorhinal cortex, corpus callosum, thalamus, basal ganglia and around the lateral ventricles. These data implicate delayed abnormal endothelial function of vessels following ischemia-reperfusion brain injury as a primary event in the pathogenesis of the recurrent cerebral infarction.