RESUMO
Thiamine deficiency is associated with cerebellar dysfunction; however, the consequences of thiamine deficiency on the electrophysiological properties of cerebellar Purkinje cells are poorly understood. Here, we evaluated these parameters in brain slices containing cerebellar vermis. Adult mice were maintained for 12-13 days on a thiamine-free diet coupled with daily injections of pyrithiamine, an inhibitor of thiamine phosphorylation. Morphological analysis revealed a 20% reduction in Purkinje cell and nuclear volume in thiamine-deficient animals compared to feeding-matched controls, with no reduction in cell count. Under whole-cell current clamp, thiamine-deficient Purkinje cells required significantly less current injection to fire an action potential. This reduction in rheobase was not due to a change in voltage threshold. Rather, thiamine-deficient neurons presented significantly higher input resistance specifically in the voltage range just below threshold, which increases their sensitivity to current at these critical membrane potentials. In addition, thiamine deficiency caused a significant decrease in the amplitude of the action potential afterhyperpolarization, broadened the action potential, and decreased the current threshold for depolarization block. When thiamine-deficient animals were allowed to recover for 1 week on a normal diet, rheobase, threshold, action potential half-width, and depolarization block threshold were no longer different from controls. We conclude that thiamine deficiency causes significant but reversible changes to the electrophysiology properties of Purkinje cells prior to pathological morphological alterations or cell loss. Thus, the data obtained in the present study indicate that increased excitability of Purkinje cells may represent a leading indicator of cerebellar dysfunction caused by lack of thiamine.
Assuntos
Células de Purkinje/patologia , Deficiência de Tiamina/patologia , Deficiência de Tiamina/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Técnicas de Patch-ClampRESUMO
Thiamine deficiency (TD) produces severe neurodegenerative lesions. Studies have suggested that primary neurodegenerative events are associated with both oxidative stress and inflammation. Very little is known about the downstream effects on intracellular signaling pathways involved in neuronal death. The primary aim of this work was to evaluate the modulation of p38MAPK and the expression of heme oxygenase 1 (HO-1) in the central nervous system (CNS). Behavioral, metabolic, and morphological parameters were assessed. Mice were separated into six groups: control (Cont), TD with pyrithiamine (Ptd), TD with pyrithiamine and Trolox (Ptd + Tr), TD with pyrithiamine and dimethyl sulfoxide (Ptd + Dmso), Trolox (Tr) and DMSO (Dmso) control groups and treated for 9 days. Control groups received standard feed (AIN-93M), while TD groups received thiamine deficient feed (AIN-93DT). All the groups were subjected to behavioral tests, and CNS samples were collected for cell viability, histopathology and western blot analyses. The Ptd group showed a reduction in weight gain and feed intake, as well as a reduction in locomotor, grooming, and motor coordination activities. Also, Ptd group showed a robust increase in p38MAPK phosphorylation and mild HO-1 expression in the cerebral cortex and thalamus. The Ptd group showed a decreased cell viability, hemorrhage, spongiosis, and astrocytic swelling in the thalamus. Groups treated with Trolox and DMSO displayed diminished p38MAPK phosphorylation in both the structures, as well as attenuated thalamic lesions and behavioral activities. These data suggest that p38MAPK and HO-1 are involved in the TD-induced neurodegeneration in vivo, possibly modulated by oxidative stress and neuroinflammation.
Assuntos
Encéfalo/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Deficiência de Tiamina/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Comportamento Animal/fisiologia , Peso Corporal/fisiologia , Encéfalo/patologia , Sobrevivência Celular/fisiologia , Cromanos/farmacologia , Dimetil Sulfóxido/farmacologia , Ingestão de Alimentos/fisiologia , Inflamação/etiologia , Inflamação/fisiopatologia , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Piritiamina , Deficiência de Tiamina/induzido quimicamente , Deficiência de Tiamina/complicações , Deficiência de Tiamina/patologiaRESUMO
BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.
Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Neurônios/fisiologia , Sinapses/fisiologia , Deficiência de Tiamina/complicações , Deficiência de Tiamina/metabolismo , Tiamina Pirofosfato/deficiência , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Western Blotting , Espinhas Dendríticas/metabolismo , Difosfotransferases/metabolismo , Glucose/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transmissão Sináptica/fisiologia , Deficiência de Tiamina/fisiopatologia , Tiamina Pirofosfato/metabolismoRESUMO
BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.
Assuntos
Animais , Masculino , Sinapses/fisiologia , Deficiência de Tiamina/complicações , Deficiência de Tiamina/metabolismo , Tiamina Pirofosfato/deficiência , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Neurônios/fisiologia , Deficiência de Tiamina/fisiopatologia , Tiamina Pirofosfato/metabolismo , Distribuição Aleatória , Western Blotting , Peptídeos beta-Amiloides/metabolismo , Ratos Sprague-Dawley , Difosfotransferases/metabolismo , Transmissão Sináptica/fisiologia , Espinhas Dendríticas/metabolismo , Doença de Alzheimer/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Glucose/metabolismo , Hipocampo/fisiopatologia , Hipocampo/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Thiamine (vitamin B1) is co-factor for three pivotal enzymes for glycolytic metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase. Thiamine deficiency leads to neurodegeneration of several brain regions, especially the cerebellum. In addition, several neurodegenerative diseases are associated with impairments of glycolytic metabolism, including Alzheimer's disease. Therefore, understanding the link between dysfunction of the glycolytic pathway and neuronal death will be an important step to comprehend the mechanism and progression of neuronal degeneration as well as the development of new treatment for neurodegenerative states. Here, using an in vitro model to study the effects of thiamine deficiency on cerebellum granule neurons, we show an increase in Ca2+ current density and CaV1.2 expression. These results indicate a link between alterations in glycolytic metabolism and changes to Ca2+ dynamics, two factors that have been implicated in neurodegeneration.
Assuntos
Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Cerebelo/patologia , Ativação do Canal Iônico , Neurônios/metabolismo , Deficiência de Tiamina/metabolismo , Animais , Animais Recém-Nascidos , Immunoblotting , Ratos Wistar , Período Refratário Eletrofisiológico , Deficiência de Tiamina/fisiopatologiaRESUMO
In modern society, thiamine deficiency (TD) remains an important medical condition linked to altered cardiac function. There have been contradictory reports about the impact of TD on heart physiology, especially in the context of cardiac excitability. In order to address this particular question, we used a TD rat model and patch-clamp technique to investigate the electrical properties of isolated cardiomyocytes from epicardium and endocardium. Neither cell type showed substantial differences on the action potential waveform and transient outward potassium current. Based on our results we can conclude that TD does not induce major electrical remodeling in isolated cardiac myocytes in either endocardium or epicardium cells.
Assuntos
Modelos Animais de Doenças , Miócitos Cardíacos/fisiologia , Deficiência de Tiamina/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Técnicas Eletrofisiológicas Cardíacas , Endocárdio/citologia , Masculino , Técnicas de Patch-Clamp , Pericárdio/citologia , Ratos Wistar , Fatores de TempoRESUMO
Chronic thiamine deficiency may be responsible for pathologic changes in the brains of alcoholics, and subclinical episodes of this vitamin deficiency may cause cumulative brain damage. In the present work, the chronic effects of ethanol and its association to a mild thiamine deficiency episode (subclinical model) on neocortical and hippocampal acetylcholinesterase activity were assessed along with their possible association to spatial cognitive dysfunction. The results indicate that in the beginning of the neurodegenerative process, before the appearance of brain lesions, chronic ethanol consumption reverses the effects of mild thiamine deficiency on both spatial cognitive performance and acetylcholinesterase activity without having significant effects on any morphometric parameter.
Assuntos
Acetilcolinesterase/metabolismo , Alcoolismo/metabolismo , Aprendizagem em Labirinto , Memória Espacial , Deficiência de Tiamina/metabolismo , Alcoolismo/complicações , Alcoolismo/fisiopatologia , Animais , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Neocórtex/metabolismo , Neocórtex/fisiopatologia , Ratos , Ratos Wistar , Deficiência de Tiamina/complicações , Deficiência de Tiamina/fisiopatologiaRESUMO
A 19-month-old, white, Pennsylvanian boy, with an unremarkable medical history, presented to our hospital with a 3-week history of nonbloody, nonbilious emesis up to 5 times a day and nonbloody diarrhea. Ten days before admission, his gait became progressively unsteady, until he finally refused to walk. A day before admission, he found it difficult to move his eyes. The patient was hypoactive. History, physical and neurologic examination, blood and cerebrospinal (CSF) fluid studies, and neuroimaging studies ruled out the most frequent causes of acute ataxia. The etiology of bilateral, complete ophthalmoplegia was also taken into consideration. Magnetic resonance imaging (MRI) findings of bilateral thalami and mammillary bodies provided diagnostic clues. Additional history and specific tests established the final diagnosis and treatment plan. The patient improved to a normal neurologic state. This case provides important practical information about an unusual malnutrition cause of acute ataxia, particularly in young children of developing countries.
Assuntos
Ataxia/fisiopatologia , Transtornos da Consciência/fisiopatologia , Oftalmoplegia/fisiopatologia , Deficiência de Tiamina/diagnóstico , Deficiência de Tiamina/fisiopatologia , Ataxia/diagnóstico , Ataxia/patologia , Transtornos da Consciência/diagnóstico , Transtornos da Consciência/patologia , Diagnóstico Diferencial , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Oftalmoplegia/diagnóstico , Oftalmoplegia/patologia , Tiamina/administração & dosagem , Deficiência de Tiamina/patologia , Deficiência de Tiamina/terapia , Estados UnidosRESUMO
Thiamine deficiency (TD) is the underlying cause of Wernicke's encephalopathy (WE), an acute neurological disorder characterized by structural damage to key periventricular structures in the brain. Increasing evidence suggests these focal histological lesions may be representative of a gliopathy in which astrocyte-related changes are a major feature of the disorder. These changes include a loss of the glutamate transporters GLT-1 and GLAST concomitant with elevated interstitial glutamate levels, lowered brain pH associated with increased lactate production, decreased levels of GFAP, reduction in the levels of glutamine synthetase, swelling, alterations in levels of aquaporin-4, and disruption of the blood-brain barrier. This review focusses on how these manifestations contribute to the pathophysiology of TD and possibly WE.
Assuntos
Astrócitos/fisiologia , Deficiência de Tiamina/fisiopatologia , Sistema X-AG de Transporte de Aminoácidos/fisiologia , Animais , Transporte Biológico , Barreira Hematoencefálica , Encéfalo/patologia , Modelos Animais de Doenças , Transportador 2 de Aminoácido Excitatório/fisiologia , Ácido Glutâmico/metabolismo , Humanos , Complexo Cetoglutarato Desidrogenase/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Piritiamina/toxicidade , Deficiência de Tiamina/induzido quimicamente , Deficiência de Tiamina/metabolismo , Encefalopatia de Wernicke/etiologia , Encefalopatia de Wernicke/metabolismo , Encefalopatia de Wernicke/fisiopatologiaRESUMO
The links between spatial behavior and hippocampal levels of synapsin I and phosphosynapsin I were assessed in normal rats and in the pyrithiamine-induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoff's syndrome. Synapsin I tethers small synaptic vesicles to the actin cytoskeleton in a phosphorylation-dependent manner, is involved in neurotransmitter release and has been implicated in hippocampal-dependent learning. Positive correlations between spontaneous alternation behavior and hippocampal levels of both synapsin I and phosphorylated synapsin I were found in control rats. However, spontaneous alternation performance was impaired in PTD rats and was accompanied by a significant reduction (30%) in phosphorylated synapsin I. Furthermore, no correlations were observed between either form of synapsin I and behavior in PTD rats. These data suggest that successful spontaneous alternation performance is related to high levels of hippocampal synapsin I and phosphorylated synapsin I. These results not only support the previous findings that implicate impaired hippocampal neurotransmission in the spatial learning and memory deficits associated with thiamine deficiency, but also suggest a presynaptic mechanism.