EXCITOTOXIC BASIS OF BRAIN DAMAGE IN THIAMINE DEFICIENCY

硫胺素缺乏导致的人类病理损害与 韦尼克-科萨科夫病，混合性感觉运动神经病，以及 婴幼儿亚急性坏死性脑病。疾病的流行 Wernicke-Korsakoff病变占1.7%-2.8% 慢性酗酒者的尸检比例高达12.5%。具有以下特征的个人 韦尼克-科萨科夫病以顺行和逆行为主 健忘症、认知功能障碍、多模式感觉辨别 缺陷和情感扁平化，因此需要持续的照顾和 制度化。这些硫胺素缺乏的一个重要特征 障碍是特定大脑区域的选择性易损性 病理性损伤。丘脑、乳头体和某些 韦尼克-柯萨科夫S病脑干核团持续受损 很可能是造成行为缺陷的原因。尽管如此 知识，负责的生化和生理机制 颅脑损伤及其在脑内的分布 急性硫胺素缺乏症仍不清楚。因此，有 目前还没有治疗方法来治疗突然停止正在进行的 急性硫胺素缺乏期间的病理事件。 该项目的长期目标是开发有效的 脑损伤的预防及相关认知治疗 以及硫胺素缺乏造成的记忆缺陷。眼前的目标 这个项目的目的是检验最近的一个假说，该假说表明谷氨酸 受体介导的神经毒性与所产生的脑损伤有关 由急性硫胺素缺乏症引起。具体目标是进行 吡硫胺致硫胺缺乏症(PTD)研究进展 Wernicke-Korsakoff病大鼠模型：I)活体测量 微透析对大鼠心肌细胞外液兴奋性氨基酸的影响 急性硫胺素缺乏时受影响和未受影响的脑区； 二)定量测量N-甲基-D-天冬氨酸(NMDA)的影响 受体拮抗剂MK-801减轻硫胺素缺乏症 脑部病变；以及iii)进行树突状细胞的超微结构分析 急性硫胺素缺乏引起的体细胞退行性改变 有“兴奋性毒性”损伤的证据。

Thiamine deficiency induced pathologic damage in humans is associated with Wernicke-Korsakoff's disease, mixed sensory motor neuropathy, and infantile subacute necrotizing encephalopathy. The prevalence of Wernicke-Korsakoff pathologic changes ranges from 1.7-2.8% among all autopsies to as high as 12.5% among chronic alcoholics. Individuals with Wernicke-Korsakoff disease suffer from anterograde and retrograde amnesia, cognitive dysfunctions, multimodal sensory discrimination deficits, and emotional flattening and thus require constant care and institutionalization. An important feature of these thiamine deficiency disorders is the selective vulnerability of specific brain regions to pathologic damage. Regions of thalamus, mammillary bodies, and certain brainstem nuclei are consistently damaged in Wernicke-Korsakoff s disease and are probably responsible for the behavioral deficits. Despite this knowledge, the biochemical and physiological mechanisms responsible for the lesions and their topographic distribution in the brain following acute thiamine deficiency remain unknown. Consequently, there is currently no therapeutic treatment for the abrupt cessation of ongoing pathologic events during acute thiamine deficiency. The long-term objective of this project is to develop effective treatments for the prevention of brain lesions and associated cognitive and memory deficits produced by thiamine deficiency. The immediate goal of this project is to test a recent hypothesis that suggests glutamate receptor-mediated neurotoxicity is involved in the brain lesions produced by acute thiamine deficiency. The specific goals are to conduct the following studies in the pyrithiamine induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoff's disease: i) measure by in vivo microdialysis the extracellular fluid levels of excitatory amino acids in affected and unaffected brain regions during acute thiamine deficiency; ii) quantitatively measure the effects of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, in reducing thiamine deficiency induced brain lesions; and iii) conduct an ultrastructural analysis of dendritic and somal degenerative changes induced by acute thiamine deficiency for evidence of 'excitotoxic' type of damage.