EXCITOTOXIC BASIS OF BRAIN DAMAGE IN THIAMINE DEFICIENCY

硫胺素缺乏引起的人类病理损伤与 Wernicke-Korsakoff病，混合感觉运动神经病， 婴儿亚急性坏死性脑病 之时尚 Wernicke-Korsakoff病理改变占1.7- 2.8 在慢性酗酒者中，尸检率高达12.5%。 人士 Wernicke-Korsakoff病是一种顺行性和逆行性 健忘症，认知功能障碍，多模式感觉辨别 赤字，情绪平淡，因此需要不断的照顾， 制度化。 这些硫胺素缺乏症的一个重要特征 疾病是特定大脑区域的选择性弱点， 病理性损伤 丘脑、乳头体和某些 脑干核团在Wernicke-Korsakoff病中持续受损 很可能是造成行为缺陷的原因 尽管如此 知识，生物化学和生理机制负责 脑内病变及其局部分布 急性硫胺素缺乏症仍然未知。 因此， 目前没有治疗突然停止正在进行的 急性硫胺素缺乏时的病理事件。 该项目的长期目标是开发有效的 用于预防脑损伤和相关认知障碍的治疗 和记忆力的缺陷。 这一近期目标 这个项目的目的是检验最近的一个假设， 受体介导的神经毒性参与脑损伤产生 急性硫胺素缺乏症 具体目标是开展 以下是关于吡硫胺诱导的硫胺素缺乏症（PTD）的研究 Wernicke-Korsakoff病大鼠模型：i）通过体内测量 微透析细胞外液兴奋性氨基酸水平 急性硫胺素缺乏时受影响和未受影响的脑区; ii）定量测量N-甲基-D-天冬氨酸（NMDA） 受体拮抗剂MK-801在减少硫胺素缺乏症中的作用 脑损伤;和iii）进行树突状细胞的超微结构分析 和急性硫胺素缺乏引起的体细胞退行性变化， 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.