HISTAMINE GLUTAMATE INTERACTION IN WERNICKE LESIONS

硫胺素缺乏导致的人类病理损害与 韦尼克-科萨科夫病、混合感觉性运动神经病和婴儿 亚急性坏死性脑病。韦尼克-科萨科夫病的流行 病理改变在所有尸检中从1.7-2.8%到高达 在慢性酗酒者中占12.5%。韦尼克-科萨科夫综合征患者 疾病患有顺行性和逆行性健忘症，认知性 功能障碍，多模式传感器辨别缺陷，以及情绪 因此，这需要持续的照料和制度化。一个 这些硫胺素缺乏症的重要特征是选择性 特定大脑区域对病理损伤的脆弱性。地区 丘脑、乳头体和某些脑干核团 在韦尼克-科萨科夫病中受损，可能是导致 行为缺陷。尽管有这样的知识，但生化和 损伤的生理机制及其地形图 急性硫胺素缺乏后脑内分布仍然存在 未知。因此，目前还没有治疗这种疾病的方法。 在急性硫胺素期间突然停止正在进行的病理事件 缺乏症。 该项目的长期目标是开发有效的治疗方法。 用于预防大脑损伤和相关的认知和记忆 因硫胺素缺乏而产生的缺陷。重要的目标是 了解大脑结构的区域性脆弱性的基础 能量代谢受损，并探索吡硫胺的用途- 诱导性硫胺素缺乏(PTD)大鼠作为研究血管的模型 脑内的水肿性坏死。这个项目的近期目标是 测试组胺释放对 谷氨酸-NMDA受体介导的兴奋性损伤在脑内的发展 丘脑。具体目标是进行以下研究： 经皮冠状动脉腔内成形术大鼠WerNicke-Korsakoff‘s病模型(L) 微透析，测量体内组胺释放的时间进程 大脑中易受影响的(丘脑)和未受影响的(海马体)区域 在病变发生之前和期间；(2)确定是否抑制 组胺释放可防止ECF谷氨酸升高和/或防止 确定直接输注组胺是否会产生 PTD丘脑和海马区即刻或延迟性神经毒性改变 和控制。(4)测定MK-801对NMDA受体的拮抗作用 防止因直接输注组胺而产生的病理变化；以及 (5)确定组胺H1和H2受体的拮抗作用是否减弱 PTD所致的病理损伤及细胞外谷氨酸的升高 丘脑的脆弱区域。

Thiamine deficiency induced pathologic damage in humans is associated with Wernicke-Korsakoff's disease, mixed sensor motor neuropathy and infantile subacute necrotizing encephalopathy. The prevalence of Wernicke-Korsakoff pathologic changes ranges from l.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 sensor 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. Important goals are to understand the bases for regional vulnerability of brain structures to impaired energy metabolism and to explore the utility of the pyrithiamine- induced thiamine deficiency (PTD) rat as a model for studying vascular edematous necrosis in the brain. The immediate goal of this project is to test the hypothesis that release of histamine is critical to the development of glutamate-NMDA receptor mediated excitotoxic lesions within thalamus. The specific goals are to conduct the following studies in the PTD rat model of Wernicke-Korsakoff's disease: (l) using in vivo microdialysis, measure the temporal course of histamine release within vulnerable (thalamus) and unaffected (hippocampus) regions of the brain prior to and during onset of lesions; (2) determine if inhibition of histamine release prevents rise in ECF glutamate and/or protects against lesions; (3) determine if direct infusion of histamine produces either immediate or delayed neurotoxic changes in thalamus and hippocampus of PTD and controls. (4) determine if antagonism of NMDA receptors with MK-801 prevents pathologic changes produced by direct infusion of histamine; and (5) determine if antagonism of H1 and H2 histamine receptors attenuates PTD-induced pathologic damage and the rise in extracellular glutamate in vulnerable regions of thalamus.