HISTAMINE GLUTAMATE INTERACTION IN WERNICKE LESIONS

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和婴儿 亚急性坏死性脑病Wernicke-Korsakoff综合征的发病率 病理变化范围从所有尸检中的1.7 -2.8%到高达 12.5%的慢性酗酒者。Wernicke-Korsakoff患者 患有顺行性和逆行性遗忘症、认知性 功能障碍，多模态传感器识别缺陷，以及情绪 扁平化，因此需要持续的护理和机构化。一个 这些硫胺素缺乏症的一个重要特征是选择性地 特定脑区对病理损伤的脆弱性。地区 丘脑、乳头体和某些脑干核团始终是 在Wernicke-Korsakoff病中受损，可能是导致 行为缺陷尽管有这些知识，生物化学和 负责病变的生理机制及其地形 急性硫胺素缺乏后脑内的分布仍然存在 未知因此，目前还没有治疗性的治疗方法。 急性硫胺素治疗期间正在进行的病理事件突然停止 缺陷 该项目的长期目标是开发有效的治疗方法 用于预防脑损伤以及相关的认知和记忆 由硫胺素缺乏引起的缺陷。重要目标是 了解大脑结构区域脆弱性的基础， 受损的能量代谢，并探讨利用吡硫胺- 诱导的硫胺素缺乏（PTD）大鼠作为研究血管的模型 脑水肿性坏死该项目的近期目标是 测试假设组胺的释放是至关重要的 谷氨酸-NMDA受体介导的兴奋性毒性病变的发展 丘脑具体目标是在2010年开展以下研究： Wernicke-Korsakoff病的PTD大鼠模型：（l）使用体内 微透析，测量组胺释放的时间过程， 大脑的脆弱（丘脑）和未受影响（海马）区域 在病变发生之前和期间;（2）确定是否抑制 组胺释放防止ECF谷氨酸盐升高和/或防止 病变;（3）确定是否直接输注组胺产生 PTD丘脑和海马神经毒性即刻或迟发性改变 和控制。(4)确定MK-801是否具有NMDA受体拮抗作用 防止直接输注组胺引起的病理变化; (5)确定H1和H2组胺受体的拮抗作用是否减弱 PTD诱导的病理性损伤和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.