HISTAMINE GLUTAMATE INTERACTION IN WERNICKE LESIONS

WERNICKE 病变中组胺谷氨酸的相互作用

• 批准号: 2735641
• 负责人: Philip Joseph Langlais
• 金额: $ 19.56万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2735641
• 关键词: NMDA receptors; Wernicke Korsakoff syndrome; antihistamines; cyclic aminoacid; decarboxylase inhibitor; dizocilpine; glutamates; hippocampus; histamine; histamine receptor; histamine release; histidine decarboxylase; laboratory rat; mast cell; microdialysis; neuropharmacology; neurotoxins; neurotransmitter transport; thalamus

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.

硫胺素缺乏引起的人类病理损伤与 韦尼克-科萨科夫病、混合感觉运动神经病和婴儿病 亚急性坏死性脑病。韦尼克-科尔萨科夫病的患病率 所有尸检中病理变化范围为l.7-2.8%，最高可达 慢性酗酒者中这一比例为 12.5%。韦尼克-科萨科夫个体 疾病患有顺行性和逆行性遗忘症，认知 功能障碍、多模式传感器辨别缺陷和情绪 扁平化，因此需要持续的护理和制度化。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始终是 在韦尼克-科萨科夫病中受损，可能是造成 行为缺陷。尽管有这些知识，生化和 造成病变及其地形的生理机制 急性硫胺素缺乏后大脑中的分布仍然存在 未知。因此，目前尚无治疗方法 急性硫胺素期间正在进行的病理事件突然停止 不足。 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 硫胺素缺乏造成的缺陷。重要目标是 了解大脑结构区域脆弱性的基础 能量代谢受损并探索吡硫胺的效用- 诱导硫胺素缺乏（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 检验组胺的释放对于 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 大脑的脆弱区域（丘脑）和未受影响的区域（海马体） 病变发生之前和期间； (2) 判断是否抑制 组胺释放可防止 ECF 谷氨酸盐升高和/或防止 病变； (3) 确定直接输注组胺是否会产生 PTD 丘脑和海马立即或延迟的神经毒性变化 和控制。 (4)确定MK-801是否拮抗NMDA受体 防止直接输注组胺引起的病理变化；和 (5)确定H1和H2组胺受体的拮抗作用是否减弱 PTD 引起的病理损伤和细胞外谷氨酸的增加 丘脑的脆弱区域。