EXCITATORY NEURODEGENERATIVE MECHANISMS-II

兴奋性神经退行性机制-II

• 批准号: 6217017
• 负责人: Michael A. Sesma
• 金额: $ 11.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217017
• 关键词: NMDA receptors; acetylcholine; aminoacid analog; autoradiography; cellular pathology; cerebral cortex; cingulate gyrus; dizocilpine; excitatory aminoacid; gamma aminobutyrate; glutamate receptor; histopathology; immunocytochemistry; in situ hybridization; laboratory rat; muscarinic receptor; neural degeneration; neuroanatomy; neuropharmacology; neuroprotectants; neurotoxins; receptor expression; second messengers; stress proteins; synapses

The principal excitatory neurotransmitters in the CNS -- glutamate (Glu) and acetylcholine -- have important physiological functions, including the mediation of cognition and memory, but also possess significant neurotoxic potential. In this project, the applicants will focus on three different forms of excitatory transmitter neurotoxicity, with an aim toward evaluating how these neurotoxic processes might relate to the pathophysiology of memory impairment or neurodegenerative processes that occur in humans. The first specific aim addresses a new form of neurotoxicity that is triggered by suppression of a Glu ionotropic receptor which, according to recent evidence, results in excessive activation of cholinergic muscarinic receptors as the proximate cause of cerebrocortical neurodegenerative changes. In essence, this type of neurotoxic reaction can properly be called "cholinergic excitotoxicity". The second specific aim pertains to recent findings that neuronal degeneration occurs in association with drug treatments that cause hyperstimulation of the second messenger functions of a newly described EAA metabotropic receptor. The third specific aim pertains to the neurotoxicity of domoate, a Glu analog recently implicated in a food poisoning incident in which adult humans, especially elderly humans, sustained brain damage and memory loss. The first two specific aims pertain to neurotoxic syndromes that are also being addressed by different methods in Dr. Olney's proposal (Project #1). The research proposed in the present project emphasizes the application of specialized histological methods, including electron microscopic immunocytochemistry, in situ hybridization histochemistry and receptor autoradiography, whereas in Dr. Olney's proposal the emphasis is predominantly on neuropharmacological and neurotoxicological approaches. This is the only project in this program projects proposal that addresses domoate neurotoxicity; however, this work will be performed in coordination with other on going studies by Dr. Wozniak pertaining to domoate-induced memory impairment.

中枢神经系统中主要的兴奋性神经递质——谷氨酸（Glu） 和乙酰胆碱——具有重要的生理功能，包括 介导认知和记忆，但也具有显着的神经毒性 潜在的。在这个项目中，申请人将重点关注三个不同的 形式的兴奋性递质神经毒性，目的是 评估这些神经毒性过程如何与 记忆障碍或神经退行性过程的病理生理学 发生在人类身上。第一个具体目标涉及一种新形式 抑制 Glu 离子型药物引发的神经毒性 根据最近的证据，受体会导致过度 胆碱能毒蕈碱受体的激活是导致胆碱能毒蕈碱受体激活的直接原因 脑皮质神经退行性改变。从本质上讲，这种类型的 神经毒性反应可以恰当地称为“胆碱能兴奋性毒性”。 第二个具体目标涉及神经元的最新发现 退化的发生与药物治疗有关，导致 新描述的第二信使功能的过度刺激 EAA 代谢型受体。第三个具体目标涉及 多摩酸的神经毒性，一种最近与食品有关的谷氨酸类似物 成年人特别是老年人的中毒事件 持续的脑损伤和记忆丧失。 前两个具体目标 与神经毒性综合征有关，这些综合征也正在通过不同的方法解决 Olney 博士的提案（项目#1）中的方法。中提出的研究 目前的项目强调专业组织学的应用 方法，包括电子显微镜免疫细胞化学、原位 杂交组织化学和受体放射自显影，而在博士。 奥尔尼的建议主要强调神经药理学和 神经毒理学方法。 这是该计划中唯一的项目 解决多莫特神经毒性的项目提案；然而，这项工作 将与 Dr. 正在进行的其他研究协调进行。 沃兹尼亚克（Wozniak）与多摩酸引起的记忆障碍有关。