EXCITATORY NEURODEGENERATIVE MECHANISMS-II

兴奋性神经退行性机制-II

• 批准号: 6267589
• 负责人: Michael A. Sesma
• 金额: $ 10.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-15 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6267589
• 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.

中枢神经系统中的主要兴奋性神经递质 - 谷氨酸（GLU） 和乙酰胆碱 - 具有重要的生理功能，包括 认知和记忆的调解，但也具有明显的神经毒性 潜在的。在这个项目中，申请人将专注于三个不同的 兴奋性发射器神经毒性的形式，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 发生在人类中。第一个特定目的解决了一种新形式 神经毒性是通过抑制GLU离子型触发的 根据最近的证据，受体导致过度 激活胆碱能毒蕈碱受体，这是近端的原因 脑皮层神经退行性变化。本质上，这种类型的 神经毒性反应可以正确称为“胆碱能兴奋性毒性”。 第二个特定目的与最近发现的神经元有关 变性与导致的药物治疗有关 新描述的第二使者功能的过度刺激 EAA代谢受体。第三个特定目标与 Domoate的神经毒性，最近与食物有关的GLU类似物 中毒事件，其中成年人，尤其是老年人 持续的大脑损伤和记忆力丧失。 前两个具体目标 与神经毒性综合征有关，这些综合征也与不同 奥尔尼博士提议中的方法（项目＃1）。这项研究提出了 目前的项目强调专业组织学的应用 原位的方法，包括电子显微镜免疫细胞化学化学 杂交组织化学和受体自显影术，而在Dr. 奥尔尼的提议重点主要是在神经药理学和 神经毒理学方法。 这是该程序中唯一的项目 涉及神经毒性的项目建议；但是，这项工作 Dr. Wozniak与Domoate诱导的记忆障碍有关。