MECHANISMS OF ACTION OF SMALL-MOLECULE NEUROTOXINS

小分子神经毒素的作用机制

• 批准号: 3074985
• 负责人: LAWRENCE M SAYRE
• 金额: $ 5.36万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3074985
• 关键词: Parkinson's disease; alkyl nitrile; aminoacid analog; axon reaction; chemical structure function; chemical synthesis; crosslink; cytotoxicity; decarboxylase inhibitor; dopamine; drug administration routes; electron microscopy; enzyme mechanism; high performance liquid chromatography; laboratory rat; mass spectrometry; methylphenyltetrahydropyridine; mitochondria; molecular pathology; neurochemistry; neurofilament; neurofilament proteins; neuropharmacology; neurotoxins; nuclear magnetic resonance spectroscopy; oxygenases; paraquat; stereotaxic techniques; substantia nigra; toxicant screening; toxin metabolism

This RCDA application is an updated version of a regular research proposal submitted by the PI in November 1984, and funded as of July 1985. This previous proposal involved a collaborative effector aimed at the elucidation of mechanistic details associated with three selected examples of chemically-induced neurotoxic syndromes that resemble naturally-occurring neurological disorders). The current proposal emphasizes the experiments to be carried out in chemistry by the PI, and describes the interactions between the PI and his biomedical collaborators in correlating the chemical and biological studies. The three areas of focus are (1) molecular mechanisms responsible for the induction of neurofilamentous axonopathies by alpha- diketones and IDPN, (2) mechanism of toxic action of lathyrogens and related aminonitriles, and (3) molecular mechanisms responsible for MPTP-induced Parkinson Disease. In the first project analogs of 2,5-hexanedione (2,5-HD) and beta, beta- iminodipropionitrile (IDPN) will be synthesized, studied chemically and biologically evaluated in an effort to clarify the structural basis of toxicity, particularly in respect to the direct chemical modification of neurofilament proteins by the neurotoxic chemical (or metabolite hereof). Additionally, in the case of IDPN, the pathway of metabolic activation will be clarified by a combination of chemical model studies and in vitro metabolism experiments. In the second project, a mechanism proposed to explain the observed irreversible inactivation of lysyl oxidase by beta-aminopropionitrile (BAPN) will be tested in chemical model studies, and correlated with enzymatic activities of BAPN analogs. A related mechanism proposed to explain the neurolathyrogenic properties of beta-cyanoalanine will be similarly tested, and may lead to a new strategy for the design of suicide inactivators of amino acid decarboxylases. The third project is directed at elucidating the molecualr basis of the selective toxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) to dopaminergic neurons in the substantia nigra. This project will combine chemical model studies, in vitro metabolic studies and the biochemical and ultrastructural in vivo evaluation of structural analogs of the suspected cytotoxic MPTP metabolites, focussing on the role of "redox cycling" (02 activation) and inhibition of mitochondrial oxidative metabolism as candidate mechanisms for cytotoxicity.

此RCDA应用程序是常规研究的更新版本 由私人投资公司于1984年11月提交的提案，资助日期为 1985年7月。之前的提案涉及一项协作性的 旨在阐明机械细节的效应器 与选择的三个化学诱导的例子有关 类似自然发生的神经毒性综合征 神经性疾病)。目前的提案强调了 由国际和平研究所在化学上进行的实验，以及 描述了PI和他的生物医学之间的相互作用 将化学和生物研究联系起来的合作者。 三个重点领域是：(1)分子机制 对于阿尔法诱导的神经丝状轴索病变 二酮类化合物与IDPN，(2)甲状腺激素的毒性作用机制 和相关的氨基腈，以及(3)分子机制 对MPTP引起的帕金森病负责。在第一个 项目类似物2，5-己二酮(2，5-HD)和Beta，Beta- 亚氨基二丙腈(IDPN)的合成、研究 进行化学和生物评估，以努力澄清 毒性的结构基础，特别是关于直接 神经丝蛋白的化学修饰 神经毒性化学物质(或其代谢物)。此外，在 在IDPN的情况下，代谢激活的途径将是 通过化学模型研究和体外实验相结合的方法阐明 新陈代谢实验。在第二个项目中，一个机制 建议解释观察到的赖氨酰不可逆失活现象 由β-氨基丙腈(BAPN)产生的氧化酶将在 化学模型研究，并与酶活性相关 BAPN类似物。提出了一个相关的机制来解释 β-氰基丙氨酸的神经甲亢特性将是 类似的测试，并可能导致设计的新战略 氨基酸脱羧酶自杀性灭活剂。第三 该项目旨在阐明分子基础 1-甲基-4-苯基-1，2，5，6-四氢吡啶的选择性毒性 (MPTP)至黑质内的多巴胺能神经元。这 该项目将结合化学模型研究，体外代谢 生物化学和超微结构的体内评价及研究 疑似细胞毒性MPTP的结构类似物 关注“氧化还原循环”作用的代谢物(02 激活)和抑制线粒体氧化代谢 作为细胞毒性的候选机制。