MECHANISMS OF ACTION OF SMALL-MOLECULE NEUROTOXINS

此RCDA应用程序是一个定期研究的更新版本 PI于1984年11月提交的提案，并于2008年11月获得资助。 1985年7月。 这一提议涉及到一个合作项目， 旨在阐明机械细节的效应器 与三个选定的化学诱导的例子有关， 类似于自然发生的神经毒性综合征 神经障碍）。 目前的建议强调， PI将进行的化学实验，以及 描述了PI和他的生物医学 在化学和生物学研究的相互关联方面的合作者。 这三个领域的重点是（1）分子机制负责 用于通过α- 二酮和IDPN;（2）lathyrogens的毒性作用机制 和相关的氨基腈，和（3）分子机制 导致MPTP诱发的帕金森病 上 2，5-己二酮（2，5-HD）和β，β- 合成了亚氨基二丙腈（IDPN）， 进行化学和生物学评价，以澄清 毒性的结构基础，特别是在直接 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 IDPN的情况下，代谢活化途径将是 通过化学模型研究和体外研究的结合来阐明 代谢实验 在第二个项目中， 建议解释观察到的赖氨酰不可逆失活 氧化酶的β-氨基丙腈（BAPN）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-氰基丙氨酸的神经性甲状腺功能将是 类似的测试，并可能导致一个新的战略设计， 氨基酸脱羧酶的自杀灭活剂。 第三 该项目旨在阐明 1-甲基-4-苯基-1，2，5，6-四氢吡啶的选择毒性 （MPTP）对黑质中多巴胺能神经元的作用。 这 该项目将联合收割机化学模型研究，体外代谢 研究以及体内生化和超微结构评价 疑似细胞毒性MPTP的结构类似物 代谢物，侧重于“氧化还原循环”的作用（02 激活）和抑制线粒体氧化代谢 作为细胞毒性的候选机制。

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.