MECHANISMS OF NEUROTOXIC ACTION AND METABOLIC ACTIVATION

神经毒作用和代谢激活的机制

• 批准号: 3405446
• 负责人: LAWRENCE M SAYRE
• 金额: $ 10.02万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3405446
• 关键词: alkyl nitrile; analog; autooxidation; axon; brain metabolism; chemical synthesis; covalent bond; crosslink; laboratory rat; liver metabolism; methylphenyltetrahydropyridine; nervous system disorder; neurochemistry; neurofilament; neurotoxins; nuclear magnetic resonance spectroscopy; positron emission tomography; pyrroles; tissue /cell culture; toxicology; toxin metabolism

This is a continuation of a collaborative effort to elucidate molecular mechanisms associated with several types of chemically-induced neurotoxic syndromes that resemble naturally-occurring neurological disorders. With ongoing development of this program, the major thrust is focusing more on specific aspects of the toxic activation mechanisms and on underlying biochemical considerations. In Project I, a major issue is whether accumulation of neurofilaments (NF) in peripheral axons induced by neurotoxic chemicals such as gamma-diketones, beta, beta'-imino- dipropionitrile (IDPN), and CS2, is a consequence of (i) simple covalent modification of NF or (ii) a subsequent NF cross-linking. Studies on gamma-diketone analogs which permit a dissociation of these two factors are proposed, as are chemical studies which address the nature of potential protein cross-linking reactions. Another area of focus is the metabolic activation of IDPN, a neurotoxin which induces a Tourette-like behavioral abnormality in addition to a peripheral axonopathy, and the related bladder neurotoxin beta-(dimethylamino)propionitrile (DMAP). The first part of Project II is directed at clarifying certain details regarding the mechanism of toxic activation of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Studies are proposed (i) to gain further insight into the mechanism of and structural dependence governing the inhibition of mitochondrial respiration by the neurotoxic MPTP metabolite, 1-- methyl-4-phenylpyridinium (MPP+), (ii) to obtain a better definition of what MPTP- or MPP+-like structures could act as endogenous or exogenous neurotoxins, (iii) to clarify the propensity for free-radical production and reactive intermediate generation in MPTP metabolism, and (iv) to develop 18F-containing MPTP analogs for positron emission tomography (PET) studies on MPTP biodistribution in primate brain. The second part of Project II focuses on basic biochemical mechanisms of metabolic activation of toxic tertiary amines related to MPTP, which are associated with suicide inactivation of metabolizing enzymes and covalent binding to proteins. A combination of model chemical oxidation, enzymologic, and in vitro metabolism studies is proposed.

这是一个合作努力的延续， 与几种化学诱导的神经毒性相关的机制 类似于自然发生的神经系统疾病的综合征。 与 该计划的持续发展，主要重点是更多地关注 毒性激活机制的具体方面和潜在的 生化考虑。 在项目I中，一个主要问题是， 神经丝（NF）在外周轴突中的积聚 神经毒性化学物质，如γ-二酮，β，β ′-亚氨基， 二丙腈（IDPN）和CS2是（i）简单共价键的结果 NF的修饰或（ii）随后的NF交联。 研究 允许这两种因子解离的γ-二酮类似物 化学研究，解决的性质， 潜在的蛋白质交联反应。 另一个重点领域是 IDPN的代谢活化，IDPN是一种诱导Tourette样 行为异常，以及外周轴突病， 相关的膀胱神经毒素β-（二甲氨基）丙腈（DMAP）。 项目II的第一部分旨在澄清某些细节 关于多巴胺能神经元的毒性激活机制， 神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）。 研究 （i）进一步深入了解 结构依赖性抑制线粒体 呼吸的神经毒性MPTP代谢物，1-- 甲基-4-苯基吡啶鎓（MPP+），（ii）以获得更好的定义， MPTP-或MPP+样结构可以作为内源性或外源性 神经毒素，（iii）澄清自由基产生的倾向 和MPTP代谢中的反应性中间体生成，以及（iv） 开发用于正电子发射断层扫描的含18 F的MPTP类似物 (PET)MPTP在灵长类动物脑内分布的研究 第二部分 项目II的重点是代谢的基本生化机制 与MPTP相关的毒性叔胺的活化， 通过代谢酶的自杀性失活和共价结合 proteins. 结合模型化学氧化，酶学， 建议进行体外代谢研究。