BIOLOGY OF GLUTATHIONE PEROXIDASE IN DOPAMINE NEURONS

多巴胺神经元中谷胱甘肽过氧化物酶的生物学

基本信息

批准号：
3415653
负责人：
Gerald Cohen
金额：
$ 19.56万
依托单位：
MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-01 至 1994-08-31
项目状态：
已结题

项目摘要

Hydrogen peroxide (H2O2) is a neurotoxic agent that is generated during the natural oxidation of dopamine (DA) by monoamine oxidase (MAO). H202 is detoxified mainly by glutathione peroxidase (GSH-Px), which produces glutathione disulfide (GSSG). Under normal circumstances, GSSG does not accumulate because it is effectively reduced by GSSG reductase. When GSSG does accumulate, it serves as an indicator of an "oxidative stress". Studies by others with non-neural tissues have shown that accumulation of GSSG is associated with toxic events. During aging, and specifically in Parkinson's disease, surviving nigrostriatal neurons exhibit increased turnover of DA; hence, both aging and Parkinson's disease are characterized by a self-generated oxidative stress, derived from the increased rate of production of H202. We have shown that increased DA turnover in rodents elevates GSSG in the striatum. This observation provides a definitive marker of oxidant stress and unlocks the study of oxidative events at dopaminergic synapses. Primary goals of the research proposal are to study in detail the extent and course of oxidative changes (pharmacokinetics) during exposure to drugs that alter DA turnover (Aim 1) and to assess gene expression and regulation of GSH-PX (mRNA and enzyme protein) in DA neurons (Aim 2). Preliminary data are available for key experimental approaches in these areas. The studies also include autopsy specimens of human brain and oxidative changes in monkey brain (Aim 3). Long range goals (Aim 4) encompass effects of enhanced DA turnover on SH-dependent enzymes and proteins, and assessment of gene expression for GSSG reductase. These studies open a new vista into the central nervous system. At a basic level, they will provide fundamental information about the dynamics of the critical glutathione status (GSSG, GSH, protein mixed-disulfides) at dopaminergic synapses, as well as the distribution and regulation of GSH-Px and GSSG reductase in brain. In practical terms, the studies should prove valuable for understanding Parkinson's disease as well as for designing new strategies for treatment. The results reflect immediately on the clinical use of deprenyl (inhibitor of MAO-B) in the treatment of Parkinson's disease. Over the long range, the developing concepts and results should also impact upon other areas where oxidative stress is implicated in the CNS, such as aging, reperfusion injury after stroke, and Alzheimer's disease.

过氧化氢（H2O2）是产生的神经毒性剂在单胺氧化酶（MAO）对多巴胺（DA）的自然氧化过程中。 H202主要由谷胱甘肽过氧化物酶（GSH-PX）排毒，该酶产生谷胱甘肽二硫化物（GSSG）。在正常情况下，GSSG 不积聚，因为它被GSSG还原酶有效降低。当GSSG确实积累时，它可以用作“氧化的指标压力”。其他人进行非神经组织的研究表明 GSSG的积累与有毒事件有关。在衰老期间特别是在帕金森氏病中幸存的骨纹状体神经元表现出DA的营业额增加；因此，衰老和帕金森氏症疾病的特征是自我产生的氧化应激，得出来自H202的生产率提高。我们已经表明啮齿动物的DA周转增加可提高纹状体中的GSSG。这观察提供了氧化应激和解锁的明确标记多巴胺能突触中氧化事件的研究。主要目标研究建议将详细研究暴露于改变的药物期间的氧化变化（药代动力学） DA转换（AIM 1）并评估基因表达和调节 DA神经元中的GSH-PX（mRNA和酶蛋白）（AIM 2）。初步数据可用于这些领域的关键实验方法。这研究还包括人脑的尸检和氧化标本猴子大脑的变化（目标3）。远程目标（AIM 4）包括增强DA离职对SH依赖性酶和蛋白质的影响，以及评估GSSG还原酶基因表达。这些研究向中枢神经系统开辟了新的远景。在一个基本层次，他们将提供有关临界谷胱甘肽状态的动力学（GSSG，GSH，蛋白质多巴胺能突触的混合二硫化物以及分布以及大脑中GSH-PX和GSSG还原酶的调节。实用术语，这些研究应该证明对于理解帕金森氏症很有价值疾病以及设计新的治疗策略。这结果立即反映了非肾上腺素的临床使用（抑制剂的抑制剂 Mao-B）在治疗帕金森氏病。在远距离范围内发展概念和结果也应影响其他领域氧化应激与中枢神经系统有关，例如衰老，再灌注中风后的受伤和阿尔茨海默氏病。