CHEMISTRY IN PARKINSONIAN DOPAMINE NEURONS

帕金森病多巴胺神经元的化学

• 批准号: 2268001
• 负责人: GLENN DRYHURST
• 金额: $ 29.01万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2268001
• 关键词: Parkinson's disease; aminoacid metabolism; antioxidants; brain metabolism; cysteine; disease /disorder model; dopamine; dopamine receptor; glutathione; high performance liquid chromatography; immunocytochemistry; laboratory mouse; laboratory rat; neural degeneration; neurochemistry; neurons; neuropharmacology; neurotoxins; neurotransmitter metabolism; oxidation; substantia nigra; thiazines

The long-term objective of the planned research is to understand the fundamental mechanisms underlying the pathological processes which occur in idiopathic Parkinson's Disease (PD). PD is a major degenerative brain disease estimated to affect at least 500,000 Americans and millions of individuals worldwide. The hallmark of PD is the degeneration of nigrostriatal dopamine (DA) neurons as a result of pathological processes of unknown origin which occur in the neuromelanin-pigmented cell bodies of these neurons located in the substantia nigra (SN) pars compacta. Based on many prior studies it appears that PD might develop as a consequence of two factors: (a) a genetically-inherited predisposition manifested by an impaired ability to detoxify and excrete environmental toxicants so that they can enter the brain; and, (b)chronic exposure to these substances. In view of the fact that selective dopaminergic neurotoxins have not been found in the environment, a new hypothesis is advanced which might contribute to an understanding of the fundamental pathoetiology of PD. It is proposed that in response to such a toxic brain insult the activity of nigral gamma-glutamyl transpeptidase is upregulated with the result that glutathione (GSH), synthesized and exported by glial cells, is translocated into the cytoplasm of SN cell bodies which normally contain little or none of this tripeptide. Because DAergic SN neurons possess a very weak antioxidant system, uniquely high levels of unsheltered DA, and high basal levels of DA autoxidation (they are pigmented with the end- product of this reaction, neuromelanin) the rise in cytoplasmic levels of GSH is proposed to cause a metabolic switch. This switch diverts the neuromelanin pathway and leads ultimately to the endogenous formation of aberrant dihydrobenzothiazine (DHBT) and benzothiazine (BT) metabolites. These are proposed to be the endotoxins which cause the death of SN neurons as a result of: (a) redox cycling reactions which generate elevated levels of cytotoxic reduced oxygen species evoking severe lipid peroxidation; and, (b) inhibition of mitochondrial complex I respiration. The specific aims of the project are: (l) to elucidate the oxidation chemistry of DA in the presence of GSM and L-cysteine under conditions which mimic those under which the proposed metabolic switch occurs; (2) to isolate and identify the major products of these reactions and determine their neurotoxicological, neuropharmacological and neurodegenerative properties using both in vivo and in vitro experiments; and, (3) to develop an experimental animal model which, in response to a chemical insult on the brain, exhibits the hypothesized GSH-mediated metabolic diversion in the SN. These investigations might ultimately lead to the development of a clinical assay for early diagnosis of PD and suggest therapeutic strategies to halt the degenerative processes.

计划中的研究的长期目标是了解 发生的病理过程的基本机制 在特发性帕金森病(PD)中。帕金森病是一种主要的退行性大脑 据估计，疾病影响到至少50万美国人和数百万人 世界各地的个人。帕金森病的特点是 黑质纹状体多巴胺(DA)神经元的病理过程 其来源不明，出现在黑素细胞的胞体中 这些神经元位于黑质致密部。基于 许多先前的研究表明，帕金森病可能是由于 两个因素：(A)遗传易感性，表现为 排毒和排泄环境毒物的能力受损，从而 它们可以进入大脑；以及，(B)长期接触这些物质。 鉴于选择性多巴胺能神经毒素尚未被 在环境中发现了一种新的假说，它可能 有助于了解帕金森病的基本病因学。它 有人提出，为了回应这样一种有毒的大脑侮辱， 黑质γ-谷氨酰转肽酶上调，结果是 谷胱甘肽(GSH)是由神经胶质细胞合成和输出的。 移位到SN细胞体的细胞质中，正常情况下含有 很少或根本没有这种三肽。因为多巴胺能神经元具有 非常弱的抗氧化系统，独一无二的高水平无保护性DA，以及 高基础水平的DA自氧化(它们与末端- 这种反应的产物，神经黑色素)细胞质水平的上升 GSH被认为是引起代谢转换的原因。此开关可将 神经黑素途径，并最终导致内源性形成 二氢苯并噻嗪(DHBT)和苯并噻嗪(BT)的异常代谢物。 这些都被认为是导致SN死亡的内毒素 神经元的结果是：(A)氧化还原循环反应产生 细胞毒性还原氧物质水平升高会引起严重的脂质 过氧化；以及(B)抑制线粒体复合体I的呼吸作用。 该项目的具体目标是：(L)阐明氧化 在GSM和L-半胱氨酸存在下DA的化学 它模仿了所提议的代谢转换发生的那些； 分离和鉴定这些反应的主要产物，并确定 它们的神经毒理、神经药理和神经退行性变 使用体内和体外实验的特性；以及，(3) 开发一种实验动物模型，该模型对一种化学物质做出反应 对大脑的侮辱，表现出假想的GSH介导的代谢 在SN中进行分流。这些调查可能最终导致 帕金森病临床早期诊断方法的建立及建议 阻止退化过程的治疗策略。