CHEMISTRY IN PARKINSONIAN DOPAMINE NEURONS

帕金森病多巴胺神经元的化学

基本信息

批准号：
2609632
负责人：
GLENN DRYHURST
金额：
$ 25.37万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-12-01 至 1999-11-30
项目状态：
已结题

项目摘要

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.

计划研究的长期目标是了解发生病理过程的基本机制在特发性帕金森氏病（PD）中。 PD是主要的退化大脑疾病估计会影响至少50万美国人和数百万的美国人全球个人。 PD的标志是病理学过程的斑纹纹状体多巴胺（DA）神经元未知来源发生在神经素素色素色素的细胞体中这些神经元位于黑质（SN）Pars commacta中。基于许多先前的研究似乎是由于PD的发展两个因素：（a）由一个遗传亲属的倾向表现为排毒和排泄环境有毒物质的能力受损他们可以进入大脑；（b）长期暴露于这些物质。鉴于选择性多巴胺能神经毒素不是在环境中发现的是一个新的假设，可能有助于理解PD的基本病理学。它有人提出，应对这种有毒的大脑侮辱 nigralγ-谷氨酰基肽酶被上调，结果是由神经胶质细胞合成和导出的谷胱甘肽（GSH）是易位到通常包含的SN细胞体的细胞质几乎没有这个三肽。因为daergic SN神经元具有非常弱的抗氧化剂系统，独特的较高的未弹药DA和 DA自氧化的高基础水平（它们用末端色素化这种反应的产物，神经元素）细胞质水平的上升建议GSH引起代谢开关。此开关转移神经苯胺途径，并最终导致内源性形成异常的二氢苯甲噻嗪（DHBT）和苯噻嗪（BT）代谢产物。这些被认为是导致SN死亡的内毒素神经元的结果是：（a）产生的氧化还原循环反应细胞毒性降低降低的氧气诱发严重脂质过氧化；（b）抑制线粒体复合物I呼吸。该项目的具体目的是：（l）阐明氧化在条件下GSM和L-半胱氨酸存在下DA的化学性质哪些模仿了提出的代谢开关的那些；（2）至分离并识别这些反应的主要产物，并确定它们的神经毒理学，神经药物和神经退行性使用体内和体外实验的性质；和，（3）to 开发一个实验动物模型，该模型响应化学侮辱大脑，表现出假设的GSH介导的代谢 SN的转移。这些调查最终可能导致开发用于早期诊断PD的临床测定法停止退化过程的治疗策略。