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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.

计划中的研究的长期目标是了解发生的病理过程的基本机制帕金森氏病（PD）帕金森病是一种主要的大脑退化估计至少有50万美国人和数百万世界各地的个人。PD的标志是黑质纹状体多巴胺（DA）神经元作为病理过程的结果来源不明，发生在神经黑色素色素细胞体，这些神经元位于黑质（substantia nigra，SN）的腹外侧部。基于许多先前的研究表明，PD可能是由于两个因素：（a）遗传易感性，表现为解毒和排泄环境毒物的能力受损，它们可以进入大脑;和（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发现，在环境中发现，一个新的假设是先进的，有助于了解PD的基本病因。它有人提出，在对这种毒性脑损伤的反应中，黑质γ-谷氨酰转肽酶被上调，结果是谷胱甘肽（GSH），由神经胶质细胞合成和输出，易位到SN细胞体的细胞质中，SN细胞体通常含有很少或没有这种三肽。由于DA能SN神经元具有抗氧化系统非常弱，未受保护的DA含量独特地高，并且高基础水平的DA自氧化（它们与末端着色，这种反应的产物，神经黑色素）的细胞质水平的上升， GSH被认为是导致代谢转换的原因。这个开关将神经黑色素途径，并最终导致内源性形成异常的二氢苯并噻嗪（DHBT）和苯并噻嗪（BT）代谢物。这些被认为是导致SN死亡的内毒素神经元的结果：（a）氧化还原循环反应，产生细胞毒性还原氧物质水平升高，引起严重脂质过氧化;和（B）抑制线粒体复合物I呼吸。该项目的具体目标是：（1）阐明氧化在GSM和L-半胱氨酸的存在下，其模拟所提出的代谢转换发生的那些;（2）分离和鉴定这些反应的主要产物，并确定它们的神经毒理学、神经药理学和神经退行性疾病使用体内和体外实验的性质;以及（3）开发一种实验动物模型，脑损伤，表现出假设的GSH介导的代谢在SN中转移。这些调查可能最终导致开发用于早期诊断PD的临床试验，并建议阻止退化过程的治疗策略。