The Role of Dopamine and its Analogs in the inhibition*

多巴胺及其类似物在抑制中的作用*

• 批准号: 6480060
• 负责人: ANTHONY L FINK
• 金额: $ 17.25万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6480060
• 关键词: Lewy body; Parkinson's disease; alpha synuclein; antiparkinson drugs; axon; dementia; dendrites; dopamine; drug discovery /isolation; electron microscopy; genetically modified animals; high performance liquid chromatography; human tissue; laboratory mouse; levodopa; ligands; neural degeneration; neural inhibition; neurochemistry; neurofilament; oxidative stress; pharmacokinetics; tissue /cell culture

DESCRIPTION (provided by applicant) The aggregation of alpha-synuclein is believed to be a critical factor in the etiology of Parkinson's disease (PD). alpha-Synuclein is the major component of Lewy bodies and Lewy neurites, the intracellular inclusions that are a pathological hallmark of Parkinson's disease. There is a critical need for an effective treatment of Parkinson's disease, since current therapies are only partially effective in treating the symptoms. Through the proposed research we plan to develop inhibitors of alpha-Synuclein fibrillation, which could lead to new therapies to halt the disease progression. We recently discovered that dopamine and several related molecules not only inhibit the formation of alpha-Synuclein fibrils in vitro, but also break down existing a-synuclein fibrils formed in vitro. This unexpected observation raises several obvious questions, including: Could a decrease in L-DOPA or dopamine production or levels be a triggering factor in PD? Will dopamine and its analogs dissolve Lewy bodies? Can we find related compounds that would form the basis of a therapeutic intervention? What is the mechanism of dopamine inhibition of alpha-Synuclein fibrillation? Our goals in this proposal are: (1) To test the hypothesis that dopamine and its analogs bind specifically and tightly to an intermediate of alpha-Synuclein fibrillation, thus inhibiting fibril formation, and to investigate exactly how dopamine and related compounds prevent fibril formation. Knowing how DA prevents fibrillation of alpha-Synuclein should provide the basis for the design of inhibitors that will be potential drags for preventing alpha-synuclein fibrillation. (2) To determine if DA and its analogs also prevent fibril formation in vivo using both tissue sections and animal models. (3) To determine the essential parts of the dopamine structure for inhibition of alpha-Synuclein fibrillation, and to design new inhibitors of a-synuclein aggregation based on this knowledge. The results of the proposed research will provide leads for inhibitors of alpha-synuclein aggregation and lay the groundwork for potential therapeutic approaches. In the long-run this research could provide new strategies for the treatment of Parkinson's disease.

描述（由申请人提供） α-突触核蛋白的聚集被认为是细胞凋亡的关键因素。 帕金森病（PD）的病因。α-突触核蛋白是 路易体和路易神经突，细胞内的内含物， 帕金森病的病理标志迫切需要一个 帕金森病的有效治疗，因为目前的治疗方法 对治疗症状部分有效。通过研究，我们 计划开发α-突触核蛋白纤维化的抑制剂，这可能导致 阻止疾病发展的新疗法我们最近发现 多巴胺和几种相关分子不仅能抑制 α-突触核蛋白纤维在体外，但也打破现有的α-突触核蛋白 纤维在体外形成。这一意想不到的观察提出了几个明显的 问题，包括：是否可以减少左旋多巴或多巴胺的生产或 是帕金森病的触发因素吗多巴胺及其类似物会溶解吗 路易体我们能否找到相关的化合物， 治疗干预？多巴胺抑制的机制是什么？ α-突触核蛋白纤维性颤动我们的目标是：（1）测试 假设多巴胺及其类似物特异性且紧密地结合于 α-突触核蛋白原纤维化的中间体，从而抑制原纤维形成， 并研究多巴胺和相关化合物是如何阻止纤维形成的， 阵了解DA如何防止α-突触核蛋白的纤颤， 为设计抑制剂提供了基础，这些抑制剂将成为 防止α-突触核蛋白纤维化。(2)为了确定多巴胺及其类似物 也可防止使用组织切片和动物切片在体内形成原纤维 模型(3)为了确定多巴胺结构的基本部分， 抑制α-突触核蛋白原纤化，并设计新的抑制剂， 基于这种知识的α-突触核蛋白聚集。建议的结果 研究将为α-突触核蛋白聚集的抑制剂提供线索， 为潜在的治疗方法奠定基础。从长远来看， 这项研究可以为帕金森病的治疗提供新的策略。