Antioxidant Strategies for Parkinson's Disease

帕金森病的抗氧化策略

• 批准号: 6637909
• 负责人: NINA F SCHOR
• 金额: $ 28.86万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637909
• 关键词: 6 hydroxydopamine; PC12 cells; Parkinson's disease; antioxidants; antiparkinson drugs; apoptosis; cAMP response element binding protein; cell line; drug design /synthesis /production; drug interactions; drug screening /evaluation; fluorescence microscopy; free radical oxygen; gel mobility shift assay; hypoxia inducible factor 1; laboratory mouse; membrane lipids; neuropharmacology; nuclear factor kappa beta; oxidation reduction reaction; phospholipids; polymerase chain reaction; protein binding; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) have been implicated in the pathogenesis of Parkinson's disease. This suggests that antioxidant strategies may be useful in the treatment and/or prevention of this neurodegenerative disorder. We have developed and implemented two models for the central movement disorder and autonomic peripheral neuropathy, respectively, associated with Parkinson's disease. We propose to use these models to design and test antioxidant strategies we have previously developed for adjunctive use with ROS-generating chemotherapeutic agents. We will further use our studies of the biochemical effects of antioxidant treatment to develop a screening test for new antioxidant agents for use in Parkinson's disease and other ROS-related disorders. Specifically, we propose to test the hypothesis that recycling antioxidants increase expression of p21 wafl/cip1,enhance binding of HIF-1 and CREB to DNA, activate NF-kappaB, prevent ROS-induced morphological apoptosis, and decrease ROS-induced membrane phospholipid and protein nitration in culture models of Parkinson's disease. We will further test recycling antioxidants for their distribution to the CNS and peripheral compartments, and use this information to test CNS-penetrating and non-CNS-penetrating agents for efficacy in the central and autonomic nervous system models, respectively, of Parkinson's disease. Finally, we will test the hypothesis that the magnitude of induced in vitro biochemical change for each drug correlates with the degree of protection from the effects of ROS in the CNS or autonomic model. This latter study will pave the way for development of an in vitro screening test for new antioxidant strategies proposed for use in Parkinson's disease. This application specifically addresses the NINDS agenda for research in Parkinson's disease in its development of in vitro screening tests for putative therapeutic agents in general and antioxidants in particular for this disease, its development of animal models for the clinical aspects of Parkinson's disease, and its potential for further elucidation of the mechanisms of ROS-induced apoptosis in the nervous system.

描述（由申请人提供）：活性氧（ROS）与帕金森病的发病机制有关。这表明抗氧化策略可能有助于治疗和/或预防这种神经退行性疾病。我们开发并实施了两种模型，分别用于与帕金森病相关的中枢运动障碍和自主周围神经病变。我们建议使用这些模型来设计和测试我们之前开发的抗氧化策略，用于与产生 ROS 的化疗药物一起辅助使用。我们将进一步利用我们对抗氧化剂治疗的生化作用的研究来开发用于帕金森病和其他 ROS 相关疾病的新型抗氧化剂的筛选测试。 具体来说，我们建议测试以下假设：回收抗氧化剂会增加 p21 wafl/cip1 的表达，增强 HIF-1 和 CREB ​​与 DNA 的结合，激活 NF-kappaB，防止 ROS 诱导的形态凋亡，并降低 ROS 诱导的膜磷脂和帕金森病培养模型中的蛋白质硝化。我们将进一步测试回收的抗氧化剂在中枢神经系统和外周室中的分布，并利用这些信息来测试中枢神经系统渗透剂和非中枢神经系统渗透剂分别在帕金森病的中枢和自主神经系统模型中的功效。最后，我们将检验以下假设：每种药物诱导的体外生化变化的程度与 CNS 或自主神经模型中免受 ROS 影响的保护程度相关。后一项研究将为开发用于治疗帕金森病的新抗氧化剂策略的体外筛选测试铺平道路。 本申请特别涉及 NINDS 帕金森病研究议程，包括开发用于该疾病的一般治疗剂和特别是抗氧化剂的体外筛选测试、开发帕金森病临床方面的动物模型及其潜力进一步阐明ROS诱导神经系统细胞凋亡的机制。