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.
