Protective Role of Mitochondrial Vitamin E in Parkinson

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DESCRIPTION (provided by applicant): It is clear that toxic oxidative stress in nigrostriatal dopaminergic neurons plays an important role in the pathogenesis of Parkinson's disease (PD). Since scientific evidence support mitochondria (mito) as a critical site for the induction of oxidative stress and cell death in PD, an attractive neuroprotective strategy would be to enrich nigrostriatal mito with the antioxidant, d-alpha-tocopherol (T). Accordingly, we contend that ineffective protection observed with vitamin E treatments in previous clinical and experimental investigations on PD resulted from the inability of these vitamin E treatments to enrich nigrostriatal mito with protective levels of T. In support of the critical role of mito T in the protection of cells against toxic oxidative stress, we have recently discovered that a single injection of d-alpha-tocopheryl succinate (TS) [but not T or d-alpha-tocopheryl acetate (TA)] as well as 7 days of dietary vitamin E (1400 IU TA/kg diet) result in dramatic T enrichment of hepatic mito membranes which completely prevented rotenone- and ferrous iron-induced necrotic cell death in rat hepatocytes. It is our working hypothesis that protection against toxic oxidative stress in experimental PD is dependent on the nigrostriatal enrichment of mito membranes with protective levels of T that attenuates mito reactive oxygen species (ROS) production and protects mito from ROS-mediated mito lipid, protein and DNA damage and these dopaminergic cells from death. This hypothesis will be tested both in vitro and in vivo using the oxidative insults: MPTP (or MPP+), rotenone or ferrous iron by: (1) determining the effect of T enrichment of mito membranes in dopaminergic cells on oxidative stress-induced mito ROS production, mito lipid, protein and DNA damage and apoptotic and necrotic cell death and (2) determining the ability of in vivo parenteral TS administration and chronic dietary vitamin E administration to enrich striatal mito membranes with T and protect against experimental PD. We believe that these novel studies will result in breakthrough discoveries that will clearly define the role of mito T in experimental PD as well as identify effective T treatment strategies for PD.