Protective Role of Mitochondrial Vitamin E in Parkinson

描述（由申请人提供）：很明显，黑质纹状体多巴胺能神经元的毒性氧化应激在帕金森病（PD）的发病机制中起重要作用。由于科学证据支持线粒体（mito）是PD中诱导氧化应激和细胞死亡的关键部位，因此一种有吸引力的神经保护策略是在黑纹状体mitto中添加抗氧化剂d- α -生育酚(T)。因此，我们认为，在之前的PD临床和实验研究中，维生素E治疗无效的保护是由于维生素E治疗无法使黑质纹状体mitto具有保护水平的T。支持mitto T在保护细胞免受毒性氧化应激中的关键作用。我们最近发现，单次注射d- α -生育酚琥珀酸酯（TS）[但不注射T或d- α -生育酚乙酸酯（TA）]以及7天的膳食维生素E （1400 IU TA/kg日粮）可导致肝丝裂膜T显著富集，从而完全阻止鱼藤酮和亚铁诱导的大鼠肝细胞坏死细胞死亡。我们的工作假设是，实验性PD对毒性氧化应激的保护依赖于黑质纹状体中含有保护水平的T的丝状体膜的富集，从而减少丝状体活性氧（ROS）的产生，保护丝状体免受ROS介导的丝状体脂质、蛋白质和DNA损伤，并保护这些多巴胺能细胞免于死亡。这一假设将在体外和体内进行测试，使用氧化损伤：MPTP（或MPP+），鱼藤酮或亚铁：(1)确定多巴胺能细胞丝裂膜T富集对氧化应激诱导的丝裂膜ROS生成、丝裂膜脂质、蛋白和DNA损伤以及细胞凋亡和坏死死亡的影响；(2)确定体内外注射TS和慢性膳食维生素E对纹状体丝裂膜T富集和实验性PD的保护作用。我们相信这些新颖的研究将带来突破性的发现，将清楚地定义mitto T在实验性PD中的作用，并确定有效的PD T治疗策略。

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.