Protective Role of Mitochondrial Vitamin E in Parkinson

描述(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)的发病机制中起着重要作用。由于科学证据支持线粒体(MITO)是帕金森病患者氧化应激和细胞死亡的关键部位，一个有吸引力的神经保护策略是用抗氧化剂d-α-生育酚(T)丰富黑质纹状体MITO。因此，我们认为，在先前的帕金森病临床和实验研究中，维生素E治疗观察到的无效保护是由于这些维生素E治疗无法用T的保护性水平丰富黑质纹状体MITO。支持MITO 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，一次注射d-α-生育酚琥珀酸酯(TS)[但不是T或d-α-生育酚醋酸酯(TA)]以及7天的饮食维生素E(1400IU TA/kg饮食)可导致肝脏有丝分裂膜上T显著浓缩，从而完全防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，对实验性PD的毒性氧化应激的保护依赖于黑质纹状体对具有保护水平的T的丝裂原膜的浓缩，T的保护水平可以减少MITO活性氧物种(ROS)的产生，并保护MITO免受ROS介导的MITO脂质、蛋白质和DNA损伤以及这些多巴胺能细胞的死亡。这一假说将在体外和体内使用氧化损伤：MPTP(或MPP+)、鱼藤酮或亚铁得到验证，方法包括：(1)确定多巴胺能细胞中T的积累对氧化应激诱导的mito ROS产生、mito脂质、蛋白质和DNA损伤以及凋亡和坏死细胞死亡的影响；(2)确定体内注射TS和长期给予维生素E使纹状体mito膜富含T和保护实验性PD的能力。我们相信，这些新的研究将导致突破性发现，将明确定义丝裂原T在实验性帕金森病中的作用，并确定有效的帕金森病的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.