Mitochondrial Metabiolites to Treat Parkinson's Disease

氧化引起的线粒体衰变是帕金森氏病(PD)和其他神经退行性疾病的重要致病因素。我们先前已经证明，给老年大鼠喂食正常的线粒体代谢物R-α-硫辛酸(LA)和乙酰基-L-肉碱(ALCAR)，可以改善老年大鼠线粒体的衰退，抑制氧化损伤，恢复老年动物线粒体的大部分结构和功能。有证据表明，某些线粒体代谢物可能对帕金森病有保护作用。例如，辅酶Q10(CoQ)在人类的临床试验中已被证明可预防帕金森病；ALCAR已被证明可预防1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)诱导的毒性，这是一种在猴子中模拟帕金森病的毒性。这些代谢物通过恢复线粒体抗氧化剂和功能来保护人体。我们假设，线粒体抗氧化剂/代谢物CoQ、Alcar和LA的混合物可以优化为在预防或治疗PD方面比任何单一化合物更有效。我们将在两个PD模型上使用行为、生化和免疫组织化学技术来验证我们的假设：慢性鱼藤酮暴露的SK-N-MC人神经母细胞瘤细胞模型和慢性鱼藤酮处理的大鼠模型。这个关于帕金森病的项目是我们预防线粒体衰变工作的一个新方向，并可能导致对帕金森病的有效和经济高效的预防/治疗。

Mitochondrial decay due to oxidation is an important contributor to Parkinson's disease (PD) and other neurodegenerative diseases of aging. We have previously shown that mitochondrial decay in old rats can be ameliorated by feeding them the normal mitochondrial metabolites R-alpha-lipoic acid (LA) and acetyl-L-carnitine (ALCAR), which inhibited oxidative damage and restored much of the mitochondrial structure and function in old animals. There is evidence that some mitochondrial metabolites may protect against PD. For example, coenzyme Q10 (CoQ) has been shown to protect against PD in clinical trials in humans; and ALCAR has been shown to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, a PD mimic in monkeys. These metabolites protect by restoring mitochondrial antioxidants and function. We hypothesize that a mixture of mitochondrial antioxidants/metabolites, CoQ, ALCAR and LA, could be optimized to be more effective than any single compound in preventing or treating PD. We will test our hypothesis using behavioral, biochemical, and immunohistochemical techniques on two models of PD: the chronic rotenone-exposed SK-N-MC human neuroblastoma cell model and the chronic rotenone-treated rat model. This project on PD is a new direction for our work on preventing mitochondrial decay and could lead to an effective and cost efficient prevention /therapy for PD.