Mitochondrial Metabolites to Treat Parkinson's Disease

氧化引起的线粒体衰退是帕金森病（PD）和其他老化的神经退行性疾病的重要因素。我们之前的研究表明，喂养正常线粒体代谢物r - α -硫辛酸（LA）和乙酰-左旋肉碱（ALCAR）可以改善老年大鼠的线粒体衰退，这两种物质可以抑制氧化损伤，恢复老年动物的线粒体结构和功能。有证据表明，一些线粒体代谢物可能对帕金森病有保护作用。例如，在人类临床试验中，辅酶Q10 （CoQ）已被证明可以预防帕金森病；ALCAR已被证明可以防止1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）引起的毒性，这是一种模拟帕金森病的猴子。这些代谢物通过恢复线粒体抗氧化剂和功能来起到保护作用。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比任何单一化合物更有效地预防或治疗帕金森病。我们将使用行为、生化和免疫组织化学技术在两种PD模型上验证我们的假设：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治疗的大鼠模型。该项目为我们预防线粒体衰变的工作开辟了一个新的方向，并可能导致有效和经济的预防/治疗帕金森病。

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.