Parkinson Disease Neuroprotection Clinical Trial

描述（由申请人提供）：没有药物被明确证明在帕金森病（PD）患者中具有临床显著的神经保护功效;即减缓或停止多巴胺能神经元和突触的持续损失。另一方面，许多药物在体外和各种体内PD模型中显示出明确的神经保护功效，为PID患者实现有效的神经保护提供了希望。选择在PD患者中靶向已证实的致病意义机制的药物将提高体外和体内成功转化为PD患者相似成功的可能性。线粒体功能障碍和氧化应激可能在PD发病机制中起重要作用。与年龄匹配的对照组相比，PD患者黑质线粒体复合物I活性受损。复合物I抑制剂（MPTP和鱼藤酮）在动物中全身给药时再现PD的许多特征的能力表明复合物I功能障碍可能在PD中起因果作用。在PD的黑质（以及MPTP治疗的动物）中，脂质、蛋白质和DNA的氧化损伤标志物水平升高。因此，复合物I功能障碍导致的氧化应激可能在PD的发病机制中发挥关键作用。关于阿尔法突触核蛋白在PD中的作用的平行工作现在也揭示了与线粒体机制的强烈联系。抑制复合物I或暴露于氧化应激促进α突触核蛋白聚集。相反，突变体或野生型α突触核蛋白的过表达诱导线粒体功能障碍和氧化应激，并且突变体α突触核蛋白的表达增强对氧化应激的易感性。PD的体外和体内模型已经证明了通过增强能量代谢、阻断自由基损伤或增强内源性抗氧化机制的策略的成功的神经保护。目前正在计划的临床试验提供了一个独特的机会，以确定类似的策略是否可以在PD中产生有临床意义的神经保护作用。

DESCRIPTION (provided by applicant): No agent has been demonstrated unequivocally to have clinically significant neuroprotective efficacy in Parkinson's disease (PD) patients; that is to slow or stop the ongoing loss of dopaminergic neurons and synapses. On the other hand, numerous agents have shown clear neuroprotective efficacy in vitro and in various in vivo models of PD, providing hope that effective neuroprotection can be achieved in PID patients. Selection of agents that target mechanisms of demonstrated pathogenetic significance in PD patients will improve the likelihood that this success in vitro and in vivo will translate into similar success in PD patients. Evidence has accumulated that mitochondrial dysfunction and oxidative stress may play key roles in the pathogenesis of PD. Mitochondrial complex I activity is impaired in the substantia nigra in PD compared to age-matched controls. The ability of complex I inhibitors (MPTP and rotenone) to reproduce many features of PD when systemically administered in animals indicates that complex I dysfunction may play a causal role in PD. Levels of markers of oxidative damage to lipids, proteins, and DNA are elevated in the substantia nigra in PD (as well as in MPTP-treated animals). Thus, complex I dysfunction resulting in oxidative stress may play a key role in the pathogenesis of PD. The parallel work on the role of alpha synuclein in PD also now is revealing a strong connection to mitochondrial mechanisms. Inhibition of complex I or exposure to oxidative stress promotes alpha synuclein aggregation. Conversely, overexpression of mutant or wild-type alpha synuclein induces mitochondrial dysfunction and oxidative stress, and expression of mutant alpha synuclein enhances susceptibility to oxidative stress. In vitro and in vivo models of PD have demonstrated successful neuroprotection with strategies to enhance energy metabolism, block free radical damage, or enhance endogenous antioxidant mechanisms. The clinical trial now being planned provides a unique opportunity to determine if similar strategies can yield clinically meaningful neuroprotection in PD.