Parkinson Disease Neuroprotection Clinical Trial

描述(由申请人提供)：没有任何药物被明确证明对帕金森病(PD)患者具有临床上显著的神经保护效果；即减缓或阻止多巴胺能神经元和突触的持续丢失。另一方面，许多药物在体外和各种帕金森病体内模型中都显示出明显的神经保护作用，为临床治疗帕金森病患者提供了有效的神经保护的希望。选择对帕金森病患者具有致病意义的靶向机制的药物将提高这种体外和体内成功转化为帕金森病患者类似成功的可能性。越来越多的证据表明，线粒体功能障碍和氧化应激可能在帕金森病的发病机制中起关键作用。与年龄匹配的对照组相比，帕金森病患者黑质线粒体复合体I活性受损。复合I类抑制剂(MPTP和鱼藤酮)在动物体内全身应用时能够复制PD的许多特征，这表明复合I类功能障碍可能在PD中起到致病作用。帕金森病患者(以及MPTP治疗的动物)黑质中脂质、蛋白质和DNA氧化损伤的标记物水平升高。因此，复杂的i功能障碍导致的氧化应激可能在帕金森病的发病机制中起关键作用。关于阿尔法突触核蛋白在帕金森病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。抑制复合体I或暴露于氧化应激可促进α-突触核蛋白聚集。相反，突变型或野生型α突触核蛋白的过度表达会导致线粒体功能障碍和氧化应激，而突变型α突触核蛋白的表达则增加了对氧化应激的易感性。在体外和体内的帕金森病模型已经证明，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，成功地保护了神经。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帕金森病患者中产生临床上有意义的神经保护。

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.