Department of Clinical Neurosciences, Institute of Neurology, UCL, Rowland Hill Street, London NW3 2PF.
Curr Top Med Chem. 2009;9(10):860-8.
Parkinson's disease (PD) is a complex neurodegenerative disorder characterised by dopaminergic cell loss in the substantia nigra. In addition, neurodegeneration occurs at a number of extra-nigral locations and involves a variety of non-dopaminergic neurotransmitter systems. Etiopathogenic mechanisms leading to cell death include oxidative stress and free radical generation, mitochondrial dysfunction, glutamate receptor mediated excitotoxicity, inflammation, oligodendrocytic interaction and neurotrophic factors, ubiquitin-proteosome system involvement, autophagy and apoptosis. Each of these is a potential target for novel pharmacotherapies including bioenergetic agents, inhibitors of excitotoxicity, neurotrophic factors, proteosomal enhancers and anti-apoptotic agents. Evidence has also been gained from cell culture and animal models for the potential disease modifying action of currently available dopaminergic therapies. These drugs have undergone clinical evaluation using studies with novel designs including "delayed start" methodology and studies using neuroimaging as a surrogate marker of dopaminergic cell loss. It is estimated from clinical, pathological and imaging studies that at least 50% of dopaminergic neurons are lost before the development of significant motor symptoms with a pre-motor phase of approximately 6-8 years. A number of pre- and post-synaptic neuroplastic homeostatic mechanisms occur during this period to maintain motor function. However these changes have been implicated in the development of motor complications (wearing "off" and dyskinesias). The evidence for treatments of motor complications in PD is discussed as are potential non-dopaminergic therapeutic targets to delay or improve motor complications.
帕金森病（PD）是一种复杂的神经退行性疾病，其特征是黑质中多巴胺能细胞的丧失。此外，神经退行性变还发生在许多黑质外的部位，并涉及多种非多巴胺能神经递质系统。导致细胞死亡的病因发病机制包括氧化应激和自由基生成、线粒体功能障碍、谷氨酸受体介导的兴奋性毒性、炎症、少突胶质细胞相互作用和神经营养因子、泛素-蛋白酶体系统参与、自噬和细胞凋亡。这些机制中的每一个都是新型药物治疗的潜在靶点，包括生物能量剂、兴奋性毒性抑制剂、神经营养因子、蛋白酶体增强剂和抗凋亡剂。细胞培养和动物模型也为现有多巴胺能疗法的潜在疾病修饰作用提供了证据。这些药物已经通过使用具有新型设计的研究进行了临床评估，包括“延迟开始”方法学和使用神经影像学作为多巴胺能细胞丢失的替代标志物的研究。从临床、病理和影像学研究估计，至少有 50%的多巴胺能神经元在出现明显运动症状之前就已经丧失，在出现运动症状前大约有 6-8 年的潜伏期。在此期间，发生了许多突触前和突触后的神经可塑性稳态机制，以维持运动功能。然而，这些变化与运动并发症（“开”期和运动障碍）的发展有关。本文讨论了 PD 运动并发症治疗的证据，以及延迟或改善运动并发症的潜在非多巴胺能治疗靶点。
