Neurodegenerative Disease Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK.
J Neural Transm (Vienna). 2011 Dec;118(12):1661-90. doi: 10.1007/s00702-011-0698-2. Epub 2011 Sep 1.
A significant proportion of patients with Parkinson's disease (PD) receiving dopamine replacement therapy in the form of levodopa develop dyskinesia that becomes a major complicating factor in treatment. Dyskinesia can only be effectively treated by a reduction in drug dose, which limits efficacy, by co-administration of the weak NMDA antagonist amantadine or by surgical treatment (pallidotomy, DBS). This raises the important question of why dyskinesia occurs in PD and how it can be avoided or suppressed by pharmacological treatment. This review assesses some of the mechanisms that underlie dyskinesia induction and expression from presynaptic changes in dopaminergic neurones to postsynaptic alterations in basal ganglia function and examines potential approaches to prevention and treatment. These include glutamatergic approaches where agents that directly or indirectly alter glutamatergic neurotransmission modify the intracellular influx of Ca(2+) and reduce the formation of nitric oxide by neuronal nitric oxide synthase that may form an integral component of the complex cascade of events leading to dyskinesia. There is increasing evidence for the role of serotoninergic neurones in dyskinesia induction related to non-physiological formation and release of dopamine and serotoninergic agonists can modify dyskinesia expression. Similarly, noradrenergic receptors may serve to alter dyskinesia intensity and α-2-adrenoceptor antagonists alter the expression of levodopa-induced dyskinesia in both experimental models of PD and in man. Finally, other potential approaches to dyskinesia treatment based on manipulation of opiate, cannabinoid, adenosine and histamine receptors are considered. The conclusion is that the cause of levodopa-induced dyskinesia remains to be fully elucidated and that new approaches to treatment through non-dopaminergic mechanisms are required to control the onset and expression of involuntary movements.
相当比例的帕金森病（PD）患者在接受左旋多巴形式的多巴胺替代治疗时会出现运动障碍，这成为治疗中的一个主要并发症。运动障碍只能通过减少药物剂量来有效治疗，这会降低疗效，可以联合使用弱 NMDA 拮抗剂金刚烷胺或通过手术治疗（苍白球切开术、DBS）。这就提出了一个重要的问题，即为什么 PD 会出现运动障碍，以及如何通过药物治疗来避免或抑制运动障碍。本综述评估了一些机制，这些机制从多巴胺能神经元的突触前变化到基底神经节功能的突触后改变，解释了运动障碍诱导和表达的原因，并探讨了潜在的预防和治疗方法。这些方法包括谷氨酸能方法，其中直接或间接改变谷氨酸能神经传递的药物改变细胞内 Ca(2+)的流入，并减少神经元一氧化氮合酶产生的一氧化氮，这可能是导致运动障碍的复杂级联事件的一个组成部分。越来越多的证据表明，5-羟色胺能神经元在与非生理形成和多巴胺释放相关的运动障碍诱导中起作用，5-羟色胺能激动剂可以修饰运动障碍的表达。同样，去甲肾上腺素能受体可能改变运动障碍的强度，α-2-肾上腺素能受体拮抗剂改变左旋多巴诱导的运动障碍在 PD 实验模型和人类中的表达。最后，还考虑了基于阿片类、大麻素、腺苷和组胺受体操纵的其他潜在的运动障碍治疗方法。结论是，左旋多巴诱导的运动障碍的原因仍有待充分阐明，需要通过非多巴胺能机制来治疗运动障碍，以控制不自主运动的发生和表达。
