Olanow C Warren, Obeso Jose A, Stocchi Fabrizio
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Lancet Neurol. 2006 Aug;5(8):677-87. doi: 10.1016/S1474-4422(06)70521-X.
Levodopa-induced motor complications are a common source of disability for patients with Parkinson's disease. Evidence suggests that motor complications are associated with non-physiological, pulsatile stimulation of dopamine receptors. In healthy brains, dopamine neurons fire continuously, striatal dopamine concentrations are relatively constant, and there is continuous activation of dopamine receptors. In the dopamine-depleted state, standard levodopa therapy does not normalise the basal ganglia. Rather, levodopa or other short-acting dopaminergic drugs induce molecular changes and altered neuronal firing patterns in basal ganglia neurons leading to motor complications. The concept of continuous dopaminergic stimulation proposes that continuous delivery of a dopaminergic drug will prevent pulsatile stimulation and avoid motor complications. In monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's disease, long-acting or continuous infusion of a dopaminergic drug reduces the risk of motor complications. The current challenge is to develop a long-acting oral formulation of levodopa that provides clinical benefits but avoids motor complications.
左旋多巴诱发的运动并发症是帕金森病患者致残的常见原因。有证据表明，运动并发症与多巴胺受体的非生理性、脉冲式刺激有关。在健康大脑中，多巴胺神经元持续放电，纹状体多巴胺浓度相对恒定，多巴胺受体持续激活。在多巴胺耗竭状态下，标准的左旋多巴治疗无法使基底神经节恢复正常。相反，左旋多巴或其他短效多巴胺能药物会诱导基底神经节神经元发生分子变化并改变神经元放电模式，从而导致运动并发症。持续多巴胺能刺激的概念提出，持续给予多巴胺能药物将防止脉冲式刺激并避免运动并发症。在用MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）治疗的猴子和帕金森病患者中，长效或持续输注多巴胺能药物可降低运动并发症的风险。当前的挑战是开发一种长效口服左旋多巴制剂，既能提供临床益处又能避免运动并发症。
