Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.
Pharmacol Rev. 2011 Dec;63(4):938-66. doi: 10.1124/pr.110.003269.
Parkinson's disease is a debilitating movement disorder characterized by a generalized dysfunction of the nervous system, with a particularly prominent decline in the nigrostriatal dopaminergic pathway. Although there is currently no cure, drugs targeting the dopaminergic system provide major symptomatic relief. As well, agents directed to other neurotransmitter systems are of therapeutic benefit. Such drugs may act by directly improving functional deficits in these other systems, or they may restore aberrant motor activity that arises as a result of a dopaminergic imbalance. Recent research attention has focused on a role for drugs targeting the nicotinic cholinergic systems. The rationale for such work stems from basic research findings that there is an extensive overlap in the organization and function of the nicotinic cholinergic and dopaminergic systems in the basal ganglia. In addition, nicotinic acetylcholine receptor (nAChR) drugs could have clinical potential for Parkinson's disease. Evidence for this proposition stems from studies with experimental animal models showing that nicotine protects against neurotoxin-induced nigrostriatal damage and improves motor complications associated with l-DOPA, the "gold standard" for Parkinson's disease treatment. Nicotine interacts with multiple central nervous system receptors to generate therapeutic responses but also produces side effects. It is important therefore to identify the nAChR subtypes most beneficial for treating Parkinson's disease. Here we review nAChRs with particular emphasis on the subtypes that contribute to basal ganglia function. Accumulating evidence suggests that drugs targeting α6β2* and α4β2* nAChR may prove useful in the management of Parkinson's disease.
帕金森病是一种使人衰弱的运动障碍,其特征是神经系统的广泛功能障碍,黑质纹状体多巴胺能通路尤其明显下降。虽然目前尚无治愈方法,但针对多巴胺能系统的药物可提供主要的症状缓解。此外,针对其他神经递质系统的药物也具有治疗益处。这些药物可能通过直接改善这些其他系统的功能缺陷起作用,或者它们可能恢复由于多巴胺能失衡而产生的异常运动活动。最近的研究重点关注针对烟碱型乙酰胆碱能系统的药物。开展此类工作的基本原理源自基础研究结果,即基底神经节中烟碱型胆碱能和多巴胺能系统在组织和功能上有广泛的重叠。此外,烟碱乙酰胆碱受体 (nAChR) 药物可能对帕金森病具有临床潜力。这一观点的证据来自于实验动物模型的研究,这些研究表明尼古丁可预防神经毒素引起的黑质纹状体损伤,并改善与左旋多巴(治疗帕金森病的“金标准”)相关的运动并发症。尼古丁与多种中枢神经系统受体相互作用产生治疗反应,但也会产生副作用。因此,确定对治疗帕金森病最有益的 nAChR 亚型非常重要。在这里,我们重点介绍对基底神经节功能有贡献的 nAChR 亚型。越来越多的证据表明,针对α6β2和α4β2 nAChR 的药物可能在帕金森病的治疗中证明有用。