Kühn Johanna, Haumesser Jens K, Beck Maximilian H, Altschüler Jennifer, Kühn Andrea A, Nikulin Vadim V, van Riesen Christoph
Charité University Medicine Berlin, Department of Neurology, Berlin, Germany.
Charité University Medicine Berlin, Department of Neurology, Berlin, Germany; Max Planck Institute for Human Cognitive and Brain Sciences, Department of Neurology, Leipzig, Germany.
Exp Neurol. 2017 Dec;298(Pt A):122-133. doi: 10.1016/j.expneurol.2017.09.005. Epub 2017 Sep 8.
The current pharmacotherapy of Parkinson's disease (PD) is primarily based on two classes of drugs: dopamine precursors, namely levodopa, and dopamine receptor agonists, such as apomorphine. Although both types of agents exert their beneficial clinical effects on motor and non-motor symptoms in PD via dopamine receptors, clinical efficiency and side effects differ substantially between levodopa and apomorphine. Levodopa can provide a greater symptomatic relief than dopamine receptor agonists. However, because long-term levodopa use is associated with early debilitating motor fluctuations, dopamine receptor agonists are often recommended in younger patients. The pharmacodynamic basis of these profound differences is incompletely understood. It has been hypothesized that levodopa and dopamine receptor agonists may have diverging effects on beta and gamma oscillations that have been shown to be of importance for the pathophysiology of PD. Here, we used electrophysiological recordings in anesthetized dopamine-intact and dopamine-depleted rats to systemically compare the impact of levodopa or apomorphine on neuronal population oscillations in three nodes of the cortico-basal ganglia loop circuit. Our results showed that levodopa had a higher potency than apomorphine to suppress the abnormal beta oscillations often associated with bradykinesia while simultaneously enhancing the gamma oscillations often associated with increased movement. Our data suggests that the higher clinical efficacy of levodopa as well as some of its side effects, as e.g. dyskinesias may be based on its characteristic ability to modulate beta-/gamma-oscillation dynamics in the cortico-basal ganglia loop circuit.
帕金森病（PD）目前的药物治疗主要基于两类药物：多巴胺前体，即左旋多巴，以及多巴胺受体激动剂，如阿扑吗啡。尽管这两类药物都通过多巴胺受体对PD的运动和非运动症状产生有益的临床效果，但左旋多巴和阿扑吗啡在临床疗效和副作用方面存在很大差异。左旋多巴比多巴胺受体激动剂能提供更大的症状缓解。然而，由于长期使用左旋多巴与早期致残性运动波动有关，因此通常建议年轻患者使用多巴胺受体激动剂。这些显著差异的药效学基础尚不完全清楚。据推测，左旋多巴和多巴胺受体激动剂可能对β和γ振荡有不同的影响，而β和γ振荡已被证明对PD的病理生理学很重要。在这里，我们在麻醉的多巴胺完整和多巴胺耗竭的大鼠中进行电生理记录，以系统地比较左旋多巴或阿扑吗啡对皮质-基底神经节环路三个节点中神经元群体振荡的影响。我们的结果表明，左旋多巴比阿扑吗啡具有更高的效力来抑制通常与运动迟缓相关的异常β振荡，同时增强通常与运动增加相关的γ振荡。我们的数据表明，左旋多巴较高的临床疗效及其一些副作用，如运动障碍，可能基于其调节皮质-基底神经节环路中β/γ振荡动力学的独特能力。
