Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble F-38043, France.
Neurobiol Dis. 2012 Dec;48(3):379-90. doi: 10.1016/j.nbd.2012.06.009. Epub 2012 Jun 30.
Dyskinesia is a major side effect of chronic levodopa (L-DOPA) administration, the reference treatment for Parkinson's disease (PD). High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inadequate stimulation can also trigger dyskinetic movements in PD patients and animal models. Here, we investigated the possible association between L-DOPA- and STN-HFS-induced dyskinesia and regulation of the NR2B subunit of NMDA receptors in the rodent model of PD. We subjected 6-OHDA-lesioned rats to HFS for 1h, at an intensity triggering forelimb dyskinesia. Other 6-OHDA-lesioned rats were treated with chronic high doses of L-DOPA for ten days, to induce abnormal involuntary movements. The 6-OHDA lesion regulated NR2B only in the SNr, where the activation of NR2B was observed (as assessed by phosphorylation of the Tyr1472 residue). Both STN-HFS and L-DOPA dyskinesiogenic treatments induced NR2B activation in the STN and EP, but only L-DOPA triggered NR2B hyperphosphorylation in the striatum. Finally, the use of CP-101,606 exacerbated L-DOPA-induced motor behavior and associated NR2B hyperphosphorylation in the striatum, STN and EP. Thus, NR2B activation in basal ganglia structures is correlated with dyskinesia.
运动障碍是慢性左旋多巴（L-DOPA）治疗的主要副作用，也是帕金森病（PD）的标准治疗方法。刺激丘脑底核高频电刺激（STN-HFS）可以减轻帕金森病患者的运动症状，并通过减少 L-DOPA 的需求间接改善运动障碍。然而，刺激不足也可能在 PD 患者和动物模型中引发运动障碍。在这里，我们研究了 L-DOPA 和 STN-HFS 诱导的运动障碍与 NMDA 受体 NR2B 亚基在 PD 啮齿动物模型中的调节之间可能存在的关联。我们使 6-OHDA 损伤的大鼠接受 1 小时的 HFS，强度足以引发前肢运动障碍。其他 6-OHDA 损伤的大鼠接受慢性高剂量 L-DOPA 治疗十天，以诱导异常不自主运动。6-OHDA 损伤仅在 SNr 中调节 NR2B，在 SNr 中观察到 NR2B 的激活（如 Tyr1472 残基的磷酸化所评估）。STN-HFS 和 L-DOPA 致运动障碍治疗均在 STN 和 EP 中诱导 NR2B 激活，但只有 L-DOPA 引发纹状体中 NR2B 的过度磷酸化。最后，CP-101,606 的使用加剧了 L-DOPA 诱导的运动行为以及纹状体、STN 和 EP 中相关的 NR2B 过度磷酸化。因此，基底神经节结构中 NR2B 的激活与运动障碍有关。
