Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Beijing Geriatric Medical Research Center, Key Laboratory for Neurodegenerative Disease of Ministry of Education, 45 Changchun Street, Beijing 100053, PR China.
Brain Res Bull. 2011 Nov 25;86(5-6):367-72. doi: 10.1016/j.brainresbull.2011.09.016. Epub 2011 Sep 24.
Chronic dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) often leads to abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia (LID), mediated by DA receptors. However, mechanisms underlying LID occurrence are still unclear. Regulator of G-protein signaling RGS9, a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, has been reported participated in LID. L-DOPA-induced AIMs can be modeled in rats with 6-hydroxydopamine (6-OHDA) lesions by chronic injection of L-DOPA. Herein, we compared the rotational responses and AIMs in 6-OHDA lesioned rats with L-DOPA/benserazide (10/2.5 mg/kg, once per day, i.p.) administration for 14 days whereas control animals received injections of saline. Furthermore, whether sub-chronic L-DOPA treatment impact RGS9 mRNA or protein expression in 6-OHDA lesion rats were also evaluated. As results shown, rotational behavior was not increased significantly, while an obvious AIMs were observed in rats with L-DOPA/benserazide (10/2.5mg/kg, i.p.) administration sub-chronically. In addition, expressions of RGS9 protein or mRNA analyzed by Western blot or real-time PCR with striatal extracts increased significantly after L-DOPA/benserazide. These data demonstrate that RGS9 expression can be modulated by sub-chronic L-DOPA/benserazide administration and increased RGS9 expression in striatum may be one of the reasons for the side effects such as dyskinesia induced by L-DOPA therapy.
在帕金森病（PD）中，慢性多巴胺（DA）替代疗法用 L-3,4-二羟基苯丙氨酸（L-DOPA）治疗常导致异常不自主运动（AIMs），称为 L-DOPA 诱导的运动障碍（LID），由 DA 受体介导。然而，LID 发生的机制仍不清楚。G 蛋白信号调节因子 RGS9 是 GTPase 加速蛋白 RGS 家族的成员，特异性表达于纹状体，据报道参与 LID。通过慢性注射 L-DOPA，用 6-羟多巴胺（6-OHDA）损伤大鼠可建立 LID 诱导的 AIMs 模型。在此，我们比较了 L-DOPA/benserazide（10/2.5mg/kg，每天一次，ip）给药 14 天后 6-OHDA 损伤大鼠的旋转反应和 AIMs，而对照组动物接受生理盐水注射。此外，还评估了亚慢性 L-DOPA 处理是否影响 6-OHDA 损伤大鼠中 RGS9 mRNA 或蛋白表达。结果表明，旋转行为没有明显增加，而在 L-DOPA/benserazide（10/2.5mg/kg，ip）亚慢性给药的大鼠中观察到明显的 AIMs。此外，用 Western blot 或实时 PCR 分析纹状体提取物后，RGS9 蛋白或 mRNA 的表达显著增加。这些数据表明，RGS9 的表达可以被亚慢性 L-DOPA/benserazide 给药调节，纹状体中 RGS9 表达的增加可能是 L-DOPA 治疗引起的运动障碍等副作用的原因之一。
