Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats.
Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats.
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DOI：
10.3389/fnins.2017.00112
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发表时间：
2017
影响因子：
4.3
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Chen G;Nie S;Han C;Ma K;Xu Y;Zhang Z;Papa SM;Cao X
左旋多巴诱发的运动障碍（LID）是帕金森病（PD）患者长期治疗的主要问题之一。虽然，LID的病理生理机制尚未完全了解，细胞外信号调节激酶（ERK）的激活被认为发挥了关键作用。ERK被丝裂原活化蛋白激酶激酶（MEK）磷酸化，因此MEK抑制剂可以阻止ERK活化。在这里，检查了MEK抑制剂PD 98059对LID的作用和相关的分子变化。黑质纹状体通路单侧6-OHDA损伤的大鼠每天接受L-DOPA治疗3周，每隔一天评估一次异常不自主运动（AIM）。从L-DOPA治疗的第10天开始，每天在侧脑室注射PD 98059，持续12天。利用基因芯片分析LID的纹状体分子标记和基因调控。PD 98059的施用显著降低了AIM。此外，ERK激活和其他相关分子变化（包括ΔFosB）在接受MEK抑制剂治疗的大鼠中逆转。PD 98059诱导纹状体中418个转录物的显著上调和378个转录物的下调。酪氨酸羟化酶（Th）和芳香烃受体核转位（Arnt）基因在受损动物中下调，在左旋多巴治疗的动物中上调。蛋白质水平分析表明，PD 98059减少纹状体TH。这些结果支持p-ERK 1/2、ΔFosB、p-H3在LID发病机制中与TH和ARNT的调控相关，并指出了其他基因的调控变化，从而为LID治疗寻找新的靶点提供了线索。
L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received daily L-DOPA treatment for 3 weeks, and abnormal involuntary movements (AIMs) were assessed every other day. PD98059 was injected in the lateral ventricle daily for 12 days starting from day 10 of L-DOPA treatment. Striatal molecular markers of LID were analyzed together with gene regulation using microarray. The administration of PD98059 significantly reduced AIMs. In addition, ERK activation and other associated molecular changes including ΔFosB were reversed in rats treated with the MEK inhibitor. PD98059 induced significant up-regulation of 418 transcripts and down-regulation of 378 transcripts in the striatum. Tyrosine hydroxylase (Th) and aryl hydrocarbon receptor nuclear translocator (Arnt) genes were down-regulated in lesioned animals and up-regulated in L-DOPA-treated animals. Analysis of protein levels showed that PD98059 reduced the striatal TH. These results support the association of p-ERK1/2, ΔFosB, p-H3 to the regulation of TH and ARNT in the mechanisms of LID, and pinpoint other gene regulatory changes, thus providing clues for identifying new targets for LID therapy.