纹状体NK1受体参与帕金森病异动症发生的实验研究  

An experimental study on the involvement of postsynaptic striatal neurokinin -1 receptor in motor complication of ParkinsonS disease

作　　者：杨新新 胡方方 江伟峰 张尊胜 项洁 YANG Xinxin;HU Fangfang;JIANG Weifeng;ZHANG Zunsheng;XIANG Jie(Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China;Department of Rehabilitation, the Affiliated Hospital of Xuzhou Medical University)

机构地区：[1]徐州医科大学附属医院神经内科,江苏徐州221002 [2]徐州医科大学附属医院康复科

出　　处：《徐州医科大学学报》2018年第5期307-311,共5页Journal of Xuzhou Medical University

基　　金：国家自然科学基金（81671269）;江苏省六大高峰人才基金（WSN-120）

摘　　要：目的探讨神经激肽1（NKl）受体参与帕金森病（PD）运动并发症发生的具体分子机制，为治疗异动症（LID）提供新的方法及靶点。方法小鼠纹状体立体定向注射6-羟基多巴胺制作PD模型，4周后筛选成功的PD模型并随机分成5组：PD组、LID组、低中高不同浓度NK1受体拮抗剂组，并设有假手术组作为对照。低中高NK1受体拮抗剂组小鼠分别给予0．005、0．05和0．5mmol／LNKI受体拮抗剂处理，假手术组、PD组及LID组小鼠分别纹状体内注射等容积生理盐水作为对照。半小时后，LID组及不同剂量NKl受体拮抗剂组小鼠给予左旋多巴（15mg／kg）及苄丝肼（12mg／kg）腹腔注射。而假手术组及PD组小鼠腹腔注射生理盐水。观察各组小鼠异常不自主运动评分（AIM），Westernblot法检测各组小鼠纹状体中环磷腺苷调节的磷酸化蛋白-32（DARPP-32）、细胞外信号调节蛋白激酶1／2（ERKl／2）、N-甲基-D-天门冬氨酸受体1（NRl）和丝氨酸谷氨酸受体1（GluRl845）的磷酸化水平。结果中浓度NKl受体拮抗剂组总AIM评分低于LID组（P〈0．01），而低、高浓度NKl受体拮抗剂组与LID组之间差异无统计学意义。Westernblot结果显示PD组DARPP-32、ERKI／2、GluR1、NRl的磷酸化水平较假手术组明显降低（均P〈0．01）。LID组DARPP-32、ERK1／2、GluR1、NR1的磷酸化水平较PD组明显升高（均P〈0．01），而中浓度NKl受体拮抗剂组DARPP-32、ERKl／2、GluR1、NRl的磷酸化水平较LID组明显降低（均P〈0．05）。结论NKl受体拮抗剂可以减少PD小鼠LID的发生，突触后NKl受体参与了LID的发生。Objective To explore the specific molecular mechanism of postsynaptic NK1 receptor involved in Parkinson＇s disease （PD） with motor complications, and to provide a new method and target for the treatment of levodopa- in- duced dyskinesia （LID）. Methods A mouse model of PD was induced by stereotaxical injection of 6 - hydroxydopamine into the left striatum. Four weeks later, the successful PD modeling animals were randomly divided into five groups ： a PD group, a LID group, and a low/moderate/high -dose NK1 receptor antagonist group. Meanwhile, sham -operated mice were selected as controls. Mice in the low/moderate/high - dose NK1 receptor antagonist group were treated with 0.005, 0.05, and 0.5 mmol/L NK1 antagonist respectively, while those in the sham - operated, PD and LID groups were injec- ted with the same volume of normal saline. After half an hour, mice in the LID and different doses of NK1 receptor antag- onist groups were administrated with levodopa （15 mg/kg） and benserazide （12 mg/kg） , while those in the sham and PD groups were given normal saline alone. Then, the abnormal involuntary movement （AIM） scores were assessed. The levels of phosphorylated DARPP - 32, ERK, N - methyl - D - aspartate receptor subunit 1 （ NR1 ） and glutamate recep- tor 1 （ GluR1 ） in the striatum of mice were detected by Western blot. Results The moderate - dose NK1 receptor antagonist group showed remarkably decreases in total AIM scores compared with the LID group （P 〈 0.01 ）. But no statistical differences were found between the low/high - dose NK1 receptor antagonist group and the LID group. Compared with the sham - operated group, the levels of phosphorylated DARPP32, ERK1/2, GluR1 and NR1 were markedly decreased in the PD group （all P 〈 0.01 ）. Compared with the PD group, the levels of phosphorylated DARPP32, ERK1/2, GluR1 and NR1 were markedly increased in the LID group （ all P 〈 0.01 ）. In contrast, the levels of phosphorylated DARPP32, ERK1/2, GluR1 and NR1 were markedl

关 键 词：帕金森病 异动症 神经激肽1受体 NKl受体拮抗剂 

分 类 号：R742.5[医药卫生—神经病学与精神病学]