代谢型谷氨酸受体5拮抗剂MPEP对左旋多巴诱发异动症大鼠行为及突触后致密物-95表达的影响  

Effects of metabotropic glutamate receptor 5 antagonist MPEP on behaviors and striatal postsynaptic density-95 protein expression in rats with levodopa-induced dyskinesia

作　　者：舒海洋 李利[1] 甄体丽 赵君焱 张琪林[1] 黄译腺[2] 罗蔚锋[1] 

机构地区：[1]苏州大学附属第二医院神经内科,苏州215004 [2]常州市第二人民医院神经内科,213003

出　　处：《中华神经医学杂志》2015年第4期463-468,共6页Chinese Journal of Neuromedicine

基　　金：国家自然科学基金（81200970）;常州市应用基础研究计划（CJ20130046）;苏州大学附属第二医院科技发展基金（SDFEYBS1105）;苏州大学科技创新培育工程重大项目（SZ123819）

摘　　要：目的观察代谢型谷氨酸受体5（mGluR5）拮抗剂2-甲基-6-乙炔基吡啶（MPEP）对左旋多巴（L-DOPA）诱发异动症大鼠行为及纹状体区突触后致密物-95（PSD-95）表达的影响。方法SD大鼠于右内侧前脑束立体定向注射6-羟基多巴（6-OHDA），建立单侧毁损帕金森病（PD）大鼠模型。按随机数字表法将32只成功建模的大鼠分为4组（每组8只）；L-DOPA组：给予L-DOPA25mg／kg＋苄丝肼6．25mg／kg（溶于0．2％维生素C无菌生理盐水1；生理盐水组：给予等体积的生理盐水：MPEP组：给予MPEP1．5mg／kg；L-DOPA＋MPEP组：给予L-DOPA25mg／kg＋苄丝肼6．25mg／kg＋MPEP1．5mg／kg。每组大鼠每日2次腹腔注射相应药物，持续21d。在给药治疗的第2、9、11、18、21天进行行为学测试。最后一次注射药物3h后采用Western bloting和实时定量PCR技术检测纹状体区PSD．95蛋白和mRNA表达水平。结果（1）治疗的第11、18、21天，与L．DOPA组（55．56±9．28、54．89±7．01、58．44±7．68）相比，L-DOPA＋M[PEP组（42．33±12．43、41．80±13．69、40．30±9．76）大鼠异常不自主运动评分显著降低，差异有统计学意义（P〈0．05）。在整个治疗过程中，与L-DOPA组相比，L-DOPA＋MPEP组大鼠损毁对侧前肢治疗后跨步数显著增加，差异均有统计学意义（P〈0．05），且前肢功能改善程度不随时间延长而减弱：单独MPEP长期治疗后也能够增加毁损对侧前肢治疗后跨步数。L-DOPA＋MPEP治疗能够逆转单独L-DOPA诱导的对侧旋转反应时间缩短。（2）L-DOPA治疗引起毁损侧纹状体PSD-95mRNA水平（3．80±1．09）和蛋白表达（1．39±0．37）升高，而联合应用MPEP能够抑制这种改变（1．65±0．81、0．76±0．66）。结论MPEP能够减轻L-DOPA诱发的异常不自主运动并增强其抗PD效应，这一作用可能与其抑制L-DOPA诱导的纹状体区PSD-95的过度表达有关。Objective To investigate the effects ofmetabotropic glutamate receptor 5 antagonist methyl-6-ethynyl-pyridine （MPEP） on behavior and striatalpostsynaptic density-95 （PSD-95） protein expression changes in rats with levodopa-induced dyskinesia （LID）. Methods Hemi-parkinsonian rat models were established by stereotaxically injection of 6 - hydroxy dopamine （6 - OHDA） in the right medial forebrain bundle; then, these 32 Parkinson＇s disease （PD） rats were randomly divided into four groups （n=8）： levodopa （L-DOPA） treatmentgroup, receiving L-DOPA25 mg/kg＋benserazide6.25 mg/kg; saline group, giving the same volume of saline; MPEP treatment group, receiving 1.5 mg/kg MPEP; and L-DOPA＋MPEP treatment group, accepted L-DOPA 25 mg/kg＋benserazide 6.25 mg/kg＋MPEP 1.5 mg/kg; All rats received intraperitoneal injections twice daily and continued for 21 days. At days 2, 9, 11, 18 and 21, behavior changes of all rats were detected; the protein and mRNA levels of PSD-95 in striatal tissues were detected by Western blotting and real-time PCR, respectively. Results （1） Abnormal involuntary movement scores were significantly decreased in rats of L-DOPA＋MPEP treatment group （42.33±12.43, 41.80±13.69 and 40.30±9.76） as compared with those in L-DOPA treatment group （55.56±9.28, 54.89±7.01 and 58.44±7.68） on days 11, 18, and 21 （P〈0.05）. Forepaw adjusting steps were significantly increased in Parkinson rats of L-DOPA＋MPEP treatment group as compared with rats of L-DOPA treatment group （P〈0.05）; and the increased extent was not decreased as time prolonging. Forepaw adjusting steps were also increased after MPEP treatment alone. Co-administration of L-DOPA with MPEP reversed the shortening of rotational response duration induced by L-DOPA. （2） The up-regulation of PSD-95 protein and mRNA levels in the lesioned striatum was noted in the L-DOPA treatment group （1.39 ±0.37 and 3.80±1.09）, while this trend could be alleviated by coadministration of L-DOPA with

关 键 词：帕金森病 异动症 代谢型谷氨酸受体5 突触后致密物-95 

分 类 号：R742.5[医药卫生—神经病学与精神病学]