雷帕霉素抑制异动症大鼠模型纹状体神经元电活动

Rapamycin inhibits the electric activities of striatal synaps in a rat model of levodopa-induced dyskinesia

目的探讨雷帕霉素对左旋多巴(L-DOPA)诱发异动症(LID)大鼠纹状体电活动的影响。方法采用序贯模式进行实验分组。采用SPF级Sprague-Daewley雄性大鼠,通过6-羟多巴(OHDA)脑立体定位微量注射制作帕金森病模型,造模成功后腹腔连续注射L-DOPA+苄丝肼制定LID模型。随后所有LID模型大鼠随机分成2组,其中实验组连续腹腔注射L-DOPA+雷帕霉素21 d,1次/d;对照模型(假手术组):在LID模型基础上,连续腹腔注射L-DOPA+DM-SO 21 d,1次/d。所有建模成功的大鼠在7%水合氯醛0.5 ml/100 g腹腔麻醉下通过脑立体定位仪植入多通道电极阵列,然后采集纹状体神经元放电频率、簇状放电、局部场电位和小鼠行为学数据,探讨雷帕霉素对苄丝肼模型纹状体区神经元放电的影响。结果在LID模型纹状体组织中,电生理显示纹状体神经元放电频率较假手术组明显升高(P<0.001)、簇状放电明显增加(P<0.001)、局部场电位发生改变;而给予雷帕霉素后,纹状体神经元放电频率明显减少(P<0.01),异常的簇状放电得到明显抑制(P<0.05,P<0.01),局部场电位得到明显改善,行为学评分显著性提高(P<0.05)。结论纹状体神经元异常电活动是LID发生的重要环节,雷帕霉素可以显著改善LID大鼠的行为学及电生理改变,为未来此类药物的开发提供了重要依据。

Objective To explore the influence of rapamycin on the electric activity of striatal synaps in a rat model of levodopa(L-DOPA)-induced dyskinesia(LID).Methods Grouping was performed in sequential mode.Sprague-Daewley male rats with SPF grade were treated with 6-hydroxydopa(OHDA)brain stereotaxic micro injection to establish Parkinson′s disease model.After successful modeling,the LID model was made by continuous intraperitoneal injection of L-DOPA+benzylserazid.Then all LID model rats were randomly divided into 2 groups,in which the experimental group was continuously injected intraperitoneally with L-DOPA+rapamycin for 21 d,once a day;control model(sham operation)group:L-DOPA+DM-SO was injected intraperitoneally for 21 d based on the LID model,once a day.All successfully modeled rats were implanted with a multi-channel electrode array using a brain stereoscope under 7%chloral hydrate 0.5 ml/100 g abdominal anesthesia.Then the data of striatal neuron discharge frequency,cluster discharge,local field potential and mouse behavior were collected to investigate the effect of rapamycin on striatal neuron discharge in benzylidene hydrazine model.Results In LID model striatal tissue,compared with sham operation group,electrophysiology showed that the frequency of electric bursts in striatal neurons were significantly increased(P<0.001),the cluster discharge was significantly increased(P<0.001)and local field potential was affected.After treating with rapamycin,the frequency of electric bursts in striatal neurons were significantly decreased(P<0.01),the abnormal cluster discharge were significantly inhibited(P<0.05,P<0.01),the locoal fiel potential was also improved,and the behaviour assay score was significantly increased(P<0.05).Conclusions The abnormal electric activities of striatal synaps were the important link of LID occurrence.Rapamycin could significantly improve the behavioral and electrophysiological changes of LID rats,provide an important basis for the development of such drugs in the future.