雷帕霉素干预对左旋多巴诱发的异动症大鼠行为学的影响

摘要

Objective To evaluate the effect of Rapamycin treatment on the behavioristics of levodopa induced dyskinesia (LID) rats.Methods Hemi-parkinsomism rat models were made by 6-hydraxydopamine microinjection stereotaxically into medial forebrain bundle.Then LID rat models were established by intraperitoneal injection of levodopa for a week.The LID rats were randomly divided into the LID control group (LID group) and Rapamycin treatment observation group (RAPA group).Then all of the rats were treated with levodopa by intraperitoneal injection for 2 weeks,and the rats in RAPA group were treated with Rapamycin by intraperitoneal injection 45 min before levodopa injection,with low dose of 0.25 mg/(kg·d),middle dose of 0.35 mg/(kg·d) and high dose of 0.5 mg/(kg·d),4 d a week for 2 weeks.The control group was given the same volume of normal saline.The abnormal involuntary movement (AIM) scores of rats were ecorded and analyzed.Results There was no significant behavior changes recorded in RAPA low dose subgroup.Rats in RAPA high dose subgroup appeared some problems such as listlessness,loss of appetite and hematuria after administration of Rapamycin for a few days,and died in about 5-10 d.The autopsy and pathologic diagnosis approved that the animals died due to pneumonia,liver and kidney function damage.The behavioral changes in RAPA middle dose subgroup were satisfying,and the animals showed well tolerance without rats died.After RAPA treatment,the dayly total AIM scores of the rats in RAPA middle dose subgroup were significantly lower than that in LID group (all P<0.05).The AIM scores of the RAPA middle dose subgroup within 120 min at 20 d after levodopa treatment were significantly lower than LID group (all P<0.05).Conclusion Rapamycin therapy can significantly improve the behavioral performance of LID rats,improve the involuntary movement symptoms of LID rats.%目的 研究雷帕霉素干预对左旋多巴诱发的异动症(LID)的行为学的影响.方法 通过6-羟基多巴胺颅内立体定向注射制作偏侧大鼠帕金森病模型.给予左旋多巴腹腔注射1周制作LID大鼠模型.将LID大鼠分为LID对照组(LID组)和雷帕霉素干预观察组(RAPA组).继续左旋多巴腹腔注射2周,RAPA组大鼠每天于左旋多巴注射前45 min腹腔注射雷帕霉素,低剂量0.25 mg/(kg·d)、中剂量0.35 mg/(kg·d)、高剂量0.5 mg/(kg·d),每周注射4 d,持续2周.对照组同时给予等体积生理盐水腹腔注射.记录大鼠异常不自主运动(AIM)评分并对比分析.结果 RAPA低剂量亚组未观察到有意义的行为学改变;RAPA高剂量亚组在雷帕霉素给药后数天出现精神萎靡、食欲减退、血尿等症状,5~10 d左右逐渐死亡,经尸体解剖及病理切片发现,动物死亡原因与肺炎、肝肾损害等原因密切相关.RAPA中剂量亚组行为学改变比较理想,且动物耐受性较好,没有出现死亡.RAPA干预治疗开始起,RAPA中剂量亚组大鼠每天AIM评分均较LID组大鼠明显降低(均P<0.05).左旋多巴注射第20 d,RAPA中剂量亚组大鼠左旋多巴治疗后120 min 内AIM评分均较LID组大鼠明显降低(均P<0.05).结论 雷帕霉素治疗能显著改善LID大鼠行为学表现,改善LID大鼠不自主运动症状.