雷帕霉素调控突触结构蛋白表达改善LID大鼠模型的行为学异常

Rapamycin regulates the expression of the synaptic structure-related protein to improve the movement disorder in a rat model of L-DOPA-induced dyskinesia

目的L-DOPA诱发异动症(LID)是帕金森病(PD)慢性L-DOPA治疗的主要运动并发症。既往研究发现使用雷帕霉素抑制哺乳动物雷帕霉素靶蛋白(mTOR)相关的信号通路可以改善LID模型的行为学异常且不影响L-DOPA的治疗效果。方法SPF级Sprague-Daewley大鼠,随机分成4组(对照组、模型组、异动症组、RAPA组),行为学实验后,断头处死各组大鼠,分离右侧纹状体组织,通过Western blot评估正突触后致密物(postsynaptic density,PSD)-95、突触相关蛋白(synaptosome-associated protein,SAP)-97等表达水平的影响。结果研究发现异动症组大鼠模型纹状体组织中,突触结构的PSD-95、SAP-97的表达水平升高(P<0.05);而给予雷帕霉素后,相应分子表达水平下降(P<0.05),行为学评分得到显著改善(P<0.05)。结论mTOR通路抑制剂雷帕霉素可以通过抑制PSD-95、SAP-97的蛋白表达,进而改善LID模型的行为学,提示mTOR通路异常可能参与了LID的发生,抑制mTOR通路的激活可作为治疗LID的靶点,为此类药物的开发提供了重要的依据。

Objective L-dopa induced dyskinesia(LID)is a major motor complication of chronic L-DOPA treatment of Parkinson’s disease(PD).Previous studies have found that inhibition of mammalian target of rapamycin(mTOR)related signal pathway by rapamycin can improve the behavioral abnormalities of lid model and does not affect the therapeutic effect of L-dopa,but the specific mechanism is not completely clear.Methods SPF Sprague Dawley rats were randomly divided into 4 groups(normal group,PD group,lid group,Rapa group),after the behavioral experiment,the rats in each group were decapitated and the right striatum was isolated.The effects of PSD-95 and sap-97 on the expression levels were evaluated by Western blot.Results It was found that the expression levels of PSD-95 and sap-97 in synaptic structure were increased in the striatum of lid rat model(P<0.05).After rapamycin administration,the expression level of corresponding molecules decreased(P<0.05).Conclusion Rapamycin,an inhibitor of mTOR pathway,can improve the behavior of LID model by inhibiting the protein expression of PSD-95 and sap-97,suggesting that the abnormality of mTOR pathway may be involved in the occurrence of LID.Inhibiting the activation of mTOR pathway can be used as a target for the treatment of LID,which provides an important basis for the development of such drugs.