晚期糖基化蛋白产物受体在帕金森病发病中的作用

ROLE OF RAGE IN PATHOGENESIS OF PARKINSON'S DISEASE

目的研究晚期糖基化蛋白产物受体(RAGE)在帕金森病(PD)模型小鼠发病中的作用。方法将30只雄性C57BL/6小鼠随机分成正常对照组、1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)组与MPTP+RAGEsiRNA组,每组10只。MPTP、正常对照组分别腹腔注射MPTP、生理盐水,连续5周;MPTP+RAGE-siRNA组提前1周向黑质定位注射RAGE-siRNA慢病毒,后续处理同MPTP组。应用免疫印迹方法检测小鼠黑质中RAGE、酪氨酸单氧化酶(TH)及环氧合酶-2(COX-2)蛋白的表达。结果与正常对照组比较,MPTP组小鼠黑质中RAGE、COX-2蛋白的相对表达量明显增高(F=62.25、17.83,q=14.92、8.15,P<0.01),TH蛋白的相对表达量明显下降(F=8.87,q=5.85,P<0.01);与MPTP组比较,MPTP+RAGE-siRNA组RAGE、COX-2蛋白的相对表达量明显降低(q=10.75、5.47,P<0.01),而TH蛋白表达明显升高(q=4.58,P<0.05)。结论 RAGE可能通过炎症机制参与PD发病,针对RAGE的靶向治疗有望成为未来PD的治疗策略。

Objective To investigate the role of receptor for advanced glycation end products （RAGE） in the pathogenesis of Parkinson＇s disease （PD）. Methods A total of 30 male C57BL/6 mice were equally and randomly divided into three groups ： normal control group, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine （MPTP） group, and MPTP ＋ RAGE-siRNA group. The MPTP group and the normal control group were injected intraperitoneally with MPTP and normal saline, respectively, for five consecutive weeks. The MPTP--RAGEsiRNA group was given RAGE-siRNA lentivirus in the substantia nigra by stereotaxic sur- gery at one week before the treatment with MPTP which was the same as that for MPTP group. The expression of RAGE, tyrosine 3-monooxygenase （TH）, and cyelooxygenase-2 （COX-2） in the substantia nigra of mice was measured by Western blot. Results Compared with the control group, the MPTP group had significantly higher levels of RAGE and COX-2 and a significantly lower levelofTH （F=62.25,q=14.92,P〈0.01;F=17.83, q=8.15,P〈0.01;F=8.87,q=5.85, P〈0.01）. Compared with the MPTP group, the MPTP＋RAGE-siRNA group had significantly lower levels of RAGE and COX-2 and a significantly higher level ofTH （q=10.75,P〈0.01;q=5.47,P〈0.01;q=4.58,P〈0.05）. Conclusion RAGE may be involved in the pathogenesis of PD through inflammatory mechanism. RAGE as a target for therapeutic intervention of PD is promising in the future.