抑制p38MAPK通路对帕金森病模型小鼠黑质BAD和caspase-3表达的影响  

Inhibition of p38MAPK Pathway Regulates BAD and Caspase-3 Expression in Substantia Nigra of the Mouse Model of Parkinson Disease

作　　者：魏子峰[1] 王永生[1] 周洪霞[1] 张作凤[1] 田清友[1] 高俊玲[1] 张宇新[1] 

机构地区：[1]华北煤炭医学院解剖学教研室,河北唐山063000

出　　处：《中国医科大学学报》2009年第7期497-500,共4页Journal of China Medical University

基　　金：河北省自然科学基金资助项目(C2004000689);河北省博士基金资助项目(05547008D-4);河北省科学技术与社会发展计划资助项目(04276135)

摘　　要：目的研究p38丝裂原活化蛋白激酶(p38MAPK)通路对亚急性帕金森病(PD)模型小鼠中脑黑质Bcl-xl/Bcl-2死亡相关因子(BAD)和半胱氨酸蛋白酶3(caspase-3)的表达调控作用,探讨PD中脑黑质多巴胺(DA)能神经元进行性变性丢失的可能机制。方法健康雄性C57BL/6N小鼠45只,随机分为3组,(1)1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)模型组:腹腔注射MPTP(30 mg/kg,溶于生理盐水),1次/d,连续5 d;(2)抑制剂组:在每次MPTP注射前1 h腹腔注射SB203580(10 mg/kg,溶于5mg/ml DMSO)1次/d,连续5 d;(3)对照组:注射与模型组和抑制剂组等量的生理盐水和DMSO。观察模型小鼠行为学变化,中脑黑质酪氨酸羟化酶(TH)、BAD、caspase-3和磷酸化p38丝裂原活化蛋白激酶(p-p38MAPK)的表达变化,及给予p38MAPK通路特异性抑制剂SB203580对上述表达变化的影响。结果模型小鼠出现典型的PD行为学症状,中脑黑质区TH阳性神经元和蛋白水平分别下降约60%和65%(P<0.01),p-p38MAPK、BAD和caspase-3阳性细胞数及蛋白水平显著增加(P<0.01);经p38MAPK特异性抑制剂SB203580处理后,PD小鼠行为学症状改善,TH阳性神经元和蛋白水平下降程度明显减轻;中脑黑质BAD、caspase-3和p-p38MAPK阳性细胞数显著减少,蛋白水平下降明显(P<0.01)。结论p38MAPK通路在亚急性PD模型小鼠黑质BAD和caspase-3表达中可能有重要调控作用,p38MAPK通路特异性抑制剂SB203580对PD小鼠具有一定的神经保护作用。Objective To investigate the effect of p38MAPK pathway on the expression of BAD and caspase-3, so as to explore the possible mechanism of dopaminergic neurons degeneration in the substania nigra （SN） of mice model of Parkinson disease （PD）. Methods 45 healthy male C57BL/6N mice were randomly divided into 3 groups： （1）MPTP model group：the mice were treated with MPTP（30 mg/kg,dissolved in saline, intraperitoneal injection ） per day for 5 days ; （ 2 ）inhibitor group ： the mice were treated with SB203580 （ 10 mg/kg, dissolved in 5 mg/ml DMSO, intraperitoneal injection） 1 hour before injection of MPTP per day for 5 days; （3） control group：the mice were treated with saline and DMSO as much as the model group received per day for 5 days. The behavior was observed,immunohistochemistry and Western blot for tyrosine hydroxylase （TH）, BAD, caspase-3 and phosphorylation of p38MAPK were used to observe the changes of positive cell numbers and the expression level in the SN of midbrain. Results The model group showed typical symptoms of PD with decreased numbers of TH-positive neurons and the protein level of TH in SN of the midbrain decreased by about 60% and 65% respectively （P 〈 0.01 ）, the number of BAD, caspase-3 and phosphorylation of p38MAPK immunoreacfive cells and their protein levels in the SN of the midbrain increased markedly （P 〈 0.01 ）. In contrast,the mice of inhibitor group presented slight behavioral symptoms,the loss degree of TH positive neumns and their protein levels were declined obviously,the positive cell numbers of BAD,caspase-3 and phosphrylation of p38MAPK were clearly reduced compared with the model group（ P 〈 0.01 ）, equally with the dereased protein level compared with the model group. Conclusion In the mice model of subacute Parkinson disease,p38MAPK pathway regulated the expression of BAD and caspase-3 in the SN of midbrain, the specific p38MAPK inhibitor SB203580 is neuroprotective to the mice model.

关 键 词：帕金森病 天冬氨酸特异性半胱氨酸蛋白酶3 磷酸化P38MAPK 酪氨酸羟化酶 1-甲基-4-苯基-1 2 3 6-四氢吡啶 Bcl-xl/Bcl-2死亡相关因子 

分 类 号：R742.5[医药卫生—神经病学与精神病学]