p38MAPK通路参与亚急性帕金森病模型小鼠黑质iNOS表达的调控

目的:研究1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)所致Parkinson病(PD)小鼠模型黑质p38丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路对诱导型一氧化氮合酶(inducible nitric oxide,iN-OS)、半胱氨酸蛋白酶-3(caspase-3)的表达调控,以探讨PD多巴胺能神经元丢失的可能机制。方法:采用MPTP制备PD小鼠模型,观察行为学变化;采用免疫组化和免疫蛋白印迹法,观察黑质区酪氨酸羟化酶(tyrosine hydroxylase,TH)、iNOS、caspase-3和磷酸化p38MAPK(p-p38MAPK)阳性细胞数和蛋白表达水平变化及给予p38MAPK特异性抑制剂SB203580后对上述变化的影响。结果:模型II组TH阳性神经元明显丢失,小鼠出现典型的PD样行为学表现;模型I组小鼠黑质区p-p38MAPK、iNOS、caspase-3阳性细胞数及蛋白水平显著增加。经SB203580处理后,上述变化明显减轻(P0.01)。结论:p38MAPK通路对PD模型小鼠黑质区细胞凋亡可能起重要的调控作用,抑制该通路具有一定神经保护作用。

p38MAPK signaling pathway regulates iNOS expression in nigral cells of the subacute mouse model of Parkinson's disease

Objective:To investigate the effects of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway on the expression of inducible nitric oxide synthase (iNOS) and caspase-3 in substantia nigra (SN) of the mouse model of Parkinson’s disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and further explore the possible mechanism of the dopaminergic (DA) neuronal loss in SN.Methods:C57BL/6N mice were administrated with MPTP to produce subacute PD model and detected the behavior change.The numbers of TH,iNOS,caspase-3 and p-p38MAPK positive cells,and their expressional level in SN were observed by immunohistochemistry and Western Blot.The above changes,after giving SB203580,the specific p38MAPK inhibitor,were also studied.Results:In the model group-II,TH-positive neurons lost markedly and the mice exhibited the typical PD-like behaviors.In the model group-I,the number of p-p38MAPK,iNOS,caspase-3 immunoreactive cells and their expression level in SN increased markedly.After giving SB203580,the above changes reduced obviously (P<0.01).Conclusion:p38MAPK pathway may play an important role in mediating neuronal apoptosis in SN in the mouse model of PD,inhibition of the pathway has the neuroprotective effect.