ERK1/2信号通路对亚急性帕金森病MPTP模型小鼠黑质COX-2,PGE2表达的影响

Effects of ERK1/2 signal pathway on COX-2,PGE2 expression in subacute MPTP-induced mouse model of Parkinson's disease

目的:研究ERK1/2信号通路对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)所致帕金森病(PD)小鼠模型中脑黑质环氧合酶-2(COX-2)和前列腺素E2(PGE2)的表达调控作用,探讨多巴胺(DA)能神经元变性失活的可能机制.方法:采用MPTP制备亚急性PD小鼠模型,应用免疫组织化学和免疫蛋白印记法观察小鼠黑质酪氨酸羟化酶(TH),COX-2,PGE2以及磷酸化ERK1/2(p-ERK1/2)的表达变化;并观察给予ERK特异性抑制剂U0126对上述因子变化的影响.结果:模型组小鼠出现典型PD样症状,在MPTP第3次注射后1h,黑质区p-ERK1/2阳性细胞数明显增加,在MPTP第5次注射后24h,黑质区出现大量COX-2,PGE2阳性细胞,伴有约50%的TH阳性神经元丢失;给予ERK特异性抑制剂U0126后小鼠PD样症状减轻,p-ERK1/2,COX-2,PGE2阳性细胞数明显减少,MPTP第5次注射后24h,TH阳性细胞数较对照组仅下降25%.结论:ERK1/2通路可能参与调控COX-2及PGE2的表达而在PD发病过程中发挥重要作用,抑制ERK信号通路对帕金森病小鼠具有一定的神经保护作用.

AIM：To investigate effects of ERK1/2 signaling pathway on the expression of Cyclooxygenase-2（COX-2）and Prostaglandin E2（PGE2）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 to further explore the possible mechanism of dopaminergic neurons loss in PD.METHODS：C57BL/6 mice were administrated with MPTP to produce the subacute PD model,and the mice were observed the behavioral changes.Immunohistochemistry and Western Blot for tyrosine hydroxylase（TH）,cyclooxygenase-2（COX-2）,prostaglandin E2（PGE2）and phosphorylated ERK1/2（p-ERK1/2）were used to observe the changes of positive cell number in SN.After treatment with U0126,a specific inhibitor of ERK,the changes of above-mentioned indices were also observed.RESULTS：Compared with the mice in control group,the mice model appears typical of PD-like symptoms.P-ERK1/2-positive cells increased significantly at 1h after the 3rd injection of MPTP.The number of COX-2-,PGE2-positive cells was increased obviously as compared with the control group at 24 h after the 5th injection of MPTP.TH-positive neurons in the PD model group were substantially reduced by about 50%.Treated with U0126,a specific inhibitor of ERK,the performance of PD-like symptoms mitigated,the expression level of p-ERK1/2,COX-2 and PGE2 were significantly decreased in SN compared with mice model group.The number of TH-positive cells in the SN was decreased by only 25% at 24 h after the 5th injection of MPTP.CONCLUSION：ERK1/2 signal pathway may play an important role in regulating COX-2 and PGE2 expression in SN in the early stage of MPTP-induced subacute PD,and inhibition of ERK1/2 signal pathway activity may provide neuroprotective effects for DA neurons in the PD mouse model.