摘要
目的:研究JNK在1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)所致小鼠帕金森病(PD)模型中对环氧合酶-2(COX-2)的表达调控作用,以探讨可能导致PD黑质多巴胺(DA)能神经元变性失活的机制.方法:采用MPTP制备亚急性PD小鼠模型,观察模型小鼠行为学变化,观察PD模型小鼠黑质区酪氨酸羟化酶(TH),COX-2,磷酸化c-Jun的表达变化;观察给予JNK通路特异性抑制剂SP600125对上述变化的影响.结果:与对照组小鼠相比,模型组小鼠出现典型PD症状,在MPTP第3次注射后6h,黑质区COX-2阳性细胞显著增加,p-c-Jun特异性表达于黑质区细胞核内,在MPTP第5次注射后7d,黑质区TH阳性神经元显著丢失65%(P<0.01);经SP600125处理后,模型小鼠PD症状减轻,与对照组比较,在MPTP第5次注射后7d,TH阳性细胞数仅下降约15%,与模型组比较,在MPTP第3次注射后6h,黑质区COX-2阳性细胞明显减少(P<0.01),黑质区p-c-Jun表达于细胞质内.结论:JNK通路在亚急性PDMPTP模型早期对黑质COX-2表达中可能起重要调控作用;抑制JNK通路对PD小鼠具有神经保护作用.
AIM： To investigate the effect of c-Jun N-terminal protein kinase （JNK） on the expression of cyclooxygenase-2 （COX-2） in substantia nigra （SN） of the mouse models of subacute Parkinson＇s disease （PD） induced by 1-Methyl-4- phenyl- 1,2,3,6-tetrahydropyfidine （MPTP） and to further explore the possible mechanism of the dopaminergic （DA） neuron death in PD. METHODS： C57BL/6N mice were administrated with MPTP to produce subacute PD model. PD mice were observed in behavioral changes. Inmmunohistochemistry for tyrosine hydroxylase（TH） , COX-2 and phosphorylated c-Jun （p-c-Jun） was used to observe the changes in positive cell number in the midbrain and further observe the number changes after treated with SP600125, a specific JNK inhibitor. RESULTS： Compared with the mice in control group, the model mice had the typical symptoms of PD. The number of COX-2 immunoreactive ceils was significantly increased and p-c-Jun was specially expressed in the nucleus of nigral neurons in SN area at 6 h after the 3rd injection of 30 mg/ kg MPTP. The number of TH-positive neurons in model group was distinctly reduced by about 65% （P 〈0.01 ） in the SN 7 d after the 5th injection of MPTP. In JNK inhibitor SP600125 group, the number of TH-positive neurons in SN was only decreased by 15% （P 〈0.01 vs control group） 7 d after the 5th injection of MPTP, the number of COX-2 positive cells was clearly reduced as compared with the model group （ P 〈 0.01 ）, p-c-Jun was expressed mainly in the cytoplasm of nigral neurons at 6 h after the 3rd injection of MPTP. CONCLUSION： JNK signaling pathway may play an important role in mediating COX-2 expression in SN in the early stage of the MPTP-induced subacute PD, so inhibiting JNK activity may have neuroprotection to the PD mouse models.
出处
《第四军医大学学报》
北大核心
2007年第11期979-982,共4页
Journal of the Fourth Military Medical University
基金
河北省自然科学基金(C2004000689)
河北省博士基金(05547008D-4)
河北省科学技术与社会发展计划(04276135)
