P38MAPK通路参与调控iNOS活化及其介导的帕金森病小鼠多巴胺能神经元丢失

目的研究1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）所致帕金森病（Parkinson＇s disease，PD）小鼠模型黑质内P38丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号转导通路对诱导型一氧化氯舍酶（inducible nitric oxide，iNOS）的表达调控作用，以探讨PD中脑黑质多巴胺能神经元变性丢失的可能机制。方法采用神经毒素MPTP制备PD小鼠模型，免疫组织化学法观察各组小鼠黑质酪氨酸羟化酶（TH）、磷酸化P38（p—P38）和诱导型一氧化氮合酶（iNOS）阳性神经元数量的改变。结果与对照组相比，模型组小鼠黑质致密带TH阳性神经元显著减少约60％（P〈0．01），黑质区p—P38、iNOS阳性细胞均显著增高（P〈0．01）;与模型组比较，P38MAPK特异性抑制剂SB203580处理组黑质致密带TH阳性神经元细胞丢失明显减轻（28％vs．60％）（P〈0．01）;黑质区p-P38、iNOS阳性细胞均显著减少（P〈0．01）。结论iNOS表迭可能在中脑黑质DA能神经元变性岳失过程中起重要作用;P38信号通路可对中脑黑质细胞iNOS表达有重要的调控作用；P38通路抑制剂对MPTP所致帕金森病小鼠具有一定的神经保护作用。

P38 mapk pathway mediates inos activation and subsequent dopaminergic neuronal loss in the mouse mptp model of parkinson's disease

Objective To investigate the effect of P38 mitogen- activated protein kinase （P38MAPK） signaling pathway on the expression of inducible nitric oxide synthase （iNOS） in substantia nigra （SN） of the mouse models of Parkinson ＇s disease （PD） induced by 1 - Methyl- 4- phenyl- 1,2,3,6- Tetrah- ydropyridine （MPTP） and further explore the possible mechanism of the dopaminergic （DA） neuron loss in SN of midbrain in PD. Methods Chronic PD model was produced by MPTP, and the expressional change of tyrosine hydroxylase （TH）, p- P38 and inducible nitric oxide synthase （iNOS） in SN of midbrain were studied with immunohistochemistry. Results Compared with those control mice, the nuraber of TH - positive neurons in SNc of midbrain in model group was distinctly reduced by about 60% （P〈 0. 01）, the number of p - P38, iNOS immunoreactive cells was specially expressed in SN area in the mice（P〈0. 01）, In P38 inhibitor group, the number of TH- positive neurons in SN was only decreased by about 28% as compared with the control mice（60 %） （P〈0.01） ; the number of p- P38, iNOS immunoreactive cells was distinctly reduced in SN area（P〈0. 01）. Conclusion iNOS mediates inflammatory process is detrimental to DA neurons; P38 MAPK signaling pathway may play an important role in mediating iNOS expression in SN in the MPTP model of subacute PD; SB203580 may be neuroprotective to DA neurons in SNc of midbrain in the MPTP mouse model of PD.