Triptolide protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats:Implication for immunosuppressive therapy in Parkinson’s disease  

雷公藤内酯可减轻MPP～(+)诱导的大鼠多巴胺神经元损伤(英文)

作　　者：高俊鹏[1] 孙珊[1] 李文伟[1] 陈依萍[1] 蔡定芳[1] 

机构地区：[1]复旦大学附属中山医院中西医结合研究所神经病学研究室,上海200032

出　　处：《Neuroscience Bulletin》2008年第3期133-142,共10页神经科学通报（英文版）

摘　　要：Objective Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson＇s disease （PD）. The present study was undertaken to evaluate the activation profile of microglia in 1-methyl-4-phenyl pyridinium （MPP^＋）-induced hemiparkinsonian rats. Triptolide, a potent immunosuppressant and microglia inhibitor, was then examined for its efficacy in protecting dopaminergic neurons from injury and ameliorating behavioral disabilities induced by MPP^＋. Methods The rat model of PD was established by intranigral microinjection of MPP^＋. At baseline and on day 1, 3, 7, 14, 21 following MPP^＋ injection, the degree of microglial activation was examined by detecting the immunodensity of OX-42 （microglia marker） in the substantia nigra （SN）. The number of viable dopaminergic neurons was determined by measuring tyrosine hydroxylase （TH） positive neurons in the SN. Behavioral performances were evaluated by counting the number of rotations induced by apomorphine, calculating scores of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry. Results Intranigral injection of MPP^＋ resulted in robust activa- tion of microglia, progressive depletion of dopaminergic neurons, and ongoing aggravation of behavioral disabilities in rats. Triptolide significantly inhibited microglial activation, partially prevented dopaminergic cells from death and improved behavioral performances. Conclusion These data demonstrated for the first time a neuroprotective effect of triptolide on dopaminergic neurons in MPP^＋ induced hemiparkinsonian rats. The protective effect of triptolide may, at least partially, be related to the inhibition of MPP^＋-induced microglial activation. Our results lend strong support to the use of immunosuppressive agents in the management of PD.目的以小胶质细胞激活为特征的神经炎性反应作为帕金森病(Parkinson’sdisease,PD)一种重要的致病原因,正受到越来越多的关注。本文的目的是研究1-甲基-4-苯基-吡啶(1-methyl-4-phenyl pyridinium,MPP+)所诱导的偏侧PD大鼠模型中小胶质细胞的激活,观察雷公藤内酯作为一种小胶质细胞抑制剂对多巴胺神经元的保护作用及其对MPP+所导致的大鼠行为学异常的改善效果。方法通过黑质区域显微注射MPP+制作偏侧PD大鼠模型。分别在基线、MPP+注射后第1、3、7、14、21天时通过测定黑质区域OX-42的免疫荧光强度评定小胶质细胞的激活程度,测定酪氨酸羟化酶的表达情况评定存活多巴胺神经元的数量;通过阿朴吗啡诱导的旋转行为、前肢跨步及触须引发的不对称放置试验得分测评行为学表现。结果黑质区域MPP+注射导致小胶质细胞的激活、多巴胺神经元进行性死亡以及行为学缺陷的不断加重。雷公藤内酯可以显著抑制小胶质细胞的激活,部分阻止MPP+对多巴胺神经元的毒性,改善行为学异常。结论上述结果显示雷公藤内酯对MPP+诱导的偏侧PD大鼠模型多巴胺神经元具有保护作用,其机制可能与抑制小胶质细胞的激活有关,这为PD免疫抑制治疗提供了实验依据。

关 键 词：Parkinson＇s disease TRIPTOLIDE MICROGLIA neurons 

分 类 号：R285[医药卫生—中药学]