Protective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's disease
Protective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's disease
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DOI：
10.1046/j.1471-4159.2002.00990.x
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发表时间：
2002-08-01
影响因子：
4.7
通讯作者：
Hirsch, EC
中科院分区：
文献类型：
--
作者：
Breidert, T;Callebert, J;Hirsch, EC
在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠帕金森病模型中，我们研究了吡格列酮（一种噻唑烷二酮类过氧化物酶体增殖体激活受体- γ (ppar - γ)激动剂）对多巴胺能神经细胞死亡和胶质细胞激活的影响。通过酪氨酸羟化酶（TH）免疫细胞化学和高效液相色谱检测纹状体多巴胺及其代谢物，证实MPTP急性中毒C57BL/6小鼠可引起黑质纹状体损伤。通过巨噬细胞抗原-1 （Mac-1）和诱导型一氧化氮合酶（iNOS）的免疫反应性可以确定，黑质纹状体多巴胺系统的损伤伴随着小胶质细胞的短暂激活，以及长时间的星形细胞反应。口服吡格列酮（类似于20mg /kg/天）可减弱mptp诱导的胶质细胞激活，并防止黑质致密部（SNpc）的多巴胺能细胞丢失。相比之下，mptp诱导的多巴胺消耗几乎没有减少，对吡格列酮治疗动物纹状体中TH免疫反应性和胶质反应的丧失没有可检测到的影响。在中脑腹侧和纹状体中检测到低水平的PPARgamma表达，并且MPTP或吡格列酮治疗不受影响。由于吡格列酮在我们的模型中主要影响SNpc，与急性MPTP中毒后多巴胺能细胞体的激活相比，不同的pparγ非依赖性机制可能调节多巴胺能末端的胶质细胞激活。
We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma)agonistofthethiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as determined by tyrosine hydroxylase (TH) immunocytochemistry, and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as determined by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (similar to 20 mg/kg/day) attenuated the MPTP-inducedglialactivation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little reduction of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARgamma expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARgamma-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.