Department of Pharmacology, College of Medicine, Hanyang University, 133-791 Seoul, Republic of Korea.
Toxicol Lett. 2012 Sep 18;213(3):332-44. doi: 10.1016/j.toxlet.2012.07.016. Epub 2012 Jul 27.
Rosiglitazone is a commonly prescribed insulin-sensitizing drug with selective agonistic activity at the peroxisome proliferator-activated receptor-γ (PPARγ). Previously, rosiglitazone was shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), an effect attributed to its anti-inflammatory properties. To elucidate the neuroprotective mechanisms of rosiglitazone, we investigated the effects of rosiglitazone on the expressions of striatal tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP) in a 6-OHDA-lesioned rat PD model. Rosiglitazone (3 mg/kg) was administered intraperitoneally at 24 h and 30 min prior to the creation of an intranigral 6-OHDA lesion. A reduction in TH protein expression began at 3 days and a prominent decrease was observed at 7 days post-lesion, and decreases of dopamine (DA) levels began at 1 day post-lesion. In contrast, GFAP expression was significantly increased at 3 days and preserved for up to 7 days post-lesion and the patterns of GFAP expression was inversely correlated to changes in TH expression. Furthermore, COX-2 expression in the rostral striatum showed a significant increase at 6h post-lesion while that of the caudal striatum was increased at 12 h. In the 6-OHDA-lesioned model, the activation of PPARγ by rosiglitazone significantly prevented TH protein expression reductions, and inhibited 6-OHDA-induced microglia activation in striatum. In addition, rosiglitazone attenuated in production of both COX-2 and TNF-α expression. In contrast, rosiglitazone pretreatment led to greater increases in striatal GFAP expression than 6-OHDA alone and changes in the expression of this protein preceded the changes that were seen with TH expression. These results suggest that the neuroprotection observed with rosiglitazone treatment may be partially due to the attenuation of COX-2 production and the strengthening of astrocyte function. Our results provide insight into the neuroprotective mechanisms of rosiglitazone against 6-OHDA-induced neuronal damages.
罗格列酮是一种常用的胰岛素增敏药物，对过氧化物酶体增殖物激活受体-γ（PPARγ）具有选择性激动作用。先前的研究表明，罗格列酮可减轻帕金森病（PD）1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中的多巴胺能神经元丢失，其作用归因于其抗炎特性。为了阐明罗格列酮的神经保护机制，我们研究了罗格列酮对 6-OHDA 损伤的大鼠 PD 模型纹状体酪氨酸羟化酶（TH）、环氧化酶-2（COX-2）和胶质纤维酸性蛋白（GFAP）表达的影响。罗格列酮（3mg/kg）在立体定向注射 6-OHDA 前 24 小时和 30 分钟腹腔内给药。TH 蛋白表达的减少始于 3 天，在损伤后 7 天观察到明显减少，多巴胺（DA）水平的减少始于损伤后 1 天。相比之下，GFAP 表达在 3 天显著增加，并在损伤后 7 天内保持不变，GFAP 表达的模式与 TH 表达的变化呈负相关。此外，损伤后 6 小时，前纹状体 COX-2 表达显著增加，而后纹状体 COX-2 表达在 12 小时增加。在 6-OHDA 损伤模型中，罗格列酮激活 PPARγ 可显著防止 TH 蛋白表达减少，并抑制纹状体中 6-OHDA 诱导的小胶质细胞激活。此外，罗格列酮抑制 COX-2 和 TNF-α 的表达。相反，罗格列酮预处理导致纹状体 GFAP 表达增加比单独使用 6-OHDA 更多，并且该蛋白表达的变化先于与 TH 表达的变化。这些结果表明，罗格列酮治疗观察到的神经保护作用可能部分归因于 COX-2 产生的减弱和星形胶质细胞功能的增强。我们的研究结果为罗格列酮对 6-OHDA 诱导的神经元损伤的神经保护机制提供了新的认识。
