Pioglitazone Reduces Secondary Brain Damage after Experimental Brain Trauma by PPAR-γ-Independent Mechanisms
Pioglitazone Reduces Secondary Brain Damage after Experimental Brain Trauma by PPAR-γ-Independent Mechanisms
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DOI：
10.1089/neu.2010.1685
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发表时间：
2011-06-01
影响因子：
4.2
通讯作者：
Engelhard, Kristin
中科院分区：
文献类型：
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作者：
Thal, Serge C.;Heinemann, Marius;Engelhard, Kristin
炎症和缺血过程有助于机械性脑损伤后继发性脑损伤的发展。最近的研究表明，噻唑烷二酮类药物（TZDs）是一类被批准用于治疗非胰岛素依赖型糖尿病的药物，它通过刺激过氧化物酶体增殖物激活受体γ (ppar - γ)有效地减少炎症和脑损伤。本研究探讨了吡格列酮和罗格列酮对实验性创伤性脑损伤（TBI）后炎症和继发性脑损伤的影响。在雄性C57BL/6小鼠中诱导可控皮质冲击（CCI）损伤，研究以下终点：(1)ppar - γ和ppar - γ靶基因（LPL、GLT1和IRAP/Lnpep）的mRNA表达，以及炎症标志物（tnf - α、IL-1 β、IL-6和iNOS）在创伤后15分钟、3小时、6小时、12小时和24小时的表达；(2)创伤后30分钟，吡格列酮（0.5和1 mg/kg）或罗格列酮（5和10 mg/kg）治疗小鼠24 h后的挫伤体积、神经功能和基因表达；(3)在吡格列酮、ppar - γ抑制剂T0070907和两者联合治疗的动物中，确定ppar - γ介导保护的作用。创伤后炎症标志物基因表达上调，而ppar - γ基因表达上调。吡格列酮以剂量依赖的方式减轻组织学损伤和炎症。相反，罗格列酮未能抑制炎症和组织损伤。吡格列酮和罗格列酮均未诱导ppar - γ和ppar - γ靶基因表达。与这些结果一致，吡格列酮介导的保护作用未被T0070907逆转。结果表明，吡格列酮的神经保护作用并不仅仅与ppar - γ依赖机制有关。
Inflammatory and ischemic processes contribute to the development of secondary brain damage after mechanical brain injury. Recent data suggest that thiazolidinediones (TZDs), a class of drugs approved for the treatment of non-insulin-dependent diabetes mellitus, effectively reduces inflammation and brain lesion by stimulation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The present study investigates the influence of the TZD pioglitazone and rosiglitazone on inflammation and secondary brain damage after experimental traumatic brain injury (TBI). A controlled cortical impact (CCI) injury was induced in male C57BL/6 mice to investigate following endpoints: (1) mRNA expression of PPAR-gamma and PPAR-gamma target genes (LPL, GLT1, and IRAP/Lnpep), and inflammatory markers (TNF-alpha, IL-1 beta, IL-6, and iNOS), at 15 min, 3 h, 6 h, 12 h, and 24 h post-trauma; (2) contusion volume, neurological function, and gene expression after 24 h in mice treated with pioglitazone (0.5 and 1 mg/kg) or rosiglitazone (5 and 10 mg/kg IP at 30 min post-trauma); and (3) the role of PPAR-gamma to mediate protection was determined in animals treated with pioglitazone, the PPAR-gamma inhibitor T0070907, and a combination of both. Inflammatory marker genes, but not PPAR-gamma gene expression, was up-regulated after trauma. Pioglitazone reduced the histological damage and inflammation in a dose-dependent fashion. In contrast, rosiglitazone failed to suppress inflammation and histological damage. PPAR-gamma and PPAR-gamma target gene expression was not induced by pioglitazone and rosiglitazone. In line with these results, pioglitazone-mediated protection was not reversed by T0070907. The results indicate that the neuroprotective effects of pioglitazone are not solely related to PPAR-gamma-dependent mechanisms.