Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-γ
Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-γ
复制标题
吡格列酮通过激活 PPAR-gamma 对 HMGB-1/RAGE 和 Rac1/ROS 通路具有抑制作用，从而对缺血引起的细胞焦亡具有神经保护作用
DOI：
10.1159/000488183
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Ye, Zhi
中科院分区：
文献类型：
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作者：
Xia, Pingping;Pan, Yundan;Ye, Zhi
背景/目标：最近的研究强调了PPAR-gamma激动剂吡格列酮在脑缺血再灌注损伤的发展中的保护作用。然而，尚未有关于吡格列酮通过涉及焦亡的机制治疗缺血性卒中的研究。方法：采用大脑中动脉阻塞（MCAO）法建立大鼠脑损伤模型。原代培养的星形胶质细胞通过氧-糖剥夺（OGD）诱导体外缺血。采用ELISA和Western Blot分析方法分别检测PPAR-gamma水平、HMGB-1的细胞质转位水平和Rac 1活性以及PPAR-γ的表达水平。结果如下：我们证明，重复腹腔注射吡格列酮显着减少梗死体积，改善神经功能缺损，抑制Rac 1活性，显着减少过量的ROS在大脑中动脉闭塞（MCAO）大鼠模型。此外，吡格列酮减轻了脑半暗带皮质中与热解相关的生物标志物的上调以及HMGB-1和HMGB-1表达的胞质转位增加。同样，吡格列酮对培养的星形胶质细胞的保护作用的特点是减少Rac 1活性，pyroptosis相关蛋白的表达和乳酸脱氢酶（LDH）的释放。然而，使用GW 9662（一种PPAR-gamma抑制剂）可中和吡格列酮的这些保护作用。有趣的是，在慢病毒中用Rac 1小毛发RNA（shRNA）敲低Rac 1可以抑制原代培养的星形胶质细胞的OGD诱导的焦亡。Rac 1-shRNA与吡格列酮联合应用可进一步增强对OGD诱导的细胞凋亡的抑制作用。结论：吡格列酮的神经保护作用可归因于减轻缺血/缺氧诱导的焦亡，也与PPAR γ介导的HGMB-1/HGMB信号通路的抑制有关。此外，Rac 1的抑制促进了这一功能。(C)2018作者由S.发布Karger AG，巴塞尔
Background/Aims: Recent researches highlighted the protective potential of pioglitazone, a PPAR-gamma agonist, in the progression of cerebral ischemia-reperfusion injury. However, there has been no study on the application of pioglitazone in treating ischemic stroke through mechanisms involving pyroptosis. Methods: The cerebral injury was established by middle cerebral artery occlusion (MCAO). in vitro ischemia in primary cultured astrocytes was induced by the oxygen-glucose deprivation (OGD). ELISA and Western Blot analysis were employed to the levels of PPAR-gamma, pyroptosis-related biomarkers and cytoplasmic translocation of HMGB-1 and RAGE expression as well as Rac1 activity, respectively. Results: We demonstrated that repeated intraperitoneal administration of pioglitazone remarkably reduced the infarct volume, improved neurological deficits and suppressed the Rac1 activity with significant reduction of excessive ROS in rat model of middle cerebral artery occlusion (MCAO). Moreover, pioglitazone alleviated the up-regulation of pyroptosis-related biomarkers and the increased cytoplasmic translocation of HMGB-1 and RAGE expression in cerebral penumbra cortex. Similarly, the protective effects of pioglitazone on cultured astrocytes were characterized by reduced Rac1 activity, pyroptosis related protein expressions and lactate dehydrogenase (LDH) release. However, these protective effects of pioglitazone were neutralized with the use of GW9662, a PPAR-gamma inhibitor. Interestingly, Rac1 knockdown in lentivirus with the Rac1 small hair RNA (shRNA) could inhibit the OGD-induced pyroptosis of primary cultured astrocytes. Furthermore, the combination of Rac1-shRNA and pioglitazone can further strengthen the inhibitory effects on pyroptosis induced by OGD. Conclusion: The neuroprotection of pioglitazone was attributable to the alleviated ischemia/hypoxia-induced pyroptosis and was also associated with the PPAR gamma-mediated suppression of HGMB-1/RAGE signaling pathway. Moreover, the inhibition of Rac1 promoted this function. (C) 2018 The Author(s) Published by S. Karger AG, Basel