OBJECTIVE Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti-inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA-induced HT after stroke. METHODS AND RESULTS We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA-induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA-treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA-treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA-alone-treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down-regulated in microglia of the RSG-treated mice. We further found that the expression of Arg-1 was also upregulated in those tPA and RSG-treated stroke mice and the protection against tPA-induced HT and BBB disruption in these mice were abolished in the presence of PPAR-γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). CONCLUSIONS RSG treatment protects against BBB damage and ameliorates HT in delayed tPA-treated stroke mice by activating PPAR-γ and favoring microglial polarization toward anti-inflammatory phenotype.

中文翻译：

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罗格列酮可改善中风后组织纤溶酶原激活物引起的脑出血。

目的采用重组组织纤溶酶原激活物（tPA）进行的延迟溶栓治疗可能会加剧缺血性中风后的血脑屏障（BBB）分解，并导致灾难性的出血性转化（HT）。罗格列酮（RSG）是一种广泛使用的抗糖尿病药物，可激活过氧化物酶体增殖物激活受体-γ（PPAR-γ），通过促进卒中后小胶质细胞的极化朝着有益的抗炎表型发展，从而预防脑缺血。然而，延迟tPA治疗后RSG是否可以缓解HT仍是未知的。在这项研究中，我们排序以检查RSG对tPA诱发的中风后HT的作用。方法和结果我们使用了中风的小鼠缝合线大脑中动脉闭塞（MCAO）模型，然后延迟给予tPA（10 mg / kg，缝合后2小时）以研究RSG对tPA诱导的HT的治疗潜力。在tPA治疗的MCAO小鼠中，在MCAO之前1小时腹膜内给予RSG（6 mg / kg），中风后1天缺血区域的HT显着减弱。在tPA治疗的MCAO小鼠中，我们发现与单独tPA治疗的中风小鼠相比，RSG显着减轻了BBB破坏和出血的发展。使用流式细胞仪和免疫染色，我们证实在经RSG处理的小鼠的小胶质细胞中，CD206的表达显着上调，而iNOS的表达下调。我们进一步发现，在那些tPA和RSG治疗的中风小鼠中，Arg-1的表达也被上调，并且在存在PPAR-γ拮抗剂GW9662（4 mg）的情况下，这些小鼠对tPA诱导的HT和BBB破坏的保护作用也被取消。 / kg，在腹腔注射dMCAO之前1小时）。结论RSG治疗可通过激活PPAR-γ并促进小胶质细胞向抗炎表型的极化作用来预防tBB治疗的中风小鼠的BBB损伤并改善HT。