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首页> 外文期刊>Molecular Neurobiology >GSK-3 beta inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/beta-catenin signaling pathway after acute ischemic stroke in rats
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GSK-3 beta inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/beta-catenin signaling pathway after acute ischemic stroke in rats

机译：GSK-3 beta抑制剂TWS119减轻rtPA诱导的大出血性转化并激活大鼠急性缺血性中风后的Wnt / beta-catenin信号通路

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Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke who are treated with tissue plasminogen activator (tPA). It is associated with high morbidity and mortality, but no effective treatments are currently available to reduce HT risk. Therefore, methods to prevent HT are urgently needed. In this study, we used TWS119, an inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta), to evaluate the role of the Wnt/beta-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague-Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke and then were administered rtPA, rtPA combined with TWS119, or vehicle at 4 h. The animals were sacrificed 24 h after infarct induction. Rats treated with rtPA showed evident HT, had more severe neurologic deficit, brain edema, and blood-brain barrier breakdown, and had larger infarction volume than did the vehicle group. Rats treated with TWS119 had significantly improved outcomes compared with those of rats treated with rtPA alone. In addition, Western blot analysis showed that TWS119 increased the protein expression of beta-catenin, claudin-3, and ZO-1 while suppressing the expression of GSK-3 beta. These results suggest that TWS119 reduces rtPA-induced HT and attenuates blood-brain barrier disruption, possibly through activation of the Wnt/beta-catenin signaling pathway. This study provides a potential therapeutic strategy to prevent tPA-induced HT after acute ischemic stroke.
机译：出血性转化（HT）是急性急性缺血性卒中的并发症，接受组织纤溶酶原激活剂（tPA）的治疗。它与高发病率和高死亡率相关，但是目前尚无有效的治疗方法可降低HT风险。因此，迫切需要预防HT的方法。在这项研究中，我们使用了糖原合酶激酶3 beta（GSK-3 beta）抑制剂TWS119来评估Wnt / beta-catenin信号通路在重组tPA（rtPA）诱导的HT中的作用。对Sprague-Dawley大鼠进行局部缺血性脑卒中的大脑中动脉闭塞（MCAO）模型，然后在4 h给予rtPA，rtPA结合TWS119或赋形剂。梗塞诱导后24小时处死动物。用rtPA治疗的大鼠表现出明显的HT，比媒介物组有更严重的神经功能缺损，脑水肿和血脑屏障破坏，并且梗死体积更大。与仅用rtPA治疗的大鼠相比，用TWS119治疗的大鼠具有明显改善的结果。此外，蛋白质印迹分析表明，TWS119增加了β-catenin，claudin-3和ZO-1的蛋白表达，同时抑制了GSK-3 beta的表达。这些结果表明，TWS119可能通过激活Wnt /β-catenin信号通路降低了rtPA诱导的HT，并减弱了血脑屏障的破坏。这项研究提供了潜在的治疗策略，以预防急性缺血性中风后tPA诱导的HT。

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