Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke (AIS) who are treated with tissue plasminogen activator (tPA). HT is associated with high morbidity and mortality, but no effective treatments are currently available to reduce the risk of HT. Therefore, methods to prevent HT are urgently needed. In this study, we used IM-12, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt-β-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 either administered rtPA, rtPA combined with IM-12, or the vehicle at 4 h after stroke was induced. Our results indicate that rats subjected to HT had more severe neurological deficits, brain edema, and blood-brain barrier (BBB) breakdown, and had a greater infarction volume than the control group. Rats treated with IM-12 had improved outcomes compared with those of rats treated with rtPA alone. Moreover, IM-12 increased the protein expression of β-catenin and downstream proteins while suppressing the expression of GSK-3β. These results suggest that IM-12 reduces rtPA-induced HT and attenuates BBB disruption, possibly through activation of the Wnt-β-catenin signaling pathway, and provides a potential therapeutic strategy for preventing tPA-induced HT after AIS.

中文翻译：

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IM-12激活了Wnt-β-catenin信号通路，并减弱了急性缺血性中风后大鼠rtPA引起的出血性转化。

出血性转化（HT）是急性急性缺血性卒中（AIS）患者的组织性纤溶酶原激活剂（tPA）的治疗。HT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的风险。因此，迫切需要预防HT的方法。在这项研究中，我们使用糖原合酶激酶3β（GSK-3β）抑制剂IM-12来评估Wnt-β-catenin信号通路在重组tPA（rtPA）诱导的HT中的作用。对Sprague-Dawley大鼠进行缺血性中风的大脑中动脉闭塞（MCAO）模型，然后在中风后4 h给予rtPA，rtPA与IM-12组合或赋形剂。我们的研究结果表明，接受HT治疗的大鼠具有更严重的神经功能缺损，脑水肿，和血脑屏障（BBB）分解，并且梗死体积比对照组大。与仅使用rtPA治疗的大鼠相比，使用IM-12治疗的大鼠的结局有所改善。此外，IM-12增加β-连环蛋白和下游蛋白的蛋白质表达，同时抑制GSK-3β的表达。这些结果表明IM-12可能通过激活Wnt-β-catenin信号传导途径降低rtPA诱导的HT并减弱BBB破坏，并提供了预防AIS后tPA诱导的HT的潜在治疗策略。IM-12增加β-连环蛋白和下游蛋白的蛋白质表达，同时抑制GSK-3β的表达。这些结果表明IM-12可能通过激活Wnt-β-catenin信号传导途径降低rtPA诱导的HT并减弱BBB破坏，并提供了预防AIS后tPA诱导的HT的潜在治疗策略。IM-12增加β-连环蛋白和下游蛋白的蛋白质表达，同时抑制GSK-3β的表达。这些结果表明IM-12可能通过激活Wnt-β-catenin信号传导途径降低rtPA诱导的HT并减弱BBB破坏，并提供了预防AIS后tPA诱导的HT的潜在治疗策略。