GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats.
GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats.
复制标题
GSK-3β 抑制剂 TWS119 减弱大鼠急性缺血性中风后 rtPA 诱导的出血性转化并激活 Wnt/β-catenin 信号通路。
DOI：
10.1007/s12035-015-9607-2
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发表时间：
2016-12
影响因子：
5.1
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wang W;Li M;Wang Y;Li Q;Deng G;Wan J;Yang Q;Chen Q;Wang J
出血性转化（HT）是接受组织纤溶酶原激活剂（tPA）治疗的急性缺血性卒中患者的毁灭性并发症。它与高发病率和死亡率相关，但目前没有有效的治疗方法来降低HT风险。因此，迫切需要预防HT的方法。在本研究中，我们使用糖原合成酶激酶3β（GSK-3β）抑制剂TWS 119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4 h时给予rtPA、rtPA与TWS 119组合或媒介物。在梗塞诱导后24小时处死动物。与溶剂组相比，rtPA治疗的大鼠表现出明显的HT，神经功能缺损、脑水肿和血脑屏障破坏更严重，梗死体积更大。与单独用rtPA治疗的大鼠相比，用TWS 119治疗的大鼠具有显著改善的结果。Western blot分析显示，TWS 119可增加β-catenin、claudin-3和ZO-1的蛋白表达，同时抑制GSK-3β的表达。这些结果表明，TWS 119减少rtPA诱导的HT并减弱血脑屏障破坏，可能通过激活Wnt/β-连环蛋白信号通路。本研究为预防急性缺血性卒中后tPA诱导的HT提供了一种潜在的治疗策略。
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 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 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 β-catenin, claudin-3, and ZO-1 while suppressing the expression of GSK-3β. These results suggest that TWS119 reduces rtPA-induced HT and attenuates blood–brain barrier disruption, possibly through activation of the Wnt/β-catenin signaling pathway. This study provides a potential therapeutic strategy to prevent tPA-induced HT after acute ischemic stroke.