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GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats

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Abstract

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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81171112, 81371272 to M.C.L., 81372683 to Q.X.C.) and grants from the National Institutes of Health (R01NS078026, R01AT007317 to J. W.). We thank Jiarui Wang and Claire Levine, MS, ELS, for assistance with the manuscript preparation.

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    1. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China

      Wei Wang, Mingchang Li, Yuefei Wang, Gang Deng & Qianxue Chen

    2. Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Bldg 370B, Baltimore, MD, 21205, USA

      Qian Li, Jieru Wan & Jian Wang

    3. Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400044, China

      Qingwu Yang

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    1. Wei Wang
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    Wei Wang and Mingchang Li contributed equally to this work.

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    Wang, W., Li, M., Wang, Y. et al. GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats. Mol Neurobiol 53, 7028–7036 (2016). https://doi.org/10.1007/s12035-015-9607-2

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