Molecular Neurobiology

, Volume 53, Issue 10, pp 7028–7036 | Cite as

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

  • Wei Wang
  • Mingchang Li
  • Yuefei Wang
  • Qian Li
  • Gang Deng
  • Jieru Wan
  • Qingwu Yang
  • Qianxue Chen
  • Jian Wang


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.


TWS119 rtPA Hemorrhagic transformation Wnt/β-catenin signaling pathway Ischemic stroke 



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.

Compliance with Ethical Standards

All protocols used in this study were approved by the Institutional Animal Care and Use Committee at Wuhan University.

Conflict of Interest

The authors declare that they have no competing interests.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Wei Wang
    • 1
  • Mingchang Li
    • 1
  • Yuefei Wang
    • 1
  • Qian Li
    • 2
  • Gang Deng
    • 1
  • Jieru Wan
    • 2
  • Qingwu Yang
    • 3
  • Qianxue Chen
    • 1
  • Jian Wang
    • 2
  1. 1.Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
  2. 2.Department of Anesthesiology and Critical Care MedicineThe Johns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of NeurologyXinqiao Hospital, Third Military Medical UniversityChongqingChina

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