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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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          Author and article information

          Contributors
          Journal
          8900963
          1466
          Mol Neurobiol
          Mol. Neurobiol.
          Molecular neurobiology
          0893-7648
          1559-1182
          6 January 2016
          15 December 2015
          December 2016
          01 December 2016
          : 53
          : 10
          : 7028-7036
          Affiliations
          [1 ]Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, People’s Repulic of China
          [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
          [3 ]Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 400044, People’s Republic of China
          Author notes

          Wei Wang and Mingchang Li contributed equally to this work.

          Article
          PMC4909586 PMC4909586 4909586 nihpa746115
          10.1007/s12035-015-9607-2
          4909586
          26671619
          28cb2882-c796-47e5-a823-cb3d74bcce7b
          History
          Categories
          Article

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

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