title: GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats.
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.
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
authors.forename: Mingchang
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
authors.forename: Yuefei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Bldg 370B, Baltimore, MD, 21205, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Bldg 370B, Baltimore, MD, 21205, USA.
authors.forename: Jieru
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400044, China.
authors.forename: Qingwu
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China. chenqx666@sohu.com.
authors.forename: Qianxue
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Bldg 370B, Baltimore, MD, 21205, USA. jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D062465:Claudin-3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010959:Tissue Plasminogen Activator; D060449:Wnt Signaling Pathway / Q000187:drug effects; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D062465:Claudin-3; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C547688:TWS 119; D062826:Zonula Occludens-1 Protein; D000071679:Glycogen Synthase Kinase 3 beta; D010959:Tissue Plasminogen Activator
keywords: Hemorrhagic transformation; Ischemic stroke; TWS119; Wnt/β-catenin signaling pathway; rtPA