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Int J Med Sci 2017; 14(4):333-339. doi:10.7150/ijms.17514 This issue Cite

Research Paper

GSK-3β as a target for protection against transient cerebral ischemia

Wei Wang^1,2*, Mingchang Li^1*, Yuefei Wang¹, Zhongyu Wang^3,4, Wei Zhang⁴, Fangxia Guan⁵, Qianxue Chen^1✉, Jian Wang^3,6✉

1. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, P.R. China;
2. Department of Traumatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China;
3. Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
4. Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P.R. China;
5. School of Life Sciences, Zhengzhou University, Zhengzhou 450000, P. R. China;
6. Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
* These authors contributed equally to the manuscript.

✉ Corresponding authors: Qianxue Chen, MD, PhD, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China. Phone: 86-27-88041911-82237. Email: chenqx666com). Jian Wang, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, 720 Rutland Ave, Ross Bldg 370B, Baltimore, MD 21205 (Phone: 1-443.287.5490; jwang79edu). More

Abstract

Stroke remains the leading cause of death and disability worldwide. This fact highlights the need to search for potential drug targets that can reduce stroke-related brain damage. We showed recently that a glycogen synthase kinase-3β (GSK-3β) inhibitor attenuates tissue plasminogen activator-induced hemorrhagic transformation after permanent focal cerebral ischemia. Here, we examined whether GSK-3β inhibition mitigates early ischemia-reperfusion stroke injury and investigated its potential mechanism of action. We used the rat middle cerebral artery occlusion (MCAO) model to mimic transient cerebral ischemia. At 3.5 h after MCAO, cerebral blood flow was restored, and rats were administered DMSO (vehicle, 1% in saline) or GSK-3β inhibitor TWS119 (30 mg/kg) by intraperitoneal injection. Animals were sacrificed 24 h after MCAO. TWS119 treatment reduced neurologic deficits, brain edema, infarct volume, and blood-brain barrier permeability compared with those in the vehicle group. TWS119 treatment also increased the protein expression of β-catenin and zonula occludens-1 but decreased β-catenin phosphorylation while suppressing the expression of GSK-3β. These results indicate that GSK-3β inhibition protects the blood-brain barrier and attenuates early ischemia-reperfusion stroke injury. This protection may be related to early activation of the Wnt/β-catenin signaling pathway.

Keywords: blood-brain barrier, ischemic stroke, Wnt/β-catenin signaling, TWS119

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