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Int J Biol Sci 2016; 12(5):518-531. doi:10.7150/ijbs.13918

Research Paper

Glycogen Synthase Kinase 3β Influences Injury Following Cerebral Ischemia/Reperfusion in Rats

Yixin Li1,2,3*, Jin Zhu1,2,3*, Yuanling Liu1,2,3, Xi Chen1,2,3, Shipeng Lei4, Lingyu Li1,2,3, Beibei Jiang1,2,3, Li Tan1,2,3, Shanshan Yu1,2,3✉, Yong Zhao1,2,3✉

1. Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China;
2. Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China;
3. Key Laboratory of Neurobiology, Chongqing Medical University, 400016 Chongqing, People's Republic of China;
4. Department of Respiratory Medicine, Jiangjin Center Hospital, 402260, Chongqing, People's Republic of China.
* Yixin Li and Jin Zhu contributed equally to this study.


Abnormal activation of GSK-3β is associated with psychiatric and neurodegenerative disorders. However, no study has examined the effect of GSK-3β on cerebral ischemia/reperfusion injury. We used oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion (MCAO) as models of ischemia/reperfusion in rats in vitro and in vivo. Our study showed that knockdown of GSK-3β with a GSK-3β siRNA virus improved injury and increased viability of neurons subjected to OGD/R. Levels of total Nrf2, nuclear Nrf2, and Nrf2 downstream proteins sulfiredoxin (Srx1) and thioredoxin (Trx1) increased after transfection with the GSK-3β siRNA virus. GSK-3β siRNA increased SOD activity and decreased MDA levels. Overexpression of GSK-3β with a pcDNA-GSK-3β virus showed opposite results. We also demonstrated that intracerebroventricular injection of GSK-3β siRNA in rats ameliorated neurological deficits, reduced brain infarct volume and water content, and reduced damage to cerebral cortical neurons after MCAO. Changes in total Nrf2, nuclear Nrf2, Srx1, Trx1, SOD, and MDA were similar to those observed in vitro. Our results show for the first time that GSK-3β can influence cerebral ischemia/reperfusion injury. The effects may be due to regulating the Nrf2/ARE pathway and decreasing oxidative stress. These results suggest a potential new drug target for clinical treatment of stroke.

Keywords: glycogen synthase kinase-3β, cerebral ischemia/reperfusion injury, NF-E2-related factor 2.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See for full terms and conditions.
How to cite this article:
Li Y, Zhu J, Liu Y, Chen X, Lei S, Li L, Jiang B, Tan L, Yu S, Zhao Y. Glycogen Synthase Kinase 3β Influences Injury Following Cerebral Ischemia/Reperfusion in Rats. Int J Biol Sci 2016; 12(5):518-531. doi:10.7150/ijbs.13918. Available from