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

Abnormal activation of GSK-3I3 is associated with psychiatric and neurodegenerative disorders. However, no study has examined the effect of GSK-3I3 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-3I3 with a GSK-3I3 siRNA virus improved injury and increased viability of neurons subjected to OGD/R. Levels of total Nrf2, nuclear Nrf2, and Nrf2 downstream proteins sulfiredoxin (Srxl) and thioredoxin (Trxl) increased after transfection with the GSK-3I3 siRNA virus. GSK-3I3 siRNA increased SOD activity and decreased MDA levels. Overexpression of GSK-3I3 with a pcDNA-GSK-3I3 virus showed opposite results. We also demonstrated that intracerebroventricular injection of GSK-3I3 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, Srxl, Trxl, SOD, and MDA were similar to those observed in vitro. Our results show for the first time that GSK-313 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.