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Glycogen Synthase Kinase 3β Influences Injury Following Cerebral Ischemia/Reperfusion in Rats
Yixin Li1, Jin Zhu1, Yuanling Liu1
1; ;
Abstract:
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.
Insights
Inhibition of GSK-3β protects against brain damage from stroke. This study reveals GSK-3β (glycogen synthase kinase 3 beta) as a potential therapeutic target for cerebral ischemia/reperfusion injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Abnormal glycogen synthase kinase 3 beta (GSK-3β) activation is linked to neurological disorders.
- The role of GSK-3β in cerebral ischemia/reperfusion (I/R) injury remains uninvestigated.
Purpose of the Study:
- To investigate the effect of GSK-3β on cerebral I/R injury.
- To explore the underlying molecular mechanisms involving the Nrf2/ARE pathway and oxidative stress.
Main Methods:
- Utilized in vitro (oxygen-glucose deprivation/reoxygenation - OGD/R) and in vivo (middle cerebral artery occlusion - MCAO) models in rats.
- Employed GSK-3β siRNA for knockdown and pcDNA-GSK-3β for overexpression.
- Assessed neuronal viability, neurological deficits, infarct volume, brain water content, and molecular markers (Nrf2, Srx1, Trx1, SOD, MDA).
Main Results:
- GSK-3β knockdown via siRNA significantly improved neuronal viability and reduced injury in OGD/R models.
- GSK-3β siRNA increased total and nuclear Nrf2, downstream proteins (Srx1, Trx1), and SOD activity, while decreasing MDA levels.
- In vivo MCAO models showed that GSK-3β siRNA ameliorated neurological deficits, reduced infarct size, and brain water content, mirroring in vitro findings.
Conclusions:
- GSK-3β plays a significant role in exacerbating cerebral ischemia/reperfusion injury.
- Inhibition of GSK-3β offers neuroprotection by modulating the Nrf2/ARE pathway and reducing oxidative stress.
- GSK-3β represents a promising therapeutic target for treating stroke.
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