Abstract
Increasing evidence has indicated that glutaredoxin 1 (GRX1) is a potent antioxidant protein that promotes cell survival under conditions of oxidative stress. Oxidative stress-induced neuronal injury contributes to cerebral ischemia/reperfusion injury. However, the role of GRX1-mediated antioxidant defense against neuronal damage during cerebral ischemia/reperfusion injury has not been thoroughly investigated. Thus, the objective of this study was to evaluate whether GRX1 protects neurons against oxygen-glucose deprivation/reoxygenation (OGD/R)-evoked oxidative stress injury in an in vitro model of cerebral ischemia/reperfusion injury. Our data revealed that GRX1 was induced by OGD/R treatment in neurons. Functional assays indicated that loss of GRX1 exacerbated OGD/R-induced apoptosis and the generation of reactive oxygen species (ROS), while GRX1 up-regulation protected against OGD/R-evoked neuronal injury. Further investigation revealed that GRX1 promoted the nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and enhanced transcription of the Nrf2/antioxidant response element (ARE) in GOD/R-exposed neurons. Furthermore, GRX1 promoted the activation of Nrf2/ARE associated with the modulation of glycogen synthase kinase-3β (GSK-3β). GSK-3β inhibition blocked GRX1 knockdown-mediated suppression of Nrf2 activation. Notably, the suppression of Nrf2 partially reversed GRX1-mediated anti-oxidative stress injury in OGD/R-exposed neurons. In summary, these findings indicate that GRX1 protects neurons against OGD/R-induced oxidative stress injury by enhancing Nrf2 activation via the modulation of GSK-3β. Our study suggests that GRX1 is a potential neuroprotective protein that protects against cerebral ischemia/reperfusion injury.