Ferrostatin-1 alleviates cerebral ischemia/reperfusion injury through activation of the AKT/GSK3β signaling pathway

Abstract

Ischemic stroke is the major cause of disability and death worldwide, but post-stroke neuronal death and related mechanisms remain unclear. Ferroptosis, a newly identified type of regulated cell death, has been shown to be associated with neurological disorders, yet the exact relationship between ferroptosis and ischemic stroke has not been elucidated. The purpose of this study is to investigate the effects of ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) on neuronal injury after cerebral ischemia/reperfusion (I/R) and the underlying mechanism. In this study, we demonstrated that ferroptosis does occur in the stroke model. We found that Fer-1 reduced the levels of iron and malondialdehyde, and increased the content of glutathione and the expression of solute carrier family 7 member 11 and glutathione peroxidase 4 in cerebral I/R models. Additionally, Fer-1 significantly reduced the infarct volume and improved neurobehavioral outcomes. Moreover, we found that Fer-1 increased the levels of phosphorylated AKT and GSK3β following cerebral I/R. To further investigate the functional role of the AKT in the neuroprotective effects of Fer-1, MCAO models and oxygen-glucose deprivation-induced HT22 cells were pretreated with the AKT inhibitor MK-2206 before treatment with Fer-1 and the protective effects of Fer-1 were reversed. In conclusion, Fer-1 has protective effects on cerebral I/R injury by activating the AKT/GSK3β pathway, indicating that ferroptosis may become a novel target in the treatment of ischemic stroke.