Neuroprotective Effects of Activin A against Cerebral Ischemia/Reperfusion Injury in Mice by Enhancing Nrf2 Expression to Attenuate Neuronal Ferroptosis

Activin A (Act A) is a member of the transforming growth factor-β (TGF-β) superfamily and can protect against ischemic cerebral injury. Ferroptosis, a newly discovered type of programmed cell death, contributes to the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). However, little is known on whether Act A can modulate neuronal ferroptosis to protect against CIRI in a mouse model of middle cerebral artery occlusion (MCAO) and an HT22 cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The results indicated that Act A treatment relieved CIRI by improving neurological deficits and reducing the infarct volume in mice. MCAO stimulated iron accumulation and malondialdehyde formation and upregulated ACSL4 expression but downregulated GPX4 expression, a hallmark of ferroptosis in the brain of mice. Treatment with Act A significantly mitigated MCAO-triggered ferroptosis in the brain of mice. Furthermore, Act A treatment enhanced the MCAO-upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression in the brains of mice. Similar results were observed in HT22 cells following OGD/R and pretreatment with Act A. The neuronal protective effect of Act A in HT22 cells was attenuated by treatment with ML385, an Nrf2 inhibitor. To conclude, Act A attenuated CIRI by enhancing Nrf2 expression and inhibiting neuronal ferroptosis.