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 growthfactor-& beta;(TGF-& beta;) superfamily and can protect against ischemic cerebralinjury. 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 neuronalferroptosis to protect against CIRI in a mouse model of middle cerebralartery occlusion (MCAO) and an HT22 cell model of oxygen-glucose deprivation/reoxygenation(OGD/R). The results indicated that Act A treatment relieved CIRIby improving neurological deficits and reducing the infarct volumein mice. MCAO stimulated iron accumulation and malondialdehyde formationand upregulated ACSL4 expression but downregulated GPX4 expression,a hallmark of ferroptosis in the brain of mice. Treatment with ActA significantly mitigated MCAO-triggered ferroptosis in the brainof mice. Furthermore, Act A treatment enhanced the MCAO-upregulatednuclear factor erythroid-2-related factor 2 (Nrf2) expression in thebrains of mice. Similar results were observed in HT22 cells followingOGD/R and pretreatment with Act A. The neuronal protective effectof Act A in HT22 cells was attenuated by treatment with ML385, anNrf2 inhibitor. To conclude, Act A attenuated CIRI by enhancing Nrf2expression and inhibiting neuronal ferroptosis.