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

Jul 20, 2023ACS chemical neuroscience

Activin A may protect mouse brain cells from stroke damage by boosting a cell defense protein to reduce iron-related cell death

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Abstract

Act A treatment reduced infarct volume by improving neurological deficits in a mouse model of cerebral ischemia-reperfusion injury (CIRI).

MCAO led to increased iron accumulation and malondialdehyde levels, indicating oxidative stress related to ferroptosis.
ACSL4 expression was upregulated while GPX4 expression was downregulated in the brains of mice subjected to MCAO.
Act A treatment significantly reduced the markers of ferroptosis observed in the brains of mice after MCAO.
Nrf2 expression was enhanced in the brains of mice treated with Act A following MCAO.
Similar protective effects of Act A were observed in HT22 cells after oxygen-glucose deprivation/reoxygenation.
The protective effect of Act A in HT22 cells was reduced when Nrf2 was inhibited.

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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.

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