Sevoflurane postconditioning mitigates cognitive impairment induced by hemorrhagic shock resuscitation through inhibition of METTL3-mediated m6A modification of Sirt1 mRNA.

Abstract

Hemorrhagic shock resuscitation (HSR) induces cognitive impairment. Sevoflurane postconditioning (SPC) exerts neuroprotection, partially via Sirt1 activation. N6-methyladenosine (m6A), a crucial eukaryotic mRNA modification regulated by methyltransferase METTL3, influences brain function. However, METTL3's role in SPC-mediated neuroprotection against HSR remains unclear. Using HSR mouse models and HT22 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), we administered SPC. Mice received METTL3-overexpressing adeno-associated virus injection into the CA1 region prior to HSR induction. Cognitive function was assessed via novel object recognition and Morris water maze tests, and cerebral infarction was evaluated by TTC staining. SPC alleviated HSR-induced cognitive deficits and cerebral infarction, concurrently reduced elevated m6A levels and METTL3 expression. Crucially, METTL3 overexpression reversed SPC's beneficial effects, reinstating cognitive impairment and infarction. In vitro, METTL3 overexpression in SPC-treated OGD/R cells exacerbated oxidative stress, inflammation, and apoptosis. Mechanistically, SPC downregulated METTL3, reducing m6A modification and degradation of Sirt1 mRNA, thereby enhancing Sirt1 expression. Furthermore, SPC inhibited HSR-triggered microglial inflammation, an effect also negated by METTL3 overexpression. These results demonstrate that SPC protects against HSR-induced cognitive impairment by suppressing METTL3-mediated m6A modification of Sirt1 mRNA, revealing a novel epigenetic mechanism for SPC and identifying METTL3/m6A/Sirt1 as a potential diagnostic and therapeutic target for HSR.