Myricetin Mitigated Sevoflurane-induced Cognitive Dysfunction in Aged-mice Through Inhibiting Histone Deacetylase 2/nuclear Factor Erythroid 2-related Factor 2/heme Oxygenase-1 Signalling-mediated Ferroptosis and Mitochondrial Dysfunction.

Sevoflurane anaesthesia induces neurotoxicity and postoperative cognitive dysfunction (POCD) after surgery. This study investigated the roles and potential mechanisms of the natural flavonoid myricetin in sevoflurane-induced cognitive dysfunction. Primary hippocampal neurons were treated with 3% sevoflurane to establish a neuron injury model. Neurons was pre-treated with different concentrations of myricetin, and ferroptosis inhibitor ferrostatin-1 (Fer-1) was used as a positive control. Moreover, mice were anaesthetised with 3% sevoflurane to establish an in-vivo model, and they were pre-treated with 50 or 100 m/kg myricetin. Cell viability and death were determined. Ferroptosis-related markers, including intracellular iron content, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), 4-hydroxy-2-nonenal (4-HNE), glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) protein levels were measured. Myricetin treatment enhanced cell viability and mitigated sevoflurane-induced cell death in the hippocampal neurons. Sevoflurane exposure increased the ROS, MDA and 4-HNE levels and reduced the GSH level, whereas myricetin treatment abrogated these effects. Meanwhile, myricetin treatment restrained sevoflurane-induced increase in intracellular iron content and GPX4 and SLC7A11 protein levels. A high dose of myricetin showed distinct protective effects. Mechanistic studies demonstrated that myricetin treatment reversed sevoflurane-induced histone deacetylase 2 (HDAC2) upregulation and nuclear factor erythroid 2-related factor 2 (Nrf2) deacetylation, thus activating the Nrf2/heme oxygenase-1 (HO-1) signalling. Myricetin treatment mitigated sevoflurane-induced cognitive dysfunction in aged mice by inhibiting hippocampal ferroptosis and mitochondrial dysfunction via the HDAC2/Nrf2/HO-1 signalling pathway. Myricetin may be a treatment option for POCD after surgery.