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<p>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&#xa0;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.</p> Graphical Abstract <p>Myricetin mitigated sevoflurane-induced cognitive dysfunction in aged-mice through inhibiting HDAC2/Nrf2/HO-1 signalling–mediated ferroptosis and mitochondrial dysfunction</p> <p></p>

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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

  • 期刊论文

  • 发表日期：

    2025年2月12日

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  • Peng Li,
  • Jingjing Liu,
  • Rui Wang,
  • Fuyang Cao,
  • Jiannan Li,
  • Henglin Wang

摘要

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.

Graphical Abstract

Myricetin mitigated sevoflurane-induced cognitive dysfunction in aged-mice through inhibiting HDAC2/Nrf2/HO-1 signalling–mediated ferroptosis and mitochondrial dysfunction