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Myricetin Mitigated Sevoflurane-induced Cognitive Dysfunction in Aged-mice Through Inhibiting Histone Deacetylase
Peng Li1, Jingjing Liu2, Rui Wang3
1Department of Anesthesiology, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
Abstract:
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.
Insights
The natural compound myricetin protects against sevoflurane-induced neurotoxicity and cognitive decline by inhibiting ferroptosis and mitochondrial dysfunction. This research highlights myricetin as a potential therapeutic agent for postoperative cognitive dysfunction (POCD).
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Sevoflurane anesthesia is linked to neurotoxicity and postoperative cognitive dysfunction (POCD).
- The natural flavonoid myricetin's role in mitigating these effects remains largely unexplored.
Purpose of the Study:
- To investigate the protective effects and underlying mechanisms of myricetin against sevoflurane-induced neurotoxicity and cognitive impairment.
- To explore myricetin's potential as a therapeutic strategy for preventing POCD.
Main Methods:
- Established in vitro (primary hippocampal neurons) and in vivo (aged mice) models of sevoflurane-induced injury.
- Assessed cell viability, ferroptosis markers (iron, ROS, MDA, GSH, 4-HNE, GPX4, SLC7A11), and mitochondrial function.
- Investigated the involvement of the HDAC2/Nrf2/HO-1 signaling pathway.
Main Results:
- Myricetin treatment significantly enhanced neuronal viability and reduced cell death induced by sevoflurane.
- Myricetin reversed sevoflurane-induced ferroptosis by decreasing iron, ROS, MDA, 4-HNE, GPX4, and SLC7A11, while increasing GSH.
- Myricetin inhibited sevoflurane-induced cognitive dysfunction in mice by modulating the HDAC2/Nrf2/HO-1 pathway, mitigating ferroptosis and mitochondrial dysfunction.
Conclusions:
- Myricetin exhibits significant neuroprotective properties against sevoflurane-induced toxicity and cognitive impairment.
- The protective mechanism involves the inhibition of hippocampal ferroptosis and mitochondrial dysfunction via the HDAC2/Nrf2/HO-1 signaling pathway.
- Myricetin presents a promising therapeutic candidate for managing postoperative cognitive dysfunction.
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