Quercetin Alleviates Postoperative Cognitive Dysfunction of Aged Mice by Regulating Microglial Polarization through...

Postoperative cognitive disorder (POCD) is a frequent complication after surgery, especially in older patients. Quercetin is a multifunctional natural active ingredient with significant potential in antioxidation, anti-inflammatory and neuroprotection. The objective of this research is to propose a potential mechanism of Quercetin in POCD. The experimental subjects underwent Open Field Test (OFT) and Morris water maze (MWM) to evaluate cognitive functions. The quantification of mRNA and protein expression was performed using Reverse Transcription Quantitative Real-time PCR (RT-qPCR) and Western blotting assay. The concentrations of pro-inflammatory cytokines were precisely quantified using ELISA with commercially available kits. The TUNEL assay was used to examine neuronal apoptosis in the hippocampal tissues. Immunofluorescence staining targeting Iba1 was used to evaluate microglial activation. The flow cytometry assay was utilized to evaluate the apoptosis and polarization of BV-2 microglia. Quercetin ameliorated cognitive impairment and locomotor capacity in aged POCD mice by relieving neuroinflammation mediated by microglia. Molecularly, both the wild type (wt) and the edited (ed) miR-379-5p stimulated microglia viability and M2 polarization. Quercetin's regulation of microglia viability and polarization depends on ADAR2-mediated editing of miR-379-5p. A-to-I RNA editing modifies the target of miR-379-5p, redirecting it from PANK1 to GSK3β, thereby regulating microglial polarization and alleviating POCD. Furthermore, Quercetin treatment regulates GSK3β expression, while exerting no effect on PANK1 expression in aged POCD mice. Functionally, PANK1 overexpression inhibited microglia viability and promoted M1 polarization by enhancing glycolysis and reducing fatty acid oxidation (FAO), as well as by interacting with wt-miR-379-5p. GSK3β overexpression suppressed microglia viability and induced M1 polarization by activating NF-κB/STAT3 signal and the NLRP3 inflammasome and interacting with ed-miR-379-5p. Quercetin promotes microglia viability and M2 polarization by downregulating GSK3β through intensifying ADAR2-mediated editing of miR-379-5p, thereby alleviating POCD of aged mice. Clinical trial number: Not applicable.