Pinocembrin Alleviates Postoperative Cognitive Dysfunction in Aged Mice by Modulating miR-384-5p/FZD1 Axis to...

Postoperative cognitive dysfunction (POCD) is a clinically recognized complication of surgery that compromises long-term neurological outcomes, though its mechanistic basis remains poorly defined. The flavonoid Pinocembrin (5,7-dihydroxyflavanone) exhibits anti-inflammatory, antioxidant, and neuroprotective effects. However, the precise mechanisms underlying Pinocembrin's role in modulating the pathogenesis and progression of POCD remain incompletely elucidated. Cognitive function was evaluated using the Morris water maze (MWM) test and open field test (OFT). Protein and mRNA expression levels were quantified by Western blotting and qRT-PCR, respectively. Neuronal apoptosis in hippocampal tissue was assessed using TUNEL staining, while BV-2 microglial apoptosis was analyzed by flow cytometry. Microglial activation was visualized via immunofluorescence staining. Pro-inflammatory cytokine concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Pinocembrin significantly improved cognitive function in elderly POCD mice, without altering locomotor activity or anxiety-like behaviors. Notably, Pinocembrin reduced neuronal apoptosis and microglia-induced inflammation in elderly POCD mice. Mechanistically, Pinocembrin attenuated BV-2 microglial apoptosis and M1 polarization by downregulating miR-384-5p. MiR-384-5p directly targets FZD1. Strikingly, Pinocembrin rescued FZD1 expression by downregulating miR-384-5p, while FZD1 knockdown abolished Pinocembrin's effects on microglial M1 polarization and apoptosis. This cascade activated the Wnt/β-catenin pathway, ultimately ameliorating cognitive deficits in POCD mice. Pinocembrin ameliorates POCD in aged mice by activating Wnt/β-catenin signaling via the miR-384-5p/FZD1 regulatory axis.