Activation of mitophagy by lidocaine limits mROS and prevents microglial M1 polarization to alleviate postoperative delirium.

OBJECTIVE

Postoperative delirium (POD) is a common complication in elderly patients, yet effective interventions remain limited. Mitochondrial dysfunction and microglial M1 polarization contribute to POD pathogenesis, but the underlying mechanisms are incompletely understood. This study aimed to investigate whether lidocaine (LID) ameliorates POD by activating mitophagy to suppress mitochondrial reactive oxygen species (mROS) and inhibit M1 microglial polarization.

METHODS

A mouse model of POD was established by laparotomy in male C57BL/6 J mice, which were randomly divided into four groups (n = 6 each): sham, POD, POD + LID (8 mg/kg, i.v.), and POD + LID + Mdivi‑1 (25 mg/kg, i.p.). Behavioral tests (open field and Y‑maze), serum inflammatory and oxidative markers, hippocampal histology, mitophagy-related proteins, microglial polarization markers, mROS, and ATP were assessed. In vitro, LPS-stimulated BV2 cells were treated with LID (10 μg/mL), Mdivi‑1 (5 μM), or the mROS scavenger Mito‑TEMPO (1.5 mM) to evaluate mitochondrial function, mROS, and polarization.

RESULTS

LID treatment significantly improved behavioral performance, as evidenced by increased central zone exploration and Y‑maze alternation rate, reduced serum TNF‑α and IL‑1β, elevated IL‑10, and attenuated oxidative stress (decreased MDA, increased SOD) in POD mice. LID also restored hippocampal mitochondrial morphology, enhanced mitophagy (reduced p62, increased PINK1, Parkin, and LC3‑II/LC3‑I ratio), and shifted microglial polarization from M1 (decreased CD86/iNOS) to M2 (increased CD206/Arg‑1). All these effects were reversed by Mdivi‑1. In BV2 cells, LID reduced pro‑inflammatory cytokines (TNF‑α, IL‑1β), increased IL‑10, restored mitochondrial membrane potential, decreased mROS, and promoted M2 polarization; these effects were blocked by Mdivi‑1 and rescued by Mito‑TEMPO.

CONCLUSION

LID activates mitophagy, reduces mROS, and promotes M2 microglial polarization, thereby alleviating POD, highlighting its therapeutic potential.