Berberine alleviates postoperative cognitive dysfunction by suppressing microglial IDO1 induction and kynurenine pathway activation in aged mice.

Postoperative cognitive dysfunction (POCD) is a common complication of surgery in elderly patients, and no pharmacological therapy has been approved. Although indoleamine 2,3-dioxygenase 1 (IDO1)-driven kynurenine pathway activation has been linked to perioperative neurocognitive impairment, neither the cellular source of this activation in the hippocampus nor its upstream transcriptional control has been defined. In a tibial fracture model in aged mice, anesthesia and surgery raised hippocampal pro-inflammatory cytokines and IDO1, the latter predominantly in microglia, increased the kynurenine-to-tryptophan ratio, and produced cognitive impairment, dendritic simplification and synaptic loss. IDO1 inhibition with 1-methyl-DL-tryptophan attenuated these deficits, whereas exogenous L-kynurenine reproduced the cognitive impairment in surgery-naive mice, indicating that IDO1-driven tryptophan catabolism contributes to postoperative cognitive injury. Berberine improved cognition dose-dependently and attenuated the dendritic, synaptic and metabolic changes; at the effective dose it reached the hippocampus at concentrations 2.6-fold those in plasma. Network pharmacology, molecular docking and molecular dynamics simulation identified STAT3 among candidate transcriptional regulators; surface plasmon resonance demonstrated direct binding, a cellular thermal shift assay confirmed engagement of endogenous STAT3 in microglia, and an Ido1 promoter-luciferase reporter showed that berberine suppressed STAT3-dependent transcription. Microglia-targeted Ido1 overexpression attenuated the protection conferred by berberine, indicating that microglial IDO1 mediates a substantial part of its action. These findings identify the microglial STAT3-IDO1 axis as a candidate target for perioperative neuroprotection and support further translational evaluation of berberine in this setting.