Trifluoperazine improves postoperative cognition by influencing astrocyte endfoot morphology and aquaporin-4 polarity.

Postoperative cognitive dysfunction (POCD) represents a debilitating neurological complication associated with progressive cognitive deterioration and heightened dementia risk in surgical populations. Despite emerging evidence implicating glymphatic dysfunction in neuroinflammatory pathogenesis, perioperative dynamics of astrocytic endfoot architecture and aquaporin-4 (AQP4) polarization remain insufficiently characterized. Aged murine models were stratified into POCD phenotypes through standardized behavioral assessments. Transmission electron microscopy (TEM) quantified perioperative astrocytic endfoot morphology, while immunofluorescence and qPCR evaluated AQP4 expression/polarization. Mechanistic investigations employed trifluoperazine (TFP), a selective AQP4 polarity inhibitor, to delineate its therapeutic effects on glymphatic clearance, cognitive performance, and neuroinflammatory pathways. POCD-positive mice exhibited significant pathological swelling of terminal feet accompanied by AQP4 polarization disruption. TFP pretreatment significantly alleviated postoperative anxiety-like behaviors and cognitive deficits. Behavioral results demonstrated that the TFP 2 mg/kg group showed 1.4-fold and 2.4-fold increases the time spent in centerarea and the time spent in novel arm, respectively, compared to the surgery group (p < 0.05). This was accompanied by the restoration of AQP4 polarization and increased perivascular CSF tracer influx. At the molecular level, TFP upregulated synaptic plasticity regulators (compared to the surgery group, Snta1 expression increased 1.9-fold and Agrin expression increased 3.4-fold in the TFP group). Additionally, TFP suppressed pro-inflammatory cytokine levels (IL-6 expression decreased by 41.2%, and TNF-α expression decreased by 35.3%, p < 0.05). This study identifies impaired AQP4 polarization as a novel mechanism underlying perioperative glymphatic failure and neuroinflammation. Pharmacological preservation of AQP4 functionality via TFP emerges as a promising therapeutic strategy for POCD mitigation.