ArticleMolecular neurobiology2025
Trifluoperazine improves postoperative cognition by influencing astrocyte endfoot morphology and aquaporin-4 polarity.
Article in Molecular neurobiology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Surgical and anesthetic rewiring of the glymphatic system in postoperative cognitive dysfunction.Neural regeneration research · 2026Article
- Glymphatic system impairment in neurological disorders: potential mechanisms and therapeutic targets.Molecular biomedicine · 2026Review
- Astrocyte-blood-brain barrier crosstalk in cerebral small vessel disease: linking barrier dysfunction to neurovascular failure.Frontiers in neurology · 2026Review
- Glymphatic-meningeal lymphatic system imbalance: a peripheral-to-central inflammatory bridge in perioperative neurocognitive disorders.Frontiers in immunology · 2026Review
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Authors and funding
7 authors.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.