Neuroinflammation in postoperative cognitive dysfunction: the multi-target potential of esketamine in modulating microglial responses and synaptic integrity

Postoperative cognitive dysfunction (POCD) remains a clinically important problem after surgery, particularly in older and neurologically vulnerable patients. Its interpretation is complicated by heterogeneous cognitive definitions and follow-up periods, while the underlying biology appears to involve interacting inflammatory, metabolic, glial, and synaptic disturbances rather than a single pathogenic cascade. Esketamine has therefore attracted interest as a potential perioperative neuroprotective agent, but the strength of evidence differs markedly across the mechanisms proposed to explain its effects. We conducted a structured narrative review with evidence mapping of clinical and experimental studies identified in PubMed/MEDLINE and the Web of Science Core Collection, using a literature cutoff of 1 May 2026. Direct perioperative clinical and preclinical studies were distinguished from non-perioperative esketamine research, ketamine/enantiomer studies, and contextual POCD/PND biology, with greater mechanistic weight assigned to experiments incorporating pathway perturbation or rescue. The direct preclinical literature favors a multi-branch model of esketamine action. Functional evidence supports contributions from TLR4/MyD88–p38 signaling, STING/TBK1-associated inflammatory cell death, and PARP1-related autophagic regulation, while changes in NF-κB signaling, microglial BDNF–TrkB activity, and ROCK2/ADD1-associated synaptic remodeling are supported mainly by convergent molecular and functional findings. NLRP3 remains relevant to postoperative neuroinflammation but has not been established as a required upstream mediator of esketamine action, and proposed effects on the blood–brain barrier, antioxidant pathways, cholinergic signaling, and neurogenesis remain less directly supported in perioperative cognitive models. Clinical findings are less uniform. Some randomized trials suggest reductions in postoperative delirium or early postoperative cognitive decline in selected populations, whereas other adequately designed studies are neutral, and evidence for sustained cognitive protection is limited. Peripheral inflammatory, neuronal-injury, and neurotrophic biomarkers indicate biological activity but do not establish central target engagement or cognitive mediation. Taken together, the current literature supports a biologically plausible, multi-target model for esketamine, but not an established preventive effect against perioperative neurocognitive disorders.