Esketamine Attenuates Postoperative Neurocognitive Disorder in Aged Mice: Associations with Bioenergetic Remodeling in Hippocampal CD11b-Enriched Cell Fractions and Glycolysis-Related Signaling.

BACKGROUND: Postoperative neurocognitive disorder (PND) is a clinically important complication in older surgical patients. Microglial inflammatory activation is frequently accompanied by altered cellular metabolism, but whether esketamine-associated neuroprotection is accompanied by bioenergetic changes in hippocampal CD11b-enriched cell fractions remains incompletely understood. METHODS: A tibial fracture model was used to induce PND in aged male mice. The public hippocampal transcriptomic dataset GSE165798 was analyzed as an exploratory, hypothesis-generating screen. Independent animal cohorts were evaluated using behavioral testing, whole-hippocampal qRT-PCR and biochemical assays, immunofluorescence, transmission electron microscopy, and Seahorse extracellular flux analysis of hippocampal CD11b-enriched cell fractions. Early hippocampal IL-1β was measured at 24 h in a tissue-analysis cohort. In a separate contemporaneous five-group pharmacological cohort, behavioral outcomes were assessed before hippocampal IL-1β and TNF-α measurement on postoperative day 14. Systemic 2-DG was used as a non-cell-specific pharmacological probe of associations between glycolytic inhibition and selected outcomes. RESULTS: Exploratory transcriptomic analysis suggested coordinated glycolysis-related and inflammatory changes in the PND hippocampus. In independent cohorts, esketamine improved spatial learning and memory, attenuated the early 24-h hippocampal IL-1β elevation, preserved synaptic ultrastructure, and reduced glycolysis-related molecular and biochemical changes measured in whole hippocampal tissue. In hippocampal CD11b-enriched cell fractions collected at 24 h, esketamine was associated with lower glycolytic activity and improved mitochondrial respiratory parameters. In the separate pharmacological cohort, hippocampal IL-1β and TNF-α were measured on day 14 after behavioral testing. Systemic 2-DG was associated with selected behavioral and day-14 cytokine differences relative to untreated PND mice; a contemporaneous Control + 2-DG group was included. In direct comparisons of the esketamine and 2-DG groups, the mean differences were -0.40s for time in the target quadrant (95% CI, -4.35 to 3.55; Tukey-adjusted P = 0.9984), 4.71 pg/mg protein for IL-1β (95% CI, -8.99 to 18.41; Tukey-adjusted P = 0.8588), and 2.38 pg/mg protein for TNF-α (95% CI, -12.69 to 17.45; Tukey-adjusted P = 0.9908). These nonsignificant comparisons neither establish therapeutic equivalence nor demonstrate that glycolytic inhibition mediates the effects of esketamine. CONCLUSION: Esketamine attenuated surgery-induced cognitive impairment, the early 24-h hippocampal IL-1β elevation, and synaptic ultrastructural damage in aged mice. In a separate pharmacological cohort assessed on day 14, esketamine and systemic 2-DG were each associated with lower hippocampal IL-1β and TNF-α than untreated PND. These findings were accompanied, in separate experimental cohorts, by improved bioenergetic profiles in hippocampal CD11b-enriched cell fractions and reduced glycolysis-related markers in whole hippocampal tissue. The data support associations among esketamine treatment, metabolic-inflammatory remodeling, and neuroprotection, but do not establish a microglia-specific HK2/PKM2-dependent mechanism, a causal role for glycolysis, or mechanistic equivalence between esketamine and 2-DG.