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

Overview

1. Anesthesia Surgery Center, the First People’s Hospital of Neijiang, Neijiang, Sichuan, 641000, People’s Republic of China
2. Department of Anesthesiology, The Second Clinical College of Chongqing Medical University, Chongqing, People’s Republic of China
3. Yulin City Center for Disease Control and Prevention, Yulin, Guangxi, People’s Republic of China

Abstract

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.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• geo:GSE165798, at NCBI GEO; found in “Data Sharing Statement”

Data Sharing Statement

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. The transcriptomic dataset GSE165798 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE165798) is publicly available in the NCBI Gene Expression Omnibus repository. RT-qPCR primer sequences are provided in Table S1 (http://ttps://www.dovepress.com/article/supplementary_file/627186/627186 Supplementary Material.docx) in the Supplementary Material (http://ttps://www.dovepress.com/article/supplementary_file/627186/627186 Supplementary Material.docx).

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

• Funding: added Health Commission of Sichuan Province; Sichuan Province Science and Technology Support Program

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 6 authors, 6 keywords, 12 MeSH terms, 38 references.

Cite

This paper

Liu, D., Li, G., Huang, H., Yang, Y., Jiang, F., & Zhang, Y. (2026). Esketamine Attenuates Postoperative Neurocognitive Disorder in Aged Mice: Associations with Bioenergetic Remodeling in Hippocampal CD11b-Enriched Cell Fractions and Glycolysis-Related Signaling. Drug design, development and therapy, 20, 627186. https://doi.org/10.2147/dddt.s627186

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.3892/ijmm.2026.5849

miR‑223‑3p promotes microglial lactylation and M1 polarization via the FBXW7/Notch1/Hes1/SIRT1 axis.

Journal: International journal of molecular medicine

In common: Alzheimer's / dementia, cellular / molecular, 3 references

[2] doi:10.2147/ijn.s621038

Protein Lactylation in Central Nervous System Diseases: Molecular Mechanisms and Targeted Therapeutic Strategies.

Journal: International journal of nanomedicine

In common: cellular / molecular, 3 references

[3] doi:10.1016/j.apsb.2026.04.017

PYGL-driven glycogenolysis impairs microglial autophagic flux <i>via</i> SNAP29 <i>O</i>-GlcNAcylation in Alzheimer's disease.

Journal: Acta pharmaceutica Sinica. B

In common: Alzheimer's / dementia, cellular / molecular, 2 references

[4] doi:10.1186/s12974-026-03838-8 [code]

Acarbose modulates microglial Pkm2 acetylation to reshape immunometabolism and preserve retinal neurons after ischemia-reperfusion.

Journal: Journal of neuroinflammation

In common: mouse, cellular / molecular, 2 references

[5] doi:10.1038/s41467-026-74037-5

Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.

Journal: Nature communications

In common: Alzheimer's / dementia, mouse, cellular / molecular, 1 reference

[6] doi:10.1126/sciadv.adx0731 [code]

Targeting glial PD-1/PD-L1 restores microglial homeostasis and reduces neuronal hyperactivity in an Alzheimer's disease model.

Journal: Science advances

In common: Alzheimer's / dementia, mouse, cellular / molecular, 1 reference

[7] doi:10.1038/s41419-026-08791-1

The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.

Journal: Cell death & disease

In common: Alzheimer's / dementia, mouse, cellular / molecular, 1 reference

[8] doi:10.1186/s13195-026-02081-w [code]

Cellular state heterogeneity underlying sex differences in Alzheimer's disease based on single-cell transcriptome.

Journal: Alzheimer's research & therapy

In common: Alzheimer's / dementia, cellular / molecular, 1 reference

[9] doi:10.1186/s12974-026-03796-1 [code]

Tryptophan-kynurenine metabolic reprogramming along the gut-brain axis alleviates Alzheimer's pathology.

Journal: Journal of neuroinflammation

In common: Alzheimer's / dementia, mouse, cellular / molecular, 1 reference

[10] doi:10.1038/s44321-026-00422-8

Hyperglycemia impairs cognitive function by inducing mitochondrial damage through lactylation of LRPPRC at K223.

Journal: EMBO molecular medicine

In common: mouse, cellular / molecular, 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.