Esketamine ameliorates postoperative cognitive dysfunction aggravated by preoperative acute sleep deprivation in aged mice via the TLR4/NF-κB pathway.

Abstract

<h4>Introduction</h4>Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients, and preoperative sleep deprivation may exacerbate its severity. Although earlier research has confirmed that esketamine can reduce the incidence of POCD, it remains unclear whether it is effective against POCD exacerbated by preoperative acute sleep deprivation. The present study is designed to examine the protective role and intrinsic mechanisms through which esketamine acts on POCD aggravated by pro operative acute sleep deprivation prior to surgery.<h4>Methods</h4>The modified multiple platform method was employed to induce acute sleep deprivation, and the POCD model was established through left lateral lobectomy of the liver after 48 h of sleep deprivation. Esketamine was administered 30 min postoperatively. The Open Field Test and Morris Water Maze were utilized to assess postoperative cognitive alterations. Hippocampal pathology results were examined via hematoxylin-eosin staining; the concentrations of key inflammatory cytokines, namely interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-<i>α</i> (TNF-α), were determined by enzyme-linked immunosorbent assay; the protein expression was analyzed using Western blotting and immunofluorescence analysis.<h4>Results</h4>Esketamine administration post surgery significantly ameliorated cognitive deficits aggravated by preoperative acute sleep deprivation in aged mice. Concomitantly, esketamine downregulated the expression of TLR4, MyD88, and phosphorylated NF-κB p65 in hippocampal microglia, reduced hippocampal levels of IL-6, IL-1β, and TNF-α, and alleviated hippocampal tissue injury.<h4>Conclusion</h4>Esketamine exerts neuroprotective effects against POCD exacerbated by preoperative acute sleep deprivation in aged mice by inhibiting the TLR4/NF-κB signaling pathway in hippocampal microglia.

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