Role of Different Doses of Ketamine in Postoperative Neurocognitive Function in Aged Mice Undergoing Partial Hepatectomy by Regulating the Bmal1/NMDA/NF-Κb Axis

Abstract

<b><i>Background:</i></b> The current study set out to probe the function of different doses of ketamine in postoperative neurocognitive disorder (PND) in aged mice undergoing partial hepatectomy (PH) with the involvement of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1)/n-methyl-D-aspartate (NMDA)/nuclear factor-kappa B (NF-κB) axis. <b><i>Methods:</i></b> First, aged mice were intraperitoneally injected with different doses of ketamine prior to surgery, followed by hepatic lobectomy. Afterward, mice cognitive function was assessed. In addition, Bmal1 mRNA expression patterns were quantified, while NMDA 2B receptor, NF-κB p65, synapsin 1, and postsynaptic density 95 (PSD95) levels were determined; the release of inflammatory factors was detected, and ionized calcium-binding adapter molecule-1 expression was measured to quantify microglia activation. In addition, Bmal1-knockout (Bmal1-KO) mice were intraperitoneally injected with a subanesthetic dose of ketamine to verify the mechanism of Bmal1 in regulating the NMDA 2B subunit (NR2B)/NF-κB axis to affect PH in aged patients. <b><i>Results:</i></b> After PH, hippocampal-dependent memory was impaired, and synapsin 1 and PSD95 levels were downregulated. On the other hand, PH diminished Bmal1 expression but elevated NR2B and NF-κB p65 levels and anesthetic doses of ketamine further regulated the Bmal1/NMDA/NF-κB axis. In Bmal1-KO mice, the NMDA/NF-κB axis was activated, the release of inflammatory cytokines was promoted, and hippocampus-dependent memory was impaired, which were reversed by a subanesthetic dose of ketamine. <b><i>Conclusion:</i></b> Altogether, findings obtained in our study indicated that a subanesthetic dose of ketamine activated Bmal1, downregulated the NMDA/NF-κB axis, and reduced inflammation and microglia activation to alleviate PND in aged mice undergoing PH.

General anesthesia with S-ketamine improves the early recovery and cognitive function in patients undergoing modified radical mastectomy: a prospective randomized controlled trial

“…Wang et al found [ 23 ] that S-ketamine can reduce the level of inflammatory factors by inhibiting TLR4/NF-κB signaling pathway of microglia cells in the central nervous system of aging mice, improve neuroinflammatory response, and then relieve postoperative cognitive dysfunction. In addition, Niu et al found that [ 24 ] preoperative administration of a subanesthetic dose of ketamine activated Bmal1 mRNA expression and down-regulated the NMDA/NF-κB axis in elderly mice undergoing partial hepatectomy. And reduced inflammation, thereby alleviating postoperative cognitive decline in mice.…”

S-Ketamine Pretreatment Alleviates Anxiety-Like Behaviors and Mechanical Allodynia and Blocks the Pro-inflammatory Response in Striatum and Periaqueductal Gray From a Post-traumatic Stress Disorder Model

“…Consistently, pro-inflammatory cytokines (e.g., TNF-α and IL-1β) and NF-κB were upregulated in those brain regions enriched in activated microglia. Previous study showed that a subanesthetic dose of ketamine could activate Bmal1, downregulate the NMDA-NF-κB signaling pathway, and reduce inflammation and microglia activation in hippocampus to alleviate postoperative neurocognitive disorder (PND) in aged mice undergoing partial hepatectomy (PH) ( Niu et al, 2021 ). So far, there is no report that S-ketamine inhibits microglia activation through NF-κB signaling pathway in SPS model.…”