Alleviating the NF-κB/NLRP3 pathway-mediated pyroptosis and ameliorating the cognitive function of aged mice post partial hepatectomy by increasing the Bmal1 level via subanesthetic doses of ketamine.

Background: As a non-competitive blocker of the N-methyl-d-aspartate receptor, ketamine is widely used for anesthesia and pain relief in clinical settings. However, certain neurological side effects may appear if it is used for the long term. According to clinical observations, anesthetic doses of ketamine trigger postoperative neurocognitive dysfunction in elderly patients, while subanesthetic doses of ketamine suppress the postoperative neuronal pyroptosis in the hippocampus, ameliorating the cognitive function. There is a certain link between brain and muscle arnt-like 1 (Bmal1) and the postoperative cognitive functions of elderly patients. Meanwhile, the Bmal1 activity can be intensified by subanesthetic doses of ketamine. How subanesthetic doses of ketamine act on the postoperative cognitive functions of elderly patients via Bmal1 is to be further investigated.

Methodology: To expound how different doses of ketamine affect the cognitive functions of 15-month-old mice (No.: C57BL/6) receiving partial hepatectomy (PH), the following assays were conducted: (1) Morris Water Maze tests were made on mice on days1, 3, and 7 post-surgery; (2) histopathological analyses (by Nissl and Tunel staining) as well as western blotting, immunofluorescence, immunohistochemical, and ELISA assays were carried out on the hippocampal tissue samples collected from the mice 3 days post-surgery. Furthermore, to verify the critical role of the Bmal1 gene in the subanesthetic doses of ketamine-based improvement of cognitive function in aged mice post-surgery, the survey on 15-month-old mice (No.: C57BL/6) with inactivated Bmal1 gene was continued. Through the aforementioned assays, the modulation mechanism of subanesthetic doses of ketamine in ameliorating postoperative cognitive functions of aged mice was elucidated.

Results: As revealed through this investigation, subanesthetic doses of ketamine compared with the sham group effectively enhanced mice's memory and learning ability, increased the expression of p-NR2B and BDNF proteins, mitigated neuronal pathologic injuries and neuroinflammation in aged mice post-surgery, upregulated the gene expression of Bmal1, and inhibited the hippocampal neuronal pyroptosis mediated by the NF-κB/NLRP3 signaling pathway. These effects are contrary to those of anesthetic doses of ketamine. Furthermore, for mice with an inactivated Bmal1 gene, injecting subanesthetic doses of ketamine helped to alleviate neuronal pathological injuries and neuroinflammation in the hippocampal tissues, suppress the expression of cytokines pertaining to the NF-κB/NLRP3 signaling pathway, and improve postoperative memory and learning competence of the mice.

Conclusion: Subanesthetic doses of ketamine can elevate the expressed level of Bmal1, dampening the NF-κB/NLRP3 pathway-mediated cell pyroptosis, alleviating neuroinflammation, and improving the postoperative cognitive functions of aged mice. The findings in this study suggest a novel approach to explore using subanesthetic doses of ketamine to ameliorate the cognitive functions of aged patients post-surgery and clinically prevent postoperative neurocognitive disorders.