Melatonin-Driven NLRP3 Inflammation Inhibition Via Regulation of NF-κB Nucleocytoplasmic Transport: Implications for Postoperative Cognitive Dysfunction

The aseptic inflammatory response of the central nervous system is one of the important causes of neurodegenerative diseases in individuals and is also recognized in postoperative cognitive dysfunction (POCD). Inflammasome is thought to be closely related to brain homeostasis. However, there are few drugs targeting the inflammasome to suppress inflammation in clinical practice. Here, we showed that the neuroinflammatory response mediated by the NLRP3 (NLR family, pyrin domain containing 3) inflammasome was involved in the pathological process of POCD. Melatonin protected mice from nerve damage by inhibiting activation of the NLRP3-caspase-1-interleukin 1 beta (IL-ss) pathway and thus reduced the secretion of IL-1 ss inflammatory factors in microglia. Further research found that melatonin has a potential binding effect with NLRP3 protein, and at the same time could reduce the phosphorylation of nuclear factor kappa-B (NF-kappa B) and inhibit its nuclear translocation. The underlying mechanism was that melatonin inhibited the expression of acetylation of histone H3 and melatonin attenuated the binding of NF-kappa b to the NLRP3 promoter region 1-200 bp, where there are two potential binding target sites of NF-.b and NLRP3, namely the sequences 5 '-GGGAACCCCC-3 ' and 5 '-GGAAATCCA -3 '. Therefore, we confirmed a novel mechanism of action of melatonin in the prevention and treatment of POCD.

Automated summary

The aseptic inflammatory response of the central nervous system is an important cause of neurodegenerative diseases and postoperative cognitive dysfunction (POCD). In this study, we found that the NLRP3 inflammasome-mediated neuroinflammatory response is involved in the pathological process of POCD. Melatonin protects against nerve damage by inhibiting the activation of the NLRP3-caspase-1-IL-1β pathway and reducing IL-1β secretion in microglia.