Inhibition of NLRP3 Inflammasome Alleviates Postoperative Cognitive Impairment by Suppressing the HMGB-1/TLR4/NF-κB Pathway

Abstract

Perioperative neurocognitive disorders (PNDs), main complications of surgery and anesthesia in the elderly, are mainly associated with neuroinflammation and remain poorly understood. This study aimed to explore the function of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in the development of PNDs. Male C57BL/6 mice underwent right carotid artery exposure surgery, with or without treatment with adeno-associated virus vectors carrying NLRP3 (AAV-NLRP3), which was administered either intracerebroventricularly or via tail vein injection. Mouse brain tissue was collected 24 h postoperatively for biochemical assays. Another group of mice was subjected to the Morris water maze and novel object recognition tests to assess their learning and memory abilities. The results revealed that surgery and anesthesia increased NLRP3 protein expression level and programmed cell death in the hippocampus of mice, leading to impaired learning and memory, while AAV-NLRP3 treatment attenuated these effects. Additionally, inhibition of high-mobility group protein box 1 (HMGB-1) expression level alleviated surgery-induced upregulation of Toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), and NLRP3 in the hippocampus of mice. The NLRP3 inflammasome emerged critical for the occurrence of neuroinflammation and postoperative cognitive impairment, which could be alleviated by inhibiting NLRP3 inflammasome via the HMGB-1/TLR4/NF-κB pathway.

Keywords: HMGB-1; Inflammation; NLRP3 inflammasome; Perioperative neurocognitive disorders; Pro-inflammatory cytokines.