Role of P2X4/NLRP3 Pathway-Mediated Neuroinflammation in Perioperative Neurocognitive Disorders.

Several studies have demonstrated that neuroinflammation is the key to perioperative neurocognitive disorders (PND); however, the specific mechanism postsurgery and anesthesia has not yet been fully clarified. The present study is aimed at exploring the effects of P2X4/NLRP3 signaling pathway in neuroinflammation and cognitive impairment after surgery. 12-14-month-old male C57BL/6 mice undergoing open tibial fracture surgery by sevoflurane anesthesia were administered P2X4R inhibitor 5-BDBD or saline was intraperitoneally for 3 consecutive days after surgery. Then, the animals were subjected to Morris water maze test or sacrificed to collect the hippocampus. The level of P2X4R and NLRP3 was estimated by Western blot, the activation of microglia was detected via immunohistochemistry, and the expression of TNF-α, IL-1ß, and IL-6 was quantified by enzyme-linked immunosorbent assay. These results indicated that tibial surgery caused cognitive impairment, increased the expression of P2X4R and NLRP3, and aggravated the neuroinflammation and microglia activation. However, intraperitoneal injection of 5-BDBD attenuated these effects. In conclusion, these findings indicated that the P2X4/NLRP3 pathway might be involved in the pathophysiology of PND.

Pericyte loss impairs the blood-brain barrier and cognitive function in aged mice after anesthesia/surgery.

AIMS: This study was designed to investigate the role of pericytes in the pathogenesis of perioperative neurocognitive disorder (PND). METHODS: In this study, we established a PND model via sevoflurane anesthesia and tibial fracture surgery in 2-month-old and 16-month-old male C57BL/6 mice. On the third postoperative day, the mice were subjected to behavioral testing or sacrificed to collect brain tissue. The progression of hippocampal blood-brain barrier (BBB) disruption and neuroinflammation was detected using transmission electron microscope and immunofluorescence. We also used western blotting to measure the levels of plasma-derived protein immunoglobulin G (IgG) and albumin in the hippocampus to assess the leakage of the BBB. RESULTS: Aged mice did not experience age-related cognitive decline and BBB disruption compared with younger mice but only increased glial cell activity. Anesthesia/Surgery damaged cognitive function, reduced pericyte coverage, decreased the length of capillaries and levels of occludin and claudin-5, destroyed the structure of the BBB, exacerbated IgG and albumin accumulation in the hippocampus, and enhanced the activation of microglia and astrocytes in the hippocampus of aged mice. However, these negative effects did not occur in young mice. CONCLUSION: Our study showed that the loss of pericytes led to increased BBB permeability and neuroinflammation after anesthesia/surgery in aged mice, ultimately resulting in cognitive dysfunction.

Effects of different types of non-cardiac surgical trauma on hippocampus-dependent memory and neuroinflammation.

Background: Older individuals have been reported to suffer from cognitive disorders after surgery. Various types of surgical trauma have been used to establish postoperative cognitive dysfunction (POCD) animal models in preclinical studies. However, few comparative analyses of these animal models were conducted. Methods: Tibial surgery, abdominal surgery, and extended abdominal surgery were performed on aged ICR mice to establish POCD models. Behavioral tests included open field, novel object recognition, fear conditioning, and Morris water maze tests. The Z-score methodology was adopted to obtain a comprehensive and integrated memory performance profile. The changes in hippocampal neuroinflammation were analyzed by ELISA, PCR, and immunofluorescence. Results: In this study, we found that each type of non-cardiac surgical trauma has a different effects on locomotor activity. Tibial and extended abdominal surgeries led to more significant cognitive impairment than abdominal surgery. Inflammatory cytokines peaked on postoperative day 1 and decreased to control levels on days 3 and 7. Hippocampal neuroinflammation indicators between the three surgery types on postoperative day 1 had no statistical differences. Conclusion: Overall, the type and intensity of non-cardiac surgical trauma can affect cognitive behavioral outcomes and central inflammation. The shortcomings and emerging issues of POCD animal research methods need to be further studied and solved.