Journal Article

Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats

Zhou, Junjie, Zhu, Zhaoqiong, Zhang, Chao, Zhang, Xiaoxi, Fang, Xu, Zhang, Naixin

2023

Overview

Aims/introduction As a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats. Method Before the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze. Results We found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1β and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury. Conclusions The activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Abdomen / Aged / Aging / Anesthesia / Animal cognition / Animal Models / Animals / Attention / Autophagy / Autophagy (Cytology) / Biomedical and Life Sciences / Biomedicine / Care and treatment / Carrier Proteins / Caspase-1 / Cognition disorders / Cognitive ability / Cognitive Dysfunction - chemically induced / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - metabolism / Complications / Complications and side effects / Cytokines - metabolism / D-Galactose / Elderly rat / Experiments / Galactose / Gene expression / Geriatrics / Health aspects / Inflammasomes / Inflammasomes - metabolism / Inflammation / Inhalation / Interleukin 18 / Medical research / Memory / Microglia / Nervous system / Neurobiology / Neurological research / Neurosciences / Neurotoxicity / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / NLRP3 / Nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome / Oligomerization / Polymerase chain reaction / Prefrontal cortex / Rapamycin / Rats / Sevoflurane / Sevoflurane - pharmacology / Short term memory / Surgery / Tumor necrosis factor-TNF