• Peng Fang, Chang Chen, Feng Zheng, Junke Jia, Ting Chen, Jinpiao Zhu, Jing Chang, and Zongze Zhang.
• Department of Anaesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China; Department of Anaesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
• Brain Res. Bull. 2021 Jul 1; 172: 79-88.

AbstractAge-related cognitive impairment is associated with diminished autophagy and progressively increased neuroinflammation. Histone acetylation has been shown to be a key process in sevoflurane-induced neurobehavioral abnormalities. Here, we investigated whether histone acetylation regulates the interaction between autophagy and the NLRP3 inflammasome in models of sevoflurane-induced cognitive impairment and explored the underlying molecular mechanisms. Aged C57BL/6 J mice and cultured primary hippocampal neurons were exposed to 3% sevoflurane for 2 h. Hippocampal tissue samples and hippocampal neurons were harvested. The processes of histone acetylation and autophagy and the activation of the NLRP3 inflammasome were observed using western blotting, immunofluorescence staining, and transmission electron microscopy. Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases, increased histone H3 and H4 acetylation in both the mouse hippocampus and primary neurons. Concomitantly, sevoflurane upregulated components of the NLRP3 inflammasome (NLRP3, cleaved caspase-1, and IL-1β) by promoting autophagic degradation in the aging brain. Cognitive deficits and inadequate autophagy induced by sevoflurane were reversed and NLRP3 inflammasome activation was inhibited by SAHA. Treatment with 3-MA, an autophagy inhibitor, eliminated the neuroprotective effects of SAHA on improving cognition in mice, activating autophagy and downregulating the NLRP3 inflammasome. Based on these results, histone acetylation activates autophagy plays an important role in inhibiting the activation of the NLRP3 inflammasome to protect the host from excessive neuroinflammation and sevoflurane-induced cognitive dysfunction in the aging brain.Copyright © 2021 Elsevier Inc. All rights reserved.

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