The inhibitory effects of class I histone deacetylases on hippocampal neuroinflammatory regulation in aging mice with postoperative cognitive dysfunction

摘要

OBJECTIVE: Neuroinflammation in the hippocampus has been determined to contribute to postoperative cognitive dysfunction (POCD) occurrence in elderly individuals. Histone deacetylases (HDACs) have been identified as important regulators of inflammation. However, the roles of different types of HDACs in POCD have never been fully explored. MATERIALS AND METHODS: POCD mouse models were established using isoflurane and validated by the Morris water maze test. The mice were pretreated with UF010 [a Class I HDAC inhibitor (HDACi)], MC1568 (a Class II HDACi) and SAHA (a Class I and II HDACi) before POCD establishment. HDAC protein levels and the activity of the NF-κB/p65, JAK/STAT and TLR/MyD88 signaling pathways in the hippocampus were investigated by Western blot (WB). The enrichment of HDACs on the promoters of genes was detected using ChIP-qPCR. RESULTS: Class I HDACs, including HDAC2 and HDAC8, and Class II HDACs, including HDAC4, HDAC7 and HDAC10, were all upregulated in the POCD group compared to the control group. Furthermore, compared to the MC1568 pretreatment group and the control group, the groups pretreated with UF010 and SAHA exhibited amelioration of the effects of anesthesia/surgery induced POCD and compromised inflammatory reactions in the hippocampus. Likewise, the NF-κB/p65, JAK/STAT and TLR/MyD88 signaling pathways were inactivated upon pretreatment with UF010 and SAHA compared to MC1568. Finally, the transcription of the genes negatively regulating these three pathways declined, and the enrichment of HDAC1, HDAC2 and HDAC8 was significantly elevated in the context of POCD. CONCLUSIONS: Class I HDACs, especially HDAC1, HDAC2 and HDAC8, play crucial roles in enhancing neuroinflammation in the hippocampus and causing POCD. Class I HDACs are potential therapeutic targets for POCD prevention and treatment via neuroinflammation inhibition.