SIRT1 Downregulation Contributes to Surgery-Induced Cognitive Impairment Through Autophagy-Mediated NLRP3 Inflammasome Activation in the Hippocampi of Aged Mice

Abstract Postoperative cognitive dysfunction (POCD) is characteristic of cognitive dysfunction in older people following anesthesia and surgery. There has remained a lack of clinical measures for effective prevention and treatment. Recent studies have shown that Sirtuin 1 (SIRT1), autophagy, and the NOD-like receptor protein 3 (NLRP3) inflammasomes are closely associated with the development of neurodegeneration. However, the relationship among SIRT1, autophagy, and NLRP3 inflammasome in microglial activation during POCD development remains largely unclear. In this study, eighteen-month-old C57BL/6 mice underwent splenectomy for POCD model construction under sevoflurane anesthesia. Some mice received the SIRT1-specific agonist SRT1720, others received SRT1720 and the autophagy blocker 3-MA or vehicle intraperitoneal injection only. Behavioral studies were performed on the first, third, and seventh after surgery using the Morris water maze, respectively. Quantitative RT-PCR, Western blots, and ELISAs were used to assess the expression of target genes at the transcriptional and translational levels. Our data indicate that surgery-induced cognitive impairments were associated with significant increases in Interleukin-1β (IL-1β), TNF-α, NLRP3, apoptosis-associated speck-like protein containing a CARD(ASC), cleaved caspase-1. Enhancement of SIRT1 expression can upregulate the level of autophagy to inhibit the activation of inflammasomes and thus improve postoperative cognition in aged mice.