Ketamine ameliorates postpartum depression-like behaviors in rats exposed to sevoflurane during pregnancy through the AMPK/SIRT1/NLRP3 pathway.

Abstract

General anesthetics can exert significant adverse effects on the central nervous system. This study aimed to investigate whether repeated exposure to sevoflurane induces depression-like behaviors in postpartum rats. Pregnant rats were exposed to 3% sevoflurane for 2 h on gestational days 13-15. Emotional behaviors were assessed on postpartum days 1, 7, 14, and 21. Hippocampal protein levels associated with the AMPK/SIRT1/NLRP3 signaling pathway were analyzed by Western blotting. Microglial activation and inflammasome expression were analyzed by immunofluorescence, and cytokine levels (IL-1β, IL-18, TNF-α) by ELISA. To explore the role of the AMPK/SIRT1/NLRP3 pathway and neuroinflammation in postpartum maternal depression, rats were treated with AICAR (an AMPK agonist), MCC950 (an NLRP3 antagonist), and minocycline (a microglial activation inhibitor). Additionally, ketamine, with or without dorsomorphin (an AMPK antagonist), was administered to assess whether ketamine's antidepressant effects are mediated through this pathway. Sevoflurane-exposed rats exhibited behavioral impairments on postpartum day 1, including increased immobility in the forced swim test, prolonged feeding latency, reduced food consumption in the novelty-suppressed feeding test, and decreased movement in the open field test. These behaviors were accompanied by decreased AMPK/SIRT1 expression, NLRP3 inflammasome activation, and microglial activation in the hippocampus, resulting in significant inflammatory cytokine release. Treatment with AICAR, MCC950, minocycline, or ketamine alleviated these effects, while dorsomorphin reversed the antidepressant effects of ketamine. Our findings indicate that repeated sevoflurane exposure during mid-gestation induces depression-like behaviors in postpartum rats, and that ketamine alleviates these behaviors by reducing microglial neuroinflammation and NLRP3 inflammasome activation via the AMPK/SIRT1 signaling pathway.