Environmental enrichment attenuates sevoflurane anesthesia-induced learning deficits in aged mice through regulating TTBK1 and phosphorylated Tau expression.

Perioperative neurocognitive disorders (PND) are a prevalent complication in elderly patients undergoing surgery with general anesthesia. Sevoflurane, a commonly used anesthetic, has been associated with cognitive impairment and neurotoxicity. In this study, we aim to explore the mechanisms through which sevoflurane impairs cognitive function in aged mice and hence identify potential therapeutic strategies. Female C57BL/6 J mice were treated with 2-h-daily Environmental enrichment (EE) for 4 weeks before being exposed to single 3% sevoflurane plus 60% oxygen inhalation for 2 h. WHI-P180, a TTBK1 inhibitor, was administered 5 min prior to anesthesia. Cognitive function, TTBK1, Tau p-Ser422, AT8 (Tau p-Ser202/p-Thr205), TNF-ɑ, IL-6, and IL-1β were measured. The results indicated that sevoflurane inhalation induced cognitive dysfunction, elevated TTBK1 expression and phosphorylated Tau levels, and increased inflammatory factors in the hippocampus of aged mice. However, EE treatment reduced elevated TTBK1, phosphorylated Tau, and inflammatory factor levels in the hippocampus. Additionally, EE alleviated cognitive impairment caused by sevoflurane in aged mice. Furthermore, WHI-P180 mitigated cognitive dysfunction by decreasing Tau phosphorylation and inflammatory cytokine levels in the hippocampus of aged mice. In conclusion, TTBK1 plays a crucial role in cognitive impairment induced by sevoflurane in aged mice, and EE mitigates sevoflurane-induced cognitive dysfunction by inhibiting TTBK1 and Tau protein phosphorylation in the hippocampus of old mice. These findings suggest that EE could be a potential therapeutic strategy for preventing or treating PND in elderly patients undergoing general surgery with sevoflurane anesthesia.