Loganin alleviates sevoflurane-induced cognitive dysfunction and neuroinflammation in aged mice via modulation of SIRT1/NF-κB signaling pathway.

Sevoflurane, a commonly used inhalational anesthetic, is implicated in neuroinflammation and postoperative cognitive dysfunction (POCD) pathogenesis. This study investigated the neuroprotective potential of loganin, a principal iridoid glycoside from Cornus officinalis, against sevoflurane-induced cognitive impairment in aged mice. An aged mouse POCD model was established by exposing 18-month-old C57BL/6 J mice to 3% sevoflurane. Cognitive and motor functions were assessed using the Morris water maze and open field tests. Hippocampal neuronal integrity, microglial activation, and neuroinflammation were evaluated via Nissl staining, immunofluorescence, and molecular analyses. Complementary in vitro studies employed primary hippocampal neuron cultures and a microglia-neuron transwell co-culture system. Neuronal viability, apoptosis, inflammatory responses, and the SIRT1/NF-κB signaling pathway were investigated using CCK-8, flow cytometry, ELISA, and Western blot. Loganin pretreatment significantly improved spatial learning and memory in sevoflurane-exposed aged mice. It attenuated sevoflurane-induced neuronal loss in the hippocampus, suppressed microglial activation, and reduced levels of hippocampal pro-inflammatory cytokines. Mechanistically, loganin reversed the sevoflurane-induced downregulation of SIRT1 and activation of NF-κB in vivo. In vitro, loganin directly protected neurons via the SIRT1/NF-κB pathway, an effect blocked by the SIRT1 inhibitor EX-527. Moreover, the microglia-neuron co-culture experiment demonstrated that loganin's neuroprotection is also mediated by its direct action on microglia: it suppressed sevoflurane-induced dysregulation of the SIRT1/NF-κB pathway and cytokine secretion, which in turn preserved neuronal viability and reduced apoptosis. This microglia-mediated protection was similarly abolished by EX-527. Our findings demonstrate that loganin effectively ameliorates sevoflurane-induced cognitive impairment in aged mice. It confers neuroprotection by by activating SIRT1 and subsequently inhibiting NF-κB signaling in hippocampal neurons, and by suppressing microglial activation and neuroinflammation via the same SIRT1/NF-κB axis.