Safflower yellow investigates AMPK/mTOR-mediated autophagy to mitigate sevoflurane-induced neuroinflammation and cognitive dysfunction

Background Perioperative neurocognitive disorders, including postoperative cognitive dysfunction (POCD), remain clinically important after surgery and anesthesia. This study evaluated the prophylactic neuroprotective effects of safflower yellow (SY) in a rat model of sevoflurane-induced cognitive impairment and investigated the involvement of AMPK/mTOR-regulated autophagy. Methods Aged male Sprague-Dawley rats were pretreated with SY before a single 2-h exposure to 3% sevoflurane. Cognitive function, hippocampal inflammatory cytokines, neurotrophic factors, neurotransmitter-related markers, and AMPK/mTOR-autophagy signaling were evaluated. Compound C was used for pharmacological AMPK inhibition with behavioral, inflammatory, and molecular assessment. In HT22 cells, autophagic flux was examined using bafilomycin A1-sensitive LC3-II turnover, and AMPK dependence was further assessed by siRNA-mediated AMPKα knockdown. Results SY pretreatment improved learning and memory, reduced hippocampal amyloid-β and pro-inflammatory cytokines, increased BDNF/TrkB and neurotransmitter-related markers, increased LC3-II/LC3-I and Beclin-1, reduced p62, increased p-AMPK/AMPK, and decreased p-mTOR/mTOR. Compound C attenuated the SY-associated improvements in cognitive performance, neuroinflammation, and AMPK/mTOR-autophagy signaling. In HT22 cells, SY increased bafilomycin A1-sensitive LC3-II accumulation, supporting enhanced autophagic flux. AMPKα knockdown significantly attenuated the SY-associated regulation of p-mTOR/mTOR, LC3-II/LC3-I, Beclin-1, and p62. Conclusion SY pretreatment mitigates sevoflurane-induced cognitive impairment and neuroinflammation and is associated with AMPK/mTOR-regulated autophagy. Pharmacological inhibition, autophagic-flux assessment, and AMPKα knockdown collectively support involvement of this pathway. These findings apply to a preventive anesthesia-only model and require validation in surgical settings.