Abstract / Summary
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.