Background: High-fat diet (HFD) induces neuroinflammation and oxidative stress, leading to cerebral injury and cognitive decline. Propofol, an intravenous anesthetic, exhibits anti-inflammatory and antioxidant effects. The present study aimed to evaluate its neuroprotective role in HFD-induced brain injury and to explore whether these effects may be associated with regulation of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway.

Methods: Rats were assigned to normal diet (ND), HFD, HFD+low-dose propofol, and HFD+high-dose propofol groups. After intervention, cognitive function was tested using the Morris water maze. Brain histopathology, apoptosis, inflammatory cytokines, oxidative stress markers, and protein expression related to apoptosis, autophagy, and AMPK/mTOR signaling were analyzed.

Results: HFD-fed rats exhibited impaired learning and memory performance, neuronal damage and apoptosis, increased levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA), as well as reduced superoxide dismutase (SOD) activity and glutathione (GSH) levels (all p < 0.05), accompanied by autophagy dysregulation characterized by LC3-II accumulation and p62 upregulation, along with suppression of AMPK with activation of mTOR (p < 0.05). Propofol treatment, particularly at the higher dose, significantly improved cognitive function, attenuated neuronal injury and apoptosis, reduced inflammatory and oxidative stress markers, restored autophagy-related alterations, which were accompanied by enhanced AMPK activation and inhibited mTOR signaling (p < 0.05).

Conclusion: Propofol alleviates HFD-induced neuroinflammation, oxidative stress, apoptosis, and autophagy-related alterations, which may be associated with modulation of the AMPK/mTOR signaling pathway, supporting its potential as a therapeutic strategy for metabolic-associated neurological disorders.