Effects of Hydroxytyrosol at graded doses on neuroinflammation and the NF-κB pathway are associated with ameliorated cognitive decline in a rat model of chronic cerebral hypoperfusion

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a key factor in vascular cognitive impairment, and persistent neuroinflammation plays a central role in its development. Studies suggested that the Mediterranean diet, which features extra virgin olive oil (EVOO) as the primary source of fat, can significantly improve cognitive function. Hydroxytyrosol (HT), a polyphenol found in EVOO, plays a crucial role in protecting cognitive function. The present study aims to investigate the effects of HT on cognition in CCH rats and the underlying mechanisms. METHODS: The rat CCH model was established by permanent bilateral common carotid artery ligation. Dl-3-n-butylphthalide (NBP) served as the positive control. HT was administered at three dose levels. Cognitive function was assessed and pathological changes in the hippocampus were examined. Levels of apoptosis, neuroinflammation, and myeloid differentiation primary response 88 (MyD88) /NF-κB pathway activity were evaluated via immunofluorescence, enzyme-linked immunosorbent assay, and western blotting. RESULTS: CCH induced cognitive impairment and increased hippocampal neuronal apoptosis, as well as neuroinflammation and activation of the MyD88/NF-κB pathway in rats. These effects were partially reversed by supplementation with NBP or HT. Notably, the medium dose of HT produced the most favorable results, while the high dose did not demonstrate superior efficacy. CONCLUSIONS: HT treatment is associated with reduced neuroinflammation and inhibition of the MyD88/NF-κB pathway, which may contribute to the alleviation of CCH-induced cognitive impairment. The optimal effect is observed at the medium dose rather than the high dose.