An acetylated nobiletin derivative alleviates methylglyoxal-induced cognitive impairment and modulates gut microbiota

Nobiletin, a citrus polymethoxyflavone recognized as a functional food component with diverse health benefits, has been reported to exhibit antioxidant, anti-inflammatory and neuroprotective properties. Methylglyoxal (MG), a highly reactive dicarbonyl compound and precursor of advanced glycation end products, contributes to oxidative stress, tau hyperphosphorylation and amyloid-β (Aβ) accumulation, which are key events linking diabetes to Alzheimer's disease. In this study, an acetylated derivative of nobiletin, 5-acetoxy-6,7,8,3',4'-pentamethoxyflavone (5-AN), was evaluated for its neuroprotective and gut microbiota-modulating effects against MG-induced Alzheimer-like cognitive deficits in mice.

Oral administration of 5-AN (10 and 20 mg kg^-1 day^-1 for 13 weeks) improved behavioral performance in MG-treated mice, with the 20 mg kg^-1 group showing significant improvement in spatial learning, recognition memory and anxiety-like behavior. Immunohistochemical and Western blot analyses showed that 5-AN reduced hippocampal tau phosphorylation and Aβ accumulation at the same time as restoring phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β signaling, enhancing brain-derived neurotrophic factor expression and reducing cleaved caspase-3 expression. Gut microbiota analysis showed that MG exposure induced dysbiosis, characterized by reduced Bacteroides_H acidifaciens and increased MG-associated taxa such as Alistipes and Dysosmobacter, whereas 5-AN supplementation significantly reversed these alterations. Functional prediction analysis further indicated that MG-induced dysbiosis was associated with disruptions in neuroimmune-related pathways, including circadian entrainment, Th17 cell differentiation, interleukin-17 signaling and PI3K/Akt signaling, whereas 5-AN supplementation significantly restored these pathways.

These findings indicate that acetylated nobiletin may serve as a promising food-derived bioactive compound for mitigating cognitive impairment through coordinated modulation of neuronal function and gut microbiota. © 2026 Society of Chemical Industry.