Advanced glycation endproducts (AGEs) accumulate on protein deposits including the beta-amyloid plaques in Alzheimer's disease. AGEs interact with the "receptor for advanced glycation endproducts", and transmit their signals using intracellular reactive oxygen species as second messengers. Ultimately, AGEs induce the expression of a variety of pro-inflammatory markers including the tumor necrosis factor (TNF-alpha) and inducible nitric oxide (NO) synthase. Antioxidants that act intracellularly, including polyphenols, have been shown to scavenge these "signaling" reactive oxygen species, and thus perform in an anti-inflammatory capacity. This study tested the pure compounds apigenin and diosmetin as well as extracts from silymarin, uva ursi (bearberry) and green olive leaf for their ability to attenuate AGE-induced NO and TNF-alpha production. All five tested samples inhibited BSA-AGE-induced NO production in a dose-dependent manner. Apigenin and diosmetin were most potent, and exhibited EC(50) values approximately 10 microM. In contrast, TNF-alpha expression was only reduced by apigenin, diosmetin and silymarin; not by the bearberry and green olive leaf extracts. In addition, the silymarin and bearberry extracts caused significant cell death at concentrations >or=10 microg/mL and >or=50 microg/mL, respectively. In conclusion, we suggest that plant-derived polyphenols might offer therapeutic opportunities to delay the progression of AGE-mediated and receptor for advanced glycation endproducts-mediated neuro-inflammatory diseases including Alzheimer's disease.