To explore the mechanisms by which chronic fluorosis damages the brain, we determined the levels of the advanced glycation end-products (AGEs), the receptor for AGE (RAGE), NADPH oxidase-2 (NOX 2 ), reactive oxygen species (ROS) and malondialdehyde (MDA) in the brains of rats and/or SH-SY5Y cells exposed to different levels of sodium fluoride (5 or 50 ppm in the drinking water for 3 or 6 months and in the incubation medium for as long as 48 h, respectively). The levels of AGEs, RAGE and NOX 2 protein and mRNA were measured by an Elisa assay, Western blotting and real-time PCR, respectively. The ROS content was assessed by fluorescein staining and MDA by thiobarbituric acid-reactive substance assay. In comparison to the unexposed controls, the protein and mRNA levels of AGEs, RAGE and NOX 2 in the brains of rats after 6 months of exposure and in SH-SY5Y cells following high-dose exposure to fluoride were elevated. In contrast, no significant changes in these parameters were detected in the rats exposed for 3 months. In addition, the levels of ROS and MDA in the SH-SY5Y cells exposed to high-dose of fluoride were elevated in a manner that correlated positively with the levels of AGE/RAGE. In conclusion, our present results indicate that excessive fluoride can activate the AGE/RAGE pathway, which might in turn enhance oxidative stress. [ABSTRACT FROM AUTHOR]