We assessed the neuroprotective effects of quercetin-feeding at doses of 5 and 10 mg/(kg day) on Kunming mice injected daily with D-gal (50 mg/(kg day)) by behavioral tests. Quercetin-fed mice showed higher activity upon induction by new environmental stimuli, lower anxiety and higher novelty-seeking behavior in the open field tasks, and significantly improved learning and memory ability in step-through and Morris water Maze tests compared with D-gal-treated mice. We further investigated the mechanisms involved in the neuroprotective effects of quercetin on mouse brain. Quercetin significantly increased superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) level. These results imply that quercetin can reverse oxidant impairment induced by D-gal in mouse brain. Neurotoxicity is also associated with Ca(2+) overload induced by oxidant stress. Quercetin could maintain the Ca(2+) homeostasis in the brain of D-gal-treated mice. Furthermore, we also examined the expression of growth-associated protein GAP43 mRNA in mouse brain by in situ hybridization. We found that quercetin dramatically elevated the GAP43 mRNA expression in the brain of D-gal-treated mice to regenerate normal function of neurons against the cellular injury caused by D-gal.