Caffeine (1,3,7-trimethylxanthine) consumption reduces the incidence of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. We have previously shown that not only caffeine but also uric acid, which is a final metabolite of caffeine, increase the intracellular glutathione (GSH) levels in the hippocampus that is due to promotion of cysteine uptake into neurons (Neuroscience 2011). In our recent study, paraxanthine (1,7-dimethylxanthine), a major metabolite of caffeine also increased cysteine uptake in mouse hippocampus slices. In this presentation, we focused on the effect of caffeine metabolites on the cysteine uptake and the GSH levels in mouse hippocampal neurons. We analyzed the cysteine and GSH levels in hippocampal neurons after an intraperitoneal injection of 10 mg/kg caffeine, uric acid or paraxanthine into C57BL/6 mice. The cysteine and GSH contents of the tissues were quantitated by HPLC-fluorescence detection and the GSH levels in neuronal cells in hippocampal slices were detected by CMFDA staining. We show that caffeine and its metabolites promote cysteine uptake leading to the increased GSH levels in hippocampal neurons.