Purine derivatives, including caffeine and uric acid, exhibit neuroprotective properties that mitigate the risk of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Our previous research has demonstrated the facilitated cysteine uptake in hippocampal slices by caffeine, uric acid, and paraxanthine. Consistently, we have established that uric acid and paraxanthine promote cysteine uptake and intracellular glutathione synthesis in HEK293 cells.
　This current investigation focused on elucidating the role of the cysteine transporter, excitatory amino acid carrier-1 (EAAC1), in mediating paraxanthine-induced cysteine uptake. In SH-SY5Y cells, the inhibition of EAAC1 using L-aspartic acid beta-hydroxamate resulted in a reduction of paraxanthine-induced cysteine uptake. Subsequently, we evaluated the neuroprotective effect against oxidative stress. Treatment with paraxanthine at concentrations of 10 and 100 mM did not show any cytotoxicity, but inhibited cell death induced by 150 mM H₂O₂ after a 20-hour exposure in SH-SY5Y cells.
　Based on these findings, it might be suggested that paraxanthine facilitates cysteine uptake through EAAC1 and provides neuroprotection against oxidative stress.