Hypoxic-brain injury is a major cause of neonatal morbidity and mortality. However, melatonin (N-acetyl-5-\r\nmethoxytryptamine) has been identified as an indirect anti-oxidant and direct free radical scavenger that could\r\npossibly reduce the injurious effects of hypoxic-ischemic brain injury in neonatal infants. Hypoxia-ischemia leads\r\nto multiple consequences such as an increase in extracellular glutamate. Yet the many mechanisms involved in\r\nmelatonin-induced neuroprotection are still under investigation. We have hypothesized that melatonin could induce\r\nneuroprotection by increasing levels of cystine glutamate exchanger (xCT), an amino acid transporter as shown in\r\nprevious work in our laboratory. Mouse neural stem cells were used for all in vitro studies for western blot analysis.\r\nIn dose-response studies, melatonin increases xCT expression by 2.43 �± 0.81, 3.58 �± 0.6, 3.21 �± 1.13, 3.30 �± 0.96\r\nand 3.48 �± 0.30 (p < 0.01) folds at 1 nM, 10 nM, 100 nM, 1 �µM and 10 �µM concentrations respectively in neural stem\r\ncells. In time-course studies, melatonin increases xCT by 2.60 �± 0.97, 2.65 �± 0.27, 3.29 �± 0.40, and 3.57 �± 0.60 fold\r\nat 4 hours, 8 hours, 12 hours, and 24 hours. Melatonin increases cystine uptake. System Xc inhibition decreased\r\ncell viability. These results suggest that melatonin may induce neuroprotection by increasing xCT expression and\r\nactivity.
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