N-acetyl-serotonin (normelatonin) and melatonin protect neurons against oxidative challenges and suppress the activity of the transcription factor NF-κB

Abstract: It is now well established that the formation of free radicals and oxidative stress-induced neuronal cell death can be involved in various neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pineal hormone melatonin has been suggested to be a neuroprotective antioxidant. To better understand the molecular mechanism of this activity, we compared the ability of melatonin and its precursor, N-acetyl-serotonin (normelatonin), to protect human neuroblastoma SK-N-MC cells and primary cerebellar granular neurons against oxidative stress. We found that normelatonin and melatonin have differential neuroprotective effects depending on the neuronal cell type. Normelatonin was more protective against hydrogen peroxide (H₂O₂) and glutamate-induced cell death in SK-N-MC cells compared to melatonin which was more effective to protect primary cerebellar granular neurons against the toxicity of H₂O₂, glutamate and N-methyl-D-aspartate when compared to normelatonin. At the molecular level, we tested the capacity of normelatonin and melatonin to inhibit the oxidative stress-induced NF-κB activation in both neuronal systems. Whereas normelatonin was more potent in the suppression of the activation of NF-κB by H₂O₂ in SK-N-MC cells compared to melatonin, no apparent differences in the extent of suppression could be detected in primary neurons. Normelatonin's and melatonin's neuroprotective activity in SK-N-MC neuroblastoma cells may be mediated by the suppression of NF-κB activation.