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-kappaB activation in both neuronal systems. Whereas normelatonin was more potent in the suppression of the activation of NF-kappaB 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-kappaB activation.

Melatonin regulation of antioxidant enzyme gene expression

“…NF-kB activation is one of the most important redox-sensitive transcription factors and plays an essential role in gene expression of MnSOD [24]. Since MLT has been reported to regulate NF-kB activation [25], the role of these factors as mediators of MLT action on AOEs should therefore be investigated. An increase in mRNA levels may be due to an increase in the rate of transcription or an increase in mRNA half-life stability.…”

Melatonin and the aging brain

“…For example, a-tocopherol treatment of humans in the DATATOP study for mitigation of Parkinson's disease (PD) revealed that even after many months of ingestion, levels of this vitamin were not equilibrated within the cerebrospinal fluid, and still rising (Vatassery et al, 1998). In addition, melatonin is potentially of specific value to the CNS where it is able to induce antioxidant genes (Kotler et al, 1998) and to attenuate the LPS (lipopolysaccharide)-induced inflammatory responses (Sewerynek et al, 1995;Lezoualch et al, 1998;Sharman et al, 2002a,b). Melatonin has also been reported to ameliorate indices of anxiety induced by LPS (Nava and Carta, 2001).…”

The melatonin immunomodulatory actions in radiotherapy

“…Thus, the inhibition of one of these transcription factors with selective inhibitors is not sufficient for managing the upregulation of these cytokines following exposure to radiation (Linard et al 2004). Melatonin has an inhibitory effect on the NF-κB gene expression in stress situations such as irradiation (Lezoualc'h et al 1998;Mohan et al 1995). Modulation of functional retinoidrelated orphan receptor-α (ROR-α) transcription factor is involved in this effect (García et al 2015).…”