Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways

Abstract

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Irradiation of cultured human melanocytes with UVB stimulated ROS production, which was reduced in cells treated with melatonin or its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT). Melatonin and its derivatives also stimulated the expression of NRF2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) and its target enzymes and proteins that play an important role in cell protection from different damaging factors including UVB. Silencing of NRF2 using siRNA diminished the protective effects of melatonin, while the membrane melatonin receptors (MT1 or MT2) did not change the activities of either melatonin or its derivatives. Melatonin and its metabolites enhanced the DNA repair in melanocytes exposed to UVB and stimulated expression of p53 phosphorylated at Ser-15. In conclusion, melatonin and its metabolites protect melanocytes from UVB-induced DNA damage and oxidative stress through activation of NRF2-dependent pathways; these actions are independent of an effect on the classic membrane melatonin receptors. Thus, melatonin and its derivatives can serve as excellent protectors of melanocytes against UVB-induced pathology.

Melatonin, mitochondria, and the skin

“…Similar effect was observed for keratinocytes, melanocytes, and dermal fibroblasts in culture [33, 55, 56]. Furthermore, melatonin derivative AMK was found to be potent singlet oxygen scavenger [57].…”

“…We have reported protective effects of melatonin and its metabolites: 6-hydroxymelatonin, AFMK, N -acetyl-serotonin, and 5-methoxytryptamine in reducing oxidative cell damage in human skin cells: keratinocytes and melanocytes, elicited by UVB [55, 56]. Pharmacological doses of melatonin and its derivatives protect both type of cells, keratinocytes and melanocytes, from UVB-induced oxidative stress.…”

“…The formation of intracellular ROS, including nitric monoxide (NO - ) and H 2 O 2 , in cells exposed to UVB is significantly reduced when cells were pretreated with either melatonin or its metabolites. Interestingly, this process is independent of membrane bound melatonin receptors, as shown in melanocytes [55]. …”

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

“…It acts as an antioxidant by reducing oxidative stress and increasing the activity of antioxidant enzymes in the body [20]. Melatonin protects melanocytes from DNA damage and oxidative stress through activation of NRF2 and its target enzymes [21]. It is well reported that melatonin can ameliorate ischaemic brain injury, preserve the functional integrity of the blood-brain barrier, and induce neurogenesis and cell proliferation through a receptor-dependent mechanism [22].…”

Nrf2 Activation by SK-119 Attenuates Oxidative Stress, UVB, and LPS-Induced Damage

“…In contrast, it was shown that UVB-induced damage is mediated almost solely by ROS generation in the skin [30, 31]. In addition, several publications reported that UV radiation can be attenuated by activating the Nrf2 signaling pathway [32-36].…”