New approach in photoprotection: alpha-Melanotropin (αMSH) analogs

Abstract

αMSH is a product of Proopiomelanocortin (POMC) enzymatic cleavage and is well known to promote eumelanogenesis through the activation of a specific G-protein-coupled receptor, MC1R, the stimulation of adenylyl cyclase and the increase of melanosomal tyrosinase activity. Since long, it has been shown that Eumelanins protect epidermic cells by acting as direct free radical scavengers; and also because they are contained in eumelanosomes, by caping the keratinocyte nucleus. On the other hand, mutated-loss-of-function MC1R receptor variants are related to a pheomelanotic phenotype that confers an increased risk for melanoma. Epidermal melanocytes and keratinocytes respond to UV exposure by increasing their MSH content, which up-regulates the expression and function of MC1R and consequently enhances melanocyte responses to melanocortins. Stimulation of p53 in keratinocytes by UV increases the expression of the POMC gene, leading to the release of MSH, the stimulation of MC1R function in neighboring melanocytes and the promotion of eumelanin synthesis. UV radiation induces DNA damage through the generation of free radicals. Interestingly, MSH is able not only to increase the activity of DNA repair enzymes but also can oppose oxidative stress by favoring different reducing steps within this pathway. Interestingly, these protective effects are also reproduced by MSH analogs and, consequently, they can be considered as potent protectors against cellular UV damage. In this context, the outcome of studies using MSH analogs in various clinical trials is eagerly awaited.