Review
Melatonin in the skin: synthesis, metabolism and functions

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Melatonin, a ubiquitous methoxyindole, is produced by and metabolized in the skin. Melatonin affects skin functions and structures through actions mediated by cell-surface and putative-nuclear receptors expressed in skin cells. Melatonin has both receptor-dependent and receptor-independent effects that protect against oxidative stress and can attenuate ultraviolet radiation-induced damage. The widespread expression and pleiotropic activity of the cutaneous melatoninergic system provides for a high level of cell-specific selectivity. Moreover, intra-, auto- and para-crine mechanisms equip this system with exquisite functional selectivity. The properties of endogenous melatonin suggest that this molecule is an important effector of stress responses in the skin. In this way, melatonin actions may counteract or buffer both environmental and endogenous stressors to maintain skin integrity.

Introduction

The strategic location of the skin as a key barrier between the environment and the internal milieu renders it a crucial instrument of preserving body homeostasis, yet also exposes it to numerous pathological agents, processes and events. Thus, the capability to locally recognize, discriminate and integrate specific signals within a highly heterogeneous environment and to launch appropriate responses immediately is a vital property of the skin [1]. These skin functions are integrated into the skin immune, pigmentary, epidermal and adnexal systems and are in continuous communication with the central immune, neural and endocrine signaling systems 1, 2, 3, 4, 5.

Coordination among these local and systemic responses is mediated by the skin neuroendocrine system 1, 2, which uses local equivalents of the hypothalamo–pituitary–adrenal axis, catecholaminergic, cholinergic, steroidogenic and secosteroidogenic systems. Given their common embryonal origins, it is not surprising that the skin shares numerous mediators with the CNS and endocrine system. Recent research has revealed that mammalian skin also harbors a complex melatoninergic system, whose role in the maintenance of cutaneous homeostasis is explored here. Unlike the pineal melatoninergic system, its intracutaneous counterpart is exposed directly to numerous environmental stressors, such as ultraviolet radiation (UVR), the importance of which is reviewed here.

Section snippets

Melatonin biology in a nutshell

Melatonin was isolated from bovine pineal gland almost 50 years ago and was shown to exhibit skin-lightening properties. Its structure was defined as N-acetyl-5-methoxytryptamine [6] (Figure 1). Melatonin is found widely in Nature, where it can be detected in vertebrates, invertebrates, plants, unicellular eukaryotes, algae and even bacteria 7, 8, 9. Melatonin is distributed ubiquitously throughout an organism because its small size and amphiphilic nature facilitate permeability to all cellular

Therapeutic perspectives

A central question in clinical dermatology presently is whether these reported effects of melatonin can be exploited therapeutically, either as a general ‘skin survival factor’ with antigenotoxic properties or as a ‘guardian’ of genome and mitochondrial DNA integrity 18, 36. Of note, melatonin use is not regulated in the USA (i.e. it does not require US FDA approval), having been explored for the treatment of androgenic alopecia [52] and as a component of sunscreens [68]. Melatonin might be

Conclusions

Melatonin and its metabolites are likely to be significant in the local regulatory systems that preserve the physical and functional integrity of the skin. Thus, when activated by environmental stressors or internal dyshomeostatic stimuli, local skin responses are envisaged to counteract or buffer the stressor by recruiting melatonin and its metabolites. In such an intracutaneous stress-response system, melatonin could have an important role through intra-, auto- or para-crine mechanisms. An

Acknowledgements

The paper is dedicated to the memory of Aaron Lerner. Specific reference to many of the excellent original papers not included, because of space restrictions, are, however, cited in comprehensive reviews listed in the reference section.

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