Melatonin Role in Ameliorating Radiation-induced Skin Damage: From Theory to Practice (A Review of Literature)

Abstract

Normal skin is composed of epidermis and dermis. Skin is susceptible to radiation damage because it is a continuously renewing organ containing rapidly proliferating mature cells. Radiation burn is a damage to the skin or other biological tissues caused by exposure to radiofrequency energy or ionizing radiation. Acute skin reaction is the most frequently occurring side effect of radiation therapy. Generally, any chemical/biological agent given before or at the time of irradiation to prevent or ameliorate damage to normal tissues is called a radioprotector. Melatonin is a highly lipophilic substance that easily penetrates organic membranes and therefore is able to protect important intracellular structures including mitochondria and DNA against oxidative damage directly at the sites where such a kind of damage would occur. Melatonin leads to an increase in the molecular level of some important antioxidative enzymes such as superoxide, dismotase and glutation-peroxidase, and also a reduction in synthetic activity of nitric oxide. There is a large body of evidence which proves the efficacy of Melatonin in ameliorating UV and X ray-induced skin damage. We propose that, in the future, Melatonin would improve the therapeutic ratio in radiation oncology and ameliorate skin damage more effectively when administered in optimal and non-toxic doses.

Keywords: Melatonin; Radiotherapy; Skin Damage; Radiation.

Figure1

Melatonin concentration in proportion with age and time per pg/ml unit [31]

Figure2

Pleiotropic effects of Melatonin in skin cells. Exogenous or endogenously synthesized Melatonin can regulate skin-cell phenotype through an interaction with membrane-bound Melatonin receptors MT1 and MT2 or with nuclear retinoid-acid orphan receptors (RORa). Among phenotypic effects of receptor activation, it is worth noting melanin-synthesis inhibition, DNA repair and overexpression of antioxidative enzymes. Non-receptor actions are mediated through an interaction with intracellular proteins, such as quinone reductase 2 (NQO2) or caldmodulin. Melatonin and its metabolites, represented in this figure by N1-acetyl-N2-formyl-methoxykynuramine (AFMK), act as direct scavengers of reactive oxygen and nitrogen species (ROS and RNS) and help to maintain mitochondrial homeostasis by interacting with cytochrome C or the electron-transport chain. In the skin, intra-, para- and auto-crine actions are envisioned, however, endocrine effects cannot be ruled out entirely. Direct effects are shown by solid lines and multiple reactions and signaling are shown by broken lines [15].

Figure3

Presumed actions of Melatonin as a direct free radical scavenger and as an indirect antioxidant. In this review only the direct detoxification of reactive oxygen and nitrogen species by Melatonin are considered. However, Melatonin also has been shown to have indirect antioxidative actions, through the stimulation of several antioxidative enzymes and the stabilization of membrane fluidity. In both in vitro and in vivo studies, Melatonin reduced free radical damage to lipids, proteins, and DNA. Because of the role of oxidative damage in disease processes, antioxidants, including Melatonin may help to resist the development of various pathophysiologies [17].