REVIEW Open Access Melatonin: its possible role in the management of viral infections-a brief review Michela Silvestri and Giovanni A Rossi * Abstract Melatonin, a versatile molecule, is synthesized by the pineal gland but also by other organs, including gastrointestinal tract, retina, thymus, bone marrow, and by leukocytes. Besides playing an important role in various functions of the body, including sleep and circadian rhythm regulation, melatonin also shows immunoregulatory, free radical scavenger and antioxidant functions. Because of these latter characteristics melatonin has also been found to be effective in fighting viral infections in a variety of experimental animal and in vitro studies. These data suggest a possible therapeutic potential of melatonin in human virus-induced disorders. Keywords: Antioxidant, Inflammation, Encephalitis viruses, Respiratory syncytial virus Introduction Melatonin (N-acetyl-5-methoxytryptamine) is the major neurohormone secreted by the pineal gland [1,2]. Initially, it was reported as a skin lightening agent in amphibians [3,4]. Further investigations showed that other functions of the molecule were the regulation and reset of circadian rhythms with involvement in the measurement of day length, an environmental variable used for seasonal timing of reproduction, metabolism and behavior in animal species [5-7] (Figure 1). Acting virtually in every cell in the organism, melatonin has been reported to possess numerous additional functions, being involved in sleep initiation, vasomotor control, anti-excitatory actions, regulation of mitochondrial functions [8]. Melatonin and its metabolites were found to have also important immunomodulatory and antioxidant properties owing to their direct and indirect antioxidant actions, i.e. by sca- venging free radicals and by upregulating antioxidant pathways [9-12]. Melatonin synthesis in the pineal gland and its metabolism In mammals, melatonin is synthesized in the pineal gland with a rhythm regulated by an endogenous circadian clock, the most important factor regulating its metabolism being the light/dark cycle. Once formed, melatonin is im- mediately released into the cerebrospinal fluid and in the blood, with a half-life in serum varying between less than 30 min to 60 min, and then metabolized in the liver and in the kidney [13]. Melatonin exerts some of its actions via binding to specific receptors and intracellular targets [1,14]. There are two types of specific high affinity membrane-associated melatonin receptors, MT1 and MT2, able to trigger intracellular signaling by adenylate cyclase or G-proteins [1,14]. A third membrane-associated receptor, named MT3, has been described pharmacologi- cally and characterized as the enzyme quinine reductase 2 [15]. This enzyme belongs to a group of reductases that participate in the protection against oxidative stress by preventing electron transfer reactions of quinines. High affinity nuclear receptors to melatonin have also been identified, belonging to the RZR/ROR nuclear hormone receptor family [16]. Additional binding to intracellular targets in the micromolar range, such as the enzymes hydroquinone [17] and calmodulin [18] have been reported, which mediate some of melatonin’ s actions, including protection of the cytoskeletal organization from damage caused by free radicals [19]. In humans, melatonin is secreted rhythmically with low levels during the daylight hours and a peaks during darkness: in normal individuals, blood concentrations begin to rise during the evening, reaching maximum values between 02:00 and 04:00 am, and then return to baseline levels during the late morning [20]. Basal plasma melatonin levels may vary in several physiological conditions: as an example, they are elevated * Correspondence: giovannirossi@ospedale-gaslini.ge.it Pediatric Pulmonology and Allergy Unit, Istituto Giannina Gaslini, Genoa, Italy ITALIAN JOURNAL OF PEDIATRICS © 2013 Silvestri and Rossi; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Silvestri and Rossi Italian Journal of Pediatrics 2013, 39:61 http://www.ijponline.net/content/39/1/61