antioxidants Review Is Melatonin the Cornucopia of the 21st Century? Nadia Ferlazzo, Giulia Andolina, Attilio Cannata, Maria Giovanna Costanzo, Valentina Rizzo, Monica Currò , Riccardo Ientile and Daniela Caccamo * Department of Biomedical Sciences, Dental Sciences, and Morpho-Functional Imaging, Polyclinic Hospital University, Via C. Valeria 1, 98125 Messina, Italy; [email protected] (N.F.); [email protected] (G.A.); [email protected] (A.C.); [email protected] (M.G.C.); [email protected] (V.R.); [email protected] (M.C.); [email protected] (R.I.) * Correspondence: [email protected]; Tel.: +39-090-221-3386 or +39-090-221-3389 Received: 21 September 2020; Accepted: 3 November 2020; Published: 5 November 2020 Abstract: Melatonin, an indoleamine hormone produced and secreted at night by pinealocytes and extra-pineal cells, plays an important role in timing circadian rhythms (24-h internal clock) and regulating the sleep/wake cycle in humans. However, in recent years melatonin has gained much attention mainly because of its demonstrated powerful lipophilic antioxidant and free radical scavenging action. Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. Melatonin-induced signal transduction through melatonin receptors promotes the expression of antioxidant enzymes as well as inflammation-related genes. Melatonin also exerts an immunomodulatory action through the stimulation of high-affinity receptors expressed in immunocompetent cells. Here, we reviewed the efficacy, safety and side effects of melatonin supplementation in treating oxidative stress- and/or inflammation-related disorders, such as obesity, cardiovascular diseases, immune disorders, infectious diseases, cancer, neurodegenerative diseases, as well as osteoporosis and infertility. Keywords: sleep–wake cycle regulation; free radical scavenging; anti-inflammatory action; immunomodulation; bone mass protection; fertility amelioration; anti-obesogenic properties; cardiovascular protection; anti-tumoral activity; neuroprotection 1. Introduction Melatonin is an indoleamine which in mammals is mainly produced by the pineal gland during the night, and is regulated by the hypothalamic suprachiasmatic nuclei and inhibited by light. However, several studies have also shown extra-pineal melatonin synthesis, that is not regulated by circadian cycles, in the gastrointestinal tract, ovaries, lymphocytes, macrophages, retina, and skin [1]. The extra-pineal melatonin production exerts a paracrine or autocrine effect, that superimposes on the neuroendocrine hormone response, mainly working as a local antioxidant [1,2]. Melatonin derives from tryptophan, which is converted to serotonin following hydroxylation and decarboxylation reactions. Serotonin is converted to melatonin in two sequential reactions catalyzed by arylalkylamine-N-acetyl transferase (AANAT) and hydroxy-indole-O-methyltransferase (HIOMT), also known, respectively, as serotonin N-acetyl-transferase (SNAT) and N-acetylserotonin O-methyltransferase (ASMT), with N-acetyl serotonin as intermediate product. Several studies have proposed that mitochondria are the primary sites of melatonin synthesis due to the presence of melatonin-forming enzymes, SNAT and ASMT, and the chaperone protein 14-3-3, that prevents SNAT degradation and increases SNAT affinity for serotonin [3] (Figure1). Antioxidants 2020, 9, 1088; doi:10.3390/antiox9111088 www.mdpi.com/journal/antioxidants Antioxidants 2020, 9, 1088 2 of 29 Antioxidants 2020, 9, x FOR PEER REVIEW 2 of 29 FigureFigure 1. 1.Melatonin Melatonin biosynthesisbiosynthesis andand intracellularintracellular signal-transduction signal-transduction pathways pathways activated activated by by stimulationstimulation of of melatonin melatonin specificspecific receptors. The The picture picture shows: shows: (figure (figure top left top) leftthe )intracerebral the intracerebral site siteof of melatonin melatonin biosynthesis, biosynthesis, that that is isthe the pineal pineal gl gland,and, the the melatonin melatonin biosynthetic biosynthetic pathway, pathway, and and the the influenceinfluence of lightof light and photoperiodand photoperiod change ch onange melatonin on melatonin biosynthesis; biosynthesis; (figure bottom (figure left )bottom mitochondrial left) melatoninmitochondrial biosynthesis melatonin and localbiosynthesis action: melatonin and loca isl synthesizedaction: melatonin within mitochondrial is synthesized matrix, within but it canmitochondrial also enter the matrix, mitochondria but it can also through enter the a specific mitochondria transporter; through melatonin a specific transporter; activates specific melatonin MT1 andactivates MT2 receptors specific MT1 on mitochondrialand MT2 receptors outer on membrane, mitochondrial also outer in an membrane, autocrine also way, in inhibitsan autocrine MPTP andway, ROS inhibits production, MPTP and and ROS stimulates producti ETCon, and and stimulates UCP; (figure ETC and right UCP;) melatonin (figure right interaction) melatonin with itsinteraction specific MT1 with and its specific MT2 receptors MT1 and andMT2 RZR receptors/ROR and orphan RZR/ROR nuclear orphan receptors, nuclear and receptors, activation and of diffactivationerent metabolic of different pathways. metabolic AAAD, pathways. aromatic A L-aminoAAD, aromatic acid decarboxylase; L-amino acid AC,decarboxylase; adenylate cyclase; AC, AFMK,adenylate N1-acetyl-N2-formyl-S-methoxykynuramine cyclase; AFMK, N1-acetyl-N2-formyl-S-methoxykynuramine (melatonin metabolite); (melatonin ASMT, N-acetylserotonin metabolite); O-methyltransferase;ASMT, N-acetylserotonin cAMP, cyclicO-methyltransferase; adenosine monophosphate; cAMP, cyclic cGMP, adenosine cyclic guanosinemonophosphate; monophosphate; cGMP, DAG,cyclic diacylglycerol; guanosine monophosphate; ETC, electron DAG, transfer diacylglycerol; chain; GC, guanylateETC, electron cyclase; transfer IP3, chain; inositol GC, triphosphate; guanylate MPTP,cyclase; mitochondrial IP3, inositol permeabilitytriphosphate; transitionMPTP, mito pore;chondrial MT1-MT3, permeability melatonin transition specific pore; receptor MT1-MT3, 1, 2, 3; PLC,melatonin phospholipase specific receptor C; QR-2, 1, 2, quinone 3; PLC, phospholipase reductase 2; C; ROS, QR-2, reactive quinone oxygen reductase species; 2; ROS, RZRreactive/ROR, retinoidoxygen Z species; receptor RZR/ROR,/retinoid acid retinoid receptor-related Z receptor/retin orphanoid acid receptor; receptor-related SNAT, serotonin orphanN receptor;-acetyltransferase; SNAT, serotonin N-acetyltransferase; TPH, tryptophan hydroxylase; UCP, uncoupling protein. TPH, tryptophan hydroxylase; UCP, uncoupling protein. TheThe lack lack of of SNAT SNAT enzyme enzyme and and the the poor poor availabilityavailability of tryptophan tryptophan are are the the two two limiting limiting factors factors of of thethe melatonin melatonin synthesis synthesis pathway. pathway. The half-life of melatonin ranges from 20 to 40 min, and after its secretion melatonin immediately The half-life of melatonin ranges from 20 to 40 min, and after its secretion melatonin immediately diffuses into the blood and the cerebrospinal fluid (CSF). Due to its lipophilic and hydrophilic diffuses into the blood and the cerebrospinal fluid (CSF). Due to its lipophilic and hydrophilic properties, properties, it diffuses easily through cell membranes and can be detected in other body fluids such it diffuses easily through cell membranes and can be detected in other body fluids such as saliva, milk, as saliva, milk, sperm, amniotic fluid, or as 6-sulfatoxymelatonin (aMT6), the primary melatonin sperm, amniotic fluid, or as 6-sulfatoxymelatonin (aMT6), the primary melatonin metabolite, in urine. metabolite, in urine. The distribution of melatonin in the body is not homogenous. In CSF, the Theconcentration distribution is of higher melatonin than that in the in bodyblood; is however, not homogenous. it is generally In CSF, accepted the concentration that changes in is melatonin higher than thatblood in blood; levels, however, ranging it from is generally few pg/mL accepted during that th changese day into melatonin50–100 pg/mL blood at levels, night, ranging represent from the few pg/variationsmL during of the levels day to 50–100throughout pg/mL the at night,body represent[4]. This thephysiological variations of range levels throughoutof concentrations the body is [ 4]. Thispharmacologically physiological range reached of concentrations by the oral administrati is pharmacologicallyon of 0.1–0.3 reached mg melatonin. by the oral However, administration studies of 0.1–0.3have mginvestigated melatonin. also However, higher doses studies (up to have 10 mg) investigated that are considered also higher supra-physiological, doses (up to 10 mg) reporting that are consideredno toxic effects. supra-physiological, Moreover, the reportingpharmacokinetic no toxic pr eopertiesffects. Moreover, of melatonin the preparations pharmacokinetic can vary properties and Antioxidants 2020, 9, 1088 3 of 29 of melatonin preparations can vary and affect the bioavailability: 1 to 10 mg can raise plasma melatonin levels from 3- to 60-fold its normal peak [5]. Light and photoperiod changes are the key regulators of melatonin synthesis, so that the seasonal changes of temperature and photoperiod significantly affect melatonin production in human body [6]. In recent decades, there has been increased interest in the measurement of melatonin in biological fluid as a marker of circadian phase or to understand