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      Melatonin: Pharmacology, Functions and Therapeutic Benefits

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          Abstract

          Abstract: Background: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock.

          Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed.

          Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects.

          Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.

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          Most cited references129

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          ISOLATION OF MELATONIN, THE PINEAL GLAND FACTOR THAT LIGHTENS MELANOCYTES1

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            The basic physiology and pathophysiology of melatonin.

            Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body physiology. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas in field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlative observations, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions could depend on the melatonin signal, for instance immune, antioxidative defences, hemostasis and glucose regulation. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where the melatonin secretion can be disturbed. The resulting alteration could increase predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder.
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              MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective.

              Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein-coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.
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                Author and article information

                Journal
                Curr Neuropharmacol
                Curr Neuropharmacol
                CN
                Current Neuropharmacology
                Bentham Science Publishers
                1570-159X
                1875-6190
                April 2017
                April 2017
                : 15
                : 3
                : 434-443
                Affiliations
                [1 ]Hospital-University Department of Child and Adolescent Psychiatry, Guillaume Régnier Hospital, Rennes 1 University, Rennes 35000, France;
                [2 ]Laboratory of Psychology of Perception, CNRS UMR 8158, Paris 75270, France;
                [3 ]Child and Adolescent Psychiatry Department, Robert Debré Hospital, Paris 7 University, Paris 75019, France;
                [4 ]Inserm CIC 1414 Clinical Investigation Centre, University Hospital, Rennes 1 University, Rennes 35033, France;
                [5 ]Department of Clinical Pharmacology, University Hospital, Rennes 1 University, Rennes 35033, France;
                [6 ]Unité de recherche clinique Pierre Deniker du Centre Hospitalier Henri Laborit, INSERM CIC-P 1402, Poitiers 86022, France;
                [7 ]INSERM U 1084 Laboratoire expérimental et clinique en Neurosciences, University of Poitiers, Poitiers 86022, France
                Author notes
                [* ]Address correspondence to this author at the Hospital-University Department of Child and Adolescent Psychiatry, Guillaume Régnier Hospital, Rennes 1 University, Rennes 35000, France; Tel: +33-6-15-38-07-48; Fax: +33-2-99-64-18-07; E-mail: s.tordjman@ 123456yahoo.fr .
                Article
                CN-15-434
                10.2174/1570159X14666161228122115
                5405617
                28503116
                ff136364-23fe-4921-9c6c-73d2ae4f64e9
                © 2017 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 21 September 2016
                : 13 November 2016
                : 27 December 2016
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                adaptation to external and internal environment,biological clocks,biomarker,clinical application,central and peripheral oscillators,melatonin,prevention and treatment,sleep-wake rhythm,synchronizer

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