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      Melatonin: Countering Chaotic Time Cues

      research-article
      *
      Frontiers in Endocrinology
      Frontiers Media S.A.
      melatonin, circadian, seasonal, health, sleep, light, desynchrony

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          Abstract

          Last year melatonin was 60 years old, or at least its discovery was 60 years ago. The molecule itself may well be almost as old as life itself. So it is time to take yet another perspective on our understanding of its functions, effects and clinical uses. This is not a formal review—there is already a multitude of systematic reviews, narrative reviews, meta-analyses and even reviews of reviews. In view of the extraordinary variety of effects attributed to melatonin in the last 25 years, it is more of an attempt to sort out some areas where a consensus opinion exists, and where placebo controlled, randomized, clinical trials have confirmed early observations on therapeutic uses. The current upsurge of concern about the multiple health problems associated with disturbed circadian rhythms has generated interest in related therapeutic interventions, of which melatonin is one. The present text will consider the physiological role of endogenous melatonin, and the mostly pharmacological effects of exogenous treatment, on the assumption that normal circulating concentrations represent endogenous pineal production. It will concentrate mainly on the most researched, and accepted area of therapeutic use and potential use of melatonin—its undoubted ability to realign circadian rhythms and sleep—since this is the author's bias. It will touch briefly upon some other systems with prominent rhythmic attributes including certain cancers, the cardiovascular system, the entero-insular axis and metabolism together with the use of melatonin to assess circadian status. Many of the ills of the developed world relate to deranged rhythms—and everything is rhythmic unless proved otherwise.

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          Most cited references168

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          Extrapineal melatonin: sources, regulation, and potential functions.

          Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.
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            Carcinogenicity of shift-work, painting, and fire-fighting.

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              Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial.

              Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms. To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin. A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia. Random assignment by facility to long-term daily treatment with whole-day bright (+/- 1000 lux) or dim (+/- 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years). Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months. Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (-0.5 points; 95% CI, -0.10 to -1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect). Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light. controlled-trials.com/isrctn Identifier: ISRCTN93133646.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                16 July 2019
                2019
                : 10
                : 391
                Affiliations
                Faculty of Health and Medical Sciences, University of Surrey , Guildford, United Kingdom
                Author notes

                Edited by: James M. Olcese, Florida State University, United States

                Reviewed by: Krystyna Skwarlo-Sonta, University of Warsaw, Poland; Hana Zemkova, Institute of Physiology (ASCR), Czechia

                *Correspondence: Josephine Arendt arendtjo@ 123456gmail.com

                This article was submitted to Cellular Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2019.00391
                6646716
                31379733
                85b8bc0d-6f6e-419b-bab7-259fdf2a975f
                Copyright © 2019 Arendt.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 March 2019
                : 30 May 2019
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 201, Pages: 16, Words: 14160
                Categories
                Endocrinology
                Hypothesis and Theory

                Endocrinology & Diabetes
                melatonin,circadian,seasonal,health,sleep,light,desynchrony
                Endocrinology & Diabetes
                melatonin, circadian, seasonal, health, sleep, light, desynchrony

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