Special Issue "Advances in the Research of Melatonin"

Guest Editor
Prof. Dr. Rudiger Hardeland
Institute of Zoology and Anthropology, University of Goettingen, Berliner Str. 28, D-37073 Goettingen, Germany
E-Mail: rhardel@gwdg.de

Dear Colleagues,

Accumulating evidence indicates an important role of melatonin and melatonergic signaling for the well-functioning of a body. Both physiological and psychological impairments can be associated with decreases of melatonin levels, as observed in the course of aging or as a consequence of various diseases and disorders. The multiplicity of possible changes reflects the extraordinary pleiotropy of this hormone. The association of deviations in melatonergic signaling with mental and metabolic disorders, in particular, diabetes type 2, is supported by knockouts and polymorphisms of genes involved in melatonin biosynthesis or signaling. An overlap with similar findings concerning genes of circadian oscillators indicates a significant chronobiological role of melatonin in the maintenance of health. High nocturnal levels of melatonin, which imply large amplitudes of the melatonin rhythm, synchronize other rhythms with external cycles and within the circadian multioscillator system. They support the maintenance of high amplitudes of peripheral rhythms, as shown by melatonin deficiency. They have also been interpreted as an indicator of youthfulness. Conversely, the decline of nocturnal melatonin leads to numerous undesired changes, including impairments in both detoxification and production of reactive oxygen and nitrogen species, increased susceptibility to these reactive compounds, mitochondrial dysfunction, reductions in immune functions, sleep disturbances and, eventually, mood disorders. To overcome these problems, prolonged-release formulations of melatonin and various synthetic melatonergic agonists have been developed, some of which combine melatonergic signaling with additional properties of possible value in the treatment of depressive symptoms and metabolic disorders.

Prof. Dr. Rudiger Hardeland
Guest Editor

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• aging
• antioxidative protection
• bipolar disorder
• chronobiotic
• diabetes
• immune system
• melatonergic drugs
• metabolic syndrome
• seasonal affective disorder
• sleep

Type of Paper: Review
Title: Chronobiology of Melatonin Beyond the Feedback to the Suprachiasmatic Nucleus
Author: Rüdiger Hardeland
Affiliation: Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Germany
Abstract: Melatonin receptors are widely expressed in numerous peripheral and central nervous tissues. Therefore, the circadian rhythm of circulating, pineal-derived melatonin has profound consequences for the temporal organization of almost all organs, without necessarily involving the melatonin feedback to the suprachiasmatic nucleus. Experiments with melatonin-deficient mouse strains, pinealectomized animals and melatonin receptor knockouts reveal a highly complex network of actions at various levels. In addition to direct steering of melatonin-regulated cellular functions, the pineal hormone is required for the rhythmic expression of circadian oscillator genes in peripheral organs, enhances the coupling of parallel oscillators based on alternate homologs or paralogs within the same organ, and indirectly controls numerous cells by influencing the secretion of other hormones.

Type of Paper: Review
Title: Melatonin: Ready for Prime Time
Authors: Russel J. Reiter and Dun-Xian Tan
Affiliation: University of Texas Health Science Center, San Antonio, Texas, USA
Abstract: Melatonin is an endogenously-produced, ubiquitously-acting molecule with numerous beneficial actions.  It is present in species throughout the animal and plant kingdoms.  Melatonin has been widely administered to animals, including humans, where its toxicity has been found to be minimal at virtually any dose.  The number of clinical trials that have used melatonin is increasing rapidly and its applications in food science and agriculture are also currently being exploited.  It is obvious that melatonin’s usefulness in clinical and veterinary medicine and plant science deserves the increased attention it is receiving.  This review will summarize many of the potential applications of melatonin and identified new directions of research.

Type of Paper: Review
Title: Buffering the Immune System
Authors: Antonio Carrillo-Vico, Patricia J. Lardone, Nuria Álvarez-Sánchez, Ana Rodríguez-Rodríguez and Juan M. Guerrero^*
Affiliation: Department of Medical Biochemistry and Molecular Biology, University of Seville School of Medicine, Seville, Spain
Abstract: Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports pointing out melatonin as an immunomodulatory compound, the way by that melatonin regulates immunity still remains unclear. While some authors argue that melatonin is an immunoenhancer agent, in several studies anti-inflammatory actions have been described. In the present review, we support the idea of melatonin as an immune buffer, acting on immunosuppression conditions as a stimulator or being an anti-inflammatory agent when the immune response is exacerbated. The clinical relevance of the several faces of melatonin on immune pathologies is also reviewed.

Type of Paper: Review
Title: Nucleus-Mitochondrion Connection During the Immune Innate Response: Modulation by Melatonin
Authors: José Antonio García, Carolina Doerrier, Huayqui Volt, Russel J. Reiter^*, Germaine Escames and Darío Acuña-Castroviejo^*
Affiliation: Instituto de Biotecnología and Departamento de Fisiología, Universidad de Granada, Granada, Spain
^*Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, USA
Abstract: Among the broad spectrum of melatonin properties, its antioxidant and anti-inflammatory actions constitute the basis for its multiple clinical applications.  Melatonin is highly efficient against NF-κB-dependent immune innate response. Several steps in the pathway of the NF-κB signaling seem to be controlled by melatonin, including the activation of NF-κB, its entry to the nucleus, and its transcriptional activity. Through these molecular targets, melatonin inhibits the innate immune response in inflammatory conditions such as sepsis. Moreover, melatonin enhances the antioxidative response of the cell, inducing the expression and activity of multiple endogenous antioxidant systems including that of the glutathione redox cycle. In parallel to these effects, melatonin reduces the mitochondrial-dependent free radical generation during inflammation, and promotes increased efficiency of the mitochondrial bioenergetics, leading to an increase in the ATP production. These conditions allow the cell to defend against the damage inducing during the inflammatory response. NF-κB pathway precedes to the activation of the inflammasome, an additional and complementary response of the innate immune response, yielding a huge production of IL-1β. The inflammasome pathway is activated by, among others, the free radicals produced by the mitochondria. Recent data point to an effect of melatonin to blunt the NF-κB and inflammasome responses, supporting the effects of the indoleamine in the modulation of the nucleus-mitochondria network during inflammation.

Type of Paper: Review
Title: Melatonin and the Metabolic Syndrome: Recent Developments
Authors: Daniel P. Cardinali et al.
Affiliation: Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
Abstract: Metabolic syndrome (MS) patients exhibit sleep/wake disturbances and other circadian abnormalities, and these may be associated with more rapid weight increase and development of diabetes and atherosclerotic disease. On this basis, the successful management of MS may require an ideal drug that besides antagonizing the trigger factors of MS could also correct the disturbed sleep-wake rhythm. Melatonin is an effective chronobiotic agent able to change the phase and amplitude of circadian rhythms. Melatonin has also significant cytoprotective properties preventing a number of MS sequels in animal models of diabetes and obesity. Recent data from our laboratory indicate a curtailing effect of melatonin given to rats at two different stages of fructose-induced MS: an initial stage, in which abnormally high blood pressure and circulating lipids coexist with an augmented glucose tolerance, and at established stage, when insulin resistance and hyperinsulinemia developed. Thus, among the several substances with the capacity to curtail the MS, melatonin merits particular attention.

Type of Paper: Article
Title: Out of the Lab into the Bathroom: Evening Short-Term Exposure to Conventional Light Suppresses Melatonin and Increases Alertness Perception
Authors: Amely Wahnschaffe ^1,*,  Sven Hädel ¹,  Andrea Rodenbeck ¹, Claudia Stoll ¹, Horst Rudolph ², Ruslan Kozakov ³, Heinz Schöpp ³ and Dieter Kunz ^1,4
Affiliations: ¹ Institute of Physiology, Charité – Universitätsmedizin Berlin (CBF), Berlin; E-Mails: sven@haedel.de, arodenb@gwdg.de, claudia.stoll@charite.de, dieter.kunz@charite.de
² Trilux GmbH & Co.KG, Arnsberg; E-Mail: hrudolph@trilux.de
³ Institut für Plasmaforschung und –Technologie (INP), Greifswald Full Affiliation, Address; E-Mail: kozakov@inp-greifswald.de, Schoepp@inp-greifswald.de
⁴ German Heart Institute, Berlin; E-Mail: amely.wahnschaffe@gmx.de
Abstract: Life in a 24-hour society relies on the use of artificial light at night and thereby disrupts synchronization of the endogenous circadian timing system to the solar day. This could negatively influence sleep-wake patterns and psychiatric symptoms. The aim of the study was to investigate the influence of evening light emitted by everyday lamps in a naturalistic setting on melatonin levels and alertness in humans. Healthy subjects (6male, 3female, 22-33yrs.) were exposed to constant dim light (<10lx) for six evenings from 7:00-12:00PM. During evenings 2-6 they were also exposed for 30 minutes to light emitted by 5 different everyday lamps 1 hour before habitual bedtime. Exposure to yellow light did not alter the increase of melatonin in saliva compared to dim light baseline (during light exposure 38±27pg/ml vs. 39±23pg/ml and after 39±22pg/ml vs. 44±26pg/ml). In contrast, lighting conditions including blue components reduced melatonin increase significantly during (office: 25±16pg/ml, bathroom white: 24±10pg/ml, warm white: 26±14pg/ml, hall lighting: 22±14pg/ml) and after light exposure (office: 25±15pg/ml, bathroom white: 23±9pg/ml, warm white: 24±13pg/ml, hall lighting: 22±26pg/ml). Subjective alertness was significantly increased at the end of three of the lighting conditions which included blue components in their spectra. Evening exposure to everyday lamps in an everyday setting influences melatonin excretion and alertness perception within 30 min.
Keywords: melatonin; circadian rhythm; light; sleep disturbances; alertness

Type of Paper: Review
Title: Role and Posibilities of Melatonin in Neurodegenerative Disease in Young Adults: Huntington’s Disease and Multiple Sclerosis
Authors: Begoña Escribano and Isaac Túnez ^*
Affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, IMIBIC, University of Cordoba, Spain; E-Mail: fm2tufii@uco.es
Abstract: Multiple sclerosis (MS), the most common cause of non-traumatic disability in young adults, is a chronic neuroinflammatory disease, characterized by demyelination, inflammation, neuronal and oxidative damage. Often requires in its early diagnosis a differential screening with other neurodegenerative diseases such as Huntington’s disease (HD), autosomal dominant disorder. The onset of both diseases occurs in the second or third decade of life. Changes in melatonin levels have been observed in theses processes, being these changes with their pathogenesis.Melatonin is produced and released by pineal gland in a circadian rhythm. This neurohormone has proven to be a powerful antioxidant able to mitigate and reduce cell damage associated to oxidative stress, and this phenomenon underlying neurodegenerative disorders.These events have drawn attention to this indole, evaluating its changes and its relationship with the processes indicated. Analyzing its role in the mechanisms involved in the beginning and development in neurodegenerative disease, as well as its therapeutic potential.This review aims to update and analyze the role played by melatonin during neurodegenerative processes, specifically affecting young adults as HD and MS, and its possible therapeutic administration in these diseases.
Key words: Huntingotn’s disease; melatonin; multiple sclerosis; oxidative stress; neurodegeneration

Type of Paper: Article
Title: Global Left Ventricular Longitudinal Strain is Closely Associated with Decreased Melatonin Levels in Patients with Acute Myocardial Infarction: A two-Dimensional Speckle Tracking Study
Authors: Alberto Dominguez-Rodriguez ^1*, Pedro Abreu-Gonzalez ² , Eduardo Arroyo-Ucar 1. Pablo Avanzas³ and Russel J. Reiter⁴.
Affiliations: ¹Complejo Hospitalario Universitario de Canarias, Department of Cardiology;  Tenerife. Spain; ² University of La Laguna, Department of Physiology, Tenerife. Spain; ³ Hospital Central de Astúrias, Department of Cardiology; Oviedo. Spain; ⁴ Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
^*Corresponding author: Alberto Dominguez-Rodriguez, Complejo Hospitalario Universitario de Canarias, Department of Cardiology. Ofra s/n La Cuesta E-38320. Tenerife. Spain; E-mail: adrvdg@hotmail.com
Abstract: Background: Low circulating melatonin levels predict poor outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). In the present study we sought to investigate whether exists a relationship between myocardial deformation in parameters measured by echocardiography and circulating melatonin levels.Methods: We prospectively included 112 patients with a first STEMI who underwent primary PCI within 6 hours from onset of symptoms and performed echocardiography within 48 h of admission. Global longitudinal myocardial function was assessed by two-dimensional speckle tracking simultaneously with measurement of serum melatonin, during the light period.Results: A negative correlation between melatonin and global longitudinal strain (GLS) was found (P = 0.006, r = -0.33); however, there was no correlation between melatonin and left ventricular ejection fraction (LVEF) (P = 0.32, r = 0.32). A multiple linear regression model demonstrated that only GLS had a significant independent linear association with melatonin (Coefficient b= -0.38, R²= 0.15, P = 0.004).Conclusion: Serum levels of melatonin in the acute phase of STEMI are more accurately reflected by longitudinal myocardial deformation assessed by two-dimensional speckle tracking-derived GLS compared with LVEF.

Type of Paper: Review
Title: Homology models of melatonin receptors: challenges and recent advances.
Author: Silvia Rivara
Affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, viale G.P. Usberti 27/A, I-43124 Parma, Italy; E-mail  silvia.rivara@unipr.it
Abstract: Melatonin exerts many of its actions through the activation of the MT1 and MT2 G protein-coupled receptors. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of (bacterio)rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been reported in the literature. These receptor models differ in the binding modes proposed for melatonin and for other melatoninergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. These receptor models will be briefly described and they will be discussed in light of the available information from mutagenesis data and ligand-based studies, such as pharmacophore models. Moreover, the ability of these ligand-receptor complexes to rationalize the structure-activity relationships of known series of melatoninergic compounds will be evaluated.

Type of Paper: Review
Title: Role of Melatonin in Schizophrenia
Authors: Armando L. Morera-Fumero and Pedro Abreu-Gonzalez
Affiliation: Departamento de Medicina Interna, Dermatologia y Psiquiatria. Facultad de Medicina. Universidad de la Laguna, Campus de Ofra, 38071- La Laguna. Santa Cruz de Tenerife. Spain. E-mail: amorera@ull.es
Abstract: Schizophrenia is a chronic mental disease that disturbs several cognitive functions, such as memory, thought, perception and volition.  Schizophrenia biological etiology is multifactorial and is still under investigation. Melatonin has been involved on schizophrenia since the first decades of the twenty century. Two different approaches have been described with respect to schizophrenia. First, the use of melatonin as a biological marker. Second, the clinical applications of melatonin as a drug treatment. In this paper we will review both facets of melatonin applications emphasizing the clinical use in schizophrenia.

Type of Paper: Article
Title: A Comparison of B16 Melanoma Cells and 3T3 Fibroblasts Concerning Cell Viability and ROS Production in the Presence of Melatonin Tested in a Wide Concentration Range
Authors: Maria Angeles Bonmati-Carrion¹, Nuria Álvarez-Sánchez², Juan Antonio Madrid¹ and Maria Angeles Rol¹
Affiliations: ¹ Department of Physiology, College of Biology, University of Murcia, Spain; mbc11365@um.es (Maria Angeles Bonmati-Carrion); jamadrid@um.es (Juan Antonio Madrid); angerol@um.es (Maria Angeles Rol); ² Instituto de Biomedicina de Sevilla (IBiS),Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla; Department of Medical Biochemistry and Molecular Biology, University of Seville School of Medicine, Seville, Spain. nuriaalvarez80@yahoo.com; E-Mail: jamadrid@um.es
Abstract: Melatonin is a pleiotropic molecule with many cellular and systemic actions, including chronobiotic effects. It has been widely documented to have a beneficial effect on the treatment of neoplastic diseases in vivo and to reduce cell viability in cultured melanoma, one of the most aggressive cancers in humans. However, there is no agreement about the range of effective melatonin concentrations in vitro. Furthermore, studies on its effects on non-tumor cells in vitro have not been focused on cell viability. The mechanisms involved in the effects on cell viability are also unclear, although increased intracellular ROS/RNS production specific to tumor cells seems to be the most plausible explanation. Our aim was to analyze the potential inhibition of tumor (B16 melanoma 4A5) and non-tumor cell (3T3 Swiss albino) viability by a wide range of melatonin concentrations (10^-11 ‒ 10^-2 M), and determine whether intracellular ROS enhancement was involved in this process. Low melatonin concentrations (10^-11–10^-5 M) reduced melanoma cell viability, with no changes in fibroblast cells in the absence of FBS. In the millimolar range, melatonin increased ROS levels and reduced the viability of both cell types, but particularly in non-tumor cells, becoming lethal at concentrations close to 10 mM. Thus, we have shown that low melatonin concentrations reduce cell viability only in this specific melanoma cell line, but high concentrations affect viability in both tumor (melanoma) and non-tumor (fibroblasts) cell lines. The ROS level increase in both cell lines indicates the role of ROS production in the reduction of cell viability at high -but not low- melatonin concentrations, albeit the mechanism of action still remains to be determined.
Keywords: melanoma; fibroblast; melatonin; cell viability; intracellular ROS; tumor cell cultures; non-tumor cell cultures; in vitro.

Type of Paper: Review
Title: Role of Melatonin on Mitochondrial Dysfunction in Metabonic Syndrome
Author: Ahmad Agil
Affiliation: Pharmacology Department and Neuroscience Institute Faculty of Medicine University of Granada; aagil@ugr.es
Abstract: The metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus that includes obesity, elevated blood pressure, insulin resistance, and dyslipidemia. The adipose tissue has shown a main role in the metabolic disease development, and the difference between both white and brown adipocytes has become an important key for research. The mitochondrial and endoplasmic reticulum dysfunction seen at metabolic syndrome correlates with the chronic inflammation, connecting the imbalance with the adipose tissue. Recent studies propose melatonin as a new approach to treat these alterations, playing an important role in body weight regulation and energy metabolism. This review relates the role of melatonin in the metabolic syndrome focusing on its effects in obesity, insulin resistance and inflammation. The overall findings suggest that melatonin may be a therapeutic tool to prevent or reverse the harmful effects of metabolic syndrome.

Type of Paper: Review
Title: The Melatonergic System in Mood and Anxiety Disorders and the Role of Agomelatine: Implications for Clinical Practice.
Authors: Domenico De Berardis ^{1 2}, Stefano Marini ^{1 2}, Michele Fornaro ³, Venkataramanujam Srinivasan ⁴, Felice Iasevoli ⁵, Alessandro Valchera ⁶, Giampaolo Perna 7, Maria-Antonia Quera-Salva ⁸, Giovanni Martinotti ² and Massimo Di Giannantonio ²
Affiliations: ¹NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL 4 Teramo, Italy; ²Department of Neuroscience and Imaging, Chair of Psychiatry, University “G. D’Annunzio”, Chieti; ³Department of “Scienze della Formazione”, University of Catania, Italy; ⁴Sri Sathya Sai Medical Educational and Research Foundation, Medical Sciences Research Study Center, Prasanthi Nilayam, 40-Kovai Thirunagar Coimbatore-641014, Tamilnadu, India; ⁵Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neuroscience, University School of Medicine “Federico II”, Naples, Italy; ⁶Villa S. Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy; ⁷Department of Clinical Neurosciences, Villa San Benedetto Hospital, Hermanas Hospitalarias, Albese con Cassano, Italy; ⁸AP-HP Sleep Unit, Department of Physiology, Raymond Poincaré Hospital, Garches, France; Correspondence: Domenico De Berardis, MD, PhD. National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, “G. Mazzini” Hospital, p.zza Italia 1, 64100 Teramo (Italy) E-mail: dodebera@aliceposta.it
Abstract: Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors which belong to the super family of G-protein coupled receptors consisting of the typical seven transmembrane domains. MT1 and MT2 receptors are expressed in various tissues of body either as single ones or as together. A growing literature suggests that the melatonergic system may be involved in the pathophysiology of mood and anxiety disorders. In fact, some core symptoms of depression show disturbance of the circadian rhythm in their clinical expression, such as diurnal mood and other symptomatic variation, or are closely linked to the circadian system functioning, such as sleep-wake cycle alterations. In addition, alterations have been described in the circadian rhythms of several biological markers in depressed patients. Therefore, there is interest in developing antidepressants that have a chronobiotic effect (i.e., treatment of circadian rhythm disorders). As melatonin produces chronobiotic effects, efforts have been aimed at developing agomelatine, an antidepressant with melatonin agonist activity. The present paper reviews the role of the melatonergic system in the pathophysiology of mood and anxiety disorders and the clinical characteristics of agomelatine. Implications of agomelatine in the “real world” clinical practice will be also discussed.

Type of Paper: Review
Title: Influence of Melatonin on the Immune System of Fish
Authors: María A. Esteban ^1*, Alberto Cuesta ¹, Elena Chávez-Pozo ² and José Meseguer ¹
Affiliations: ¹ Fish Innate Immune System Group, Department of Cell Biology and Histology, Faculty of Biology, Campus Regional de Excelencia Internacional “Campus Mare Nostrum”, University of Murcia, 30100 Murcia, Spain; ² Centro Oceanográfico de Murcia, Instituto Español de Oceanografía (IEO), Carretera de la Azohía s/n, Puerto de Mazarrón, 30860 Murcia, Spain ;E-Mail: aesteban@um.es
Abstract: Endocrine-immune system interactions have been widely demonstrated in mammals, whereas in fish these relationships are still under investigation. Among the endocrine system, the pineal gland via its secretory product, melatonin, influences the light–dark rhythm in most vertebrates including fish. It is well established that seasonality dominates the life history of fish by controlling the timing of physiological events such as reproduction, food intake, locomotor activity and growth performance. Seasonal differences in immune competence and prevalence of disease have been well documented in humans. Nevertheless, apart from the information concerning this circadian rhythm, the interrelation of the melatonin with other physiological processes has not been deeply considered in fish. The purpose of this review is to summarise the current knowledge of the effects of the melatonin on fish immune system. Interest in defence mechanism of fish arises from a need to develop health management tools to support a growing finfish aquaculture industry, while at the same time addressing questions concerning origins and evolution of immunity in vertebrates.
Keywords: endocrine-immune system; seasons; rhythms; melatonin; immunity; fish