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Cellular and Molecular Neurobiology Aug 2023Melatonin is ubiquitous molecule with wide distribution in nature and is produced by many living organisms. In human beings, pineal gland is the major site for melatonin... (Review)
Review
Melatonin is ubiquitous molecule with wide distribution in nature and is produced by many living organisms. In human beings, pineal gland is the major site for melatonin production and to lesser extent by retina, lymphocytes, bone marrow, gastrointestinal tract, and thymus. Melatonin as a neurohormone is released into circulation wherein it penetrates all tissues of the body. Melatonin synthesis and secretion is supressed by light and enhanced by dark. Melatonin mostly exerts its effect through different pathways with melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) being the predominant type of receptor that are mainly expressed by many mammalian organs. Melatonin helps to regulate sleep patterns and circadian rhythms. In addition, melatonin acts as an antioxidant and scavenges excessive free radicals generated in the body by anti-excitatory and anti-inflammatory properties. A multiple array of other functions are displayed by melatonin that include oncostatic, hypnotic, immune regulation, reproduction, puberty timing, mood disorders, and transplantation. Deficiencies in the production or synthesis of melatonin have been found to be associated with onset of many disorders like breast cancer and neurodegenerative disorders. Melatonin could be used as potential analgesic drug in diseases associated with pain and it has quite promising role there. In the past century, a growing interest has been developed regarding the wide use of melatonin in treating various diseases like inflammatory, gastrointestinal, cancer, mood disorders, and others. Several melatonin agonists have been synthesized and are widely used in disease treatment. In this review, an effort has been made to describe the biochemistry of melatonin along with its therapeutic potential in various diseases of humans.
Topics: Animals; Humans; Melatonin; Receptors, Melatonin; Antioxidants; Circadian Rhythm; Pineal Gland; Mammals
PubMed: 36752886
DOI: 10.1007/s10571-023-01324-w -
Trends in Endocrinology and Metabolism:... Mar 2020The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B - the melatonin... (Review)
Review
The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B - the melatonin receptor gene - is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework - anchored in the dimension of 'time' - to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease.
Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Circadian Rhythm; Diabetes Mellitus, Type 2; Genetic Variation; Glucose; Humans; Insulin; Melatonin; Polymorphism, Single Nucleotide; Receptor, Melatonin, MT2
PubMed: 31901302
DOI: 10.1016/j.tem.2019.11.011 -
International Journal of Molecular... Dec 2022Anxiety disorders are the most common mental diseases. Anxiety and the associated physical symptoms may disturb social and occupational life and increase the risk of... (Review)
Review
Anxiety disorders are the most common mental diseases. Anxiety and the associated physical symptoms may disturb social and occupational life and increase the risk of somatic diseases. The pathophysiology of anxiety development is complex and involves alterations in stress hormone production, neurosignaling pathways or free radical production. The various manifestations of anxiety, its complex pathophysiological background and the side effects of available treatments underlie the quest for constantly seeking therapies for these conditions. Melatonin, an indolamine produced in the pineal gland and released into the blood on a nightly basis, has been demonstrated to exert anxiolytic action in animal experiments and different clinical conditions. This hormone influences a number of physiological actions either via specific melatonin receptors or by receptor-independent pleiotropic effects. The underlying pathomechanism of melatonin's benefit in anxiety may reside in its sympatholytic action, interaction with the renin-angiotensin and glucocorticoid systems, modulation of interneuronal signaling and its extraordinary antioxidant and radical scavenging nature. Of importance, the concentration of this indolamine is significantly higher in cerebrospinal fluid than in the blood. Thus, ensuring sufficient melatonin production by reducing light pollution, which suppresses melatonin levels, may represent an endogenous neuroprotective and anxiolytic treatment. Since melatonin is freely available, economically undemanding and has limited side effects, it may be considered an additional or alternative treatment for various conditions associated with anxiety.
Topics: Animals; Melatonin; Anti-Anxiety Agents; Antioxidants; Free Radicals; Anxiety
PubMed: 36555831
DOI: 10.3390/ijms232416187 -
International Journal of Molecular... Feb 2021The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been... (Review)
Review
The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.
Topics: Administration, Oral; Adult; Autism Spectrum Disorder; Biological Availability; Child; Child, Preschool; Circadian Rhythm; Delayed-Action Preparations; Dietary Supplements; Female; Humans; Injections, Intravenous; Male; Melatonin; Receptors, Melatonin; Saliva; Seasons; Serotonin; Sleep Disorders, Intrinsic; Sleep Latency; Social Behavior Disorders; Tryptophan
PubMed: 33540815
DOI: 10.3390/ijms22031490 -
Cell Death and Differentiation Apr 2022The circadian clock is a master regulator in coordinating daily oscillations of physiology and behaviors. Nevertheless, how the circadian rhythm affects endochondral...
The circadian clock is a master regulator in coordinating daily oscillations of physiology and behaviors. Nevertheless, how the circadian rhythm affects endochondral ossification is poorly understood. Here we showed that endochondral bone formation exhibits circadian rhythms, manifested as fast DNA replication in the daytime, active cell mitosis, and matrix synthesis at night. Circadian rhythm disruption led to endochondral ossification deformities. The mechanistic dissection revealed that melatonin receptor 1 (MTR1) periodically activates the AMPKβ1 phosphorylation, which then orchestrates the rhythms of cell proliferation and matrix synthesis via destabilizing the clock component CRY1 and triggering BMAL1 expression. Accordingly, the AMPKβ1 agonist is capable of alleviating the abnormity of endochondral ossification caused by circadian dysrhythmias. Taken together, these findings indicated that the central circadian clock could control endochondral bone formation via the MTR1/AMPKβ1/BMAL1 signaling axis in chondrocytes. Also, our results suggested that the AMPKβ1 signaling activators are promising medications toward endochondral ossification deformities.
Topics: ARNTL Transcription Factors; Circadian Rhythm; Melatonin; Osteogenesis; Receptors, Melatonin
PubMed: 35094018
DOI: 10.1038/s41418-021-00919-4 -
Journal of Pineal Research Jan 2021Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain...
Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury by improving mitochondrial quality control: Role of SIRT6.
Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high-fat diet-streptozotocin-induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK-PGC-1α-AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia-reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re-activating SIRT6 and AMPK-PGC-1α-AKT signaling. After the induction of diabetes, adeno-associated virus carrying SIRT6-specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin-induced AMPK-PGC-1α-AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long-term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor-mediated SIRT6-AMPK-PGC-1α-AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia-reperfusion injury in diabetic patients.
Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Forkhead Box Protein O3; Male; Melatonin; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocytes, Cardiac; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Sirtuins; Time Factors; Rats
PubMed: 33016468
DOI: 10.1111/jpi.12698 -
Journal of Pineal Research Apr 2024Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which... (Review)
Review
Melatonin (5-methoxy-N-acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT and MT receptors are the best-characterized. They are members of the G protein-coupled receptor superfamily, preferentially coupling to G proteins but also to other G proteins in a cell-context-depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT and MT receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state-of-the-art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round-up this review.
Topics: Animals; Humans; Receptors, Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Melatonin; Signal Transduction; Receptors, G-Protein-Coupled; Mammals
PubMed: 38587234
DOI: 10.1111/jpi.12952 -
Current Opinion in Pharmacology Dec 2021Osteoporosis and neurodegenerative diseases are common diseases in the aging population. Studies demonstrate the complex communication among skeletal, muscular, and... (Review)
Review
Osteoporosis and neurodegenerative diseases are common diseases in the aging population. Studies demonstrate the complex communication among skeletal, muscular, and nervous systems and point to the emerging roles of neuromuscular systems in bone homeostasis. The discovery that the nervous system directly regulates bone remodeling implies that osteoporosis is a neuroskeletal disease. Melatonin, a hormone secreted from the pineal gland, is a melatonin receptor 1A (MT1) and 1B (MT2) agonist and influences the function of diverse systems. Melatonin is a pharmaceutical ingredient in numerous medicines, over-the-counter medicines, nutraceuticals, and dietary supplements, which benefit disease prevention and treatment, including osteoporosis and neurodegenerative diseases. This review aims to summarize the recent advances in preventing senile, postmenopausal, and neurodegenerative osteoporosis with melatonin and provide new insights into how neuromuscular systems influence bone homeostasis. More preclinical and clinical studies in neuroskeletal biology will eventually improve the lives of people fighting osteoporosis.
Topics: Aged; Biology; Humans; Melatonin; Osteoporosis; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2
PubMed: 34607253
DOI: 10.1016/j.coph.2021.08.016 -
Sleep Medicine Clinics Sep 2022Insomnia disorder is common in adults and children. The estimated prevalence ranges from 9% to 15% in the general population, with higher prevalence in certain... (Review)
Review
Insomnia disorder is common in adults and children. The estimated prevalence ranges from 9% to 15% in the general population, with higher prevalence in certain subpopulations. Hypnotic medications are those that tend to produce sleep and are frequently used to treat insomnia. Commonly used hypnotics in adults include benzodiazepines (BZDs), BZD receptor agonists, antihistamines, antidepressants, melatonin receptor agonists, orexin receptor antagonists, and antipsychotics. However, hypnotic discontinuation is difficult and often unsuccessful. This article discusses strategies to discontinue hypnotics and evidence supporting their use.
Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Child; Humans; Hypnotics and Sedatives; Orexin Receptor Antagonists; Receptors, Melatonin; Sleep Initiation and Maintenance Disorders
PubMed: 36150811
DOI: 10.1016/j.jsmc.2022.06.014 -
The FEBS Journal Apr 2020The long-anticipated high-resolution structures of the human melatonin G protein-coupled receptors MT and MT , involved in establishing and maintaining circadian rhythm,... (Review)
Review
The long-anticipated high-resolution structures of the human melatonin G protein-coupled receptors MT and MT , involved in establishing and maintaining circadian rhythm, were obtained in complex with two melatonin analogs and two approved anti-insomnia and antidepression drugs using X-ray free-electron laser serial femtosecond crystallography. The structures shed light on the overall conformation and unusual structural features of melatonin receptors, as well as their ligand binding sites and the melatonergic pharmacophore, thereby providing insights into receptor subtype selectivity. The structures revealed an occluded orthosteric ligand binding site with a membrane-buried channel for ligand entry in both receptors, and an additional putative ligand entry path in MT from the extracellular side. This unexpected ligand entry mode contributes to facilitating the high specificity with which melatonin receptors bind their cognate ligand and exclude structurally similar molecules such as serotonin, the biosynthetic precursor of melatonin. Finally, the MT structure allowed accurate mapping of type 2 diabetes-related single-nucleotide polymorphisms, where a clustering of residues in helices I and II on the protein-membrane interface was observed which could potentially influence receptor oligomerization. The role of receptor oligomerization is further discussed in light of the differential interaction of MT and MT with GPR50, a regulatory melatonin coreceptor. The melatonin receptor structures will facilitate design of selective tool compounds to further dissect the specific physiological function of each receptor subtype as well as provide a structural basis for next-generation sleeping aids and other drugs targeting these receptors with higher specificity and fewer side effects.
Topics: Animals; Drug Design; Humans; Protein Conformation; Receptors, Melatonin; Sleep Aids, Pharmaceutical
PubMed: 31693784
DOI: 10.1111/febs.15128