Therapeutic Potential Of Melatonin Research Articles

Therapeutic Potential of Melatonin: Multifaceted Applications in Muscle Health, Metabolic Disorders and Cardiovascular Disease

Melatonin, a hormone primarily synthesized by the pineal gland, is traditionally associated with the regulation of circadian rhythms. However, recent research has unveiled its broad spectrum of biological effects, positioning it as a valuable therapeutic agent in diverse health contexts. Known for its potent antioxidant and anti-inflammatory properties, melatonin plays a crucial role in maintaining homeostasis and protecting cellular integrity. This review explores melatonin’s therapeutic applications across multiple medical domains, including muscle health, metabolic disorders, chronic pain management, and cardiovascular health. In muscle health, melatonin facilitates muscle hypertrophy and regeneration by mitigating oxidative stress and enhancing the activity of satellite cells responsible for muscle repair. This action is particularly beneficial for individuals undergoing intense physical exertion, recovering from injuries, or combating age-related muscle. In metabolic disorders, such as type 2 diabetes, melatonin improves insulin sensitivity and reduces cellular oxidative damage, which supports beta-cell function and glucose regulation, potentially minimizing diabetes-related complications. Furthermore, in fibromyalgia - a condition marked by widespread pain and sleep disturbances - melatonin has demonstrated efficacy in alleviating pain and improving sleep quality, thus enhancing the overall quality of life for patients. In cardiovascular health, melatonin has shown promise in preventing and managing heart failure by reducing oxidative damage, modulating inflammatory pathways, and supporting endothelial function, which collectively contribute to improved cardiac health and reduced disease progression. This comprehensive review underscores melatonin’s emerging role as an integrative therapeutic agent in modern medicine.

The Role and Therapeutic Potential of Melatonin in Degenerative Fundus Diseases: Diabetes Retinopathy and Age-Related Macular Degeneration.

Degenerative fundus disease encompasses a spectrum of ocular diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), which are major contributors to visual impairment and blindness worldwide. The development and implementation of effective strategies for managing and preventing the onset and progression of these diseases are crucial for preserving patients' visual acuity. Melatonin, a neurohormone primarily produced by the pineal gland, exhibits properties such as circadian rhythm modulation, antioxidant activity, anti-inflammatory effects, and neuroprotection within the ocular environment. Furthermore, melatonin has been shown to suppress neovascularization and reduce vascular leakage, both of which are critical in the pathogenesis of degenerative fundus lesions. Consequently, melatonin emerges as a promising therapeutic candidate for degenerative ocular diseases. This review provides a comprehensive overview of melatonin synthesis, its localization within ocular tissues, and its mechanisms of action, particularly in regulating melatonin production, thereby underscoring its potential as a therapeutic agent for degenerative fundus diseases.

New Perspectives on the Role and Therapeutic Potential of Melatonin in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. It is essential to develop novel interventions to prevent/delay CVDs by targeting their fundamental cellular and molecular processes. Melatonin is a small indole molecule acting both as a hormone of the pineal gland and as a local regulator molecule in various tissues. It has multiple features that may contribute to its cardiovascular protection. Moreover, melatonin enters all cells and subcellular compartments and crosses morphophysiological barriers. Additionally, this indoleamine also serves as a safe exogenous therapeutic agent. Increasing evidence has demonstrated the beneficial effects of melatonin in preventing and improving cardiovascular risk factors. Exogenous administration of melatonin, as a result of its antioxidant and anti-inflammatory properties, has been reported to decrease blood pressure, protect against atherosclerosis, attenuate molecular and cellular damage resulting from cardiac ischemia/reperfusion, and improve the prognosis of myocardial infarction and heart failure. This review aims to summarize the beneficial effects of melatonin against these conditions, the possible protective mechanisms of melatonin, and its potential clinical applicability in CVDs.

The therapeutic potential of melatonin against hepatotoxicity caused by obesity and NSAIDs: A comprehensive review

The obesity and increased free fatty acid level are considered the etiology of hepatotoxicity leading to steatohepatitis and hepatic fibrosis. Obesity promotes inflammatory response and oxidative stress. Adipocytes secrete various proinflammatory cytokines including TNF-α, IL-1β, IL-6 and leptin to initiate a vicious cycle and cause further fat accumulation and weight gain. Specifically, to liver, the fat accumulation will cause non-alcoholic fatty liver disease (NAFLD), the most prevailing chronic liver ailment, if it is not properly treated, then it will cause severe outcomes including fatality. In addition, obesity also cause other inflammatory disorders including osteoarthritis of the knee, joint pain, etc. Non-steroidal anti-inflammatory drugs (NSAIDs) are most often used medicines for treatment of inflammation but their serious side effects are concerning. These include gastric mucosal damage, liver injury with elevated aminotransferase (AST/ALT) levels, hepatitis, jaundice and more fatal liver diseases. Melatonin, an antioxidant and anti-inflammatory molecule can be used to treat diverse kind of inflammatory diseases. It remarkably reduces the mRNA levels of pro-inflammatory cytokines of TNF-α, IL-6, IL-1β, etc. Melatonin and its metabolites retain the properties as an effective free radical scavenger and regulate various antioxidative and pro-oxidative enzymes. This molecule can potentially abate the ill effects of hepatotoxicity induced by both NSAIDs and obesity. Therefore, this review briefly summarizes the recent available knowledge on the protective effects of melatonin against various disorders involving weight gain and hepatotoxicity.

Hepatoprotective actions of melatonin by mainly modulating oxidative status and apoptosis rate in lipopolysaccharide-induced liver damage

Aim One of the serious complications of sepsis is liver damage and liver failure. This study aimed to evaluate the protective and therapeutic potential of melatonin in rats with lipopolysaccharide-induced sepsis. Main methods Female Spraque–Dawley rats received single a dose of 7.5 mg/kg lipopolysaccharide in saline to create a 24-h sepsis model. One of the other groups received melatonin at a dose of 10 mg/kg/day beginning 1 week before sepsis induction to the end of the experiment. The melatonin group received the same doses of melatonin for the same duration but not lipopolysaccharide. The vehicle group received the same doses of saline, the vehicle of melatonin, for the same duration. Twenty-four hours after the last injection, the rats were decapitated. By appropriate histochemical, immunohistochemical, biochemical, and molecular techniques, anti-necrotic, anti-apoptotic, anti-necroptotic, anti-inflammatory, and antioxidant effects of melatonin were assessed. Key findings Lipopolysaccharide has disrupted liver functions by inducing oxidative stress, inflammation, necrotic, apoptotic, and necroptotic cell death, thus disrupting liver functions. Melatonin was found to be beneficial in terms of inhibiting the intrinsic pathway of apoptosis and tissue oxidant levels, stimulating tissue antioxidant enzyme levels, and restoring hepatocyte functions. Significance Melatonin, at those doses and duration, was found to be hepatoprotective by mainly modulating oxidative status and apoptosis rate, however, failed to significantly reduce histopathological damage. We suggest that longer-term melatonin administration may produce anti-inflammatory and anti-necrotic effects as well.

From Chronodisruption to Sarcopenia: The Therapeutic Potential of Melatonin.

Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria and organelle, where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.

Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis.

Fibrosis, the excessive deposition of fibrous connective tissue in an organ in response to injury, is a pathological condition affecting many individuals worldwide. Fibrosis causes the failure of tissue function and is largely irreversible as the disease progresses. Pharmacologic treatment options for organ fibrosis are limited, but studies suggest that antioxidants, particularly melatonin, can aid in preventing and controlling fibrotic damage to the organs. Melatonin, an indole nocturnally released from the pineal gland, is commonly used to regulate circadian and seasonal biological rhythms and is indicated for treating sleep disorders. While it is often effective in treating sleep disorders, melatonin's anti-inflammatory and antioxidant properties also make it a promising molecule for treating other disorders such as organ fibrosis. Melatonin ameliorates the necrotic and apoptotic changes that lead to fibrosis in various organs including the heart, liver, lung, and kidney. Moreover, melatonin reduces the infiltration of inflammatory cells during fibrosis development. This article outlines the protective effects of melatonin against fibrosis, including its safety and potential therapeutic effects. The goal of this article is to provide a summary of data accumulated to date and to encourage further experimentation with melatonin and increase its use as an anti-fibrotic agent in clinical settings.

Therapeutic potential of melatonin in the intervertebral disc degeneration through inhibiting the ferroptosis of nucleus pulpous cells.

Ferroptosis, a novel type of cell death mediated by the iron-dependent lipid peroxidation, contributes to the pathogenesis of the intervertebral disc degeneration (IDD). Increasing evidence demonstrated that melatonin (MLT) displayed the therapeutic potential to prevent the development of IDD. Current mechanistic study aims to explore whether the downregulation of ferroptosis contributes to the therapeutic capability of MLT in IDD. Current studies demonstrated that conditioned medium (CM) from the lipopolysaccharide (LPS)-stimulated macrophages caused a series of changes about IDD, including increased intracellular oxidative stress (increased reactive oxygen species and malondialdehyde levels, but decreased glutathione levels), upregulated expression of inflammation-associated factors (IL-1β, COX-2 and iNOS), increased expression of key matrix catabolic molecules (MMP-13, ADAMTS4 and ADAMTS5), reduced the expression of major matrix anabolic molecules (COL2A1 and ACAN), and increased ferroptosis (downregulated GPX4 and SLC7A11 levels, but upregulated ACSL4 and LPCAT3 levels) in nucleus pulposus (NP) cells. MLT could alleviate CM-induced NP cell injury in a dose-dependent manner. Moreover, the data substantiated that intercellular iron overload was involved in CM-induced ferroptosis in NP cells, and MLT treatment alleviated intercellular iron overload and protected NP cells against ferroptosis, and those protective effects of MLT in NP cells further attenuated with erastin and enhanced with ferrostatin-1(Fer-1). This study demonstrated that CM from the LPS-stimulated RAW264.7 macrophages promoted the NP cell injury. MLT alleviated the CM-induced NP cell injury partly through inhibiting ferroptosis. The findings support the role of ferroptosis in the pathogenesis of IDD, and suggest that MLT may serve as a potential therapeutic approach for clinical treatment of IDD.

In silico study to unravel molecular networking of melatonin in the regulation of gametogenesis.

Melatonin, a pineal hormone, has potential role on steroidogenesis, growth and maturation of sperm and ovum during gametogenesis. The possible use of this indolamine as an antioxidant in the production of good quality gametes opens up a new area of current research. Nowadays, a large number of reproductive dysfunctions like infertility, failure in fertilization due to gametic malformations are major concern worldwide. So, understanding molecular mechanisms including interacting genes and their action is a prerequisite to the therapeutic approach against these issues. The aim of present bioinformatic study is the detection of molecular network concerning therapeutic potential of melatonin in gametogenesis. It includes target genes identification, gene ontology, KEGG pathway enrichment, network analysis, prediction of signaling pathways and molecular docking. We obtained common top 52 targets of melatonin in the process of gametogenesis. They are involved in biological processes related to the development of gonads and primary sexual characteristics, sex differentiation. We took top ten pathways out of total 190 enriched pathways for further analysis. Subsequently, principal component analysis also revealed that among top ten hub targets (TP53, CASP3, MAPK1, JUN, ESR1, CDK1, CDK2, TNF, GNRH1, CDKN1A) only TP53, JUN and ESR1were significantly interacted with melatonin on the basis of squared cosine value. So, present in silico investigation provides considerable information on the interactive network between therapeutic targets of melatonin along with the involvement of intracellular signalling cascade regulating biological processes associated with the gametogenesis. This novel approach may be pertinent in improving modern research on reproductive dysfunctions associated abnormalities.

Melatonin, circadian rhythms and breast cancer

Breast cancer (BC) is the leading cause of morbidity and mortality of malignant neoplasms in women worldwide. In spite of a large number of studies devoted to the etiopathogenesis of this group of malignant tumors, many questions concerning specific mechanisms of their origin and development are still unresearched. Based on numerous studies in recent years, in addition to traditional risk factors (such as hereditary factors, hormonal disorders, environmental factors, etc.), foreign and Russian authors have identified a new risk factor for BC development - the sphere of molecular disorders affecting circadian rhythms and circadian genes, as well as metabolic and regulatory intracellular pathways regulated by them. It has been shown that the balance between oncogenes and suppressor genes and processes such as neoangiogenesis, metastasis and antitumor immune response depend on the functioning of the circadian rhythm system. One of the key metabolites in the circadian rhythm regulation system is melatonin, which physiological effects extend not only to the central nervous system, but also to peripheral tissue cells. The study of the relationship between circadian rhythm disturbances, melatonin secretion and malignant tumors is one of the important tasks of modern oncology. In the present review the following aspects of this problem are considered in detail: relationships between circadian rhythms, melatonin and BC; molecular mechanisms of melatonin antitumor action in BC; therapeutic potential of melatonin in prevention and treatment of malignant breast tumors as a direct antitumor agent, a component of accompanying treatment, and as a radiosensitizer and radioprotector for radiotherapy. The purpose of this review is to investigate the problem of the relationship between the circadian rhythm system, melatonin and molecular mechanisms of development and progression of breast malignancies, as well as the therapeutic potential of melatonin in their prevention and treatment. The review is based on the study of relevant and reliable scientific articles, reviews, meta-analyses, systematic reviews, and clinical trials published in Scopus, PubMed, Web of Science and in peer-reviewed Russian journals mainly during the last 5 years.

Melatonin: Potential avenue for treating iron overload disorders.

Iron overload as a highly risk factor, can be found in almost all human chronic and common diseases. Iron chelators are often used to treat iron overload; however, patient adherence to these chelators is poor due to obvious side effects and other disadvantages. Numerous studies have shown that melatonin has a high iron chelation ability and direct free radical scavenging activity, and can inhibit the lipid peroxidation process caused by iron overload. Therefore, melatonin may become potential complementary therapy for iron overload-related disorders due to its iron chelating and antioxidant activities. Here, the research progress of iron overload is reviewed and the therapeutic potential of melatonin in the treatment of iron overload is analyzed. In addition, studies related to the protective effects of melatonin on oxidative damage induced by iron overload are discussed. This review provides a foundation for preventing and treating iron homeostasis disorders with melatonin.

The therapeutic effect and mechanism of melatonin on osteoarthritis: From the perspective of non-coding RNAs.

Osteoarthritis (OA) is a slowly progressing and irreversible joint disease. The existing non-surgical treatment can only delay its progress, making the early treatment of OA a research hotspot in recent years. Melatonin, a neurohormone mainly secreted by the pineal gland, has a variety of regulatory functions in different organs, and numerous studies have confirmed its therapeutic effect on OA. Non-coding RNAs (ncRNAs) constitute the majority of the human transcribed genome. Various ncRNAs show significant differentially expressed between healthy people and OA patients. ncRNAs play diverse roles in many cellular processes and have been implicated in many pathological conditions, especially OA. Interestingly, the latest research found a close interaction between ncRNAs and melatonin in regulating the pathogenesis of OA. This review discusses the current understanding of the melatonin-mediated modulation of ncRNAs in the early stage of OA. We also delineate the potential link between rhythm genes and ncRNAs in chondrocytes. This review will serve as a solid foundation to formulate ideas for future mechanistic studies on the therapeutic potential of melatonin and ncRNAs in OA and better explore the emerging functions of the ncRNAs.

Melatonin supplementation preserves testicular function by attenuating lactate production and oxidative stress in high fat diet-induced obese rat model

Metabolic syndrome, including obesity has been documented as a critical factor in male reproductive dysfunction with subsequent reduction in male fertility. The therapeutic potential of melatonin has been demonstrated against oxidative stress-induced pathologies. Therefore, the present study investigated the effects of melatonin on testicular dysfunction associated with high fat diet (FD)-induced obese rat model, and the possible involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ). Adult male Wistar rats (n = 6/group) were used: control group received vehicle (normal saline), obese group received 40% FD, melatonin-treated group received melatonin (4 mg/kg), and obese plus melatonin group received melatonin and 40% FD and the treatment lasted for 12 weeks. High fat diet caused increased body weight and testicular triglyceride, total cholesterol, malondialdehyde, γ-glutamyl transferase, lactate production and lactate/pyruvate ratio as well as decreased glutathione/glutathione peroxidase, nitric oxide and PPAR-γ and circulating testosterone. Nevertheless, all these alterations were attenuated when supplemented with melatonin. Taken together, these results demonstrates that FD-induced obesity causes testicular dysfunction. In addition, the results suggest that melatonin supplementation protects against obesity-associated testicular dysfunction and this effect is accompanied by upregulation of PPAR-γ.

Uterine anomalies in cell proliferation, energy homeostasis and oxidative stress in PCOS hamsters, M. auratus: Therapeutic potentials of melatonin

AimsPolycystic ovarian syndrome (PCOS) is a reproductive, endocrine and metabolic disorder. Less is known about the mechanism of its effect on uterine function and therapeutic potential of melatonin. Our aim was to evaluate uterine dysfunction(s) in letrozole induced PCOS and its possible rectification by melatonin. Main methodsAdult female golden hamsters were divided into groups of Control (C), Melatonin (M; 1 mg/kg b.w.), Letrozole (L; 3 mg/kg b.w.) and combination of Letrozole+Melatonin (L + M; 3 mg/kg b.w. + 1 mg/kg b.w.) which were treated for 40 days. Analysis of serum testosterone/estradiol/progesterone/leptin/insulin, uterine histomorphometry, immunohistochemistry for proliferation cell nuclear antigen (PCNA), homeostatic assessment model of insulin resistance (HOMA-IR), western blotting for PCNA, androgen receptor (AR), insulin receptor (InsR), glucose tansporter-4 (GLUT-4), nuclear factor-kappa B (NFκB), cyclooxygenase-2 (COX-2) and biochemical analysis of superoxide dismutase (SOD)/catalase/lipid peroxidation (LPO) were done. Key findingsSerum testosterone, leptin and insulin increased while uterine InsR/GLUT-4 expression decreased in L group indicating metabolic abnormalities. Endometrial hyperplasia, increased expression of PCNA and AR indicated abnormal proliferation in L compared to C. Increased uterine oxidative load (SOD/catalase/LPO) and inflammatory markers NFκB/COX-2 expression in L was responsible for high tissue oxidative stress and inflammation. M administration normalized all the above parameters suggesting its ameliorative effect in L + M group. SignificanceWe report PCOS induced uterine dysfunction in Mesocricetus auratus for the first time. M administration restores uterine functions modulating cellular dynamicity, metabolic status, decreased oxidative and inflammatory load in PCOS hamsters. Therefore, we suggest the therapeutic potential of M against PCOS led uterine abnormalities to restore female fertility.

Melatonin prevents blood-retinal barrier breakdown and mitochondrial dysfunction in high glucose and hypoxia-induced in vitro diabetic macular edema model

Diabetic macular edema (DME) is a leading cause of blindness in diabetic retinopathy. Prolonged hyperglycemia plus hypoxia contributes to DME pathogenesis. Retinal pigmented epithelial cells comprise the outer blood-retinal barrier and are essential for maintaining physiological functioning of the retina. Melatonin acts as an antioxidant and regulator of mitochondrial bioenergetics and has a protective effect against ocular diseases. However, the role of mitochondrial dysfunction and the therapeutic potential of melatonin in DME remain largely unexplored. Here, we used an in vitro model of DME to investigate blood-retinal barrier integrity and permeability, angiogenesis, mitochondrial dynamics, and apoptosis signaling to evaluate the potential protective efficacy of melatonin in DME. We found that melatonin prevents cell hyper-permeability and outer barrier breakdown by reducing HIF-1α, HIF-1β and VEGF and VEGF receptor gene expression. In addition, melatonin reduced the expression of genes involved in mitochondrial fission (DRP1, hFis1, MIEF2, MFF), mitophagy (PINK, BNip3, NIX), and increased the expression of genes involved in mitochondrial biogenesis (PGC-1α, NRF2, PPAR-γ) to maintain mitochondrial homeostasis. Moreover, melatonin prevented apoptosis of retinal pigmented epithelial cells. Our results suggest that mitochondrial dysfunction may be involved in DME pathology, and melatonin may have therapeutic value in DME, by targeting signaling in mitochondria.

Role and Therapeutic Potential of Melatonin in Various Type of Cancers.

Cancer is a large group of diseases and the second leading cause of death worldwide. Lung, prostate, colorectal, stomach, and liver cancers are the most common types of cancer in men, whereas breast, colorectal, lung, cervical, and thyroid cancers are the most common among women. Presently, various treatment strategies, including surgical resection combined with chemotherapy, radiotherapy, nanotherapy, and immunotherapy, have been used as conventional treatments for patients with cancer. However, the clinical outcomes of advanced-stage disease remain relatively unfavorable owing to the emergence of chemoresistance, toxicity, and other undesired detrimental side effects. Therefore, new therapies to overcome these limitations are indispensable. Recently, there has been considerable evidence from experimental and clinical studies suggesting that melatonin can be used to prevent and treat cancer. Studies have confirmed that melatonin mitigates the pathogenesis of cancer by directly affecting carcinogenesis and indirectly disrupting the circadian cycle. Melatonin (MLT) is nontoxic and exhibits a range of beneficial effects against cancer via apoptotic, antiangiogenic, antiproliferative, and metastasis-inhibitory pathways. The combination of melatonin with conventional drugs improves the drug sensitivity of cancers, including solid and liquid tumors. In this manuscript, we will comprehensively review some of the cellular, animal, and human studies from the literature that provide evidence that melatonin has oncostatic and anticancer properties. Further, this comprehensive review compiles the available experimental and clinical data analyzing the history, epidemiology, risk factors, therapeutic effect, clinical significance, of melatonin alone or in combination with chemotherapeutic agents or radiotherapy, as well as the underlying molecular mechanisms of its anticancer effect against lung, breast, prostate, colorectal, skin, liver, cervical, and ovarian cancers. Nonetheless, in the interest of readership clarity and ease of reading, we have discussed the overall mechanism of the anticancer activity of melatonin against different types of cancer. We have ended this report with general conclusions and future perspectives.

THE ROLE OF MELATONIN IN THE IMMUNE RESPONSE REGULATION

In this paper, it is shown that melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system, including immunoregulatory, free radical and antioxidant, including anti-inflammatory effects. These data indicate the possible therapeutic potential of melatonin in various human diseases.

A potential protection of melatonin on pathogenesis of oral sub-mucous fibrosis (OSMF) : a current update

Oral submucous fibrosisis (OSMF) is a clinical condition of the oral cavity which is caused predominantly by areca nut consumption. This fibrotic condition affects almost all parts of the oral cavity and can cause significant reduction in mouth opening, thereby, resulting in functional impairment. The other potential risk of OSMF is its malignant transformation into oral squamous cell carcinoma, which occurs in a significant number of afflicted patients. Extensive researches have been conducted to understand the pathogenesis of OSMF for identification of tangible therapeutic modalities. To date, there is no effective therapeutic modality for this disorder. It is well known that melatonin has a potent anti-fibrotic, anti-oxidant, and pro-angiogenic effects. The therapeutic potential of melatonin on OSM cannot be ignored. In this article we have explored the potential mechanisms of melatonin as an adjuvant in the prevention and treatment of OSMF.

Can Melatonin Be a Potential "Silver Bullet" in Treating COVID-19 Patients?

The therapeutic potential of melatonin as a chronobiotic cytoprotective agent to counteract the consequences of COVID-19 infections has been advocated. Because of its wide-ranging effects as an antioxidant, anti-inflammatory, and immunomodulatory compound, melatonin could be unique in impairing the consequences of SARS-CoV-2 infection. Moreover, indirect evidence points out to a possible antiviral action of melatonin by interfering with SARS-CoV-2/angiotensin-converting enzyme 2 association. Melatonin is also an effective chronobiotic agent to reverse the circadian disruption of social isolation and to control delirium in severely affected patients. As a cytoprotector, melatonin serves to combat several comorbidities such as diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases, which aggravate COVID-19 disease. In view of evidence on the occurrence of neurological sequels in COVID-19-infected patients, another putative application of melatonin emerges based on its neuroprotective properties. Since melatonin is an effective means to control cognitive decay in minimal cognitive impairment, its therapeutic significance for the neurological sequels of SARS-CoV-2 infection should be considered. Finally, yet importantly, exogenous melatonin can be an adjuvant capable of augmenting the efficacy of anti-SARS-CoV-2 vaccines. We discuss in this review the experimental evidence suggesting that melatonin is a potential “silver bullet” in the COVID 19 pandemic.

Elderly as a High-risk Group during COVID-19 Pandemic: Effect of Circadian Misalignment, Sleep Dysregulation and Melatonin Administration.

The association of age with a higher vulnerability to COVID-19 infection is a subject of major importance. Several factors, including higher stress due to social isolation, diminished melatonin levels with age, and higher exposure of individuals to light at the evening, which reduces melatonin levels and disrupts circadian rhythmicity are relevant for maintaining the circadian health in aged individuals. Properly administered, chronotherapy restores the optimal circadian pattern of the sleep–wake cycle in the elderly. It involves adequate sleep hygiene, timed light exposure, and the use of a chronobiotic medication like melatonin, which affects the output phase of circadian rhythms thus controlling the biological clock. Besides, the therapeutic potential of melatonin as an agent to counteract the consequences of COVID-19 infections has been advocated due to its wide-ranging effects as an antioxidant, anti-inflammatory, and as an immunomodulatory agent, as well as to a possible antiviral action. This article discusses how chronotherapy may reverse the detrimental circadian condition of the elderly in the COVID-19 pandemic.