Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial

Farnoosh, Gholamreza; Akbariqomi, Mostafa; Badri, Taleb; Bagheri, Mahdi; Izadi, Morteza; Saeedi-Boroujeni, Ali; Rezaie, Ehsan; Ghaleh, Hadi Esmaeili Gouvarchin; Aghamollaei, Hossein; Fasihi-Ramandi, Mahdi; Hassanpour, Kazem; Alishiri, Gholam Hossein

doi:10.1016/j.arcmed.2021.06.006

Cited by 65 publications

(72 citation statements)

References 20 publications

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“…This higher effectiveness of melatonin in some parameters of mutant mice could be due to an adjuvant effect of melatonin and lack of NLRP3 inflammasome. The adjuvant effect of melatonin has been used in several therapies against different pathologies including atherosclerotic carotid arterial stenosis, cancer, COVID-19, and diabetic neuropathy [69][70][71][72]. Recently, activation of mitochondrial calcium uptake 1 (MICU1) induced by melatonin has been suggested as a mechanism underlying the protective effect of melatonin against cardiac hypertrophy [73].…”

Section: Discussionmentioning

confidence: 99%

The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage

et al. 2021

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To investigate the role of NLRP3 inflammasome in cardiac aging, we evaluate here morphological and ultrastructural age-related changes of cardiac muscles fibers in wild-type and NLRP3-knockout mice, as well as studying the beneficial effect of melatonin therapy. The results clarified the beginning of the cardiac sarcopenia at the age of 12 months, with hypertrophy of cardiac myocytes, increased expression of β-MHC, appearance of small necrotic fibers, decline of cadiomyocyte number, destruction of mitochondrial cristae, appearance of small-sized residual bodies, and increased apoptotic nuclei ratio. These changes were progressed in the cardiac myocytes of 24 old mice, accompanied by excessive collagen deposition, higher expressions of IL-1α, IL-6, and TNFα, complete mitochondrial vacuolation and damage, myofibrils disorganization, multivesicular bodies formation, and nuclear fragmentation. Interestingly, cardiac myocytes of NLRP3−/− mice showed less detectable age-related changes compared with WT mice. Oral melatonin therapy preserved the normal cardiomyocytes structure, restored cardiomyocytes number, and reduced β-MHC expression of cardiac hypertrophy. In addition, melatonin recovered mitochondrial architecture, reduced apoptosis and multivesicular bodies’ formation, and decreased expressions of β-MHC, IL-1α, and IL-6. Fewer cardiac sarcopenic changes and highly remarkable protective effects of melatonin treatment detected in aged cardiomyocytes of NLRP3−/− mice compared with aged WT animals, confirming implication of the NLRP3 inflammasome in cardiac aging. Thus, NLRP3 suppression and melatonin therapy may be therapeutic approaches for age-related cardiac sarcopenia.

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Section: Discussionmentioning

confidence: 99%

The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage

et al. 2021

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Section: Potential Covid-19 Treatments and Role Of Mitochondriamentioning

confidence: 99%

“…Recently, melatonin has emerged as one of the potential enhancers/adjuvants in COVID-19 treatment [187]. Melatonin is a multifunctional molecule synthesized in mitochondria and possesses antioxidant, anti-inflammatory, and immunomodulatory functions that are shown to have a protective effect against COVID-19 [187][188][189]. As melatonin improves mitochondrial function by increasing oxidative phosphorylation, ATP production, upregulation of antioxidant enzymes, scavenging ROS and reactive nitrogen species (RNS), it has been proposed to test for its protective action against COVID-19 [188][189][190][191][192][193][194].…”

Section: Potential Covid-19 Treatments and Role Of Mitochondriamentioning

confidence: 99%

Roles of host mitochondria in the development of COVID-19 pathology: Could mitochondria be a potential therapeutic target?

et al. 2021

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The recent emergence of severe acute respiratory syndrome-Corona Virus 2 (SARS-CoV-2) in late 2019 and its spread worldwide caused an acute pandemic of Coronavirus disease 19 (COVID-19). Since then, COVID-19 has been under intense scrutiny as its outbreak led to significant changes in healthcare, social activities, and economic settings worldwide. Although angiotensin-converting enzyme-2 (ACE-2) receptor is shown to be the primary port of SARS-CoV-2 entry in cells, the mechanisms behind the establishment and pathologies of COVID-19 are poorly understood. As recent studies have shown that host mitochondria play an essential role in virus-mediated innate immune response, pathologies, and infection, in this review, we will discuss in detail the entry and progression of SARS-CoV-2 and how mitochondria could play roles in COVID-19 disease. We will also review the potential interactions between SARS-CoV-2 and mitochondria and discuss possible treatments, including whether mitochondria as a potential therapeutic target in COVID-19. Understanding SARS-CoV-2 and mitochondrial interactions mediated virus establishment, inflammation, and other consequences may provide a unique mechanism and conceptual advancement in finding a novel treatment for COVID-19.

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“…for elderly patients with comorbidities such as sleep disruption. The first paper primarily describes the clinical results in the 44 hospitalized patients with confirmed mild to moderate COVID-19 seen at the Baqiyatallah Hospital in Tehran who completed the study [ 38 ]. Patients had been randomly assigned to receive standard of care or standard of care in addition to melatonin at a dose of 3 mg three times daily for 14 days.…”

Section: Applicability To Covid-19mentioning

confidence: 99%

“…The 24 patients in the melatonin-treated group exhibited a significant improvement in clinical symptoms (cough, dyspnea, and fatigue) and pulmonary involvement, as well as significantly lower levels of circulating C-reactive protein as compared to 20 controls. Moreover, both the mean time of the hospital discharge of patients and return to baseline health were significantly shorter in the intervention group [ 38 ]. The second paper describes a cohort from the same study in which Th1 and Th2-mediated cellular and humoral immunity were evaluated in 40 male and female patients (20 receiving melatonin and 20 controls) [ 39 ].…”

Section: Applicability To Covid-19mentioning

confidence: 99%

Melatonin as an Add-On Treatment of COVID-19 Infection: Current Status

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Pandi-Perumal

Pupko³

et al. 2021

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This brief review was written to provide a perspective on the flurry of reports suggesting that melatonin can be an important add-on therapy for COVID-19. Despite the passage of more than 60 years since its discovery and much evidence representing the contrary, there has been great reluctance to conceive melatonin as anything other than a hormone. Many other body chemicals are known to have multiple roles. Melatonin was first shown to be a hormone derived from the pineal gland, to be actively synthesized there only at night, and to act on targets directly or via the G-protein-coupled receptors (GPCRs) superfamily. It is of note that over 40 years ago, it was also established that melatonin is present, synthesized locally, and acts within the gastrointestinal tract. A wider distribution was then found, including the retina and multiple body tissues. In addition, melatonin is now known to have non-hormonal actions, acting as a free radical scavenger, an antioxidant, and as modulating immunity, dampening down innate tissue responses to invaders while boosting the production of antibodies against them. These actions make it a potentially excellent weapon against infection by the SARS-CoV-2 virus. Early published results support that thesis. Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity. It is now critical that these trials be repeated, with dose-response studies conducted and safety proven. Numerous randomized controlled trials are ongoing, which should complete those objectives while also allowing for a more thorough evaluation of the mechanisms of action and possible applications to other severe diseases.

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Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial

Cited by 65 publications

References 20 publications

The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage

The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage

Roles of host mitochondria in the development of COVID-19 pathology: Could mitochondria be a potential therapeutic target?

Melatonin as an Add-On Treatment of COVID-19 Infection: Current Status

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