key: cord-0798480-rx1k9hu5
authors: Parlakpinar, Hakan; Polat, Seyhan; Acet, Hacı Ahmet
title: Pharmacological agents under investigation in the treatment of coronavirus disease 2019 and the importance of melatonin
date: 2020-07-13
journal: Fundam Clin Pharmacol
DOI: 10.1111/fcp.12589
sha: c8987f12fa246bdb2347ec01dc210c35074476fa
doc_id: 798480
cord_uid: rx1k9hu5

Coronavirus disease 2019 (COVID‐19) is a life‐threatening infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). COVID‐19 pandemic causing morbidities and even deaths worldwide revealed that there is urgent need to find pharmacological agents or vaccines. Although there are a lot of agents under investigation, there is no approved agent for the prevention or treatment of the COVID‐19 yet. Treatment of patients remains mainly supportive as well as compassionate use of the agents under investigation. It is well established that excessive inflammatory and immune response as well as oxidative injury play a critical role in the pathogenesis of COVID‐19. In this review, we aimed to update knowledge about pathogenesis, clinical features and pharmacological treatment of COVID‐19 and review the potential beneficial effects of ancient antioxidant, anti‐inflammatory and immunomodulatory molecule melatonin for prevention and treatment of COVID‐19.

S1 subunit of S protein is necessary for atttachment whereas S2 subunit is necessary for viral fusion and cell entry. Recently, it was shown that, transmembrane serine protease 2 (TMPRSS2), cleaves the S protein from S1/S2 and the S2' site for allowing viral fusion, primes S2 subunit for entry, and a serine protease inhibitor camostat mesylate hinders SARS-CoV-2 infection of lung cells (11, 12) . The S protein of SARS-CoV-2 binds ACE2 with higher affinity than SARS-CoV (6) . As a result of proinflammatory cytokine/chemokine response during SARS-CoV and MERS-CoV infections, a cytokine storm may occurs; lung epithelial and endothelial cells may undergo apoptosis (5, 6) . These changes induce damaging of the alveolarcapillary barrier, alveolar edema and disruption of gas exchange resulting in ARDS (6) .

More recently, it was reported that the nucleotide sequence of SARS-CoV-2 is 79.7% identical to the SARS-CoV and 51.8% identical to the MERS-CoV (1) . As with SARS-CoV and MERS-CoV infections, in the critical patients with COVID-19 a process called "cytokine storm" is known to play an important role in the development of ARDS and multiple organ failure (5, 6) .

Elevated levels in IL-1β, IFN-γ, interferon-inducible protein 10 (IP-10), and monocyte chemoattractant protein 1 (MCP-1), as well as anti-inflammatory cytokines IL-4 and IL-10, have shown in patients with COVID-19 (13) .

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Although a considerable amount of experimental researchs and clinical trials have been conducted to date, currently there is no FDA-approved drug for the prevention and treatment of the COVID-19. As a result, the treatment of patients with COVID-19 is mostly based on supportive care including oxygen therapy and control of fever, prevention and/or treatment of complications, and mechanical ventilation support in severe cases (7) . 

This article is protected by copyright. All rights reserved Camostat mesylate is used for the treatment of pancreatitis. It inhibits TMPRSS2, thereby hinder host cell entry of the virus (22).

Tocilizumab which is used for RA has off-label use for COVID-19 treatment, based on anti-inflammatory effects. It is a recombinant humanized anti-human IL-6 receptor monoclonal antibody. In a retrospective study, tocilizumab was found to be associated with improve in the symptoms, oxygenation of blood, and pulmonary opacities in patients with severe COVID-19 (45) . Tocilizumab was reported to cause abnormal liver function tests, neutropenia and anaphylaxis (46) .

Remdesivir is a broad-spectrum antiviral nucleotide prodrug with potent in vitro antiviral activity against Ebola virus (EBOV), MERS-CoV, SARS-CoV, respiratory syncytial virus (RSV) and SARS-CoV-2 (47, 48) . Remdesivir, an investigational nucleotide analogue, inhibits viral RdRP (49) . Its proposed dose is 200 mg loading dose, followed by 100 mg daily infusion for COVID-19 treatment in a clinical trial (22). In a randomized controlled trial of Ebola virus disease (EVD) therapeutics, remdesivir was reported to may be associated with hypotension followed by cardiac arrest in a patient (50) .

Favipiravir is used for influenza in Japan. It acts through its active metabolite favipiravir ribofuranosyl-5′-triphosphate, a purine nucleotide which inhibits viral RdRP. It has in vitro activity against SARS-CoV-2 (22). In an open-label control study, favipiravir was given at an oral dose of 1600 mg twice a day on first day and 600 mg twice a day on days 2-14 to patients with COVID-19. It has been reported following side effects due to favipravir; diarrhea, liver injury and poor diet (51) .

Knowledge about proposed drugs for the treatment of COVID-19 depends on in vitro and animal studies as well as clinical data with low level of evidence such as case reports, case series and clinical trials with insufficient sample size and risk of bias in the literature (22). There is an urgent need for the development of effective prevention and treatment strategies for COVID-19. In addition, it should not be forgotten that there is also need to continuous public drug information service regarding COVID-19 treatment (52).

This article is protected by copyright. All rights reserved Melatonin, also called as N-acetyl-5-methoxytryptamine, is an indolamine molecule ( Figure 2 ). In humans, this hormone is mainly produced by pinealocytes in the pineal gland, then released in blood. Melatonin both regulates circadian rhythm (53) and its biosynthesis in the pineal gland is correlated with the circadian rhythm which is provided by When β 1 -adrenergic receptor on the pinealocyte's memrane is being stimulated, cAMP level and PKA activity increases, respectively, and CREB is being stimulated followed by the increase in production of N-acetyltransferase (NAT). Alpha 1 -adrenergic receptors strengthen β 1adrenergic activity by increasing PLC activity which leads to subsequently increase in the level of cytosolic Ca 2+ and the activity of protein kinase C (PKC) and prostaglandins (55) .

Melatonin is synthesied from tryptophan through four consecutive enzymatic reaction.

First step is the conversion of tryptophan to 5-hydroxytryptophan by tryptophan hydroxylase. In the second step, 5-hydroxytryptophan is decarboxylated to serotonin. Then, serotonin is converted to N-acetylserotonin (NAS) by AANAT followed by conversion of NAS to melatonin by acetylserotonin O-methyltransferase (ASMT) (54, 57) .

This article is protected by copyright. All rights reserved Melatonin exerts both lipophilic and hydrophilic properties. Melatonin is not stored in the pinealocytes and can easily across the blood brain barrier depend on its amphiphilic feature. It immediately enters the cerebrospinal fluid (CSF) and blood, once synthesized in the pineal gland [53] . Melatonin binds to albumin about 70 % in the blood. It has been reported to have a half life of about 3-45 min based on its biphasic elimination when orally administered. Also, it has a half life of about 30 min following intravenous infusion (55) .

Melatonin is transformed to 6-hydroxymelatonin (6-HM) by CYP 1 A 2 and conjugated to 6sulfatoxymelatonin (6-SM) in the liver and also kidney. These metabolites eliminated through urine (54) . The main urinary metabolite of melatonin is 6-SM in humans (55) .

In the central nervous system (CNS), melatonin is enzymatically, pseudoenzymatically or nonenzymatically metabolized to N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) which is converted to N-acetyl-5-methoxykynuramine (AMK) by undergoing deformylation (56).

Melatonin, AFMK and AMK have free radical scavenging activity and protective effects against oxidative damage. AFMK is the poorest scavenger among them. Generally, protective effects against oxidative damage may be ordered as follows: AMK>melatonin>AFMK (58).

Melatonin, is known to have substantial anti-inflammatory properties and activates a number of antioxidative enzymes such as glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT), regulates expression of several defensive enzymes, and diminishes lipid peroxidation and apoptosis. It is clear that, oxidative stress markedly triggers apoptosis (9) .

Also, melatonin has several pleiotropic effects by distinct mechanisms. In this regard, melatonin, one of the most powerful natural antioxidants, directly interacts with reactive oxygen and nitrogen species, providing antioxidant effects independently of its cellular receptors and mobilizing the intracellular antioxidant enzymatic system. Moreover, melatonin has specific cellular membrane receptors including MT1 (MTNR1A in humans) and MT2 (MTNR1B in humans). These receptors are heterotrimeric Gi/Go and Gq/11 protein-coupled receptors which interact with adenylyl cyclase (AC), phospholipase A2 (PLA2) and PLC, resulting in reduced cAMP and cGMP production and/or increment in diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)

formation. MT1 and MT2 receptors are found in nearly all peripheral tissues in addition to the CNS. Melatonin has been reported to bind to retinoid orphan receptors/retinoid Z receptors

This article is protected by copyright. All rights reserved (ROR/RZR nuclear receptors) (54) . Also, melatonin have been shown to bind to a cytosolic enzyme, quinone reductase 2 (QR2), previously called as MT3 receptor (59) .

Melatonin has been reported to be effective against several viral infections (60). Melatonin exerts indirect antiviral properties by reducing inflammation and oxidative stress, and also by modulating immune responses (5).

EVD is a rapidly progressive and highly lethal disease caused by EBOV. RSV may leads to severe lung disease because of excessive inflammatory immune response in childhood. In this regard, oral pre-administration of melatonin at dose of 5 mg/kg twice daily for 3 days was shown to result in a significant decerement of oxidative lung damage and inflammation in mice infected with RSV. It was reported that melatonin, markedly inhibited the increment of malondialdehyde (MDA), nitric oxide (NO) and hydroxyl radical (·OH) levels and restored the reduced glutathione (GSH) and SOD levels in the lung due to its antioxidant and free radical scavenger effects. Also, melatonin significantly inhibited inflammation by reducing elevated level of serum TNF-α (63). The protective effect of melatonin against RSV infection has also been shown in vitro study. According to the result of this study, melatonin pre-treatment was observed to inhibit the elevation of toll-like receptor 3 (TLR3)-mediated inflammatory gene expression including nuclear nuclear factor kappa-light-chain-enhancer of activated B cells (NF-

This article is protected by copyright. All rights reserved κB), TNF-α and inducible nitric oxide synthase (iNOS) without affecting TLR3 protein, in RSVinfected macrophages. It was suggested that melatonin supress the elevation of TNF-α and iNOS expression by inhibiting NF-κB nuclear translocation (64) .

which especially affects human and equines. The inflammation induced by VEEV is associated with a high mortality rate in mice. According to data obtained from an experimental study; while melatonin application for pre-treatment (three days before the infection and continuing until the end of the experiment) and treatment (during the infection) increased the survival rate; melatonin application for post-treatment (24 h after the infection) was found to be ineffective on survival in mice infected with VEEV, suggesting melatonin has a preventive effect on VEE infection.

experiments of mentioned study. Melatonin reduced the apoptosis in the brain of infected mice and in the VEEV-infected neuroblastoma cells. On the contrary, melatonin was reported to cause apoptosis of uninfected neuroblastoma cells (65) . Melatonin was also shown to protect mice infected with the VEEV by decreasing mortality rate, postponing the onset of the disease, reducing viral load in the brain as well as in the blood. Also, it has been reported that melatonin diminishes the cell destruction in the chicken embryo fibroblasts infected with the VEEV (66).

Melatonin also was shown to have protective effect against acute liver failure caused by rabbit hemorrhagic disease virus (RHDV) in an experimental study. It was reported that melatonin exerts anti-inflammatory effect including decrement in TNF-α and IL-6, and decreases viral replication by inhibiting hepatic sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway in rabbits infected with RHDV (67).

Melatonin also was reported to protect minks from Aleutian disease (AD) is a viral disease which leads to lesions in the kidney, liver, lungs and, arteries beacuse of hypergammaglobulinemia and immune complexes caused by AD parvovirus. Melatonin was observed to markedly reduced mortality rate in minks infected with AD virus. It was suggested that protective effect of melatonin may be due to its free radical scavenger, immunomodulator and antioxidant enzyme-inducing properties (68) . 

Oxidized products are released during viral infections and replication (5 has an important role in the protection from I/R injury in the body (71) . In this context, we

This article is protected by copyright. All rights reserved previously observed that melatonin is a protective agent against liver damage, induced by pinealectomy, renal I/R or myocardial I/R (72-74), I/R injury of brain (75) , heart (76) and flap injury (77), testicular injury (78), radiation damage (79), cerebral vasospasm after subarachnoidal hemorrhage (80) and colitis (9) in rats. In this context, there are several possible conditions increasing free radicals in COVID-19 patients as follows; excessive inflammation, cytokine storm, hypoxemia and respiratory support by mechanical ventilation. It is well known that mechanical ventilation can causes ventilator-induced lung injury (VILI) which includes alveolar damage, lung edema, accumulation of immune cells, proinflammatory cytokine discharge, and the exaggerated ROS generation. Unfortunately, VILI is a condition which can result in sequelae and even death.

Recently, ramelteon, a melatonin receptor agonist, has been reported to protect lung from VILI by increasing IL-10 production in a rat model (81) . Decreased level of intracellular heme oxygenase 1 (HO-1), an antiviral, anti-inflammatory, antioxidant and cytoprotective stress protein, may exert an important role in the pathogenesis of COVID-19 (82) . Melatonin is known to increase a group of antioxidant proteins including HO-1 by activating NF-E2-related factor 2 (Nrf2) (83, 84) . In this regard, melatonin was proposed to use for COVID-19 treatment because of its HO-1 enhancing property (82) . According to our experiences and available literature data, it seems to us that melatonin may also be beneficial in COVID-19 treatment (5), and anti-inflammatory properties COVID-19 blockade of heme synthesis could limit the HO-1 stress tolerance function, contributing to host fragility.

As a good news, recently, melatonin was proposed to be a potential candidate drug as an adjuvant treatment for patients with COVID-19 (5). Also, melatonin was found to be candidate drug for COVID-19 in a network-based drug repurposing study. Melatonin was predicted to indirectly interact with the human CoVs-associated cellular proteins, including ACE2, B-cell lymphoma 2 (Bcl-2)-like protein 1 (BCL2L1), JUN, and inhibitor of NF-κB kinase subunit beta (IKBKB). Also, according to this study, combination of mercaptopurine and melatonin may be a potential treatment for COVID-19 by synergistically targeting papainlike protease, ACE2, c-Jun signaling, and anti-inflammatory cascades (1).

The possible anti-inflammatory effects of melatonin that may be beneficial in the ALI/ARDS induced by COVID-19 involves upregulation of sirtuin-1 (SIRT1), suppression of NF-

This article is protected by copyright. All rights reserved κB activation, stimulation of NF-E2-related factor 2 (Nrf2), thus a decrement in the proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) and increment in the level of antiinflammatory cytokine IL-10 (5). In addition, exerts cardioprotective effects by modulating apoptosis and autophagy via elevating expression of SIRT1 in septic mice (85) . Preclinical and clinical studies have reported that melatonin reduces pro-inflammatory cytokines in many diverse conditions. In this regard, melatonin has been reported to dose-dependently reduce TNF-α and IL-1β production but not IL-6 in human RA synovial fibroblasts (86) . Melatonin administration (orally 25 mg daily for 6 months) has been reported to reduce serum levels of TNF-α, IL-1β, IL-6, lipoperoxides, NO catabolites in patients with relapsing-remitting multiple sclerosis (RRMS) (87) .

In a a double-blind, placebo-controlled clinical trial, melatonin (orally 6 mg daily for 8 weeks)

administration significantly decreased serum level of IL-6 and high-sensitivity C-reactive protein (hs-CRP) but not TNF-α in type 2 diabetes mellitus (DM) patients with chronic periodontitis (88) .

Melatonin has been reported to reduce TNF and IL-6 levels, and increase IL-10 level in human placental trophoblasts which have been undergone hypoxia/reoxygenation (89) . Melatonin administration (10 mg at 09:00 h and 60 mg at 21:00 h for 3 months) has been reported to reduce plasma levels of IL-1β, IL-2, IL-6, and TNF-α in patients with Charcot-Marie-Tooth Neuropathy (90) . In a double-blind, placebo-controlled clinical trial, melatonin administration (6 mg daily for 40 days) has been reported to reduce plasma levels of TNF-α and IL-6 in obese women (91) .

Melatonin administration (25 mg/kg ip 30 min before each caerulein injection) has been reported to result in decrease in IL-1β and TNF-α, and increase in IL-4 serum levels in rats with caeruleininduced acute pancreatitis (92) . Melatonin administration (10 mg/kg ip) has been reported to reduce TNF-α serum level in rats with Escherichia coli-induced pyelonephritis (93) . These data of in vivo, in vitro and clinical studies indicate that melatonin may be potential supportive agent in counteracting with cytokine storm in patients with COVID-19.

lymphocytes, granulocytes and monocytes, thus supports immune response. Melatonin augments antigen presentation in macrophages, thus complement receptor 3, MHC class I and class II, and CD4 antigens are up-regulated. Given the level of neutrophils, lymphocytes and CD8 + T cells may decrease in peripheral blood in COVID-19 patients, melatonin may also be useful as an immunoregulator (5) . Also, melatonin has been reported to blunt the NF-kB induction and decrease the NLRP3 expression in heart of mice with polymicrobial sepsis induced by the cecal

This article is protected by copyright. All rights reserved ligation and puncture (CLP) model. It is well established that the nucleotide oligomerization domain (NOD)-like receptor 3 (NLRP3) inflammasome play an important role in the innate immune response during inflammatory states (94) . In addition, melatonin has been reported to reduce the macrophage and neutrophil infiltration in the lung by inhibiting NLRP3 inflammasome in experimental models. This effect, may be another reason for using melatonin in the treatment of COVID-19 (5).

Currently, in Spain, there is an ongoing multicenter randomized placebo-controlled phase 2/3 clinical trial "MeCOVID" investigating whether melatonin has an efficacy in the prophylaxis of COVID-19 among healthcare workers. Status of this trial is not yet recruiting. Four hundred fifty participants between the ages of 18-65 are estimated to be included in the study. It is known that that the peak blood level of melatonin is higher in younger children and SARS-CoV-2 appears to less affect them when compared to other groups of age. In this regard, the researchers supposed that approximately reaching the melatonin levels in children may protect from infection or hinder progression to severe disease even if the infection occurs. For this purpose, melatonin with prolonged release will be administered orally at a dose of 2 mg daily before bedtime for 12 weeks.

Confirmed symptomatic infection rate will be considered as primary outcome measure of the study (95).

Inhibition of melatonin by most viruses suggest that modulation of melatonin may be useful in the management of viral infections (96) . Although melatonin has not direct effects on viral replication or transcription, based on its antioxidant and anti-inflammatory properties, it may be a potential drug to reduce the severity of clinical symptoms. Melatonin also may decrease mortality rate among patients with viral disease and save them time to recover (1). Given the antioxidant and anti-inflammatory effects, melatonin seems to be a potential agent for attenuation of COVID-19 infection. As an adjuvant therapeutic agent, melatonin may be useful in COVID-19

and related complications including ALI and ARDS likely by immune regulation, antiinflammation and antioxidation (5) . There is urgent necessity to a lot of well-designed preclinical and clinical studies investigating efficacy of melatonin for COVID-19 treatment.

This article is protected by copyright. All rights reserved ACE2, a homologue of ACE, is found as two types: membrane-bound and soluble. Membranebound ACE2 is a type I transmembrane metallopeptidase which comprises an extracellular catalytic domain, receptor for SARS-CoV-2, and a transmembrane anchor. Soluble ACE2 circulates in the blood and has no anchor (97) . ACE2 operates as a monocarboxypeptidase with its extracellular catalytic domain which degrades angiotensin II (Ang II) and angiotensin I (Ang I) into angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9), respectively (98) . In addition, ACE2 possibly exerts enzymatic effect on other substrates including apelin, des-arginine bradykinin and neurotensin. Ang 1-7-mitochondrial assembly (MAS) receptor binding leads to vasodilation, anti-inflammatory and anti-fibrotic effects. Thus, Ang 1-7 establishes the balance by eliminating the harmful effects caused by Ang II (97).

ACE2 is located primarily in the lung (airways and type II alveolar cells), heart, kidney and intestine. It is also found in oral and nasal mucosa, skin, lymph nodes, thymus, bone marrow, spleen, liver, testis and brain (97) .

Endocytosis of viral particles-ACE2 complex leads to decrease in membrane-bound ACE2

expression. In addition, upregulation in protease activity of a disintegrin and metalloproteinase 17 (ADAM17) which separating 2 domains of ACE2 from each other results in sheds extracellular catalytic domain of ACE2 into the circulation. Thus, while activity of the protective ACE2/Ang 1-7/MAS receptor axis is decreasing, increased activity of harmful ACE/Ang II/ Angiotensin II receptor type 1 (AT1 receptor) axis is occured. Increased level of Ang II leads to further upregulation of ADAM17 activity through the AT1 receptors and downstream extracellular signalregulated kinase (ERK) / p38 mitogen-activated protein kinase (MAPK) signaling pathways.

ADAM17 also associated with the liberation of membrane bound precursors of TNF-α, IFN-γ, and IL-4 into the circulation. It is well established that IL-4 and IFN-γ, reduce ACE2 expression (99) .

Thefore, reduction in tissue ACE2 levels may result in increased lung damage and tissue fibrosis seen in COVID-19 cases (97) . COVID-19 not only affects the lungs but also causes acute cardiac and renal damage, myocarditis, arrhythmias, and gut and liver pathologies. These events are considered to be related to the loss of tissue ACE2 as a result of COVID-19 (99) . In this context, SARS-CoV infection is also known to cause cardiac dysfunction, arrhythmias and even cardiac death. SARS-CoV infection has been reported to cause myocardial dysfunction by reducing myocardial ACE2 expression in mice (96) . Remarkably high Ang II plasma levels which correlated with viral load and pulmonary damage have been reported in patients with COVID-19

This article is protected by copyright. All rights reserved (100) . This increase in Ang II levels in patients with COVID-19 seems to be result of a decrease in tissue ACE2 levels. Also, reduced plasma Ang II / Ang There is an ongoing open label, randomized and controlled phase 1 clinical trial in Egypt.

In this study, it is aimed to investigate the potential beneficial effects of recombinant bacterial ACE2 receptors-like enzyme of B38-CAP (rbACE2) on an estimated 24 adult patients with COVID-19. The study has not started to be recruited yet. 0.4 mg/kg rbACE2 will be intravenously administrated to the intervention group twice a day for 7 days (104).

According to the aforementioned preclinical and clinical data, reduced tissue expression of ACE2 and thus shift of RAS balance towards ACE/Ang II/AT1 pathway seems to be an important factor in the pathogenesis of multipl organ damage including lung, heart, kidney and liver in patients with COVID-19. This data suggest that restoring tissue ACE2 levels and also preventing shift of RAS balance towards ACE/Ang II/AT1 pathway may be an effective approach in the treatment of COVID-19. RAS modulating effects of melatonin has been reported in several experimental studies (Table I) .

Maternal melatonin application (0.01% melatonin in drinking water during pregnancy and lactation) has been reported to increase ACE2 and AT2R expression as well as MAS receptor protein levels in the kidney of male offspring rats with prenatal dexamethasone (DEX)-induced

This article is protected by copyright. All rights reserved programmed hypertension. In this study, investigators have suggested that elevated renal MAS protein levels play an important role in the prevention of DEX-induced programmed hypertension by melatonin (105) .

Melatonin administration to pups (0.01% melatonin in drinking water during the lactation period) has been reported to increase ACE2 expression in the kidney and heart of male offspring rats with neonatal DEX-induced programmed hypertension (106) . Maternal melatonin treatment (0.01% melatonin in drinking water during pregnancy) increased ACE2 expression and protein levels in the kidney of the adult offspring exposed to maternal caloric restriction (107) .

In an experimental study investigating effects of maternal agomelatine (melatonin receptor agonist) and melatonin treatment during pregnancy and lactation on programmed hypertension in male offspring rats of mother exposed to continuous light, several changes have been reported on RAS. In this study, it has been reported that, maternal agomelatine (50 mg/day ip) administration decreased expression of ACE and ACE2 but increased expression of ang II type 2 receptor (AT2 receptor) (mediating beneficial effects of Ang II) and MAS receptor in kidney. Additionally, maternal melatonin application (0.01% in drinking water) reduced renal ACE expression (108) .

Maternal melatonin therapy (0.01% melatonin in drinking water during pregnancy and lactation) has been reported to increase renal expression of AT2 receptor and MAS receptor in prenatal DEX and postnatal high-fat diet induced programmed hypertension in male offspring rats (109) .

Considering the limited number of studies mentioned above, melatonin may be a potential agent to prevent multiple organ injuries and subsequent disease progression as well as sequelae in patients with COVID-19 due to its modulating effects on RAS, and antioxidant, anti-inflammatory, free radical scavenger, antiviral and immunomodulatory effects. Ultimately, the results of the ongoing trial of melatonin in the prophylaxis of COVID-19 on healthcare workers, and additional clinical and preclinical studies will offer more strong evidences to science world. 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

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Accepted Article This article is protected by copyright. All rights reserved 14

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Accepted Article This article is protected by copyright. All rights reserved 79

Melatonin protects inner ear against radiation damage in rats

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Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Accepted Article This article is protected by copyright. All rights reserved

A consensus statement on the use of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in relation to COVID-19 (corona virus disease 2019). The New Zealand medical journal

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Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP Could be Promising

Infection-and Lung Injury Preventing Drug Better Than Recombinant Human ACE2 (Bacterial ACE2) 2020

Melatonin attenuates prenatal dexamethasone-induced blood pressure increase in a rat model

Melatonin prevents neonatal dexamethasone induced programmed hypertension: histone deacetylase inhibition. The Journal of steroid biochemistry and molecular biology

Melatonin therapy prevents programmed hypertension and nitric oxide deficiency in offspring exposed to maternal caloric restriction. Oxidative medicine and cellular longevity

Maternal melatonin or agomelatine therapy prevents programmed hypertension in male offspring of mother exposed to continuous light

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Authors declare no conflict of interest.

The study is not supported by any source of funding.

This article is protected by copyright. All rights reserved