Please cite this paper as:

Chacin-Bonilla, L. and Bonilla, E. 2023. Melatonin and Covid-19: An opened Pandora’s box and the hope for the time being. Melatonin Research. 6, 4 (Dec. 2023), 474-484. DOI:https://doi.org/https://doi.org/10.32794/mr112500163.


Review

Melatonin and COVID-19: An opened Pandora’s box and the hope

Leonor Chacín-Bonilla1*, Ernesto Bonilla1

1Instituto de Investigaciones Clinicas, Universidad del Zulia, Apartado Postal 23, Maracaibo 4001- A, Venezuela

*Correspondence: leonorbonilla42@yahoo.com, TEL: +202-340-1787

Running title: Melatonin and COVID-19

Received: June 8, 2023; Accepted: December 8, 2023


ABSTRACT

    The SARS-CoV-2 pandemic is still an ongoing global health concern. No efficacious single therapeutic intervention is available, which is a severe problematic issue given that the mutated variants of this virus continue to evade immune surveillance and decrease vaccine efficacy. Therapy targeting symptoms and immune responses is of some importance. The symptoms of SARS-CoV-2 infection include hyperinflammation, cytokine storm and oxidative stress. Given the anti-inflammatory, anti-oxidative and cytoprotective effects of melatonin (MEL) in viral infections, the efficiency of MEL on SARS-CoV-2 is deserved for further study, especially on its direct-viricidal action and promotion of SARS-CoV-2 vaccine efficacy. MEL is a potentially efficacious, therapeutic option for SARS-CoV-2 infection but it is somehow ignored in the field.  Here, we strongly support and encourage the use of MEL in SARS-CoV-2 therapy.

Key words: Melatonin, SARS‐CoV‐2, COVID-19, anti-inflammation, antioxidation, immunomodulation, cytoprotection.

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1.      INTRODUCTION

    The SARS-CoV-2 pandemic remains a global health concern. No specifically effective treatment of SARS-CoV-2 infection is currently available (1). This is of a great concern given that the mutated variants continue to evade immune surveillance (2).  Alternative therapies which target hyperinflammation, the cytokine storm and oxidative stress, the crucial players in the evolution of disease, require further investigations (3-5). The therapeutic benefit of melatonin (MEL) in bacterial, fungal, parasitic, and viral infections has been well documented (6-11). MEL is a neglected but a potentially auspicious treatment option for COVID-19. MEL’s efficiency in treatment of this disease has been proven and its use to combat COVID-19 is increasingly recommended (3-5, 12, 13). Accordingly, Russel Reiter, a pioneer in MEL research, has emphasized its inclusion as an alternative or adjuvant therapy for COVID-19 (3, 4).

Our research indicates the effectiveness of MEL protecting against a viral infection, i.e., the Venezuelan equine encephalomyelitis virus (VEEV) infection. In mice infected with VEEV, MEL modified the progress of infection and time of death, increased survival rate compared to the untreated mice. At the molecular level. Melatonin treatment elevated production of interleukin-1b, decreased production of tumor necrosis factor-alpha (TNF-a), reduced viral replication, and lowered neural apoptosis and lipoperoxide concentrations (14-21). These observations have not confirmed in human VEEV infection since the last VEEV outbreak in Venezuela occurred in 1995 (21). However, based on the evidence collected by our group in decades of research on VEEV infection, we strongly support and encourage MEL use in COVID-19 therapy. Herein, we briefly discuss evidence documenting the therapeutic effect of MEL in SARS-CoV-2 infection during the COVID-19 pandemic indicating its comorbidities and mechanisms of action, as well as highlighting MEL as a potential medicine to counteract this devastating virus.


2.      MELATONIN- COVID-19 INTERACTIONS

     Melatonin cannot be classified as a viricidal; however, it can target viruses, through its anti‐inflammatory, anti-oxidative, and immunoregulatory actions (3-5) (Figure1). The potential links between SARS-CoV-2 severity and MEL still require further investigation.

 

Figure 1.jpg


Fig. 1.  The major biological activities of melatonin in organisms.

2.1.    Melatonin and its anti-inflammatory/immunoregulatory effects.

    The predominant pathophysiology of SARS-CoV-2 infection involves up-regulation of pro-inflammatory cytokines, which promote apoptosis, increase blood vessel permeability and inflammatory cell aggregation (3, 22). Hyperinflammatory monocytes/macrophages switch their energy metabolism from mitochondrial oxidative phosphorylation to the cytosolic glycolysis (Warburg effect), which stabilizes hypoxia inducible factor-1α (HIF-1α), thereby producing more cytokines (23). Since MEL is a powerful antioxidant/anti-inflammatory molecule, its use might help to overcome the cytokine storm (3).

    Melatonin exerts anti-inflammatory effects through several pathways (Figure 2). It reduces pro-inflammatory cytokines and increases anti-inflammatory cytokines. Sirtuin-1 may mediate the anti-inflammatory effects of MEL, which include the regulation of macrophage polarization (24). MEL is a suppressor of vascular endothelial growth factor, which contributes to edema and immune cells release (25). Exogenous MEL administration decreased pro-inflammatory cytokines during surgical stress (12, 26, 27) and in highly inflammatory diseases (28, 29), further indicating its ubiquitous anti-inflammatory utility. 

    Melatonin suppresses HIF-1α under experimental conditions (30, 31), as well as inhibits the activation of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB), as shown in acute respiratory distress syndrome (ARDS) (32) where MEL reduces lung damage. MEL also stimulates the production of the endogenous antioxidant regulator, nuclear factor E2-related factor 2 (Nrf2), thereby providing organ protection (33) (Figure 2). MEL has been administered to patients with cardiac and pulmonary diseases improving the overall health and preventing complications (34), further supporting its therapeutic utility.

Patients with severe infections have an increased risk of sepsis or septic shock leading to multiple organ failure and death, primarily driven by hyperinflammation and extensive oxidative damage. MEL may reduce the damage from septicemia by quelling HIF-1α, suppressing NF-κB, inhibiting the inflammasome, converting M1 macrophages to M2 macrophages, and impeding Warburg-type metabolism (4, 34) (Figure2).

Figure 2.jpg

Fig. 2. The potential mechanisms of melatonin against SARS-CoV-19 infection.

     M1: pro-inflammatory macrophage, M2: anti-inflammatory macrophage, ROS: reactive oxygen species, RNS: reactive nitrogen species, HIF-1α: hypoxia-inducible factor 1 alpha, MMP: Matrix metalloproteinase, PLA2: phospholipase A2, Nrf2: nuclear factor E2-related factor 2, SOD2: superoxide dismutase, NF-κB: nuclear factor kappa B, mtDNA: mitochondrial DNA, CRP: C-reactive protein, LDH: lactate dehydrogenase. Pointed up arrows: stimulation, pointed down arrows: inhibition.

     Melatonin improves radiation-induced lung damage and septic shock via inhibition of the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway, thereby preventing the death of premature newborns with bacterial sepsis or septic shock (4, 35). MEL enhances the immune response by improving proliferation and maturation of natural killer cells, T and B lymphocytes, granulocytes and monocytes. Antigen presentation, in macrophages, is also augmented after MEL application (3). The evidence mentioned above highlights the immune regulatory effects of melatonin, thereby increasing the capacity of the body more optimally responding to viral infection.

2.2.    Melatonin and its anti-oxidative capacity.

      Melatonin has direct and indirect antioxidant effects, mainly through free radical scavenging, endogenous anti-oxidative enzyme stimulation, down-regulation of pro-oxidative enzymes, and enhancement of other antioxidants. MEL inhibits metal-induced oxidation and protects mitochondria facilitating electron transfer antioxidant processes (12, 36). In respiratory syncytial virus (RSV) infectious models, MEL down-regulated acute lung oxidative injury, pro-inflammatory cytokine discharge, and inflammatory cell contracting (3), the crucial properties under intensive care conditions.

     Pulmonary fibrosis is an important complication of SARS-CoV-2 infection (37). MEL counteracts the oxidative stress driving pulmonary fibrosis. In idiopathic pulmonary fibrosis, MEL also has an anti-fibrotic effect, by inhibiting transforming growth factor (TGF)-β (35).

2.3.    Melatonin and chronobiotic effect.

      Melatonin exerts chronobiotic effects by stimulating G protein-dependent melatonin receptor types 1 and 2. In the elderly, the increased oxidative stress, decreased MEL production make them be greater susceptibility to severe COVID-19. MEL has been widely used in older individuals to reduce aging-related oxidative stress and improve their quality of life via circadian regulation (38).

     About 15% of hospitalized COVID-19 patients show impaired consciousness (39). Delirium is frequently seen in elderly patients and those undergoing mechanical ventilation. MEL also reduces the prevalence of this chronodisruption and improves sleep quality. By attenuating the emergence of delirium MEL minimizes the requirements for benzodiazepines or antipsychotics, which can complicate delirium treatment (12). The poor SARS-CoV-2 outcome in depressed patients may be linked to the decreased salivary MEL levels which also negatively correlate with depression severity (40).

2.4.    Melatonin and cytoprotection/anti-apoptosis.

      Melatonin levels are reduced in cardiovascular diseases, diabetes mellitus and metabolic syndrome, which all associate to the increased SARS-CoV-2 severity/fatality. MEL has beneficial effects on these diseases (12), indicating that the utilization of melatonin will decrease severity of SARS-CoV-2 outcomes associated with these conditions. In addition, more than 60% of COVID-19 survivors suffer post-COVID-19 syndrome, or long haul COVID-19. Severe long haul COVID symptoms are associated with myocarditis, especially in the elderly. As MEL significantly improves coxsackie-virus B3 (CVB3)-induced myocarditis (38), it may also have utility against long haul COVID linked myocarditis.

     MEL protects against virus-induced cellular death by regulating the anti-apoptotic and pro-apoptotic signaling pathways (20). MEL synthesis mainly occurs in mitochondria, which are crucial in apoptosis regulation (35). MEL reduces oxidative stress in VEEV (16, 19-21), RSV, CVB3, and Rabbit hemorrhagic virus infections (11). High levels of apoptosis as well as nitrite and malondialdehyde production are evident in VEEV infected neuroblastoma cells, which can be reduced by MEL (20), allowing MEL to have utility in offsetting virus-linked neurological damage (19). The anti-apoptotic effects of MEL on virus-infected cells are well documented (20, 35).

2.5.    Melatonin and neuroprotection.

      Melatonin exerts a significant neuroprotection against viral infections (11, 41-43). In COVID-19 patients, neurological complications such as anosmia, stroke, meningitis, and seizures have been documented (12). MEL counteracts most of the pathophysiological processes that trigger neurodegenerative disorders (43, 44), including elevated neuroinflammation and oxidative stress (41). Pineal MEL release at night is proposed to dampen any residual inflammation and oxidative stress caused by daytime stressors. The suppression of pineal MEL in the elderly, neuropsychiatric disorders and many other medical conditions attenuates its capacity to not only regulate these conditions but also underpins how these conditions may be associated with SARS-CoV-2 infection severity and fatality (38).


3.      CLINICAL TRAILS OF MELATONIN ON COVID-19

     Clinical trials using MEL in the treatment of SARS-CoV-2 infection indicate its clinical utility. MEL improves the clinical outcome of patients and reduces ICU stay, the likelihood of coagulopathy or sepsis, and the mortality rate (4, 13, 45). MEL is a safe drug, reduces the adverse effects of other drugs in COVID-19 patients, and helps to reduce reinfections (3, 12, 45). The ability of MEL to suppress the cytokine storm and inflammation during SARS-CoV-2 infection has been shown in clinical trials (45), with network analysis indicting the high likelihood of MEL being an effective COVID-19 treatment (4).


4.      MELATONIN’S VIRICIDAL EFFECT ON SARS-CoV-2

     There are findings that support the viricidal effect of MEL and its therapeutic use in COVID-19. MEL inhibits angiotensin converting enzyme 2 (ACE2)-SARS-CoV-2 coupling during virus fusion with the cells (12), modifies ion flux inside the cell (preventing viral entry), interacts with SARS-CoV-2 membrane and its genetic material, regulates gene expression, controls the spread of animal coronaviruses (35) and reduces VEEV (21), Ebola virus (10), and JEV (11) replication.


5.      MELATONIN AND SARS-COV-2 VACCINATION

     Exogenous MEL improves humoral responses against several pathogens, including the CD8+ T cell response in cancer vaccines (12). The immune-enhancing properties of MEL are evident in mice vaccinated with the TC-83 VEEV (46). MEL enhances the immune response to vaccines by increasing CD4+ T cells and IgG-expressing B cells. In COVID-19 patients, a vigorous response of CD4+ T cells to the virus correlated with the level of anti-SARS-CoV-2 IgG and IgA (12). The use of MEL in SARS-CoV-2 vaccination can enhance the immunity against the virus in healthy and immune-compromised patients as well as preventing the adverse effects of the vaccine (8).

The potential implications of the immune-regulatory role of intestinal helminthes in humans co-infected by SARS-CoV-2 on outcome and vaccination effectiveness is an increasing concern in areas where geohelminths and other infectious agents are evident, frequently in association with poverty (47-49). A preexisting helminth infection can impair the host’s ability to fight off SARS-CoV-2 infection, thereby increasing severity and mortality, as well as vaccine efficacy (50-52). Such complications of helminthiases with SARS-CoV-2 infection in countries less resourced to deal with complicated pathophysiologies will increase fatality. The beneficial effects of MEL must be considered in the context of such co-infection, including in the course of mass vaccination.


6.      MELATONIN AND GUT MICROBIOME

As with many medical conditions, a growing body of data shows a clinically relevant role for alterations in the gut microbiome (53), as predicted at the beginning of the initial COVID-19 pandemic (54). Some of melatonin’s effects are mediated via the maintenance of the gut barrier and the prevention of gut dysbiosis (55), involving the maintenance or upregulation of the short-chain fatty acid, butyrate (56). As butyrate optimizes mitochondrial function (57), antiviral immune response (53) and increases the mitochondrial melatonergic pathway (58), some of the effects of melatonin may be in conjunction with its capacity to upregulate butyrate as well as dampening the mucosal immune system. Alterations in the gut and gut microbiome are significant determinants of immune responses including the priming of antibody responses by B-cells, as recently highlighted for autoimmune disorders (59).


7.      CONCLUDING REMARKS

      An effective SARS-CoV-2 therapy must target both the virus and subsequent hyperinflammation. General immunity is impaired in compromised SARS-CoV-2 patients, with the suppressed MEL levels in the elderly, and in people with chronic inflammatory diseases further exacerbating infection severity. MEL with its pleiotropic role would be an excellent option as an alternative or adjuvant treatment of the disease, including via its potential viricidal efficacy. MEL can increase the survival rate of the severe COVID-19 patients and no other drug has the capacity to achieve this goal. In addition, MEL can even restrict the invasion of virus by blocking its receptors in the cell membrane.

     Bacterial infections and cardiovascular disease are major risk factors of disease severity and mortality during SARS-CoV-2 infection. Given the beneficial effects of MEL in multiple organs, its use in the treatment of SARS-CoV-2 infection may be crucial. The data highlighted above indicate that MEL can prevent or reduce severe symptoms and decrease the immunopathology of infection, including SARS-CoV-2 infection. The ability of MEL to suppress the cytokine storm in COVID-19 is shown in clinical trials, and network analysis supports MEL as an effective treatment.

     Given the efficacy and safety of MEL in SARS-CoV-2 infection, future randomized controlled clinical trials will be required to refine relevant processes and modes of application. Prospective studies are already on their way. The present review is a call to introduce MEL supplementation in the management of SARS-CoV-2 infection. This is urgent and an ethical duty, given that it is clear that MEL will save lives in SARS-CoV-2 infected patients. Although the emergency state of the COVID-19 pandemic might be over, the virus persists among us, with a strong possibility of future new, highly lethal COVID-19 waves. This storm may have lost its strength for the time being, but we should be ready for any future emerging SARS-CoV-2 variants by exploiting the clinical utility of MEL, especially given its low cost and the ready capacity to rapidly upregulate its production.

 

ACKNOWLEDGEMENT

      No funding was received for this study.

 

AUTHORSHIP

      All authors contributed to the conceptualization, writing, and editing of this manuscript.

 

CONFLICTS OF INTEREST

     The authors declare no conflict of interest.

 

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