Possible Benefits of Melatonin in Mitigating COVID-19

In this article, we will explore the potential advantages of melatonin in mitigating the effects of COVID-19 based on its presumed pathogenesis. The recent outbreak of COVID-19 has escalated into a global pandemic, affecting tens of thousands of individuals worldwide. Given the clinical characteristics and the pathophysiology of acute respiratory distress syndrome (ARDS) caused by highly homogenous coronaviruses or other pathogenic microorganisms, evidence suggests that excessive inflammation, oxidative stress, and an exaggerated immune response likely contribute to the pathology of COVID-19. This leads to a cytokine storm and the subsequent progression to acute lung injury (ALI) / ARDS, often resulting in fatalities. Melatonin, a well-known anti-inflammatory and antioxidant molecule, offers protection against ALI / ARDS triggered by viral and other pathogens. Melatonin has proven effective in intensive care patients by reducing vascular permeability, anxiety, sedative use, and improving sleep quality, which can also be beneficial in enhancing clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is substantial data indicating that melatonin limits virus-associated illnesses and is likely to be beneficial in COVID-19 patients. Additional experiments and clinical studies are needed to confirm this hypothesis.

Coronaviruses (CoVs) are RNA viruses that infect both humans and animals, causing respiratory, gastrointestinal, and central nervous system infections. Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are contagious and deadly, resulting in thousands of deaths over the past two decades. The recent outbreak was identified in Wuhan, China, and has rapidly spread throughout China and other countries. Despite the use of antiviral therapy, corticosteroid treatment, and mechanical respiratory support, there is no specific treatment for COVID-19.

Melatonin (N-acetyl-5-methoxytryptamine) is a biologically active molecule with a range of health-promoting properties. Melatonin is successfully used to treat sleep disorders, delirium, atherosclerosis, respiratory diseases, and viral infections. Previous research has documented the positive effects of melatonin in alleviating acute respiratory stress caused by viruses, bacteria, radiation, and more. In this article, we will discuss the evidence supporting melatonin’s utility as an adjuvant therapy for the treatment of COVID-19 pneumonia, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS)

Pathogenesis of COVID-19 and the Rationale for Using Melatonin

Patients with COVID-19 (infected with SARS-CoV-2) commonly report symptoms such as fever, dry cough, myalgia, fatigue, and diarrhea, with variations depending on the patient’s age. In some cases, the disease progresses severely, leading to ALI / ARDS, respiratory failure, heart failure, sepsis, and sudden cardiac arrest within a few days. Pathological examination of lung specimens from moderate COVID-19 patients (who were retrospectively diagnosed with COVID-19 during lung cancer surgery) revealed edema, protein exudate with globules, focal inflammatory cellular infiltration, and moderate hyaline membrane formation. Postmortem examination of a COVID-19 patient with severe ARDS demonstrated bilateral diffuse alveolar damage with edema, pneumocyte desquamation, and hyaline membrane formation (9).

Figure 1. COVID-19 Pathogenesis and Potential Adjuvant Use of Melatonin.

We hypothesize that the lungs infected by SARS-CoV-2 exhibit suppressed immune responses, persistent inflammation, and excessive oxidative stress, leading to the activation of a cytokine storm. ALI / ARDS may follow, accompanied by a range of complications with outcomes varying depending on disease severity. Melatonin may play a role as an adjunct medication in regulating the immune system, inflammation, and oxidative stress, providing support to patients with ALI / ARDS and related complications. ALI: Acute Lung Injury; ARDS: Acute Respiratory Distress Syndrome.

While these pathological findings have been observed in only a limited number of cases, they resemble the pathological features found in SARS- and MERS-induced pneumonia [10]. SARS-CoVs, MERSCoVs, and SARS-CoV-2 are classified as members of the beta-coronavirus family [11].

Recent published research indicates that SARS-CoV-2 shares 79.0% nucleotide identity with SARS-CoV and 51.8% identity with MERSCoV [12], suggesting a high genetic homology among SARS-CoV-2, MERS-CoV, and SARS-CoV. In animal models infected with SARS-CoV and MERS-CoV, marked inflammatory and immune responses can activate a “cytokine storm” and result in apoptosis of epithelial and endothelial cells, subsequent vascular leakage, abnormal T cells, and macrophages. This response can lead to the development of ALI / ARDS or even death [13].

Based on genetic homology and the pathological characteristics of infected individuals, we predicted that patients with COVID-19 experience a significant immune response suppression, heightened inflammation, and excessive oxidative stress, leading to the activation of a cytokine storm. In the blood of COVID-19 patients, notable increases in interleukin-1β (IL-1β), interferon-gamma (IFN-γ), interferon-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), as well as IL-4 and IL-10, were observed when compared to SARS patients. This suggests some potential differences in the pathogenesis of the coronavirus compared to SARS and MERS [2]. There is also potential immune function suppression in COVID-19 patients with hypoalbuminemia, lymphopenia, neutropenia, and a decreased percentage of CD8+ T cells [2,7]. Recent reports suggest that some COVID-19 patients, even when testing negative for viral nucleic acid, still exhibit high levels of inflammation. Clinical trials using certolizumab pegol (a TNF blocker) in conjunction with other antiviral therapies may have positive effects in COVID-19 patients. Cumulatively, these findings indicate that inflammation is a key feature of COVID-19 patients. Therefore, we hypothesize that excessive inflammation, immune system depression, and cytokine storm activation significantly contribute to the pathogenesis of COVID-19. Based on genetic homology and the pathological characteristics of infected individuals, we predicted that patients with COVID-19 experience a significant immune response suppression, heightened inflammation, and excessive oxidative

In the early stages of coronavirus infection, dendritic cells and epithelial cells become activated and express pro-inflammatory clusters of cytokines and chemokines, including IL-1β, IL-2, IL-6, IL-8, both IFN-α/β, tumor necrosis factor (TNF), C-C motif chemokine 3 (CCL3), CCL5, CCL2, IP-10, and more. They are under the control of the immune system. Thus, the overproduction of these cytokines and chemokines contributes to the development of the disease [14–16]. IL-10, produced by T-helper-2 (Th2), has antiviral properties, leading to a significant decrease in this agent during coronavirus infections [17,18]. Interestingly, COVID-19 patients sometimes have significantly elevated levels of IL-10 [2]. Whether this is a feature of COVID-19 infection or a result of treatment is unknown. The amplification of the inflammatory response will promote cellular apoptosis or necrosis of affected cells, leading to inflammation, followed by increased vascular permeability and abnormal accumulation of inflammatory monocytes, macrophages, and neutrophils in the lung alveoli [19]. This vicious cycle exacerbates the situation as the regulation of the immune response is lost, and the cytokine storm is further activated, leading to severe consequences.

This hypothesized “cytokine storm” pathology associated with coronaviruses is also supported by experimental models of SARS-CoV, one of which demonstrated that the severity of ALI was accompanied by increased gene expression related to inflammation rather than an increase in viral titers. In another case, ablation of the IFN-α/β receptor or depletion of inflammatory monocytes/macrophages resulted in a notable increase in the survival of coronavirus hosts without changing the viral load [19,20]. Both situations suggest a potential mechanism for exacerbating CoV-induced ALI/ARDS independent of viral load. If a similar pathology also exists in COVID-19, dampening the cytokine storm by targeting several key steps in the process may lead to improved outcomes.

Melatonin does not possess direct antiviral action but has indirect antiviral effects [3] due to its anti-inflammatory, antioxidant, and immune-enhancing properties [21–24]. There are instances in which melatonin suppresses features of viral infections. In mice infected with viruses of the central nervous system (e.g., encephalitis), the use of melatonin resulted in lower viremia, reduced paralysis and mortality, and decreased viral load [25]. In previous models of respiratory syncytial virus, melatonin caused the suppression of acute oxidative lung damage, the release of pro-inflammatory cytokines, and the recruitment of inflammatory cells. These findings, along with recent summaries by Reiter et al. [3], support the rationale for using melatonin in viral diseases. Furthermore, melatonin’s anti-inflammatory, antioxidant, and immune-stimulating actions contribute to its potential in attenuating COVID-19 infection (see Figure 1).

Melatonin and its Anti-Inflammatory Effects

Melatonin exerts anti-inflammatory effects through various pathways. Sirtuin-1 (SIRT1) may mediate melatonin’s anti-inflammatory action by inhibiting the high mobility group box 1 (HMGB1) protein, thus suppressing macrophage polarization toward a pro-inflammatory type [26]. Proper regulation of SIRT1 attenuates lung damage and inflammation induced by sepsis-related ALI, making melatonin application potentially beneficial [27]. Nuclear factor kappa-B (NF-κB) is closely associated with pro-inflammatory and pro-oxidative responses, serving as a mediator of inflammation in ALI.

Melatonin’s anti-inflammatory action includes the suppression of NF-κB activation in ARDS [28, 29]. Melatonin has been reported to inhibit NF-κB activation in T cells and lung tissues [30,31]. Stimulation of Nuclear Factor-E2-related factor 2 (Nrf2) is crucial for protecting the lungs from injury.

In related studies, melatonin induces Nrf2 activation with therapeutic effects in hepatoprotection, cardioprotection, and more [32]. Whether Nrf2 is involved in CoV-induced ALI remains unknown, but the close interaction between SIRT1, NF-κB, and Nrf2 suggests their involvement in CoV-induced ALI/ARDS.

Thus, the data support the potential anti-inflammatory action of melatonin. Inflammation is typically associated with increased cytokine and chemokine production, whereas melatonin induces a reduction in pro-inflammatory cytokines. This includes TNF-α, IL-1β, IL-6, and IL-8, along with an increase in the anti-inflammatory cytokine IL-10 [33,34]. However, there may be some concerns about potential pro-inflammatory actions of melatonin when used in very high doses or in suppressed immune conditions where it may lead to increased production of pro-inflammatory cytokines like IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ [35].

On the contrary, in ALI infection models, melatonin demonstrates anti-inflammatory and protective effects [6].

Melatonin and its Antioxidant Effects

The antioxidant effect of melatonin interacts with its anti-inflammatory action, enhancing antioxidant enzymes (e.g., superoxide dismutase), suppressing pro-oxidant enzymes (e.g., nitric oxide synthase), and it can also directly interact with free radicals, functioning as a free radical scavenger [3,4]. Viral infections and their replication continually generate oxidative products. In the context of ALI in viral infections, the production of oxidized low-density lipoprotein activates the innate immune response by overproducing alveolar macrophage IL-6 through Toll-like receptor 4 (TLR4)/NF-kB signaling, thereby leading to ALI [36]. TLR4 is a receptor of the innate immune system and is also a therapeutic target for melatonin. In models of brain ischemia, gastritis, and periodontitis, melatonin has been documented to exert anti-inflammatory effects via TLR4 signaling [37–39].

The antioxidant effect of melatonin has also been confirmed in radiation-induced ALI, sepsis, and ischemia-reperfusion injury [4,40,41]. In patients with ALI/ARDS, especially as the disease progresses and in patients being treated in intensive care units (ICUs), excessive inflammation, hypoxemia, and mechanical ventilation with high oxygen concentrations inevitably lead to increased production of oxidants locally and systemically [42,43].

Accordingly, we presume that excessive oxidative stress is likely involved in COVID-19. Extensive studies by Gitto et al. [44,45], who used melatonin to treat newborns with respiratory distress, have documented the antioxidant and anti-inflammatory effects of melatonin in the lungs. Therefore, it is highly likely that the use of melatonin would be beneficial in combating inflammation and oxidation in individuals infected with the coronavirus.

Influence of Melatonin on Cytokine Levels in Humans

Although there are no specific reports related to the use of melatonin in COVID-19 patients, studies involving subjects with other diseases and elevated levels of inflammation have shown promising results regarding the reduction of circulating cytokine levels. In a randomized controlled trial, the oral administration of 6 mg/day of melatonin for 8 weeks led to a significant reduction in serum levels of IL-6, TNF-α, and hs-CRP in patients with diabetes and periodontitis [56].

Another study involving patients with severe multiple sclerosis found that oral melatonin at a dose of 25 mg/day for 6 months also contributed to a significant decrease in serum concentrations of TNF-α, IL-6, IL-1β, and lipid peroxides [57]. During the acute phase of inflammation, including surgical stress [58], cerebral reperfusion [59], and coronary artery reperfusion [60], the administration of melatonin at doses of 10 mg/day, 6 mg/day, and 5 mg/day for less than 5 days resulted in a reduction in pro-inflammatory cytokine levels.

A recent meta-analysis of a total of 22 randomized controlled trials suggested that the supplemental use of melatonin is associated with a significant reduction in TNF-α and IL-6 levels [61].

These clinical findings indicate that the use of melatonin as a supplement can effectively reduce circulating cytokine levels, potentially also lowering pro-inflammatory cytokine levels in COVID-19 patients.

Melatonin and Safety

When considering the use of melatonin for the treatment of COVID-19, the safety of melatonin is of paramount importance to consider. As previously mentioned, short-term use of melatonin is generally safe, even at relatively high doses, and reported side effects are limited to occasional dizziness, headache, nausea, and drowsiness.

Overall, melatonin safety in humans is very high [72]. In clinical trials, doses of 3 mg, 6 mg, and 10 mg of orally administered melatonin in intensive care unit patients demonstrated satisfactory safety compared to placebo [70,73,74]. Furthermore, even when melatonin was given to individuals at a dose of 1 g/day for a month, no adverse treatment-related events were reported [75]. Importantly, no adverse effects were registered in animal studies following the use of melatonin in ALI/ARDS [3,4,28].

While the safety of melatonin has been assessed in numerous human studies, its effects when administered to COVID-19 patients should be closely monitored, despite its very high safety profile.

Conclusion

The potential positive effects of melatonin as an adjuvant in COVID-19, in terms of its anti-inflammatory, antioxidant, and immune-regulatory properties, have been repeatedly demonstrated in respiratory disorder models caused by infections and their associated complications. Melatonin has a high safety profile. While direct evidence of melatonin’s application in COVID-19 is unclear, its use in experimental animal models and human studies has consistently documented its effectiveness and safety. Therefore, its use in COVID-19 patients is expected to be highly beneficial.

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