Therapeutic Benefits of Melatonin against COVID-19

Abstract

The assumption of the pineal hormone melatonin as a therapeutic use for COVID-19-affected people seems promising. Its intake has shown significant improvement in the patients’ conditions. Higher melatonin titers in children may provide a protective shield against this disease. The hormone melatonin works as an anti-inflammatory, antioxidant, immunomodulator, and strategically slows down the cytokine release which is observed in the COVID-19 disease, thereby improving the overall health of afflicted patients. The medical community is expected shortly to use remedial attributes like anti-inflammatory, antioxidant, antivirals, etc., of melatonin in the successful prevention and cure of COVID-19 morbidity. Thus, the administration of melatonin seems auspicious in the cure and prevention of this COVID-19 fatality. Moreover, melatonin does not seem to reduce the efficiency of approved vaccines against the SARS-CoV-2 virus. Melatonin increases the production of inflammatory cytokines and Th1 and enhances both humoral and cell-mediated responses. Through the enhanced humoral immunity, melatonin exhibits antiviral activities by suppressing multiple inflammatory products such as IL-6, IL1β, and tumor necrosis factor α, which are immediately released during lung injury of severe COVID-19. Hence, the novel use of melatonin along with other antivirals as an early treatment option against COVID-19 infection is suggested. Here, we have chalked out the invasion mechanisms and appropriate implications of the latest findings concerned with melatonin against the virus SARS-CoV-2. Nevertheless, within the setting of a clinical intervention, the promising compounds must go through a series of studies before their recommendation. In the clinical field, this is done in a time-ordered sequence, in line with the phase label affixed to proper protocol of trials: phase I–phase II and the final phase III. Nevertheless, while medical recommendations can only be made on the basis of reassuring evidence, there are still three issues worth considering before implementation: representativeness, validity, and lastly generalizability.

Introduction

COVID-19, a devastating viral disease spread out throughout the world, first struck human society in December 2019 [1]. So far what has been observed is that children, as compared to elderly ones, and the nocturnal animal bats possess high levels of the pineal hormone melatonin, which may contribute to their high antiviral resistance. Precise discovery of the pineal hormone melatonin was made in 1958 by Lerner and his coworkers from the bovine pineal gland [2]. Melatonin, as we know, is generally involved in circadian rhythm entrainment and pigmentary aggregations [3–5]. Melatonin, which is also a well-known anti-oxidative and anti-inflammatory molecule, limits virus-related diseases and induces antiviral immuno-stimuli in COVID-19 patients who may even have comorbidities of diabetes and obesity [6–8]. Ancillary treatment involving the hormone melatonin along with an antiviral drug proves beneficial against general viruses, and thus could even counteract COVID-19 as well [9]. This review highlights about prominent benefits of melatonin in the medication of the COVID-19 fatal infection inferred by the virus SARS-CoV-2.

Invasion of Host Cells by SARS-CoV-2

SARS-CoV-2 virus is transmitted through respiratory drops and aerosols among the masses. Inside the host’s tissues, this virus attaches to targeted cell receptors and penetrates the cells of the host either through plasma membrane fusion or endocytosis. Coronaviruses are composed of four types of structural classes of proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins [10, 11]. Spike protein is composed of two active subunits (S1 and S2) in which S1 binds with the host cell membrane receptor while the S2 subunit plays an important role in the binding of viral and host cell membranes This protein protrudes from the viral cell membrane and plays a vital role in host cell binding and then enter into the cell [11].

The operative cell membrane receptor for SARS-CoV is ACE-2 which is characteristically expressed on epithelial cells of the lungs [12]. ACE-2 receptor is quite ubiquitous because of its fundamental role in many cardiovascular functions. S protein binds initially with this ACE-2 receptor and thus host cell intrusion by the virus begins [13–15]. With the coupling of the SARS-CoV-2 virus to ACE-2 receptor, the S protein now activates through dual cleavage of a protease, the first one while priming at S1/S2 cleavage site and the second while triggering at the location next after fusion protein within an S2 subunit [16–18]. First cleavage makes the S2 subunit stable at the binding site and further cleavage possibly stimulates the S protein leading to conformational changes that result in the host cell and viral membrane bindings [19].

After cell membrane integration, the virus invades the alveolar epithelial cells of the respiratory tract to release viral contents inside the cells. Within the host cell, viral replication undergoes to form −ve strands of RNA by the pre-existing single-strands (ss) +ve RNA through transcription. This new −ve strand RNA serves as the template to form daughter strands of +ve RNAs. During translation, these new RNAs produce newer proteins in the cell cytoplasm [20–22]. N protein of the virus binds with these new RNAs and the protein M helps in channelizing into the endoplasmic reticulum. These nucleocapsids are enclosed within lumen of endoplasmic reticulum from where they are transported through Golgi vesicles to cell membrane and ultimately to the extracellular fluid space through exocytosis. These newly synthesized viral particles proceed to invade adjacent epithelial cells. Moreover, they produce virginal infective materials for mass community transmission through respiratory aerosols [11]. Life cycle of the SARS-CoV-2 is shown in Figure 1.

Fig. 1.

An outline of the SARS-CoV-2 virus life cycle (Source: Parasher [20]).

Melatonin

(Melatonin)

[N-Acetyl-5-methoxytryptamine, MF: C₁₃H₁₆N₂O₂, FW: 232.278]

Melatonin shows its photoperiodic, circadian effects, and several chronobiological processes through the pharmacologically specific, high-affinity receptors [23–29]. Generally synthesized at night hours, melatonin may act as a signal of darkness to the body [3, 30, 31]. Vanecek [24] has also reported that the hormone melatonin shows its effects through the distinguished high-affinity receptors present on the cell membrane that is coupled with the GTP binding proteins. Three types of melatonin receptors do exist: Mel1A, Mel1B, and Mel1C.

According to Sack et al. [32], the administration of melatonin hormone can commence circadian rhythms in blind people who have independent rhythms. Melatonin inhibits cellular cAMP accumulation. It regulates the transcription factors (third messengers), i.e., cAMP binding protein gets phosphorylated and expression of c-Fos occurs. Although the phenomenon of the molecular mechanisms of melatonin-induced effects is still in its infancy, it could engage minimum of two analogous transduction mechanisms: one controlling phospholipid metabolism along with [Ca⁺² ]_i. transport and the next blocking adenylyl cyclase [24].

Melatonin is formed in a biosynthetic pathway from an essential amino acid L-Tryptophan, via 5-hydroxylation by tryptophan-5-hydroxylase enzyme into 5-hydroxytryptophan, which is decarboxylated by another enzyme aromatic amino acid decarboxylase to 5-hydroxytryptamine (serotonin) that is converted to N-acetylserotonin by the enzyme serotonin N-acetyltransferase (SNAT/AA-NAT – arylalkylamine N-acetyltransferase), whereafter N-acetylserotonin is ultimately converted into the hormone melatonin (N-acetyl-5-methoxytryptamine) by the enzyme hydroxyindole-O-methyltransferase (HIOMT, also known as acetylserotonin methyltransferase) [3, 28, 33–35].

Potential Clinical Applications of Melatonin

COVID-19 disease spread throughout the world where millions of people showed COVID positive results and over 6.5 million people have lost their lives due to this disease [1]. To avoid emergencies, treatment of COVID-19 must start shortly after diagnosis. Compounds that can relieve inflammation and oxidative damage can reduce the rates and deaths by infection [36]. Physicians and scientists have been trying for early breakthroughs in COVID-19 prevention [9]. This disease, as described before, develops as the virus SARS-CoV-2 clings to receptors of angiotensin-converting enzyme 2 (ACE2) in lungs’ epithelial cells, causing a pro-inflammatory response which often leads to cytokine gust and acute respiratory distress syndrome [6, 37]. Further pro-oxidant response stimulates reactive oxygen species (ROS) mediated injury to air sacs in the lungs [38].

Melatonin has been used in the treatment of respiratory syncytial virus (RSV) morbidity, by activating toll-like receptor (TLR3), RSV leads to signal cascade and this initiates nuclear factor kappa B (NF-κB) activity which is a transcription factor upregulating the formation of cytokines that are pro-inflammatory. RSV-infected macrophages show a reduced TLR3-guided downstream expression of the gene when treated with this pineal hormone melatonin [39]. Melatonin characteristically inhibits the activity of NF-κB, thereby diminishing the response of hyperinflammation caused by such infectious viruses in our respiratory system [40]. In the case of mice, having infected with influenza A, when they were treated with melatonin, then they showed decreased tumor necrosis factor (TNF)-α producing CD8 cells in spleen and lungs, and this can profoundly diminish the lethality of our lungs injury [41].

Through the murine models, it appears that melatonin possesses protective functions against the Ebola virus, which is the causing factor for acute vascular endothelial rupture that results in multi-organ hemorrhage. Such fatal consequences occur because of an excessive rise in inflammatory cytokines and chemokines like interferon-α, TNF-α, IL-6, IL-8, monocyte chemoattractant protein-1, and tissue factors that lead to fibrinolysis and coagulation irregularities [42]. Melatonin neutralizes ROS and weakens this cytokine surge that is correlated with infection by the virus while increasing the T_H type 2-produced cytokines, interferon-gamma response, and natural killer cell activity to combat the Ebola viral infection mechanisms. Thus, melatonin reduces pro-inflammatory conditions, induces autogenous antioxidants, counterbalances ROS of viral infections, and upgrades mitochondrial functioning, thereby stopping injury to endothelial layers which can cause putrefying severance and distributed intravascular clottings [43–45]. Melatonin plays a preventive role in hemorrhagic fevers as seen in patients who had significantly reduced blood plasma melatonin titers than the control people [46–49]. Melatonin increases the production of inflammatory cytokines and Th1-type in rheumatoid arthritis and enhances both humoral and cell-mediated responses [50]. However, in the case of rheumatoid arthritis, administration of exogenous melatonin hardly exerts any significant therapeutic benefits [51]. Melatonin when added with vaccines against diarrhea for cattles increased the production of IFN-α and IFN-β and stimulated the production of T lymphocytes [52]. This indirectly implicates a stronger effect of melatonin on COVID vaccination and efficacy.

Melatonin can significantly decrease the viral load in blood, death rate, and lethality of the disease, e.g., as in encephalitis and myocarditis [39]. The decreased anti-inflammatory response occurs because of melatonin-mediated down-regulation of TNF-α of the central nervous system [53]. Increased volumes of cytokine IL-1B also determine the shielding effect of melatonin against central nervous system attacking viruses [54, 55]. Melatonin administration reduces the death rate caused by these viruses and remarkably postpones the beginning of the disease; this supporting evidence goes in favor of melatonin to be used in the treatment of many viral diseases [39].

Melatonin against COVID-19

Ample evidences for the promising use of melatonin as an adjuvant in the treatment of COVID-19 now exist [56]. Acute oxidative stress and inflammatory responses are caused due to the SARS-CoV-2 viral infection. Administration of melatonin may suppress quite a few of these reactions. SARS-CoV-2 penetrates the epithelial cells of alveoli by attaching with ACE2, this is assisted by S1 and S2 subunits of spike protein present on the virus [57]. S1 facilitates binding with ACE2, while S2 directs merging of the virus with plasma membrane [58]. Surface expression and retention of ACE2 in cell membranes are controlled by calmodulin. Melatonin inhibits the binding of ACE2 receptors with the virus SARS-CoV-2 by blocking calmodulin. Splitting of polyproteins of the virus is regulated by SARS-CoV-2 protease (chymotrypsin-like protease), but this enzyme is inhibited by melatonin [59]. SARS-CoV-2 couples with ACE2 thereby producing angiotensin II and inhibits the shielding effects of angiotensin 1–7 [60]. On the contrary, providing a rescue, melatonin comes as a significant blocker of angiotensin II activation and induces angiotensin 1–7 action [61].

Activation of NOD-like receptors family pyrin group containing 3 (NLRP3) initiates pro-inflammatory cytokines release such as IL-18 and IL-1B. Pieces of evidence show that melatonin functions as a blocker of NLRP3 inflammasome, thereby shutting down pyroptosis and finally showing an anti-inflammatory effect [62]. Induction of a cytokine surge by SARS-CoV-2 infection leads to IL-1B, IL-6, IL-17, C-reactive protein, and TNF-α upregulations because there is a rise in the activation of macrophages, mast cells, and neutrophils [8, 63]. Melatonin inhibits signaling of NF-κB, downregulates inducible nitric oxide synthase and cyclooxygenase-2, and inhibits TLR4 activation. Blocking of TLR4 reduces the levels of TNF-α, IL-1B, IL-6, and IL-8 [64]. Melatonin by reducing pro-inflammatory cytokines shows anti-inflammatory effects, the elevation of anti-inflammatory cytokines like IL-10 and inhibition of NF-κB. It even changes the hyperinflammatory glycolytic macrophages into anti-inflammatory macrophages which go through the process of oxidative phosphorylation, this further downregulates cytokine production. Moreover, this pineal hormone activates sirtuin 1 protein, which obstructs the formation of hyperinflammatory macrophages. By inhibiting chymotrypsin type protease and calmodulin, melatonin diminishes virus entry and multiplication in host cell [59].

The hormone melatonin is likely to exert antioxidative actions against SARS-CoV-2 virus by the direct destruction of oxygen and nitrogen-based-free radicals, inactivation of pro-oxidant enzymes, homeostasis regulation of mitochondria and activation of antioxidant enzymes like catalase, superoxide dismutase (SOD), and GSH [38, 65–68]. Even regulates autophagy, endoplasmic reticulum stress, and apoptosis through its antioxidant properties [69]. Melatonin helps in the reduction of severe lung oxidative destructions by suppressing ROS and reestablishment of SOD and GSH titers in the pulmonary organs of RSV-infected mice [41, 70]. Melatonin antagonizes ROS injury by preserving the inner membrane of mitochondria and stimulating the electron transport chain to enhance mitochondrial citric acid cycles and production of ATPs, thereby decreasing electrons leakage and ROS formation [65].

Preliminary pieces of evidence of successful melatonin treatments for COVID-19 patients having respiratory problems do exist [36–38]. Having anti-inflammatory and ROS-scavenging properties, melatonin is projected and even used in the treatment of varied viral infections which are causing excessive immunoinflammatory responses [42, 43, 71, 72]. Most viruses, inclusive of those that are causing cytokine storms, lead to a decrease in pineal melatonin production, which adversely hits the patient’s immune system [73]. SARS-CoV-2 disrupts the host’s mechanism of melatonin production to avoid self-disruption and begins multiplying inside the patient’s respiratory tract cells. Viruses diminish the anti-inflammatory effects of melatonin by repressing the expression of the gene of several melatonin synthesizing enzymes and also deplete tryptophan which is the antecedent for melatonin. These melatonin depleting phenomena lead to enhanced lethality of several viral ailments [38]. Melatonin is a tryptophan-derived hormone produced in the pineal gland and cells of the immune system. It is a promising treatment option to suppress the lethality of COVID-19 manifestations due to its known protective antioxidant, immunomodulatory and anti-inflammatory qualities [43, 62, 74, 75].

SARS-CoV-2 causing this pandemic may never disappear totally and will keep on appearing as novel strains through mutations. Being immunomodulatory, antioxidant, anti-inflammatory, and antiviral, melatonin can be the right choice for therapeutic use alone or in combination with other drugs to ameliorate the consequences of COVID-19 infections [76–79]. Being a hydroxyl radicals scavenger and stimulator of antioxidative enzymes like glutathione peroxidase (GSH) and SOD, the hormone melatonin even protects against oxidative damage of the cells significantly [9]. It also controls cognitive decay following SARS-CoV-2 infection and thus could serve as the “silver bullet” against the current COVID-19 pandemic even in high doses. Today our prime social responsibility is to combat this disease along with all the safety measures [80, 81].

Melatonin may lower COVID-19 infection severity by targeting human physiological processes [73]. Based on practical pieces of evidence, Kleszczyński et al. [70] have encouraged physicians to test the potential role of melatonin against this infection. The hormone regulates COVID-19-associated proteins directly or indirectly through G-Protein coupled receptors and nuclear melatonin receptors, thereby demanding the need for placebo-controlled randomized clinical trials of melatonin against these virus infections [82]. Melatonin may enhance the efficacy of COVID-19 vaccination [83]. Even reduces the ROS-stimulated damage, cytokine-induced lymphopenia and inflammation in COVID-19 like infections. Potential benefits do exist in melatonin use for COVID-19 treatment at the earliest possible [9]. Several findings reiterate the idea that exogenous melatonin administration may boost the efficacy of immune response and duration of immunity conferred by COVID-19 vaccination [84, 85] by increasing the peripheral blood IgG-expressing B cells and CD4+ T cells [86]. Moreover, additional implications of melatonin may effectively diminish sepsis, mortality and thrombosis in COVID-19 subjects [87]. As mentioned earlier, this disease establishes as SARS-CoV-2 binds with ACE2 receptors in respiratory tract epithelial cells. This initiates a pro-inflammatory effect that generally leads to a cytokine storm and proliferous beginning of acute respiratory distress syndrome [6, 37]. Figures 2–4 give the concepts and outlines for controlling the COVID-19 infection.

Fig. 2.

COVID-19 pathology – cytokine storm leading to death could effectively be reduced by the administration of melatonin (Source: Vlachou et al. [88]). The figure shows the probable mechanistic routes, where melatonin could deplete the infection process. Severe oxidation, inflammation, and a hyperactive immune response contribute to COVID-19 pathology, leading to a cytokine surge that causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and frequent deaths, which can be significantly lowered by the administration of melatonin.

Fig. 4.

Humoral immunity and melatonin – a therapeutic approach with toremifene (Source: Cheng et al. [89]) – melatonin is evolutionarily conserved from bacteria to humans. Melatonin suppresses inflammatory pathways that include IL-6, IL1β, and TNFα, which are released during lung injury of severe COVID-19 infection. Toremifene which is a selective estrogen receptor modulator and FDA-approved to treat advanced breast cancer has shown several antiviral activities such as against the Ebola virus, MRES-CoV, SARS-CoV-1, and SARS-CoV-2. Hence, the synergistic antiviral and anti-inflammatory effects of melatonin and toremifene offer a promising treatment approach for COVID-19.

Fig. 3.

Adjuvant therapeutic action of melatonin during COVID-19 infection (Source: Reiter et al. [76]). Melatonin was found to curtail the toxicity of hydroxychloroquine and increase its potency. This can be an exploratory protocol, a preliminary phase I/II study.

Early Intervention in COVID-19 by Melatonin

Potential benefits do exist in the earliest use of melatonin for COVID-19 treatment. Melatonin possesses reasonable features of minimizing inflammation and most probably repressing the cytokine surge caused by SARS-CoV-2. If administered at the early stages of infection, it can dispense benefits at a tolerable safety profile and at a reduced cost. Even though this hormone fights early virus multiplications, its administration in patients with COVID-19 infection is not destined to be used as a remedy but rather as an assistive envoy that prepares the body to smartly defeat virus infections. Melatonin can augment drug efficacy and diminish toxicity and thus appears appropriate to be used together with other treatments for COVID-19 infection [9]. In case studies where the body’s immunity is repressed, melatonin stimulates the immune response, and in patients having inflammation, melatonin shows an immunosuppressive effect [88]. Also now it seems quite clear that in COVID-19, the oxidative and inflammatory effects due to the virus get eliminated by melatonin which also escalates the immunity of the patient to tactfully counter the infection and recover effectively within a short recovery period [85, 90]. Along with an antiviral, melatonin serves for a speedy recovery of patients afflicted with COVID-19 disease and can be best administered as chronotherapy in such patients [81].

Melatonin can also act against the virus itself. Seeing the safe profile of melatonin, it can be applied as a precautionary measure and therapeutic agent against COVID-19 and should be started seriously even before the clinical trials due to the emergency of the pandemic [91, 92]. Patients having comorbidities must receive treatment at the earliest possible. Melatonin would be an effective first-line, safe and cheap remedy for COVID-19, specifically in critical and high-risk susceptible populations. CDC-USA has charted out the patients at exposure for acquiring serious cases of COVID-19, like – cancer, diseases of kidney, COPD, cardiac anomalies, history of smoking, etc [9, 93]. Moreover, being highly safe, accessible in abundance, and even cheap at cost, Cross et al. [9] have recommended the administration of melatonin about 2.5–10 mg dose before sleep at night to all adults infected with SARS-CoV-2 immediately on the very first day of diagnosis, especially for the patients having comorbidities and higher mortality risk. Ample shreds of evidence as anti-cancerous [94], antioxidant, anti-inflammatory [95], and immunomodulatory prove that the effects of melatonin through the specific nuclear and plasma membrane melatonin receptors [96] can significantly deplete the gravity of symptoms and motility to cells caused by viral diseases when started as an early remedy. The pineal product melatonin strategically slows down the cytokine surge seen in COVID-19 subjects, reduces oxidized destruction to upgrade the resistive capabilities of patients and thus provides an increased life span. Synergistic antiviral and anti-inflammatory effects of melatonin and toremifene seem promising in the protection against COVID-19 through the enhanced humoral immunity by inhibition of IL-6, IL1β, and TNFα release (Fig. 4) [89].

Summary and Conclusion

Already there have been retrospective studies for the administration of pineal hormone melatonin in the therapy for COVID-19 with other types of drugs like antivirals, but it needs to be escalated to reach larger geographical scales, and even to the vaccinated people as an adjuvant alone or in combination with other COVID-19 therapeutic medicines. The combo effects of anti-inflammation and antioxidation by melatonin provide an effective treatment for SARS-CoV-2. This pineal product disrupts all the chronological stages of the viral life cycle that includes cell entry, replication, and deleterious downstream signaling cascades. Melatonin stimulates the production of inflammatory cytokines and Th1 and intensifies both humoral and cell-mediated responses. Melatonin exhibits multiple antiviral activities through the increased humoral immunity. Melatonin significantly interrupts at each level of the virus life cycle to support the immune system of the host and squelch a harmful overreaction. The safety parameters of melatonin have been verified in many human studies. However, in order to ascertain further confirmations, we need to evaluate first of all safety and then efficacy of the pineal hormone melatonin against COVID-19. Its effects, when administered to COVID-19 patients, definitely require the rigorous clinical studies as the pandemic has recently shown its devastating effects in the year 2020-21.

Conflict of Interest Statement

The authors report no conflict of interest.

Funding Sources

No funding was received.

Author Contributions

Major contributions to the conception, analysis, acquisition, design, and interpretation of information were performed by Dr M. Mubashshir. Compilation of the pieces of literature was jointly done by Dr. T. Negi and Ms R.B. Sharma. The best possible chronological sequence of events and findings was laid down by the dual collaboration of Dr. Rawal and Dr. H. Khatoon. Major scientific and language upgradations were together achieved by Dr. V. Laxmi and Mr. O. Dubey. The first draft was cross-examined for its proper citations and references by Dr. N. Singhvi and Ms. G. Negi. The final critical revisions of the manuscript that came through the above team of experts were checked twice by Prof N. Ahmad and Prof M. Ovais. All the authors have read and approved the manuscript.

Funding Statement

No funding was received.