Melatonin may be a powerful auxiliary therapy in the prevention and treatment of viral
infections, such as coronavirus disease 2019 (COVID-19) [1]. Casually, the so-called
‘super immunity’ of bats and the usually high levels of melatonin in children could
contribute to their high resistance to the SARS-CoV-2 virus [2]. Melatonin seems to
play a key role in suppressing COVID-19 infections. This endogenous antioxidant inhibits
cell apoptosis, blocks the inflammasomes that mediate lung inflammation, reduces blood
vessel permeability which limits alveolar edema, improves anxiety and sleeps habits
that stimulate general immunity and prevents lung fibrosis [3]. These complications,
which are usually the main consequences of COVID-19, may be significantly attenuated
by melatonin [4].
Melatonin theoretically provokes a switch from reactive to quiescent phenotypes in
immune cells, through a shift in their metabolism from glycolytic metabolism to oxidative
phosphorylation. Moreover, melatonin inhibits neutrophil recruitment. Furthermore,
a SARS-CoV-2 infection suppresses mitochondrial melatonin production by inducing cytosolic
glycolytic metabolism which deprives the mitochondria of acetyl-co-enzyme A, a necessary
cosubstrate for melatonin synthesis; the loss of mitochondrial melatonin contributes
to the typical ‘cytokine storm’ observed in COVID-19 infection. The glycolytic metabolism
that causes mitochondrial dysfunction is likely reversed by melatonin [5]. In addition
to its mitochondrial protective effects, melatonin has also important immunomodulatory,
anti-inflammatory and antiviral properties, which have been documented in multiple
experimental models of lung diseases [6]. Melatonin also downregulates the expression
of matrix metallopeptidase 9, which is involved with the immunoinflammatory response
mediated by neutrophils and the methoxyindole modulates the function of angiotensin
converting enzyme 2, the main receptor that allows the entrance of SARS-CoV-2 into
the cells [7]. It has also been suggested that the administration of high doses of
melatonin may attenuate the exacerbated neuroinflammation caused by SARS-CoV-2, which
would lessen the brain damage observed in many patients with COVID-19 [8]. A recent
study examined the structural and physicochemical features of melatonin with the aid
of different electronic structure and molecular-mechanics methods. The electronic
properties of melatonin allow predictions of its bio-activity. In this study, it was
reported that melatonin has potent activity against SARS-CoV-2 proteins. The collective
results strongly suggest that melatonin would be highly useful in the mitigation of
COVID-19 severity [9].
Noteworthy is that COVID-19 mortality rates increase with age of the patient. Aging
is known to be related to an increased mitochondrial dysfunction and elevated oxidative
damage accompanied by a drop in melatonin production. Since melatonin is an important
antioxidant, melatonin supplementation in the elderly would be potentially beneficial
in the prevention of mortality due to COVID-19 [10]. Additionally, melatonin not only
directly exerts important actions against COVID-19, it may also synergistically potentiate
the anti-inflammatory actions of other endogenous substances, such as vitamin D, which
also seems to be beneficial in the prevention and treatment of this viral infection
[11]. In other clinical conditions that co-exist with a COVID-19 infection. In other
words, diabetics, obesity and cardiovascular disease, melatonin has been suggested
as an adjuvant in the therapeutic protocols to improve clinical outcomes in these
patients with increased risk of mortality [12].
The exogenous administration of melatonin does, however, have some issues. One of
the main physicochemical and pharmacokinetic limitations of this substance is its
short half-life in the physiological microenvironment after its administration due
to its high susceptibility to oxidative degradation [13]. Another limitation with
regard to the conventional administration of melatonin may be its high lipophilicity,
which negatively influences its oral bio-availability [14].
Therapeutic nanoformulations offer several advantages over conventional pharmaceutical
preparations since drug release kinetics are modulated by the choice of nanomaterials
with specific features. The use of nanoformulations also allows programming of the
drug release site in response to a remote or site-specific trigger, such as changes
in pH, temperature or enzymatic activity [15]. Moreover, nanoformulations allow greater
efficacy of therapies. This is because nanomaterials have a high surface area to volume
ratio, which provides a greater contact surface with the physiological medium, favoring
the rapid dissolution of poorly water-soluble drugs. Furthermore, the stability of
molecules contained in the nanoformulations is greater than that of drugs in free
form. This is because the nanostructures act as protective coatings against different
destabilizing factors, such as pH, enzymes, hydrolysis, etc.; this also results in
prolonged pharmacological effects [16]. In addition, therapeutic nanoformulations
usually have less toxicity than conventional pharmaceutical formulations. This happens
because drug nanocarriers may be directed to specific target sites using pharmacological
targeting strategies (active, passive and/or physical targeting), thereby avoiding
or reducing side effects associated to systemic drug distribution. Moreover, nanoformulations
require significantly less drug than conventional formulations, which reduces their
toxicity [17]. With specific regard to melatonin, its mitochondrial targeting would
represent an attractive therapeutic goal. Melatonin’s side effects are generally not
be a limitation for its exogenous administration, since this substance has a high
safety profile and are considered an especially innocuous drug [4].
Several nanoplatforms for the dermal delivery of melatonin were developed in the last
several years; these include ethosomes, liposomes, niosomes, solid lipid nanoparticles,
polymeric nanoparticles and cyclodextrins. The use of these nanoplatforms for melatonin
delivery as an antioxidant agent would improve its efficacy in comparison with conventional
melatonin formulations due to its greater protection from premature oxidation and
the enhancement in cell uptake and bio-availability [18]. Cationic solid lipid nanoparticle
carriers of melatonin have been developed to potentiate the ocular hypotensive effect
of this drug. This nanoformulation not only caused a significant reduction in intraocular
pressure but also had good tolerability on the ocular surface [19]. Nanoformulated
melatonin also proved to be more effective in the protection against genotoxicity
induced by etoposide in the HepG2 cell line compared with conventionally administered
melatonin. The reduction of both reactive oxygen species production and DNA damage,
and the increase in intracellular glutathione concentrations in this cultured cell
line was more significant with the use of nanoformulated melatonin compared with solubilized
melatonin added to the incubation medium [20]. Moreover, it has also been demonstrated
that the protective effect of melatonin incorporated into polymeric nanoparticles
on adipose-derived mesenchymal stem cells cultured under oxidative stress conditions
was better than that of conventional melatonin [13]. One of the most advanced and
complex nanosystems developed for melatonin delivery is based on ‘smart nanocarriers’.
Thus, biosmart nanoparticles which concentrate in mitochondria and repair tissue damaged
by ischemia have been designed. These core/shell nanoparticles are composed of the two
layers. The core is loaded with melatonin and the shell is loaded with circular DNA.
At the acute stage of ischemia, the pro-oxidative cell microenvironment stimulates
the release of melatonin from these biosmart nanoparticles and prevents apoptosis
induced by reactive oxygen species. At the chronic stage of ischemia, circular DNA
senses hypoxia and produces VEGF for inducing revascularization of ischemic tissue
[21].
On the basis of the technology available, melatonin delivery nanosystems should be
examined with the aim of improving the stability, selectivity and efficacy of melatonin
to create new therapeutic alternatives for the treatment of COVID-19 and/or other
viral infections.