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Beneficial actions of melatonin in the management of viral infections: A new use for this “molecular handyman”?

  • Centro de Investigación Biomédica de Occidente del IMSS


Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein. Copyright © 2012 John Wiley & Sons, Ltd.
REVIEW Benecial actions of melatonin in the
management of viral infections: a new use for
this molecular handyman?
Jose Antonio Boga, Ana Coto-Montes, Sergio A. Rosales-Corral,
Dun-Xian Tan and Russel J. Reiter*
Department of Cellular and Structural Biology, UT Health Science Center, San Antonio Texas, USA
Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important
functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different elds of
medicine. Clinical trials have shown that melatonin is efcient in preventing cell damage under acute (sepsis,
asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inammation,
aging). The benecial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant
enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of
melatonin in viral infections, which are often associated with inammatory injury and increases in oxidative stress.
In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The
role of melatonin in infections is also discussed herein. Copyright © 2012 John Wiley & Sons, Ltd.
Received: 22 November 2011; Revised: 8 February 2012; Accepted: 9 February 2012
The methoxyindole melatonin (N-acetyl-5-metho-
xytryptamine) is a secretory product of the pineal
gland. It was rst reported as a skin lightening
agent in amphibians [1,2]. Further investigations
showed that another function, supported by its
direct effects in regions containing high densities
of melatonin receptors, such as the circadian
pacemaker (the suprachiasmatic nucleus) and the
pars tuberalis, is to regulate and reset circadian
rhythms as well as to be involved in the measure-
ment of day length, an environmental variable
used for seasonal timing of reproduction, metabo-
lism and behavior in species responding to photo-
periodic changes [37].
In recent decades, melatonin has been reported
to possess numerous additional functions and act
in neural and non-neural tissues or cells that
express melatonin receptors that are at lower densi-
ties than in the suprachiasmatic nucleus. Thus,
melatonin is involved in sleep initiation, vasomotor
control, anti-excitatory actions, immunomodulation
including possessing anti-inammatory proper-
ties, antioxidant actions, and actions on energy
*Corresponding author: R. J. Reiter, Department of Cellular and Struc-
tural Biology, UT Health Science Center, 7703 Floyd Curl Drive, San
Antonio, Texas 78229, USA
ALRs, AIM2-like receptors; AMDV, Aleutian mink disease virus; AP-
1, activating protein-1; ATF-2, activation transcription factor 2; BBB,
bloodbrain barrier; CAT, catalase; DISC, death-inducing signaling
complex; EMCV, encephalomyocarditis virus; GM-CSF, granulocyte-
macrophage colony-stimulating factor; GPx, glutathione peroxidase;
GST, glutathione-s-transferase; HPV, human papillomavirus; IFIT,
interferon-induced protein with tetratricopeptide; iNOS, inducible
NO synthase; IRF3, interferon regulatory factor 3; IRF7, interferon
regulatory factor 7; ISG, interferon-stimulated genes; JNK, Janus
kinase; MCP-1, monocyte chemotactic protein-1; MDA, malondialde-
hyde; MLV, murine leukemia virus; mtPTP, mitochondrial permeabil-
ity transition pore; NF-kB, nuclear factor kappa B; NK, natural
killer cells; NKT cells, natural killer T cells; NLRs, Nod-like receptors;
Nrf2, nuclear factor erythroid 2; OAS, oligoadenylate synthetases;
PAMPs, pathogen-associated molecular patterns; PCD, programmed
cell death; pDC, plasmacytoid dendritic cells; PKR, dsRNA-activated
protein kinase; PRRs, pattern recognition receptors; RANTES, regu-
lated upon activation, normal T cell expressed and secreted; RHDV,
rabbit hemorrhagic disease virus; RLRs, RIG-I-like receptors; SeV,
Sendai virus; SFV, Semliki Forest virus; SOD, superoxide dismutases;
TBE-V, tickborn encephalitis virus; TGFb, transforming growth
factor-b; Th1, type 1 T helper cell; Th2, type 2 T helper cell; TLRs,
Toll-like receptors; TNF-R, tumor necrosis factor receptor; VEE,
Venezuelan equine encephalomyelitis; VEEV, Venezuelan equine
encephalomyelitis virus; VSV, vesicular stomatitis virus; WNV, West
Nile virus; XO, xanthine oxidase.
Rev. Med. Virol. (2012)
Published online in Wiley Online Library
DOI: 10.1002/rmv.1714Reviews in Medical Virology
Copyright © 2012 John Wiley & Sons, Ltd.
metabolism, inuences on mitochondrial electron
ux, regulation of the mitochondrial permeability
transition pore (mtPTP), and mitochondrial protec-
tion against free radicals [813]. Deciencies in mela-
tonin production or melatonin receptor expression
and decreases in melatonin levels (such as those that
occur during aging) are likely to contribute to
numerous dysfunctions [1416]. In fact, several
clinical trials have shown that melatonin is efcient
in preventing cell damage under acute (sepsis,
asphyxia in newborns) and chronic states (metabolic
and neurodegenerative diseases, cancer, inamma-
tion, aging) [1722]. In humans, the efcacy of
melatonin as a treatment of ocular diseases, cardio-
vascular diseases, sleep disturbances and several
other pathologies, as well as a complementary
treatment in anesthesia, haemodialysis, in vitro
fertilization and neonatal care, has been assessed
and reported to be benecial [23]. Likewise, melato-
nin reduces the toxicity and increases the efcacy of
a large number of drugs whose side effects are well
documented [24].
The benecial effects of melatonin are explained
by its properties as a potent antioxidant, a modulator
of apoptosis and a positive regulator of immune
functions [2529]. These actions suggest the potential
to treat viral infections, which usually cause inam-
matory injury and elevated oxidative stress [30,31].
A number of reports examining the ability of
melatonin to protect against viral infections have
been published, as summarized in the following
Encephalomyocarditis virus (EMCV) is a highly
pathogenic and aggressive virus that causes enceph-
alitis and myocarditis in rodents. Administration of
melatonin prevented paralysis and death of mice
infected with sublethal doses of EMCV [32].
infected with Semliki Forest virus (SFV), a classic
encephalitis arbovirus, that invades the CNS and
whose replication in the mouse brain eventually
leads to death. Melatonin administration not only
reduced the death rate but also signicantly
postponed the onset of the disease. Furthermore,
the level of virus in the blood in melatonin-treated
mice was lower than in non-treated mice [33].
Although attenuated West Nile virus (WNV) strain
WN-25 is an encephalitis virus that does not invade
the brain and does not normally cause encephalitis,
exposure of mice to various stressful stimuli induces
WN-25 encephalitis. Melatonin counteracts the
immunodepressive effect of stress exposure and
prevents the stress-related encephalitis and death
of WN-25 infected mice [33].
Venezuelan equine encephalomyelitis (VEE) is an
important human and equine disease caused by
VEE virus (VEEV), a mosquito-borne organism.
Outbreaks have occurred in northern South
America from the 1920s to the 1970s with
thousands of people and horses, donkeys and
related species being infected. Mice have been used
as an animal model for this condition, because
VEEV-infected mice show excitation and hypermo-
tility followed by hypomotility, paralysis, coma
and death. Melatonin administration protects mice
infected with VEEV by decreasing the virus load
in brain and serum, reducing mortality rates,
delaying the onset of the disease and deferring the
time to death. Furthermore, in surviving mice
treated with melatonin, the VEEV-mediated IgM
antibody titres are highly elevated [34].
Aleutian mink disease is a natural condition
caused by persistent infection with the Aleutian mink
disease virus (AMDV). Animals in the progressive
state of the disease show a marked hypergammaglo-
bulinemia, because of high titers of non-neutralizing
ADMV antibodies. This is thought to cause lesions
in the kidney, liver, lungs and arteries. Melatonin
implants reduced mortality in ADMV-infected
mink [35].
The ndings in these reports document the
ability of the melatonin to protect against viral
infections [Table 1]. The potential protective
mechanisms include melatonin acting as a free
radical scavenger, an antioxidant enzyme inducer,
a positive regulator of immune functions and an
inhibitor of inammation, as well as a regulator of
programmed cell death (PCD) [Table 2].
Free radicals are molecules formed naturally
during many metabolic processes. They contain
an unpaired electron in their valence orbital that
makes them unstable and reactive. These reactive
agents damage essential molecules in cells including
lipids, proteins and DNA [36,37]. Among these
J. A. Boga
et al
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
reactants, the superoxide anion radical (O
), nitric
oxide (NO) and especially their derivatives, the
hydroxyl radical (OH) and peroxynitrite (ONOO
are highly biologically damaging elements produced
in the host during microbial infections [3841].
Phagocytes, such as neutrophils and macro-
phages are assumed to be the major generators
of free radicals. Elevated levels of O
Table 1. First evidence related to the ability of melatonin to protect against viral infections
Virus Animals Doses of melatonin Effects Ref.
EMCV 25 female 2-3-months-old
BALB/cj mice
1mg i.p./mouse daily
for 10 days
Prevention of paralysis
and death of infected mice
SFV 18 Charles River outbred ICR
female mice (CD1)
500 mg/kg s.c. daily, 3 days
before until 10 days
after virus inoculation
Reduction of the death rate 33
Delay of the onset of
the disease
10 Charles River outbred ICR
female mice (CD1)
500 mg/kg s.c. daily, 3 days
before until 10 days
after virus inoculation
Decrease the virus load
in blood
WN-25* 16 Charles River outbred ICR
female mice (CD1)
5mg/mouse s.c. daily,
2 days before until 8 days
after virus inoculation
Counteracts the
immunodepressive effect
of stress exposure
Prevention of the stress-
related encephalitis
Prevention of the death
of infected mice
VEEV 25 male albino mice
(NMRI- IVIC strain)/group
250500 mg1 mg/kg s.c.
3 days before until
10 days after inoculation
Reduction of mortality
Delay of the onset
of the disease
Deferring of the time
to death
6 male albino mice
(NMRI- IVIC strain)
500 mg/kg s.c. daily, 3 days
before until 10 days after
Decrease the virus load
in brain
Decrease the virus load
in serum
3 male albino mice
(NMRI- IVIC strain)/group
250500 mg/kg s.c. daily,
3 days before until 10 days
after inoculation
Increase the VEEV-
mediated IgM antibody
AMDV 90 wild type (demi-buff
or demi strain) minks
6000 male and female
demi strain minks
3000 male and female demi
and mahogany strains
of kit minks
Silastic implants
(0.65 cm length,
0.21 cm diameter)
containing 2.7 mg melatonin
crystals homogeneously
suspended in medical
grade silastic polymer
Reduction of mortality
EMCV, encephalomyocarditis virus; SFV, Semliki Forest virus; VEEV, Venezuelan equine encephalomyelitis virus;
AMDV, Aleutian mink disease virus; i.p., intraperitoneal; s.c., subcutaneal.
*an atenuated West Nile virus strain
Melatonin and viral infections
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
generated by both phagocyte NADPH oxidase
and xanthine oxidase (XO) during viral infec-
tions [4246]. O
reduces ferric iron to ferrous
iron, which catalyzes the Fenton reaction and
generates OH from hydrogen peroxide. ONOO
is formed by the coupling of O
and NO.
Overproduction of NOis primarily caused by
activation of inducible NO synthase (iNOS), which
is usually expressed by inammatory phagocytes
and other cell types (e.g. epithelial and neuronal
cells) [37,38,40,47]. iNOS is regulated by cytokine-
dependent mechanisms in HIV-1, HBV and HCV
infections [4851], as well as in a variety of
experimental viral infections in rats and mice,
including neurotropicviruses (Borna disease virus,
HSV-1 and rabies virus), and pneumotropic and
Table 2. Effects of melatonin in protecting against viral infections
Properties Virus
Effects of melatonin
administration Ref.
Free radical
VEEV Murine splenocytes Reduction of NOconcentrations in tissue 105
Decrease of both NOand lipid peroxidation 106
Mice Reduces nitrite concentrations
in the brain and serum
Lowering lipid peroxidation products
RSV Mice Reduction of acute lung oxidative injury 31
Suppression of MDA, NO
and OH generation
Restoration of GSH and SOD levels
in the lungs
enzyme inducer
RHDV Rabbits Restoration of activity and mRNA
expression of GPx, GST and Mn-SOD
Rise in protein expression of Nrf2
Regulator of immune
MLV Mice Prevention of reduction
in B- and T-cell proliferation
Prevention in Th1 cytokine secretion
Prevention of overproduction
of Th2 cytokines and TNF-a
VEEV Mice Stimulation of endogenous production
of IL-1bin brain
Reduction of the concentration
of TNF-ain brain
Stimulation of endogenous production
of IFN-g, IL-1b, and TNF-ain serum
RSV Mouse
Decrease of TLR3-mediated downstream
gene expression
Regulator of PCD RHDV Rabbits Reduction of Bax expression 179
Reduction of cytosolic cytochrome c release
Increased expression of Bcl-2 and Bcl-xL
Inhibition of caspase-9 activity
Reduction in caspase-8 activity
Reduction in TNF-R1 and JNK expression
Increased expression of c-FLIP
VEEV, Venezuelan equine encephalomyelitis virus; RHDV, rabbit hemorrhagic disease virus; MLV, murine leukemia virus.
J. A. Boga
et al
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
cardiotropic viruses (inuenza virus, SeV and
coxsackie virus) [5259].
Although IFN-gis the major cytokine inducing
iNOS and NOoverproduction in the pathogenesis
of these viral infections, iNOS expression is down-
regulated by IL-4, IL-10 and transforming growth
factor-b(TGF-b) [6062]. IFN-gis known to be asso-
ciated with type 1 helper T cell (Th1) responses, and
IL-4 and IL-10 are induced by type 2 helper T cell
(Th2) responses; NObiosynthesis catalyzed by
iNOS is precisely regulated by a polarized Th1
Th2 balance. In other viral diseases, viral replica-
tion or viral components directly induce iNOS
without mediation by pro-inammatory cytokines.
Thus, the HIV envelope glycoprotein gp41 triggers
iNOS expression in human astrocytes and murine
cortical brain cells in culture [63,64]. RSV directly
upregulates iNOS in human type 2 alveolar epithe-
lial cells (A549 cells) [65].
Free radicals are produced to eliminate the path-
ogenic agent or to kill the virus-infected cells by a
non-specic response. Thus, antiviral effects of
NOhave been described for some DNA viruses
such as murine poxvirus (ectromelia virus) and
herpes viruses including HSV, EBV and some
RNA viruses such as Coxsackie virus [6671]. The
toxic oxygen and nitrogen-based reactants, unfor-
tunately, cannot discriminate between exogenous
invading pathogens and the host cells themselves,
and therefore, they also damage the host. To
minimize such self-damage during the elimination
of pathogens, the host employs several primitive
tactics; it uses recruited phagocytes for the physical
containment of pathogens in infectious foci. Most
bacteria, for example, can be phagocytosed and
conned to septic foci, which are typically
abscesses or granulomas. Under these conditions,
free radicals can affect bacteria rather selectively
with the surrounding normal tissue remaining
mostly intact.
In viral infections, in contrast, free radical
mediators cause non-specic oxidative/nitrosative
damage in virus-infected tissue and produce oxida-
tive stress; this occurs when the virus cannot be
conned to limited areas by the non-specic host
defense [56,58,72]. Thus, NOhas appreciable anti-
viral actions on several types of viruses including
ortho- and paramyxovirus, murine vaccinia virus,
coronavirus (mouse hepatitis virus), lymphocytic
choriomeningitis virus, murine EMCV, tickborn
encephalitis virus (TBE-V) [7378]; also, NOand
its derivatives, especially ONOO
, can be consid-
ered pathogenic in some viral infections. Indeed,
NOinhibition or lack of NOgeneration reduces
the pathological consequences of viral pneumonia
in mice caused by inuenza virus, SeV and HSV-1,
HSV-1-induced encephalitis in rats, EMCV-induced
carditis and diabetes, and murine encephalitis
induced by avivirus (Murray Valley encephalitis
virus, TBE-V) [55,57,74,7882]. A similar pathoge-
nicity with a lack of antiviral effects has been
observed for O
in several experimental models
of virus-induced pneumonia including those caused
by inuenza virus and CMV [4345,56,72,83,84].
HCV-induced oxidative stress is emerging as a
key step and a major initiator in the development
and the progression of liver damage [85]. NS3,
one of the non-structural proteins of HCV, was
reported to induce reactive oxygen species by
NADPH oxidase in neutrophils [86]. High-risk
human papilloma virus (HPV), which causes
cervical cancer, promotes iNOS-dependent DNA
damage, leading to dysplastic changes and carcino-
genesis [87].
EpsteinBarr virus is a herpes virus that infects
the majority of the world population, generally
during childhood; it has been linked to the genesis
of a number of lymphoproliferative diseases and
neoplasia such as the African Burkitt lymphoma,
nasopharyngeal carcinoma or gastric carcinoma.
Early stages of EBV infection generate oxidative
stress either in B lymphocytes or in epithelial cells,
so contributing to pathology [88]. Inuenza A virus
causes a respiratory disease, which ranges from
mild upper respiratory tract illness with or without
fever to severe complications such as pneumonia.
The latter disease results in respiratory failure,
acute respiratory distress syndrome, multi-organ
failure and even death. An abrupt increase in
production occurs during phagocytosis,
which induces injury in non-infected cells. These
-mediated pathways contribute to a portion
of the extensive tissue injury observed during
severe inuenza-associated complications [56].
To protect themselves against free radical-
mediated damage, cells have developed an anti-
oxidant defense that includes enzymatic and
non-enzymatic mechanisms. Free radical generation
and a functionally efcient antioxidant defense
system must be in equilibrium to avoid cellular
damage caused by radicals and their derivatives.
Enzymes involved in the elimination of free radicals
Melatonin and viral infections
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
include the superoxide dismutases (SOD), catalase
(CAT) and glutathione peroxidase (GPx). In addi-
tion to the enzymatic antioxidant system, organisms
possess non-enzymatic free radical scavengers,
which directly remove toxic reactants because of their
electron donating ability. The best known non-
enzymatic antioxidants are vitamin E (a-tocopherol),
vitamin C (ascorbate), glutathione (GSH), b-carotene
and, as recently described, melatonin [25]. Sev-
eral radical scavengers have been efcacious
in ameliorating the severity of viral diseases.
N-acetylcysteine, a GSH precursor, inhibits HIV
in vitro [89] as did the natural thiol antioxidant,
alpha-lipoic acid [90]. Glutathione administration
to HIV seropositive individuals by aerosol treat-
ment can correct the glutathione deciency [91].
The combination of several antioxidants with
antiviral drugs synergistically reduces the lethal
effects of inuenza virus infections [92]. Thus,
any agent that functions as a direct radical scav-
enger and also stimulates antioxidative enzymes
with severe complications of viral infections.
Melatonin is a powerful and effective OH scav-
enger, which provides protection against oxidative
damage of cell components. It also scavenges
the peroxyl radical to a lesser degree generated
during lipid peroxidation with an activity that, in
some situations, is reportedly greater than that of
vitamin E [22,9396]. Also, melatonin directly
detoxies the ONOO
and possibly peroxynitrous
acid (ONOOH) [97]. In vivo, melatonin stimulates
several antioxidative enzymes including GPx,
CAT and SOD, thereby potentiating its antioxidant
properties [98101]. Melatonin can cross anatomical
barriers, including the placenta and the bloodbrain
barrier [102,103], and easily enter cells [104].
Splenocytes infected with VEEV generated less
of NO, when treated with melatonin; this nding
suggests that the indoleamine protected mice
infected with the VEEV by a mechanism involving
a reduction in NOconcentrations in tissue [105].
Elevated production of NOand lipid peroxidation
products were also found in supernatants and
cellular elements of VEEV-infected neuroblastoma
cell cultures. Both NOand lipid peroxidation were
decreased by melatonin treatment in a time-
dependent manner with an associated reduction
in iNOS expression [106]. Production of brain and
serum nitrite, as well as neural lipid peroxidation
products, was increased in VEEV-infected mice.
Melatonin treatment curtailed nitrite concentrations
in the brain and serum of infected mice and lowered
lipid peroxidation products [107].
Respiratory syncytial virus is a common cause of
bronchiolitis, a severe lower respiratory tract
afiction that infects nearly all infants by age three
worldwide. Mice inoculated intranasal with RSV
showed elevated oxidative stress due to rises in
NOand OH. Also elevated malondialdehyde
(MDA) and decreases in GSH and SOD activities
were observed. Pre-administration of melatonin
in vivo resulted in marked reduction of acute lung
oxidative injury induced by RSV, suppressed
MDA, NOand OH generation, and restored
GSH and SOD levels in the lungs of RSV-infected
mice [31].
Rabbit hemorrhagic disease virus (RHDV)
causes bleeding in the respiratory system, liver,
spleen, cardiac muscle,and occasionally in the
kidneys of infected rabbits with mortality over
90% in adults [108]. The activity and mRNA
expression of the antioxidants enzymes GPx,
glutathione-s-transferase (GST) and Mn-SOD were
signicantly reduced in the liver of RHDV-
infected rabbits used as a model of fulminant
hepatic failure; these changes were reduced by
melatonin administration in a concentration-
dependent manner. Melatonin treatment also
caused a rise in protein expression of the nuclear
factor erythroid 2 (Nrf2), a transcription factor that
plays a critical role by binding to the antioxidant
response element in the promoter region of a number
of genes encoding for antioxidant and detoxifying
enzymes in several types of cells and tissues [109].
The activation of Nrf2 during prevention of oxida-
tive liver injury by melatonin in rats treated with
dimethylnitrosamine has been reported [110].
During the early phase of infection and depend-
ing on the nature of the infected cells and the
infecting virus, early innate defense mechanisms
may be triggered to limit the extent of viral
spread. The rst mechanism to limit the extent
of viral spread is the recognition of pathogen-
associated molecular patterns (PAMPs), which
are mostly viral nucleic acids, or their synthetic
analogs produced during the viral infection, by
a large repertoire of pattern recognition receptors
J. A. Boga
et al
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
(PRRs), including Toll-like receptors (TLRs), Nod-
like receptors (NLRs), RIG-I-like receptors (RLRs)
and AIM2-like receptors (ALRs) [111114]. Such
recognition initiates signaling cascades that culmi-
nate in the activation of transcription factors
including nuclear factor kappa B (NF-kB), acti-
vating transcription factor 2 (ATF-2), activating
protein-1 (AP-1) and interferon regulatory factors
3 (IRF3) and 7 (IRF7). These stimulate the expres-
sion of type I IFN genes that are synthesized in
most cell types and especially in plasmacytoid
dendritic cells (pDC) [115]. All IFNs bind to specic
ubiquitously expressed cell surface receptors and
induce a large number of interferon-stimulated
genes (ISG), whose encoded proteins mediate the
antiviral effects of interferons.
Among these ISGs, dsRNA-activated protein
kinase (PKR) primarily inhibits replication of
RNA viruses such as vesicular stomatitis virus
(VSV), EMCV, WNV, HCV and DNA viruses
including HSV-1 [116]. Another group of ISGs is
the 2050-oligoadenylate synthetases (OAS) that
requires dsRNA for its activation and is a major
antiviral effector against picornaviruses (e.g.
EMCV) and inuenza A virus, as well as other
RNA viruses [117] . Non-specic ssRNA cleavage also
occurs after induction of ISG20, a 30-exoribonuclease,
which contributes to inhibition of RNA viruses
such as VSV [118]. An additional, non-enzymatic
mechanism of translation inhibition is pursued by
the ISG56/IFIT family proteins, which act against
HCV [119121]. Another IFN-induced protein is the
human MxA, which is a key component in innate
defense against orthomyxoviruses such as inuenza
virus as well as measles virus, VSV, Hanta virus and
SFV [116,122], the Viperin (CIG5), which might
interfere with viral budding of enveloped viruses,
s u c h a s C M V, H C V, a n d i n uenza virus [123], and
the nucleic acid-editing enzymes APOBEC3G and
3 F, which inhibit retroviruses [124].
A second mechanism is the triggering of effector
functions of cellular components of the innate
immune system, such as granulocytes, natural
killer cells (NK) and natural killer T cells (NKT
cells), macrophages, and dendritic cells, which are
normally rapidly recruited and/or activated at the
site of virus infection, causing a local inammation
[125]. During this early phase, activated NK cells
release IFN-g, which is not stimulated by viral
PAMPs but by IL-12 and IL-18 released by acti-
vated macrophages [126]. All of the cellular
components of the innate immune system can par-
ticipate in the antiviral response by killing infected
cells, by producing chemokines (including eotaxin,
RANTES, MCP-1, IL-8) that recruit inammatory
cells into the infected tissue and by producing anti-
viral and immunoregulatory cytokines (including
TNF-a, IL-1, IL-3, IL-4, IL-5, IL-6, IL-12, IL-18,
GM-CSF) that enable the adaptive immune
response to recognize infected cells and perform
antiviral effector functions [127130]. Lymphocytes
are cells of this adaptive immune system. Among
them, two subsets of CD4
T cells, Th1 and Th2,
play a key role in antiviral immunity. After being
stimulated by antigen presenting cells, Th1 cells
produce IL-2, TNF-aand IFN-g, which possess
antiviral activities and regulate activation of CD8
cytotoxic T cells, whereas Th2 cells produce IL-4,
IL-5, IL-10 and IL-13, which stimulate B cells to
produce antibodies [131]. Despite the fact that
virus-specic Th2 cells can be detected following
primary infection by any virus, virus-specic Th1
cells are usually much more abundant and reach
very high numbers at the peak of the acute infec-
tion [132]. Moreover, their frequencies remain
elevated following resolution of the infection.
Melatonin is synthesized in lymphoid organs,
such as the bone marrow, thymus and lymphocytes
[133135], and there are high afnity membrane
melatonin receptors as well as nuclear binding sites
in circulating lymphocytes, spleen cells and thymo-
cytes [136138]. Melatonin is known to activate
both innate and adaptive immune responses
leading to an increase in immune responsiveness
and regulation of several immune functions
[27,28,139143]. Melatonin has properties as an
inammatory regulator, because it differen-
tially modulates pro-inammatory enzymes, and
controls the production of inammatory mediators
such as cytokines and leukotrienes. The timing of
its pro-inammatory and anti-inammatory effects
suggests that melatonin might promote early
phases of inammation, on the one hand, and
contribute to its attenuation on the other hand, to
avoid complications of chronic inammation
[144]. Melatonin enhances the production of IL-1,
IL-6, TNF-aand IL-12 from the monocytes [145]
and of IL-2, IFN-gand IL-6 from cultured human
peripheral blood mononuclear cells [137]. It has
been suggested that melatonin and IFN-gcreate
an immunoregulatory circuit responsible for the
antiviral, antiproliferative and immunomodulatory
Melatonin and viral infections
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
actions of IFN-g[146]. This cytokine increases sero-
tonin and melatonin levels in lymphocytes and
macrophages. The early stimulation in the produc-
tion of IFN-gby melatonin suggests that earlier
treatment with this indoleamine could increase
the antiviral activity of IFN-g[147]. In addition to
stimulating the production of several cytokines that
regulate immune function, melatonin enhances
immune function by directly stimulating polymor-
phonuclear cells, macrophages, NK cells and lym-
phocytes [148]. Recently, considerable attention
has been focused on the fact that melatonin
treatment has been found to augment CD4+ T cells
in lymph nodes of rats [149]. Consequently,
melatonin is considered an immunoenhancing
agent [141,150].
In retrovirus-infected people and mice, whereas
Th1 cytokine (IL-2 and IFN-g) production
declines, Th2 cytokine (IL-4, IL-5, IL-6, and IL-10)
production increases [151153]. The excessive Th2
cytokines suppress Th1 cells, causing anergy of
cell-mediated immunity, thus allowing the retrovi-
rusaswellasnormalora to reproduce and pro-
mote free radical generation by macrophages
[154]. Female C57BL/6 mice infected with the
LP-BM5 MLV develop murine AIDS. Treatment
with melatonin, alone or with dehydroepian-
drosterone (DHEA), prevented retrovirus-induced
reduction in B-cell and T-cell proliferation and in
Th1 cytokine secretion, as well as overproduction
of Th2 cytokines and TNF-a[155]. In fact, melato-
nin alters the balance of Th1 and Th2 cells mainly
towards Th1 responses increasing the production
of Th1 cytokines [156].
A link between melatonin and the immune
system has been also reported in patients infected
with HIV-1. Although mean serum IL-12 levels in
HIV-1-affected individuals did not signicantly
differ from healthy controls, the IL-12 levels of
HIV-1 patients with advanced disease (CDC stage
C) were signicantly lower than those of patients
in less advanced CDC stages B and A. Taking into
account that serum IL-12 levels run parallel with
serum melatonin concentrations as the disease
advances, a relationship between immune function
and melatonin has been suggested; a reduction in
serum melatonin could possibly affect IL-12
production thereby contributing to the progress of
HIV-1 infection [157].
The protective effect of melatonin against VEEV
by regulation of the immune system has been
described by Bonilla et al. [158]. The endogenous
production of IFN-g, IL-1band TNF-a, but not of
IL-2 and IL-4, is stimulated in VEEV-infected mice
treated with melatonin [159]. Nevertheless, the
average mortality obtained during neutralization
experiments with the corresponding anticytokine
antibody suggests that although neither TNF-a
nor IFN-gis essential for the protective effect of
melatonin observed in murine VEEV infection,
IL-1binduced by melatonin treatment is a target
cytokine to promote the immune enhanced state.
This in turn causes the viral clearance or helps
generate an earlier immune response against the
VEEV infection [160]. In contrast, in the brain of
VEEV-infected mice, melatonin stimulates the
endogenous production of IL-1bbut reduces the
concentration of TNF-a[158]. IL-1bis considered
one of the earliest host mediators during infectious
diseases of the CNS and its role in infectious
processes of the brain parallels its role in the
peripheral immune system [160]. Although IL-1b
deciency is protective against fatal Sindbis virus
infection [161], mice decient in IL-1bhave
increased susceptibility to inuenza virus [162]. In
poxvirus animal models, the viral induction of this
cytokine is also benecial for the host [163]. The
increase in IL-1blevels detected in blood and
in brain of VEEV-infected mice after melatonin
treatment also plays a protective role, possibly by
neuronal support and protection by inducing nerve
growth factor secretion by astrocytes [164]. This
supplies a trophic factor for many neuronal cell types
in times of stress such as that produced by VEEV
The signicant reduction in the concentration of
brain TNF-ainduced by melatonin in VEEV-
infected mice likely diminishes the inammatory
response caused by the migration of granulocytes
and macrophages to inammatory sites within the
CNS [165]. These cells are recruited by colony-
stimulating factors produced by astrocytes stimulated
by TNF-aand as a consequence of alterations in
bloodbrain barrier (BBB) permeability caused by
the adhesive properties of astrocytes stimulated by
TNF-a.TNF-ais known to induce intercellular adhe-
sion molecules on neighboring endothelial cells [166],
alter BBB permeability and promote inammatory
cell inltration into the CNS. By reducing adhesion
molecule production, which melatonin is known to
do [167], the indole would protect the brain infected
with VEEV.
J. A. Boga
et al
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
Respiratory syncytial virus bronchiolitis in
infants is characterized by a massive inltration of
inammatory cells into the airways. Of the diverse
intracellular signaling pathways, RSV is recognized
by TLR3, which initiates a signaling cascade that
culminates in the activation of the transcription factor
NF-kB; NF-kB is a central mediator of RSV-induced
airway inammation in vivo [145,168,169]. RSV in-
fection of RAW264.7 macrophages time-dependently
stimulates the rapid activation of TLR3 and NF-kB, as
well as subsequent NF-kB dependent genes, many of
which encode for pro-inammatory cytokines
and chemokines including TNF-aand IL-1b.
Melatonin decreases TLR3-mediated downstream
gene expression in RSV-infected macrophages in a
dose-dependent and time-dependent manner. Such
inhibition of NF-kB activity, as well as of TNF-ain
serum, seems to be the key event required to explain
the reduction in inammatory gene expression
caused by melatonin [31,170].
As obligate intracellular parasites, viruses are
dependent on the host for each stage of replication
and, therefore, constantly interface with multiple
components of the host cell machinery, including
cellular receptors and uptake pathways, gene
expression mechanisms and the cell division appara-
tus. Viral utilization of these systems likely causes
cell stress and activates death-signaling pathways
or alters expression of genes that control cell
survival, evoking PCD [171,172].
Apoptosis is one type of PCD, which is depen-
dent on cleavage of important cellular factors by
effector caspases such as caspase-3 and caspase-7.
Two major pathways govern the activation of such
effector caspases. In the intrinsic pathway, intracel-
lular stresses sensed by the BH3-only members of
the bcl-2 family promote the formation of the apop-
tosome by activation of caspase-9 through release
of proapoptotic molecules such as cytochrome c
and Smac/Diablo from the mitochondria. The
apoptosome directly activates effector caspases. In
the extrinsic pathway, occupation of death recep-
tors such as Fas and tumor necrosis factor receptor
(TNF-R) by death ligands including FasL and
TNFaforms a death-inducing signaling complex
(DISC). This results in the activation of the initiator
caspase, caspase-8, which directly mediates effector
caspase activation and causes cell death.
The ability of melatonin to modulate apoptosis
and to differentially regulate the expression of
pro-apoptotic and anti-apoptotic mediators has
been reported in many studies [29,173177].
RHDV infection induces liver apoptosis with
increased caspase-3 expression and activity
[178,179]. These effects are attenuated by mela-
tonin in a concentration-dependent manner.
Anti-apoptotic actions of melatonin on the intrin-
sic pathway were related to a reduced expression
of Bax and cytosolic cytochrome c release,
increased expression of Bcl-2 and Bcl-xL, and
inhibition of caspase-9 activity. Melatonin treatment
also has effects on extrinsic pathway resulting in a
reduction in caspase-8 activity, TNF-R1 expression
and phosphorylated Janus kinase (JNK) expres-
sion, and increased expression of cellular FLICE-
inhibitory protein (c-FLIP), an inhibitor of
caspase-8 [179]. These ndings show that inhibi-
tion of apoptotic mechanisms contributes to the
benecial effects of melatonin in rabbits with
experimental infection by RHDV and supports a
potential hepatoprotective role of melatonin in
fulminated hepatic failure.
Autophagy is a type of PCD characterized by the
formation of autophagosomes to remove excessive
proteins and thereby maintains homeostasis within
the cell. Autophagy is now recognized as a compo-
nent of both innate and adaptive immune responses
to bacterial and viral pathogens [180]. Varicella
zoster virus infection provides an excellent example
of autophagy in humans, because abundant autop-
hagosomes are easily detected in the skin vesicles
of both varicella and zoster [181]. Autophagy is also
found during viral replication of HCV [182], rabbit
calicivirus [183] and poliovirus [184]. Given that
melatonin modulates autophagy through redox-
sensitive transcription factors [185], the role of
melatonin in such viral infections involving autop-
hagy should be examined.
Benecial effects of melatonin when combined
with several drugs, such as doxorubicin, cisplatin,
epirubicin, cytarabine, bleomycin, gentamicin,
cyclosporin, indometacin, acetylsalicylic acid, ranit-
idine, omeprazole, isoniazid, iron and erythropoie-
tin, phenobarbital, carbamazepine, haloperidol,
Melatonin and viral infections
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
caposide-50, morphine, cyclophosphamide and
L-cysteine have been reported [24]. Recently, a sin-
gle blind randomized study showed a higher per-
cent of a complete regression of symptoms of
HSV-1 infection after a treatment with melatonin
plus SB-73 (an extract of Aspergillus sp. with anti-
herpetic properties) compared with the treatment
with acyclovir alone [186]. Effects of melatonin to
increase the efcacy of other antivirals should
be studied.
Melatonin is an endogenously produced and ubiq-
uitously acting molecule [187189]. Because of its
highly diverse actions, this indoleamine has poten-
tial to combat a wide variety of pathophysiological
conditions [190194]; it has been tested in numer-
ous clinical trials [23] with the outcomes of the
treatments always being benecial. Because of its
essential and basic actions on cell physiology,
melatonin qualies for the moniker molecular
handyman,as indicated in the title of this review.
In relation to viral infections, melatonin also seems
to be benecial as indicated in the experimental
studies summarized herein. Its favorable actions
against viral infections likely relate to its ability to
limit the negative molecular processes normally
activated when viruses invade cells. Melatonins
actions include an ability to promote immune
surveillance, to scavenge free radicals thereby signif-
icantly reducing the associated molecular des-
truction and to modulate the processes related to
apoptosis. These multiple actions suggest that mela-
tonin should be evaluated in randomized controlled
trials as a preventive agent or as a treatment of viral
infections particularly in older individuals where
endogenous levels of melatonin have declined. It is
the hope of the authors that this summary will
stimulate interest in experimental examination of
The authors have no competing interest.
JAB is a researcher of ISCIII/FICYT. His stay at
UTHSCSA has been subsidized by ISCIII (BA 11/
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... When RSVinfected macrophages were given melatonin, TLR3-mediated downstream gene expression was shown to be reduced. Further, melatonin supplementation in RSV-infected mice reduced the severity of damage to lung cells which was supported by increased levels of glutathione production and antioxidant enzymes (SOD) and decreased production of ROS and RNS (Boga et al., 2012). ...
... Similarly, the influenza A virus is another virus that affects the respiratory tract and causes significant tissue damage. In all these illnesses, lymphocytes, neutrophils, and macrophages infiltrate the lung parenchyma, causing pro-inflammatory and nonspecific oxidative stress-related damage (Boga et al., 2012). Melatonin treatment significantly reduced the number of CD8+ T cells responsible for producing TNFα in Influenza A-infected mice in the spleen and lungs, which might help to minimize the degree of lung damage (Huang et al., 2010). ...
Full-text available
SARS‐CoV‐2 infection has now become the world's most significant health hazard, with the World Health Organization declaring a pandemic on March 11, 2020. COVID‐19 enters the lungs through angiotensin‐converting enzyme 2 (ACE2) receptors, alters various signaling pathways, and causes immune cells to overproduce cytokines, resulting in mucosal inflammation, lung damage, and multiple organ failure in COVID‐19 patients. Although several antiviral medications have been effective in managing the virus, they have not been effective in lowering the inflammation and symptoms of the illness. Several studies have found that epigallocatechin‐3‐gallate and melatonin upregulate sirtuins proteins, which leads to downregulation of pro‐inflammatory gene transcription and NF‐κB, protecting organisms from oxidative stress in autoimmune, respiratory, and cardiovascular illnesses. As a result, the purpose of this research is to understand more about the molecular pathways through which these phytochemicals affect COVID‐19 patients' impaired immune systems, perhaps reducing hyperinflammation and symptom severity. Practical applications Polyphenols are natural secondary metabolites that are found to be present in plants. EGCG a polyphenol belonging to the flavonoid family in tea has potent anti‐inflammatory and antioxidative properties that helps to counter the inflammation and oxidative stress associated with many neurodegenerative diseases. Melatonin, another strong antioxidant in plants, has been shown to possess antiviral function and alleviate oxidative stress in many inflammatory diseases. In this review, we propose an alternative therapy for COVID‐19 patients by supplementing their diet with these nutraceuticals that perhaps by modulating sirtuin signaling pathways counteract cytokine storm and oxidative stress, the root causes of severe inflammation and symptoms in these patients.
... The benefits of melatonin in the treatment of viral infections can be attributed to its properties as an immune function stimulator, an antioxidant enzyme inducer, a free radical scavenger, and an apoptosis regulator (Boga et al., 2012). Some studies on animals also support the anti-viral effects of melatonin against certain infections such as those caused by encephalomyocarditis virus, Semliki Forest virus, West Nile virus, Venezuelan equine encephalitis virus, and Aleutian mink disease virus (Ben-Nathan et al., 1995;Bonilla et al., 1997;Ellis, 1996). ...
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Introduction Since November 2019, the world has been grappling with the rapid spread of the Coronavirus disease 2019 (COVID-19). In response to this major health crisis, the first vaccination rollout was launched in December 2020. However, even fully vaccinated individuals are not completely immune to infection, albeit with less severe symptoms. Melatonin is known as an anti-oxidant, anti-inflammatory, and immunomodulatory agent whose anti-viral properties, cost-effectiveness, and relatively few side effects make it a potential adjuvant in the treatment of COVID-19. This systematic review aims to summarize the clinical studies on the effects of melatonin on COVID-19 patients. Methods The search of articles was carried out in the Web of Science, PubMed/MEDLINE, Cochrane library, and Scopus databases up to January 2022. Results Ten articles were included in our study. It seems melatonin can decrease inflammatory markers, inflammatory cytokines, and the expression of some genes, including the signal transducer and activator of transcription (STAT)4, STAT6, T-box expressed in T cell (T-bet), GATA binding protein 3 (GATA3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 (CASP1). In addition, melatonin appears to alleviate some clinical signs and symptoms and accelerate recovery. The use of melatonin in severe cases reduces thrombosis, sepsis, and mortality rate. Conclusion This systematic review highlights the probable role of melatonin as a potential adjuvant in the treatment of COVID-19 after about two weeks of consumption. However, further high-quality randomized clinical trials are required.
... La melatonina no es antivírica pero ha demostrado presentar acciones indirectas de ese tipo [25] debido a sus acciones antiinflamatorias ,antioxidantes y efectos potenciadores del sistema inmunitario (21,37,38 ).La utilización de la melatonina en ratones infectados con el virus de la encefalitis determina una disminución de la viremia de la parálisis, de mortalidad y de la carga viral (39). Todos estos hechos además de los recientemente resumidos por Reiter et al. (26), apoyan el uso de la melatonina en enfermedades virales . ...
Melatonin is a hormone that acts facilitating the appearance of physiological sleep It has also a very evident antinflammatory and antioxidant capacities that result in beneficial actions on the aging processes in the cardiovascular system and in the lungs where our group has detected a protective action against oxidative stress , inflammation and apoptosis . Although melatonin is not viricidal by itself in some models of viral infections it has demonstrated its ability to reduce viral load and also inflammation and oxidation, reducing the severity of the disease. In COVID 19 melatonin has been shown to be able to interfere with the infectious process that takes place through ACE2 and EGF receptors being able to block these interactions thus reducing viremia .It is able to block the activation of the NLRP3 inflammasome thus dramatically reducing the massive secretion of cytokines and markedly reducing hyperinflammation and apoptosis leading to a better evolution of the disease .For all these reasons melatonin could play an important role in the treatment of COVID 19.
... 240 The antiviral action of melatonin has been previously reported against viruses other than COVID-19. 242,243 Results obtained on many experimental models involving inflammation and/or oxidative stress proved that both antioxidant and anti-inflammatory abilities of melatonin protect from lung impairment. 244 The immunomodulatory roles of melatonin involve a dual aspect, with proinflammatory and anti-inflammatory actions. ...
Viral pathologies encompass activation of pro-oxidative pathways and inflammatory burst. Alleviating overproduction of reactive oxygen species and cytokine storm in COVID-19 is essential to counteract the immunogenic damage in endothelium and alveolar membranes. Antioxidants alleviate oxidative stress, cytokine storm, hyperinflammation, and diminish the risk of organ failure. Direct antiviral roles imply: impact on viral spike protein, interference with the ACE2 receptor, inhibition of dipeptidyl peptidase 4, transmembrane protease serine 2 or furin, and impact on of helicase, papain-like protease, 3-chyomotrypsin like protease, and RNA-dependent RNA polymerase. Prooxidative environment favors conformational changes in the receptor binding domain, promoting the affinity of the spike protein for the host receptor. Viral pathologies imply a vicious cycle, oxidative stress promoting inflammatory responses, and vice versa. The same was noticed with respect to the relationship antioxidant impairment-viral replication. Timing, dosage, pro-oxidative activities, mutual influences, and interference with other antioxidants should be carefully regarded. Deficiency is linked to illness severity.
... Melatonin affects the immune responses and both anti-inflammatory and enhancing effects were reported for it (54). Beneficial effects were suggested for melatonin in some viral infections (55). This provides rationale for a potential therapeutic effect in the infection with SARS-CoV-2. ...
... A number of studies have documented the ability of melatonin in neutralizing the effects of nematocyst and snake venom toxins which are largely a result of massive free radical generation [34,35]. The use of melatonin as an anti-viral agent has recently come into focus as well and it has been proposed as a treatment for Ebola, COVID-19 and other viral infections [36,37]. There are currently 185 publications suggesting the utility of melatonin to treat COVID and all it variants [38][39][40]. ...
Severe COVID-19 is associated with the dynamic changes in coagulation parameters. Coagulopathy is considered as a major extra-pulmonary risk factor for severity and mortality of COVID-19; patients with elevated levels of coagulation biomarkers have poorer in-hospital outcomes. Oxidative stress, alterations in the activity of cytochrome P450 enzymes, development of the cytokine storm and inflammation, endothelial dysfunction, angiotensin-converting enzyme 2 (ACE2) enzyme malfunction and renin–angiotensin system (RAS) imbalance are among other mechanisms suggested to be involved in the coagulopathy induced by severe acute respiratory syndrome coronavirus (SARS-CoV-2). The activity and function of coagulation factors are reported to have a circadian component. Melatonin, a multipotential neurohormone secreted by the pineal gland exclusively at night, regulates the cytokine system and the coagulation cascade in infections such as those caused by coronaviruses. Herein, we review the mechanisms and beneficial effects of melatonin against coagulopathy induced by SARS-CoV-2 infection.
... Melatonin is extensively reviewed and documented for its potent antiviral properties [140][141][142][143][144][145] that can activate type I IFN-⍺ responsible for promoting JAK1/2 signaling and phosphorylation of STAT3 [146][147][148][149]. Leukocytes, including neutrophils, are largely responsible for the production of IFN-⍺ [150,151], and melatonin can increase the production of leukocytes. Human volunteers supplemented with 20 mg melatonin exhibited enhanced leukocyte chemokine expression and leukocyte chemotactic response, while 1 nM physiological concentration of melatonin via intraperitoneal (i.p.) injection increased the leukocyte count, with statistically significant increases in neutrophils in the peritoneal cavities of rats [152]. ...
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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.
... Besides clinical trials, etc., which indicate that melatonin is effective in aiding the recovery of COVID patients, measured by any parameter considered, there is a vast amount of experimental information (150 publications to date) which clarifies why it is effective [9,11]. Melatonin is a powerful antioxidant and anti-inflammatory molecule that modifies the innate immune system and functions as a pan-antiviral agent [12]. Melatonin lowers virus uptake into cells and hinders their replication, inhibits sepsis, reduces phospholipase A2 levels, lowers inflammatory cytokines, etc., which contribute to acute respiratory disease and systemic multiorgan dysfunction (Fig. 1). ...
No single treatment will eliminate the COVID-19 pandemic. It is imperative that all available tactics and medications be used to overcome this disease, although it will probably never totally disappear. Melatonin is inexpensive so it is affordable throughout the world, it does not require refrigeration and it has a very long shelf-life. Melatonin has no substantial side effects even at extremely high doses, no overdose has ever occurred, and it can be self-administered via several routes. Considering its efficacy in both experimental studies and clinical trials, the portfolio of medications used to a curtail COVID-19 infections should clearly include melatonin. Since melatonin inhibits many types of viruses, it should also be considered a potential treatment of Ebola, Zika, and hantavirus infections, and possibly others.
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Melatonin, an endogenous indoleamine, is an antioxidant and anti-inflammatory molecule widely distributed in the body. It efficiently regulates pro-inflammatory and anti-inflammatory cytokines under various pathophysiological conditions. The melatonin rhythm, which is strongly associated with oxidative lesions and mitochondrial dysfunction, is also observed during the biological process of aging. Melatonin levels decline considerably with age and are related to numerous age-related illnesses. The signs of aging, including immune aging, increased basal inflammation, mitochondrial dysfunction, significant telomeric abrasion, and disrupted autophagy, contribute to the increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These characteristics can worsen the pathophysiological response of the elderly to SARS-CoV-2 and pose an additional risk of accelerating biological aging even after recovery. This review explains that the death rate of coronavirus disease (COVID-19) increases with chronic diseases and age, and the decline in melatonin levels, which is closely related to the mitochondrial dysfunction in the patient, affects the virus-related death rate. Further, melatonin can enhance mitochondrial function and limit virus-related diseases. Hence, melatonin supplementation in older people may be beneficial for the treatment of COVID-19.
Purpose Melatonin, a natural hormone mainly synthesized by the pineal gland, is regulated by circadian rhythm. Synthetic melatonin is not approved by the US Food and Drug Administration for any indication. However, melatonin receptor agonists such as ramelteon and tasimelteon are US Food and Drug Administration approved and are considered by the American Academy of Family Physicians for the treatment of insomnia. Due to the availability of over-the-counter products in some countries and the increasing use of melatonin, it is interesting to highlight knowledge regarding the potential benefits of melatonin outside sleep disorders. Methods This narrative review included published reports in EMBASE and MEDLINE databases between 1975 and 2021 relating to the therapeutic applications of melatonin. Findings: Based on the quality of the evidence published to date, the most promising non-insomnia indications are for treating ischemia/reperfusion injury, primary headache disorders, fibromyalgia, glucose control, and blood pressure control. Implications Most of the studies were preclinical and in in vivo and in vitro phases. More clinical trials are needed before recommending melatonin as a treatment in clinical practice.
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Although basal and moderately elevated levels of nitric oxide are physiologically necessary and beneficial, excessive upregulations of this signaling molecule can be a cause of damage and cellular dysfunctions. In the presence of increased amounts of superoxide anions (•O2–) and carbon dioxide, peroxynitrite (ONOO–) and the peroxynitrite-CO2 adduct (ONOOCO2–) generate hydroxyl (•OH), nitrogen dioxide (•NO2) and carbonate (•CO3–) radicals, which damage biomolecules by oxidation/peroxidation, nitration and nitrosation reactions. Nitrosation also occurs with all three NO congeners (NO+, •NO, and HNO = protonated NO–), with •NO especially in combination with electron/hydrogen-abstracting compounds, or with N2O3. 3-Nitrotyrosine, found in low-density lipoprotein particles (LDL), atherosclerotic plaques, ion channels, receptors, transporters, enzymes and respirasomal subunits, is associated with numerous dysfunctions. Damage to the mitochondrial electron transport chain (ETC) is of particular significance and involves nitration, nitrosation and oxidation of proteins, cardiolipin peroxidation, and binding of •NO to ETC irons. Resulting bottlenecks of electron flux cause enhanced electron leakage which leads to elevated •O2–. In combination with high •NO, •O2– initiates a vicious cycle by generating more peroxynitrite that leads to further blockades and electron dissipation. Mitochondrial dysfunction, as induced via the •NO/peroxynitrite pathway, is of utmost importance in inflammatory diseases, especially sepsis, but also relevant to neurodegenerative and various other disorders. It may contribute to processes of aging. Melatonin, hormone of the pineal gland and product of other organs, interacts directly with reactive nitrogen species, but, more importantly, has antiinflammatory properties and downregulates inducible and neuronal NO synthases (iNOS, nNOS). It does not block moderately elevated •NO formation, but rather blunts excessive rises as occurring in sepsis and breaks the vicious cycle of mitochondrial electron leakage. The melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK) forms stable nitrosation products and efficiently inhibits iNOS and nNOS, in conjunction with other antiinflammatory properties. [J Exp Integr Med 2011; 1(2.000): 67-81]
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Activated mouse peritoneal macrophages produce nitric oxide (NO) via a nitric oxide synthase that is inducible by interferon gamma (IFN-gamma): iNOS. We have studied the mechanisms by which transforming growth factor beta 1 (TGF-beta) suppresses IFN-gamma-stimulated NO production. TGF-beta treatment reduced iNOS specific activity and iNOS protein in both cytosolic and particulate fractions as assessed by Western blot with monospecific anti-iNOS immunoglobulin G. TGF-beta reduced iNOS mRNA without affecting the transcription of iNOS by decreasing iNOS mRNA stability. Even after iNOS was already expressed, TGF-beta reduced the amount of iNOS protein. This was due to reduction of iNOS mRNA translation and increased degradation of iNOS protein. The potency of TGF-beta as a deactivator of NO production (50% inhibitory concentration, 5.6 +/- 2 pM) may reflect its ability to suppress iNOS expression by three distinct mechanisms: decreased stability and translation of iNOS mRNA, and increased degradation of iNOS protein. This is the first evidence that iNOS is subject to other than transcriptional regulation.
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Age-associated rises in oxidative damage are assumed to be a central phenomenon of aging. Their attenuation is an aim for both healthy aging and life extension. This review intends to critically discuss the potential of anti-oxidant actions, but even more to direct the attention to the modes of radical avoidance and to regulatory networks involved. Mitochondria seem to play a decisive role in radical formation and cellular decline. Avoidance and repair of disruptions in the electron transport chain reduce electron leakage and, thus, oxidative damage. Several low molecular weight compounds, such as melatonin, its metabolite N 1 -acetyl-5-methoxykynuramine, resveratrol, -lipoic acid, and various mitochondrially targeted nitrones are capable of supporting mitochondrial electron flux. Some of them have been successfully used for extending the lifespan of experimental animals. Importantly, chemopreventive effects of these substances against cancer development should not be confused with a slowing of the aging process. We also focus on connections between these compounds and mitochondrial biogenesis, including the roles of sirtuins and signaling via peroxisome proliferator-activated receptor-coactivator-1, the participation of the circadian oscillator system in radical avoidance, as well as the potentially beneficial or detrimental effects of NO, as either a regulator or a source of mitochondrial dysfunction. Especially in the central nervous system, anti-excitatory actions by melatonin, kynurenic acid and theanine are discussed, which seem to prevent calcium overload that results in mitochondrial dysfunction. New findings on direct binding of melatonin to the amphipathic ramp of Complex I may indicate an additional regulatory role in the avoidance of electron leakage.
Circadian production and secretion of melatonin from mammalian pineal gland provides animals with information concerning the light/dark environment. Melatonin passes easily through cell membranes;thus each organ, provided it can interpret the melatonin message, can adjust its physiological activity accordingly.
Intranasal Herpes simplex virus type 1 (HSV-1) infection of mice caused pneumonia. Manifestations of the disease included: histological pneumonitis, pulmonary influx of lymphocytes, decreased pulmonary compliance, and decreased survival. Immunohistochemical staining demonstrated iNOS induction and the nitrotyrosine antigen in the lungs of infected, but not uninfected mice, suggesting that nitric oxide contributes to the development of pneumonia. To elucidate the role of nitric oxide in the pathogenesis of HSV-1 pneumonia, infected mice were treated either with the inhibitor of nitric oxide synthase activity, NG-monomethyl-l-arginine (l-NMMA), or, as a control, with PBS or d-NMMA. l-NMMA treatment decreased the histological evidence of pneumonia and reduced the bronchoalveolar lavage lymphocyte number to one-quarter of the total measured in control-treated mice. l-NMMA treatment significantly improved survival and pulmonary compliance of HSV-1–infected mice. Strikingly, the l-NMMA–mediated suppression of pneumonia occurred despite the presence of a 17-fold higher pulmonary viral titer. Taken together, these data demonstrated a previously unrecognized role of nitric oxide in HSV-1–induced pneumonia. Of note, suppression of pneumonia occurred despite higher pulmonary virus content; therefore, our data suggest that HSV-1 pneumonia is due to aspects of the inflammatory response rather than to direct viral cytopathic effects.
In the past two decades, the results of a number of epidemiological studies have uncovered an association between excessive light exposure at night and the prevalence of cancer. Whereas the evidence supporting this link is strongest between nighttime light and female breast and male prostate cancer, the frequency of other tumor types may also be elevated. Individuals who have the highest reported increase in cancer are chronic night shift workers and flight attendants who routinely fly across numerous time zones. There are at least two obvious physiological consequences of nighttime light exposure, i.e., a reduction in circulating melatonin levels and disruption of the circadian system (chronodisruption). Both these perturbations in experimental animals aggravate tumor growth. Melatonin has a long investigative history in terms of its ability to stymie the growth of many tumor types. Likewise, in the last decade chronodisruption has been unequivocally linked to a variety of abnormal metabolic conditions including excessive tumor growth. This brief review summarizes the processes by which light after darkness onset impedes melatonin production and disturbs circadian rhythms. The survey also reviews the evidence associating the ostensible danger of excessive nighttime light pollution to cancer risk. If an elevated tumor frequency is definitively proven to be a consequence of light at night and/or chronodisruption, it seems likely that cancer will not be the exclusive pathophysiological change associated with the rampant light pollution characteristic of modern societies. [J Exp Integr Med 2011; 1(1): 13-22]
Melatonin protects cells against oxidative stress-induced apoptosis due primarily to its ability to effectively scavenge pathological condition-augmented generation of mitochondrial reactive oxygen species (mROS). Once produced, mROS in addition to indiscriminately damage mitochondrial components they crucially activate directly the mitochondrial permeability transition (MPT), one of the critical mechanisms for initiating post mitochondrial apoptotic signaling. Whether or not melatonin targets directly the MPT, however, remains inconclusive, particularly during oxidative stress. Thus, we investigated this possibility of an “oxidation free Ca2+ stress” in the presence of vitamin E after ionomycin exposure as a sole Ca2+-mediated MPT in order to exclude melatonin's primary antioxidative effects as well as Ca2+-mediated oxidative stress. With the application of laser scanning fluorescence imaging microscopy, we visualized for the first time multiple mitochondrial protections provided by melatonin during Ca2+ stress in cultured rat brain astrocytes RBA-1. Melatonin, due to its primary antioxidative actions, completely prevented mCa2+-induced mROS formation for a reduced mROS-activated MPT during ionomycin exposure. In the presence of vitamin E, melatonin, significantly reduced cyclosporin A (CsA) sensitive mitochondrial depolarization and MPT during ionomycin exposure suggesting its direct targeting of the MPT. Moreover, when the MPT was inhibited by CsA, melatonin reduced further MPT-independent mitochondrial depolarization and apoptosis suggesting its targeting beyond the MPT. As astrocytes play active role in regulating neuronal pathophysiology, these multiple mitochondrial protections provided by melatonin against mCa2+- and/or mROS-mediated apoptosis may thus be crucial for the future therapeutic prevention and treatment of astrocyte-mediated neurodegeneration in the CNS.
This chapter discusses the pathophysiological effects of nitric oxide (NO), oxygen free radicals, and reactive nitrogen oxide species in biological systems. Particular emphasis is placed on host responses to various viral and bacterial infections, and to solid tumors, in view of consequent pathological manifestations that result from reactive NO derivatives. The focus is primarily on biochemical and immunological data, including induction of inducible NO synthase, and production of superoxide anion radical and peroxynitrite. Furthermore, the discovery of an accelerated viral mutation rate in the host during viral infection is discussed from the perspective of NO-induced oxidative stress. Mechanisms of carcinogenesis involving free radicals formed in the course of chronic infectious diseases are also described. The most critical common denominator of carcinogenesis is free radicals, which are formed during microbial infections, after exposure to chemical carcinogens and by electromagnetic radiation.