ArticlePDF AvailableLiterature Review

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

Authors:
  • Centro de Investigación Biomédica de Occidente del IMSS

Abstract

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
ABSTRACT
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
INTRODUCTION
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
E-mail: reiter@uthscsa.edu
Abbreviations
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
(wileyonlinelibrary.com)
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
section.
FIRST EVIDENCE RELATED TO THE ABILITY
OF MELATONIN TO PROTECT AGAINST TO
VIRAL INFECTIONS
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].
Melatoninalsohasaprotectiveeffectinmice
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].
MELATONIN AS A FREE RADICAL
SCAVENGER AND ANTIOXIDANT ENZYME
INDUCER IN VIRAL INFECTIONS
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
2
), 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
2
are
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
32
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
33
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
33
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.
daily,
3 days before until
10 days after inoculation
Reduction of mortality
rates
34
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
inoculation
Decrease the virus load
in brain
Decrease the virus load
in serum
34
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
titres
34
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
rates
35
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
2
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
2
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
Animal/cell
cultures
Effects of melatonin
administration Ref.
Free radical
scavenger
VEEV Murine splenocytes Reduction of NOconcentrations in tissue 105
Murine
neuroblastoma
Decrease of both NOand lipid peroxidation 106
Mice Reduces nitrite concentrations
in the brain and serum
107
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
Antioxidant
enzyme inducer
RHDV Rabbits Restoration of activity and mRNA
expression of GPx, GST and Mn-SOD
109
Rise in protein expression of Nrf2
Regulator of immune
functions
MLV Mice Prevention of reduction
in B- and T-cell proliferation
156
Prevention in Th1 cytokine secretion
Prevention of overproduction
of Th2 cytokines and TNF-a
VEEV Mice Stimulation of endogenous production
of IL-1bin brain
158
Reduction of the concentration
of TNF-ain brain
Stimulation of endogenous production
of IFN-g, IL-1b, and TNF-ain serum
159
RSV Mouse
macrophages
Decrease of TLR3-mediated downstream
gene expression
170
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
2
-
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
O
2
production occurs during phagocytosis,
which induces injury in non-infected cells. These
O
2
-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
couldhaveutilityinthetreatmentofpatients
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].
MELATONIN AS A POSITIVE REGULATOR OF
IMMUNE FUNCTIONS IN VIRAL
INFECTIONS
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
infection.
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].
MELATONIN AS A REGULATOR OF
PROGRAMMED CELL DEATH IN VIRAL
INFECTIONS
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.
MELATONIN AS A CO-TREATMENT IN
VIRAL INFECTIONS
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.
CONCLUDING REMARKS AND
PERSPECTIVES
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
melatoninsantiviralactions.
CONFLICT OF INTEREST
The authors have no competing interest.
ACKNOWLEDGMENTS
JAB is a researcher of ISCIII/FICYT. His stay at
UTHSCSA has been subsidized by ISCIII (BA 11/
00084).
REFERENCES
1. Lerner AB, Case JD, Takahashi Y, Lee TH,
Mori N. Isolation of melatonin, a pineal
factor that lightens melanocytes. Journal of
the American Chemical Society 1958; 80:2587.
2. LernerAB, Case JD, HeinzelmannRV. Struc-
ture of melatonin. Journal of the American
Chemical Society 1959; 81:60846085.
3. Tamarkin L, Baird CJ, Alameida OF. Melato-
nin: a coordinating signal for mammalian
reproduction. Science 1985; 227:714720.
4. Armstrong SM, Cassone VM, Chesworth
MJ, Redman JR, Short RV. Synchronization
of mammalian circadian rhythms by mela-
tonin. Journal of Neural Transmission.
Supplementum 1986; 21: 375394.
5. Reiter RJ. The melatonin rhythm: both a
clock and a calendar. Experientia 1993; 49:
654664.
6. Reiter RJ, Tan DX, Manchester LC, Paredes
SD, Mayo JC, Sainz RM. Melatonin and
reproduction revisited. Biology of Reproduc-
tion 2009; 81: 445456.
7. Reiter RJ, Tan DX, Sanchez-Barcelo E,
Mediavilla MD, Gitto E, Korkmaz A.
Circadian mechanisms in the regulation
of melatonin synthesis: disruption with
light at night and pathophysiological
consequences. Journal of Experimental and
Integrative Medicine 2011; 1:1322.
8. Reiter RJ. Melatonin: that ubiquitously
acting pineal hormone. News in Physiology
Science 1991; 6: 223227.
9. Jou MJ, Peng TI, Yu PZ, et al. Melatonin
protects against common deletion of mito-
chondrial DNA-augmented mitochondrial
oxidative stress and apoptosis. Journal of
Pineal Research 2007, 43:389404.
10. Hardeland R, Poeggeler B. Melatonin
beyond its classical functions. Open Physi-
ology Journal 2008; 1:123.
11. Hardeland R, Coto-Montes A. New vistas
on oxidative damage and aging. Open
Biology Journal 2010; 3:3952.
12. Acuna-Castroviejo D, Lopez LC, Escames G,
LopezA,GarciaJA,ReiterRJ.Melatonin-
mitochondrial interplay in health and
disease. Current Topics in Medicinal Chemistry
2011; 11: 221240.
13. Jou MJ, Peng TI, Hsu LF, et al. Visualiza-
tion of melatonins multiple mitochondrial
levels of protection against mitochondrial
Ca
2+
-mediated permeability transition
and beyond in rat brain astrocytes. Journal
of Pineal Research 2010; 48:2038.
14. Reiter RJ, Richardson BA, Johnson LY,
Ferguson BN, Dinh DT. Pineal melatonin
rhythm: reduction in aging Syrian
hamsters. Science 1980; 210: 12721273.
15. Reiter RJ, Craft CM, Johnson JE Jr, et al.
Age-associated reduction in nocturnal
pineal melatonin levels in female rats.
Endocrinology 1981; 109: 12951297.
16. Sack RL, Lewy AJ, Erb DL, Vollmer WM,
Singer CM. Human melatonin production
decreases with age. Journal of Pineal
Research 1986; 3: 379388.
17. de Castro Silva C, de Bruin VMS, Cunho
GMA, Nunes DM, Medieros CAM, de
Bruin PFC. Melatonin improves sleep and
reduces nitrite in the exhaled breath con-
densate in cystic brosisrandomized,
double-blind, placebo-controlled study.
Journal of Pineal Research 2010; 48:6571.
18. Rodella LF, Fillipini F, Bonomini F,
Bresciani R, Reiter RJ, Rezzani R.
J. A. Boga
et al
.
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
Benecial effects of melatonin on nicotine-
induced vasculopathy. Journal of Pineal
Research 2010; 48: 126132.
19. Park SY, Jang WJ, Yi EY, et al. Melatonin
suppresses tumor angiogenesis by inhi-
biting HIF-1astabilization under hyp-
oxia. Journal of Pineal Research 2010; 48:
178184.
20. Chen CF, Wang D, Reiter RJ, Yeh DY. Oral
melatonin attenuates lung inammation
and airway hyperactivity induced by aero-
solized pancreatic uid in rats. Journal of
Pineal Research 2011; 50:4653.
21. Gitto E, Aversa S, Reiter RJ, Barberi I,
Pellegrino S. Update on the use of melato-
nin in pediatrics. Journal of Pineal Research
2011; 50:2128.
22. Bonnefont-Rousselot D, Collin F. Melato-
nin: action as antioxidant and potential
applications in human disease and aging.
Toxicology 2010; 278:5567.
23. Sánchez-Barceló EJ, Mediavilla MD, Tan
DX, Reiter RJ. Clinical uses of melatonin:
evaluation of human trials. Current Medic-
inal Chemistry 2010; 17: 20702095.
24. Reiter RJ, Tan DX, Sainz RM, Mayo JC,
Lopez-Burillo S. Melatonin: reducing the
toxicity and increasing the efcacy of
drugs. Journal of Pharmacy and Pharmacol-
ogy 2002; 54: 12991321.
25. Tan DX, Chen LD, Poeggeler B,
Manchester LC, Reiter RJ. Melatonin: a
potent, endogenous hydroxyl radical scav-
enger. Endocrine Journal 1993; 1:5760.
26. Reiter RJ, Tan DX, Manchester LC, Qi W.
Biochemical reactivity of melatonin with
reactive oxygen and nitrogen species: a re-
view of the evidence. Cell Biochemistry and
Biophysics 2001; 34: 237256.
27. Guerrero JM, Pozo D, García-Mauriño S,
Osuna C, Molinero P, Calvo JR. Involve-
ment of nuclear receptors in the enhanced
IL-2 production by melatonin in Jurkat
cells. Annals of the New York Academy of
Sciences 2000; 917: 397403.
28. Guerrero JM, Reiter RJ, Melatonin-im-
mune system relationships. Current Topics
in Medicinal Chemistry 2002; 2: 167179.
29. Mediavilla MD, Sanchez-Barcelo EJ, Tan
DX, Manchester L, Reiter RJ. Basic
mechanisms involved in the anti-cancer
effects of melatonin. Current Medicinal
Chemistry 2010; 17: 44624481.
30. Maestroni GJ. Therapeutic potential of
melatonin in immunodeciency states,
viral diseases, and cancer. Advances in
Experimental Medicine and Biology 1999;
467: 217226.
31. Huang SH, Cao XJ, Liu W, Shi XY, Wei W.
Inhibitory effect of melatonin on lung
oxidative stress induced by respiratory
syncytial virus infection in mice. Journal
of Pineal Research 2010; 48: 109116.
32. Maestroni GJ, Conti A, Pierpaoli W. Pineal
melatonin, its fundamental immunoregu-
latory role in aging and cancer. Annals of
the New York Academy of Sciences 1988;
521: 140148.
33. Ben-Nathan D, Maestroni GJM, Lustig S,
Conti A. Protective effects of melatonin in
mice infected with encephalitis viruses.
Archives of Virology 1995; 140: 223230.
34. Bonilla E, Valero-Fuenmayor N, Pons H,
Chacín-Bonilla L. Melatonin protects mice
infected with Venezuelan equine encepha-
lomyelitis virus. Cellular and Molecular Life
Sciences 1997; 53: 430434.
35. Ellis LC. Melatonin reduces mortality from
Aleutian disease in mink (Mustela vison).
Journal of Pineal Research 1996; 21: 214217.
36. de Groot H. Reactive oxygen species in tis-
sue injury. Hepato-Gastroenterology 1994;
41: 328332.
37. Toyokuni S. Reactive oxygen species-
induced molecular damage and its appli-
cation in pathology. Pathology International
1999; 49:91102.
38. Granger DL, Hibbs JB Jr, Perfect JR, Dur-
ack DT. Specic amino acid (L-arginine) re-
quirement for microbiostatic activity of
murine macrophages. The Journal of Clini-
cal Investigation 1988; 81: 11291136.
39. Nathan CF, Hibbs JB Jr. Role of nitric oxide
synthesis in macrophage antimicrobial ac-
tivity. Current Opinion in Immunology
1991; 3:6570.
40. James SL. Role of nitric oxide in parasitic
infections. Microbiological Reviews 1995;
59: 533547.
41. Nathan C, Shiloh MU. Reactive oxygen
and nitrogen intermediates in the relation-
ship between mammalian hosts and mi-
crobial pathogens. The Journal of Clinical
Investigation 2000; 97: 88418848.
42. Peterhans E, Grob M, Bürge T, Zanoni R.
Virus-induced formation of reactive
oxygen intermediates in phagocytic cells.
Free Radical Research Communications 1987;
3:3946.
43. Oda T, Akaike T, Hamamoto T, Suzuki F,
Hirano T, Maeda H. Oxygen radicals in
inuenza-induced pathogenesis and
treatment with pyran polymer-conjugated
SOD. Science 1989; 244: 974976.
44. Akaike T, Ando M, Oda T, et al. Depen-
dence on O
2
generation by xanthine oxi-
dase of pathogenesis of inuenza virus
infection in mice. The Journal of Clinical In-
vestigation 1990; 85: 739745.
45. Ikeda T, Shimokata K, Daikoku T, Fukatsu
T, Tsutsui Y, Nishiyama Y. Pathogenesis of
cytomegalovirus-associated pneumonitis
in ICR mice: possible involvement of su-
peroxide radicals. Archives of Virology
1992; 127:1124.
46. Schwartz KB. Oxidative stress during viral
infection: a review. Free Radical Biology &
Medicine 1996; 21: 641649.
47. Stuehr DJ, Grifth OW. Mammalian nitric
oxide synthase. Advances in Enzymology
and Related Areas of Molecular Biology
1992; 65: 287346.
48. Bukrinsky MI, Nottet HS, Schmidtmayer-
ova H, et al. Regulation of nitric oxide
synthase activity in human immunode-
ciency virus type 1 (HIV-1)-infected mono-
cytes: implications for HIV-associated
neurological disease. The Journal of Experi-
mental Medicine 1995; 181: 735745.
49. Majano PL, García-Monzón C, López-
Cabrera M, et al. Inducible nitric oxide
synthase expression in chronic viral hepa-
titis. Evidence for a virus-induced gene
upregulation. The Journal of Clinical Investi-
gation 1998; 101: 13431352.
50. Dustin LB, Rice CM. Flying under the
radar: the immunobiology of hepatitis C.
Annual Review of Immunology 2007; 25:
7199.
51. Zaki Mel S, Saudy N, El Diasty A. Study
of nitric oxide in patients with chronic
hepatitis C genotype 4: relationship to
viremia and response to antiviral therapy.
Immunological Investigations 2010; 39:
598610.
52. Koprowski H, Zheng YM, Heber-Katz E,
et al. In vivo expression of inducible nitric
oxide synthase in experimentally induced
neurologic diseases. Proceedings of the
Melatonin and viral infections
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
National Academy of Science USA 1993; 90:
30247.
53. Zheng YM, Schäfer MK, Weihe E, et al. Se-
verity of neurological signs and degree of
inammatory lesions in the brains of the
rats with Borna disease correlate with the
induction of nitric oxide synthase. Journal
of Virology 1993; 67: 57865791.
54. Karupiah G, Xie QW, Buller RM, Nathan
C, Duarte C, MacMicking JD. Inhibition
of viral replication by interferon-gamma-
induced nitric oxide synthase. Science
1993; 261: 14451448.
55. Akaike T, Noguchi Y, Ijiri S, et al. Patho-
genesis of inuenza virus-induced pneu-
monia: involvement of both nitric oxide
and oxygen radicals. Proceedings of the
National Academy of Science USA 1996; 93:
24482453.
56. Akaike T, Suga M, Maeda H. Free radicals
in viral pathogenesis: molecular mechan-
isms involving superoxide and NO. Pro-
ceedings of the Society for Experimental
Biology and Medicine 1998; 217:6473.
57. Fujii S, Akaike T, Maeda H. Role of nitric
oxide in pathogenesis of herpes simplex
virus encephalitis in rats. Virology 1999;
256: 203212.
58. Akaike T, Maeda H. Pathophysiological
effects of high-output production of nitric
oxide. In Nitric Oxide: Biology and Patho-
biology, Ignarro LJ (ed.). Academic Press:
San Diego, CA, 2000; 733745.
59. Akaike T, Maeda H. Nitric oxide and virus
infection. Immunology 2000; 101: 300308.
60. Cunha FQ, Moncada S, Liew FY. Interleu-
kin-10 (IL-10) inhibits the induction of
nitric oxide synthase by interferon-gamma
in murine macrophages. Biochemical and
Biophysical Research Communications 1992;
182: 11551159.
61. Vodovotz Y, Bogdan C, Paik J, Xie QW,
Nathan C.Mechanisms of suppression
of macrophage nitric oxide release by
transforming growth factor beta. The
Journal of Experimental Medicine 1993;
178:605613.
62. Bogdan C, Vodovotz Y, Paik J Xie QW,
Nathan C. Mechanism of suppression
of nitric oxide synthase expression by
interleukin-4 in primary mouse macro-
phages. Journal of Leukocyte Biology
1994; 55:227233.
63. Adamson DC, Kopnisky KL, Dawson TM,
Dawson VL. Mechanisms and structural
determinants of HIV-1coat protein, gp41-
induced neurotoxicity. Journal of Neurosci-
ence 1999; 19:6471.
64. Hori K, Burd PR, Furuke K, et al. Human
immunodeciency virus-1-infected macro-
phages induce inducible nitric oxide
synthase and nitric oxide (NO) production
on astrocytes: astrocytic NO as a possible
mediator of neuronal damage in acquired
immunodeciency syndrome. Blood 1999;
93: 18431850.
65. Tsutsumi H, Takeuchi R, Ohsaki M, Seki K,
Chiba S. Respiratory syncytial virus infec-
tion of human respiratory epithelial cells
enhances inducible nitric oxide synthase
gene expression. Journal of Leukocyte Biol-
ogy 1999; 66:99104.
66. Croen KD. Evidence for an antiviral effect
of nitric oxide. Inhibition of herpes sim-
plex virus type 1 replication. The Journal
of Clinical Investigation 1993; 91: 24462452.
67. Mannick JB, Asano K, Izumi K, Kieff E,
Stamler JS. Nitric oxide produced by hu-
man B lymphocytes inhibits apoptosis
and EpsteinBarr virus reactivation. Cell
1994; 79: 11371146.
68. Karupiah G, Chen JH, Nathan CF,
Mahalingam S, MacMicking JD. Identi-
cation of nitric oxide synthase 2 as an
innate resistance locus against ectrome-
lia virus infection. Journal of Virology
1998; 72:77037706.
69. Gao X, Tajima M, Sairenji T. Nitric oxide
downregulates EpsteinBarr virus reacti-
vation in epithelial cell lines. Virology
1999; 258: 375381.
70. Saura M, Zaragoza C, McMillan A, et al.
An antiviral mechanism of nitric oxide:
inhibition of a viral proteinase. Immunity
1999; 10:2128.
71. Zaragoza C, Ocampo CJ, Saura M, et al.
Inducible nitric oxide synthase protection
against coxsackievirus pancreatitis.Journal
of Immunology 1999; 163: 54975504.
72. Akaike T, Maeda H. Nitric oxide in inu-
enza. In Nitric Oxide in Infection, Fang
FC (ed.). Kluwer Academic/Plenum Pub-
lishers: New York, 1999; 397415.
73. van den Broek M, Bachmann MF, Köhler
G, et al. IL-4 and IL-10 antagonize IL-12-
mediated protection against acute vaccinia
virus infection with a limited role of IFN-
gamma and nitric oxide synthetase 2. Jour-
nal of Immunology 2000; 164: 371378.
74. Karupiah G, Chen JH, Mahalingam S,
Nathan CF, MacMicking JD. Rapid inter-
feron gamma-dependent clearance of in-
uenza A virus and protection from
consolidating pneumonitis in nitric ox-
idesynthase2-decient mice. The Jour-
nal of Experimental Medicine 1998; 188:
15411546.
75. Bartholdy C, Nansen A, Christensen JE,
Marker O, Thomsen AR. Inducible
nitric-oxide synthase plays a minimal
role in lymphocytic choriomeningitis
virus induced, T cell-mediated protec-
tive immunity and immunopathology.
The Journal of General Virology 1999; 80:
29973005.
76. Wu GF, Pewe L, Perlman S. Coronavirus-
induced demyelination occurs in the ab-
sence of inducible nitric oxide synthase.
Journal of Virology 2000; 74: 76837686.
77. Guillemard E, Varano B, Belardelli F,
Quero AM, Gessani S. Inhibitory activity
of constitutive nitric oxide on the expres-
sion of alpha/beta interferon genes in mu-
rine peritoneal macrophages. Journal of
Virology 1999; 73: 73287333.
78. Kreil TR, Eibl MM. Nitric oxide and vi-
ral infection: no antiviral activity against
aavivirus in vitro, and evidence for
contribution to pathogenesis in experi-
mental infection in vivo. Vi rolog y 1996;
219:304306.
79. Adler H, Beland JL, Del-Pan NC, et al.
Suppression of herpes simplex virus type
1 (HSV-1)-induced pneumonia in mice by
inhibition of inducible nitric oxide
synthase (iNOS, NOS2). The Journal of Ex-
perimental Medicine 1997; 185: 15331540.
80. Nishio R, Matsumori A, Shioi T, Ishida H,
Sasayama S. Treatment of experimental vi-
ral myocarditis with interleukin-10. Circu-
lation 1999; 100: 11021108.
81. Hirasawa K, Jun HS, Han HS, Zhang ML,
Hollenberg MD, Yoon JW. Prevention of
encephalomyocarditis virus-induced dia-
betes in mice by inhibition of the tyrosine
kinase signaling pathway and subsequent
suppression of nitric oxide production in
macrophages. Journal of Virology 1999; 73:
85418548.
J. A. Boga
et al
.
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
82. Andrews DM, Matthews VB, Sammels
LM, Carrello AC, McMinn PC. The sever-
ity of Murray Valley encephalitis in mice
is linked to neutrophil inltration and in-
ducible nitric oxide synthase activity in
the central nervous system. Journal of Virol-
ogy 1999; 73: 87818790.
83. Maeda H, Akaike T. Oxygen free radicals
as pathogenic molecules in viral diseases.
Proceedings of the Society for Experimental
Biology and Medicine 1991; 198: 721727.
84. Sidwell RW, Huffman JH, Bailey KW,
Wong MH, Nimrod A, Panet A. Inhibitory
effects of recombinant manganese
superoxide dismutase on inuenza virus
infections in mice. Antimicrobial Agents
and Chemotherapy 1996; 40: 26262631.
85. González-Gallego J, García-Mediavilla
MV, Sánchez-Campos S. Hepatitis C virus,
oxidative stress and steatosis: current
status and perspectives. Current Molecular
Medicine 2011; 11: 373390.
86. Bureau C, Bernad J, Chaouche N, et al.
Non-structural 3 protein of hepatitis C
virus triggers ROS production in human
monocytes via activation of NADPH
oxidase. Journal of Biological Chemistry
2001; 276: 2307723083.
87. Hiraku Y, Tabata T, Ma N, Murata M, Ding
X, Kawanishi S. Nitrative and oxidative
DNA damage in cervical intraepithelial
neoplasia associated with human papil-
loma virus infection. Cancer Science 2007;
98: 964972.
88. Lassoued S, Ben Ameur R, Ayadi W,
Gargouri B, Ben Mansour R, Attia H.
EpsteinBarr virus induces an oxidative
stress during the early stages of infection
in B lymphocytes, epithelial, and lympho-
blastoid cell lines. Molecular and Cellular
Biochemistry 2008; 313: 179186.
89. Newman GW, Balcewicz-Sablinska MK,
Guarnaccia JR, Remold HG, Silberstein DS.
Opposing regulatory effects of thioredoxin
and eosinophil cytotoxicity-enhancing
factor on the development of human
immunodeciency virus 1. The Journal of
Experimental Medicine 1994; 180:359363.
90. Suzuki YJ, Aggarwal BB, Packer L. Alpha-
lipoic acid is a potent inhibitor of NF-
kappa B activation in human T cells.
Biochemical and Biophysical Research Com-
munications 1992; 189: 17091715.
91. Holroyd KJ, Buhl R, Borok Z, et al.
Correction of glutathione deciency in
the lower respiratory tract of HIV seropos-
itive individuals by glutathione aerosol
treatment. Thorax 1993; 48: 985989.
92. Uchide N, Toyoda H. Antioxidant therapy
as a potential approach to severe inu-
enza-associated complications. Molecules
2011; 16: 20322052.
93. Pieri C, Marra M, Moroni F, Recchioni
R, Marcheselli F. Melatonin: a peroxyl
radical scavenger more effective than
vitamin E. Life Sciences 1994; 55:
PL271-PL276.
94. Reiter RJ, Melchiorri D, Sewerynek E, et al.
A review of the evidence supporting mela-
tonins role as an antioxidant. Journal of
Pineal Research 1995; 18:111 .
95. Reiter RJ. Functional aspects of the pineal
hormone melatonin in combating cell and
tissue damage induced by free radicals.
European Journal of Endocrinology 1996;
134: 412420.
96. Galano A, Tan DX, Reiter RJ. Melatonin as
a natural ally against oxidative stress: a
physiochemical examination. Journal of
Pineal Research 2011; 51:116.
97. Hardeland R. Melatonin and its metabo-
lites as anti-nitrosating and anti-nitrating
agents. Journal of Experimental and Integra-
tive Medicine 2011; 1:6781.
98. Pablos MI, Agapito MT, Gutierrez R, et al.
Melatonin stimulates the activity of the
detoxifying enzyme glutathione in several
tissues of chicks. Journal of Pineal Research
1995, 19:111115.
99. Coto-Montes A, Boga JA, Tomás-Zapico C,
et al. Physiological oxidative stress
model: Syrian hamster Harderian gland-
sex differences in antioxidant enzymes.
Free Radical Biology & Medicine 2001,
30:785792.
100. Rodriguez C, Mayo JC, Sainz RM, et al.
Regulation of antioxidant enzymes: a sig-
nicant role for melatonin. Journal of Pineal
Research 2004; 36:19.
101. Tomas-Zapico C, Coto-Montes A. A pro-
posed mechanism to explain the stimula-
tory effect of melatonin on antioxidative
enzymes. Journal of Pineal Research 2005;
39:99104.
102. Reiter RJ, Acuña-Castroviejo D, Tan
DX, Burkhardt S. Free radical-mediated
molecular damage. Ann NY Academy
Sciences 2001; 939: 200215.
103. Lanoix D, Lacasse AA, Reiter RJ,Vaillancourt
C. Melatonin, the smart killer. The human
trophoblast as a model. Molecular and Cellular
Endocrinology 2012; 348:1111.
104. Venegas C, Garcia JA, Escames G, et al.
Extra pineal melatonin: analysis of sub-
cellular distribution and daily uctua-
tions. Journal of Pineal Research 2012;
52: 217227.
105. Valero N, Meleán E, Bonilla E, et al. In
vitro, melatonin treatment decreases nitric
oxide levels in murine splenocytes cul-
tured with the Venezuelan equine enceph-
alomyelitis virus. Neurochemical Research
2005; 30: 14391442.
106. Valero N, Espina LM, Mosquera J. Melato-
nin decreases nitric oxide production,
inducible nitric oxide synthase expression
and lipid peroxidation induced by Vene-
zuelan encephalitis equine virus in neuro-
blastoma cell cultures. Neurochemical
Research 2006; 31: 925932.
107. Valero N, Espina LM, Bonilla E, Mosquera
J. Melatonin decreases nitric oxide produc-
tion and lipid peroxidation and increases
interleukin-1 beta in the brain of mice
infected by the Venezuelan equine enceph-
alomyelitis virus. Journal of Pineal Research
2007; 42: 107112.
108. Parra F, Prieto M. Purication and char-
acterization of a calicivirus as the causa-
tive agent of a lethal hemorrhagic
disease in rabbits. Journal of Virology
1990; 64: 40134015.
109. Crespo I, Miguel BS, Laliena A, et al. Mel-
atonin prevents the decreased activity of
antioxidant enzymes and activates nuclear
erythroid 2-related factor 2 signaling in an
animal model of fulminant hepatic failure
of viral origin. Journal of Pineal Research
2010; 49: 193200.
110. Jung KH, Hong SW, Zheng HM, et al.
Melatonin ameliorates cerulein-induced
pancreatitis by the modulation of nuclear
erythroid 2-related factor 2 and nuclear
factor-kappaB in rats. Journal of Pineal
Research 2010; 48: 239250.
111. Brennan K, Bowie AG. Activation of host
pattern recognition receptors by viruses.
Current Opinion in Microbiology 2010; 13:
503507.
Melatonin and viral infections
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
112. Kanneganti TD. Central roles of NLRs and
inammasomes in viral infection. Nature
Reviews Immunology 2010; 10: 688698.
113. Mikula I Jr, Pastoreková S, Mikula I Sr. Toll-
like receptors in immune response to the viral
infections. Acta Virologica 2010; 54:231245.
114. Loo YM, Gale M Jr. Immune signaling by
RIG-I-like receptors. Immunity 2011; 34:
680692.
115. Fensteri V, Sen GC. Interferons and viral
infections. BioFactors 2009; 35:1420.
116. Sadler AJ, Williams BR. Interferon-inducible
antiviral effectors. Nature Reviews Immunol-
ogy 2008; 8:559568.
117. Silverman RH. Viral encounters with
20,50-oligoadenylate synthetase and
RNase L during the interferon antiviral
response. Journal of Virology 2007; 81:
1272012729.
118. Espert L, Degols G, Gongora C, et al.
ISG20, a new interferon-induced RNase
specic for single-stranded RNA, denes
an alternative antiviral pathway against
RNA genomic viruses. Journal of Biological
Chemistry 2003; 278: 1615116158.
119. White CL, Sen GC. Interferons and anti-
viral action. In Cellular Signaling and
Innate Immune Responses to RNA Virus
Infections. Brasier AR, Garcia-Sastre A,
Lemon SM (eds.) ASM Press: Washington,
DC, 2002; 91106.
120. Terenzi F, Hui DJ, Merrick WC, Sen GC.
Distinct induction patterns and func-
tions of two closely related interferon-
inducible human genes, ISG54 and
ISG56. Journal of Biological Chemistry
2006; 281: 3406434071.
121. Wang C, Pugheber J, Sumpter R Jr, et al.
Alpha interferon induces distinct transla-
tional control programs to suppress hepa-
titis C virus RNA replication. Journal of
Virology 2003; 77: 38983912.
122. Haller O, Kochs G, Weber F. Interferon,
Mx, and viral countermeasures. Cytokine
& Growth Factor Reviews 2007; 18: 425433.
123. Randall RE, Goodbourn S. Interferons and
viruses: an interplay between induction,
signaling, antiviral responses and virus
countermeasures. The Journal of General
Virology 2008; 89:147.
124. Aguiar RS, Peterlin BM. APOBEC3
proteins and reverse transcription. Virus
Research 2008; 134:7485.
125. Guidotti LG, Chisari FV. Noncytolytic
control of viral infections by the innate
and adaptive immune response. Annual
Review of Immunology 2001; 19:6591.
126. Malmgaard L. Induction and regulation of
IFNs during viral infections. Journal of In-
terferon and Cytokine Research 2004; 24:
439454.
127. Benyon RC, Bissonnette EY, Befus AD.
Tumor necrosis factor-alpha dependent
cytotoxicity of human skin mast cells is
enhanced by anti-IgE antibodies. Journal
of Immunology 1991; 147: 22532258.
128. Bradding P, Feather IH, Wilson S, et al.
Immunolocalization of cytokines in the
nasal mucosa of normal and perennial
rhinitic subjects. The mast cell as a source
of IL-4, IL-5, and IL-6 in human allergic
mucosal inammation. Journal of Immunol-
ogy 1993; 151: 38533865.
129. Kaplan AP, Kuna P, Reddigari SR. Chemo-
kines and the allergic response. Experimen-
tal Dermatology 1995; 4: 260265.
130. Sampson AP. The role of eosinophils
and neutrophils in inammation. Clinical
and Experimental Allergy 2000; 1(Suppl.):
2227.
131. Mosmann TR, Coffman RL. Th-1and Th-2
cells: different patterns of lymphokine
secretion lead to different functional
properties. Annual Review of Immunology
1989; 7: 145173.
132. Varga SM, Welsh RM. High frequency of
virus-specic interleukin-2- producing
CD4(
+
) T cells and Th1 dominance
during lymphocytic choriomeningitis
virus infection. Journal of Virology 2000;
74:44294432.
133. Tan DX, Manchester LC, Reiter RJ, et al.
Identication of highly elevated levels of
melatonin in bone marrow: its origin and
signicance. Biochimica et Biophysica Acta
1999; 1471: 206214.
134. Kvetnoy IM. Extrapineal melatonin: loca-
tion and role within diffuse neuroendo-
crine system. The Histochemical Journal
1999; 31:112.
135. Carrillo-Vico A, Calvo JR, Abreu P, et al.
Evidence of melatonin synthesis by
human lymphocytes and its physiological
signicance: possible role as intracrine,
autocrine, and/or paracrine substance.
The FASEB Journal 2004; 18: 537539.
136. Pozo D, Delgado M, Fernandez-Santos JM,
et al. Expression of the Mel1a-melatonin
receptor mRNA in T and B subsets of
lymphocytes from rat thymus and spleen.
The FASEB Journal 1997; 11: 466473.
137. Garcia-Mauriño S, Gonzalez-Haba MG,
Calvo IR, et al. Melatonin enhances IL-2,
lL-6, and IFN-gamma production by
human circulating CD4+ cells: a possible
nuclear receptor-mediated mechanism
involving T helper type I lymphocytes
and monocytes. Journal of Immunology
1997; 159: 574581.
138. Lardone PJ, Carrillo-Vico A, Molinero P,
Rubio A, Guerrero JM. A novel interplay
between membrane and nuclear melato-
nin receptors in human lymphocytes: sig-
nicance in IL-2 production. Cellular and
Molecular Life Sciences 2009; 66: 516525.
139. Carrillo-Vico A, Guerrero JM, Lardone PJ,
Reiter RJ. A review of the multiple actions
of melatonin on the immune system. Endo-
crine 2005; 27: 189200.
140. Lardone PJ, Alvarez-García O, Carrillo-
Vico A, et al. Inverse correlation between
endogenous melatonin levels and oxida-
tive damage in some tissues of SAMP8
mice. Journal of Pineal Research 2006; 40:
153157.
141. Szczepanik M. Melatonin and its inuence
on immune system. Journal of Physiology
and Pharmacology 2007; 58:115124.
142. Caballero B, Vega-Naredo I, Sierra V,
et al. Autophagy upregulation and loss
of NF-kappaB in oxidative stress-related
immunodecient SAMP8 mice. Mechan-
isms of Ageing and Development 2009;
130: 722730.
143. Belyaer O, Herzog T, Munding J, et al. Pro-
tective role of endogenous melatonin in
the early course of acute pancreatitis.
Journal of Pineal Research 2011; 50:7177.
144. Radogna F, Diederich M, Ghibelli L.
Melatonin: a pleiotropic molecule regulat-
ing inammation. Biochemical Pharmacol-
ogy 2010; 80: 18441852.
145. Morrey KM, McLachlan JA, Serkin CD,
Bakouche O. Activation of human
monocytes by the pineal hormone mela-
tonin. Journal of Immunology 1994; 153:
26712680.
146. Finocchiaro LM, Arzt ES, Fernandez-Castelo
S, Crisculo M, Finkielman S, Nahmod VE.
J. A. Boga
et al
.
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
Serotonin and melatonin synthesis in periph-
eral blood mononuclear cells: stimulation by
interferon-gamma as part of an immuno-
modulatory pathway. JournalofInterferon
Research 1988; 8:705716
147. Bonilla E, Nereida V, Chacín-Bonilla L,
Medina-Leendertz S. Melatonin and viral
infections. Journal of Pineal Research 2004;
36:7379.
148. Currier NL, Sun LZ, Miller SC. Exogenous
melatonin: quantitative enhancement
in vivo of cells mediating non-specic
immunity. Journal of Neuroimmunology
2000; 104: 101108.
149. Castrillon PO, Esquino AI, Varas A,
Zapata A, Cutrera RA, Cardinali DP. Effect
of melatonin treatment on 24-h variations
in responses to mitogens and lymphocyte
subset populations in rat submaxillary
lymph nodes. Journal of Neuroendocrinology
2000; 12: 758765.
150. Carrillo-Vico A, Reiter RJ, Lardone PJ,
et al. The modulatory role of melatonin
on immune responsiveness. Current
Opinion in Investigational Drugs 2006; 7:
423431.
151. Gazzinelli RT, Makino M, Chattopadhyay
SK, et al. CD4+ subset regulation in viral
infection. Preferential activation of Th2
cells during progression of retrovirus-
induced immunodeciency in mice.
Journal of Immunology 1992; 148: 182188.
152. Bradley WG, Ogata N, Good RA, Day NK.
Alteration of in vivo cytokine gene expres-
sion in mice infected with a molecular
clone of the defective MAIDS virus. Journal
of Acquired Immune Deciency Syndromes
1994; 7:19.
153. Clerici M, Hakim FT, Venzon DJ, et al.
Changes in interleukin-2 and interleukin-
4 production in asymptomatic, human
immunodeciency virus-seropositive indi-
viduals. The Journal of Clinical Investigation
1993; 91: 759765.
154. Wang Y, Huang DS, Liang B, Watson RR.
Nutritional status and immune responses
in mice with murine AIDS are normalized
by vitamin E supplementation. Journal of
Nutrition 1994; 124: 20242032.
155. Zhang Z, Araghi-Niknam M, Liang B,
et al. Prevention of immune dysfunction
and vitamin E loss by dehydroepiandros-
terone and melatonin supplementation
during murine retrovirus infection. Immu-
nology 1999; 96: 291297.
156. Srinivasan V, Spence DW, Trakhi I, Pandi-
Perumal SR, Cardinali DP, Maestroni GJ.
lmmunomodulation by melatonin: its sig-
nicance for seasonally occurring diseases.
Neuroimmuno-modulation 2008; 15:93101.
157. Nunnari G, Nigro L, Palermo F, Leto D,
Pomerantz RJ, Cacopardo B. Reduction of
serum melatonin levels in HIV-1-infected
individualsparallel disease progression:
correlation with serum interleukin-12
levels. Infection 2003; 31: 379382.
158. Bonilla E, Rodón C, Valero N, et al.
Melatonin prolongs survival of immunode-
pressed mice infected with the Venezuelan
equine encephalomyelitis virus. Transactions
of the Royal Society of Tropical Medicine and
Hygiene 2001; 95:207210.
159. Valero N, Bonilla E, Pons H, et al. Melato-
nin induces changes to serum cytokines in
mice infected with the Venezuelan equine
encephalomyelitis virus. Transactions of
the Royal Society of Tropical Medicine and
Hygiene 2002; 96: 348351.
160. Dinarello CA. The biological properties of
interleukin-1. European Cytokine Network
1994; 5: 517531.
161. Liang XH, Goldman JE, Jiang HH, Levine
B. Resistance of interleukin-1 beta-decient
mice to fatal Sindbis virus encephalitis.
Journal of Virology 1999; 73: 25632567.
162. Kozak W. Thermal and behavioural effects
of lipopolysaccharide and inuenza in in-
terleukin-1 beta decient mice. American
Journal of Physiology 1995; 269: R969R977.
163. Spriggs MK, Hruby DE, Maliszewski CR,
et al. Vaccinia and cowpox viruses encode
a novel secreted interleukin-1-binding pro-
tein. Cell 1992; 71: 145152.
164. Carman-Krzan M, Wise BC. Arachidonic
acid lipoxygenation may mediate interleu-
kin-1 stimulation of nerve growth factor
secretion in astroglial cultures. Journal of
Neuroscience Research 1993; 34: 225232.
165. Tweardy DJ, Glazer EW, Mott PL, Ander-
son K. Modulation by tumor necrosis fac-
tor-a of human astroglial cell production
of granulocyte-macrophage colony stimu-
lating factor (G-CSF).Journal of Neuroimmu-
nology 1991; 32: 269278.
166. McCarron RM, Wang L, Racke MK,
McFarlin DE, Spatz M. Cytokine-regulated
adhesion between encephalitogenic T lym-
phocytes and cerebrovascular endothelial
cells. Journal of Neuroimmunology 1993; 43:
2330.
167. Baydas G, Nedzvetsky NS, Nerush PA,
Kiricheuko SV, Demchenko HM, Reiter
RJ. A novel role for melatonin: regulation
of the expression of cell adhesion mole-
cules in the rat hippocampus and cortex.
Neuroscience Letters 2002; 326: 109112.
168. Alexopoulou L, Holt AC, Medzhitov R,
Flavell RA. Recognition of double-
stranded RNA and activation of NF-jB
by Toll-like receptor 3. Nature 2001; 413:
732738.
169. Tian B, Zhang Y, Luxon BA, et al. Identi-
cation of NF-kappaB-dependent gene
networks in respiratory syncytial virus-
infected cells. Journal of Virology 2002; 76:
68006814.
170. Huang SH, Cao XJ, Wei W. Melatonin
decreases TLR3-mediated inammatory
factor expression via inhibition of NF-
kappa B activation in respiratory syncytial
virus-infected RAW264.7 macrophages.
Journal of Pineal Research 2008; 45:93100.
171. Koyama AH, Irie H, Fukumori T, Hata S,
Iida S, et al. Role of virus-induced apopto-
sis in a host defense mechanism against
virus infection. The Journal of Medical Inves-
tigation 1998, 45:3745.
172. Danthi P. Enter the kill zone: initiation of
death signaling during virus entry.
Virology 2011; 411: 316324.
173. Sainz RM, Mayo JC, Rodriguez C, Tan
DX, Lopez-Burillo S, Reiter RJ. Melatonin
and cell death: differential actions on
apoptosis in normal and cancer cells.
Cellular and Molecular Life Sciences 2003;
60: 14071426.
174. Casao A, Mendoza N, Perez-Pe R, et al.
Melatonin prevents capacitation and apo-
ptotic-like changes in ram spermatozoa
and increases fertility. Journal of Pineal
Research 2010; 48:3946.
175. Kim CH, Kim KH, Yoo YM. Melatonin
protects against apoptotic and autophagic
cell death in C2 C12 murine myoblast
cells. Journal of Pineal Research 2011; 50:
241249.
176. Espino J, Bejarano I, Paredes SD, Barriga
C, Rodriguez AB, Pariente JA. Protective
effect of melatonin against human
Melatonin and viral infections
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
leucocyte apoptosis induced by intracellu-
lar calcium overload: relation with its anti-
oxidant actions. Journal of Pineal Research
2011; 51: 195206.
177. Koh W, Jeong SJ, LeeHJ, et al. Melatonin pro-
motes puromycin-induced apoptosis with
activation of caspase-3 and 5
1
-adenosine
monophosphate-activated kinase-alpha in
human leukemia HL-60 cells. Journal of Pineal
Research 2011; 50: 369373.
178. Alonso C, Oviedo JM, Martín-Alonso JM,
Díaz E, Boga JA, Parra F. Programmed cell
death in the pathogenesis of rabbit hemor-
rhagic disease. Archives of Virology 1998;
143: 321332.
179. Tuñón MJ, San Miguel B, Crespo I,
et al. Melatonin attenuates apoptotic liver
damage in fulminant hepatic failure
induced by the rabbit hemorrhagic disease
virus. Journal of Pineal Research 2011; 50:
3845.
180. Grose C. Autophagy during common
bacterial and viral infections of children.
Pediatric Infectious Disease Journal 2010; 29:
10401042.
181. Takahashi MN, Jackson W, Laird DT, et al.
Varicella-zoster virus infection induces
autophagy in both cultured cells and hu-
man skin vesicles. Journal of Virology 2009;
83: 54665476.
182. Dreux M, Chisari FV. Autophagy proteins
promote hepatitis C virus replication.
Autophagy 2009; 5: 12241225.
183. Casais R, Molleda LG, Machín A, et al.
Structural and functional analysis of
virus factories puried from Rabbit
vesivirus-infected Vero cells. Virus Research
2008; 137:112121.
184. Suhy DA, Giddings TH Jr., Kirkegaard K.
Remodeling the endoplasmic reticulum
by poliovirus infection and by individual
viral proteins: an autophagy-like origin
for virus-induced vesicles. Journal of
Virology 2000; 74: 89538965.
185. Vega-Naredo I, Caballero B, Sierra V,
et al. Melatonin modulates autophagy
through a redox-mediated action in
female Syrian hamster Harderian gland
controlling cell types and gland acti-
vity. Journal of Pineal Research 2012; 52:
8092.
186. Nunes Oda S, Pereira Rde S. Regression of
herpes viral infection symptoms using
melatonin and SB-73: comparison with
Acyclovir. Journal of Pineal Research 2008;
44: 373378.
187. Reiter RJ. Pineal melatonin: cell biology
of its synthesis and of its physiological
interactions. Endocrine Reviews 1991; 12:
151180.
188. Reiter RJ, Tan DX, Fuentes-Broto L. Mela-
tonin: a multitasking molecule. Progress in
Brain Research 2010; 181: 127151.
189. Stehle J, SaadeA, Rawashdeh O, et al. A sur-
vey of moleculardetails in the human pineal
gland in the light of phylogeny, structure,
function and chronobiological diseases.
JournalofPinealResearch2011; 51:1743.
190. Jung-Hynes B, Reiter RJ, Ahmad N. Sir-
tuins, melatonin and circadian rhythms:
building a bridge between aging and can-
cer. Journal of Pineal Research 2010; 48:919.
191. Paradies G, Petroillo G, Paradies V, Reiter
RJ, Ruggiero FM. Melatonin, cardiolipin
and mitochondrial bioenergetics in health
and disease. Journal of Pineal Research
2010; 48: 297310.
192. Rosenstein RE, Pandi-Perumal SR,Srinivasan
V,SpenceDW,BrownGM,CardinaliDP.
Melatonin as a therapeutic tool in ophthal-
mology: implications for glaucoma and uve-
itis. Journal of Pineal Research 2010; 49:113.
193. Reiter RJ, Tan DX, Korkmaz A, Fuentes-Broto
C. Drug-mediated ototoxicity and tinnitus:
alleviation with melatonin. Journal of Physiol-
ogy and Pharmacology 2011; 62:151154.
194. Swarnakar S, Paul S, Singh LP, Reiter RJ.
Matrix metalloproteinases in health and
disease: regulation by melatonin. Journal
of Pineal Research 2011; 50:820.
J. A. Boga
et al
.
Copyright © 2012 John Wiley & Sons, Ltd. Rev. Med. Virol. (2012)
DOI: 10.1002/rmv
... 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
Article
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). ...
Full-text available
Article
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 . ...
Article
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. ...
Article
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]. ...
Article
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]. ...
Full-text available
Article
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). ...
Article
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.
Full-text available
Article
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.
Article
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.
Full-text available
Article
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]
Full-text available
Article
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.
Full-text available
Article
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.
Article
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.
Article
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.
Article
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]
Article
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.
Article
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.