Tài liệu Báo cáo khoa học: Melatonin Nature’s most versatile biological signal? pdf

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example on Ca
2+
-activated K
+
channels [97]. A third
binding site, initially described as MT
3
, has been sub-
sequently characterized as the enzyme quinone reduc-
tase 2 [98]. Quinone reductases participate in the
protection against oxidative stress by preventing elec-
tron transfer reactions of quinones [99]. Melatonin also
binds with relevant, but somewhat lower, affinities to
calmodulin [100], as well as to nuclear receptors of the
retinoic acid receptor family, RORa1, RORa2 and
RZRb [101,102]. RORa1 and RORa2 seem to be
involved in some aspects of immune modulation,
whereas RZRb is expressed in the central nervous sys-
tem, including the pineal gland. Direct inhibition of
the mitochondrial permeability transition pore by
melatonin [103] may indicate that another, mitochond-
rial-binding, site is involved, although at the present
time this has not been confirmed. Although antioxida-
tive protection by melatonin is partially based on
receptor mechanisms, as far as gene expression is
concerned some other antioxidant actions do not
require receptors. These include direct scavenging of
free radicals and electron exchange reactions with the
mitochondrial respiratory chain (Fig. 3).
Melatonin as an antioxidant
Since the discovery that melatonin is oxidized by pho-
tocatalytic mechanisms involving free radicals, its scav-
enging actions have become a matter of particular
interest [1,37]. Melatonin’s capability for rapidly scav-
enging hydroxyl radicals has stimulated numerous
investigations into radical detoxification and antioxida-
tive protection. Evidence has shown that melatonin is
considerably more efficient than the majority of its
naturally occurring analogs [46], indicating that the
substituents of this indole moiety strongly influence
reactivity and selectivity [5]. Rate constants deter-
mined for the reaction with hydroxyl radicals were
Fig. 3. The pleiotropy of melatonin: an overview of several major actions. AFMK, N
1
-acetyl-N
2
-formyl-5-methoxykynuramine; AMK, N
1
-acetyl-
5-methoxykynuramine; c3OHM, cyclic 3-hydroxymelatonin; MT
1
,MT
2
, melatonin membrane receptors 1 and 2; mtPTP, mitochondrial
permeability transition pore; RORa, RZRb, nuclear receptors of retinoic acid receptor superfamily. *Several reactive oxygen species (ROS)
scavenged by melatonin: •OH, CO
3
•–
,O
2
(
1
D
g
), O
3
, in catalyzed systems also O
2
•–
species [1,5,36–38,40,46,49,51,52,67–72] reactive nitrogen
species (RNS) scavenged by melatonin: •NO, •NO
2
(in conjunction with •OH or CO
3
•–
), perhaps peroxynitrite (ONOO
–
) [5,40,70,72–75];
organic radicals scavenged by melatonin: protoporphyrinyl cation radicals, 2,2¢-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) cation
radicals, substituted anthranylyl radicals, some peroxyl radicals [1,5,36,47,49,67]; radical scavenging by c3OHM, AFMK and AMK
[38,40,41,47,49,76–78]. **Antioxidant enzymes up-regulated by melatonin: glutathione peroxidase (GPx) (consistently in different tissues),
glutathione reductase (GRoad), c-glutamylcysteine synthase, glucose 6-phosphate dehydrogenase [5,5,49,79–85]; hemoperoxidase ⁄ catalase,
Cu-, Zn- and Mn-superoxide dismutases (SODs) (extent of stimulation cell type-specific, sometimes small) [5,49,83,84,86]; pro-oxidant
enzymes down-regulated by melatonin: neuronal and inducible nitric oxide synthases [52,87–90], 5- and 12-lipoxygenases [91–93].
S. R. Pandi-Perumal et al. Melatonin: a versatile signal
FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS 2817
1.2 · 10
10
)7.5 · 10
10
m
)1
Æs
)1
, depending on the
method applied [67–69,104]. Regardless of the differ-
ences in the precision of determination, melatonin has
been shown independently, by different groups, to be a
remarkably good scavenger for hydroxyl radicals. Con-
trary to most of its analogs, melatonin is largely
devoid of pro-oxidant side-effects (Fig. 3).
Contrary to initial claims in the literature that
almost all melatonin is metabolized in the liver to
aMT6S followed by conjugation and excretion, recent
estimates attribute % 30% of overall melatonin degra-
dation to pyrrole ring cleavage [45]. The rate of
AFMK formation may be even higher in certain tis-
sues because extrahepatic P
450
mono-oxygenase activit-
ies are frequently low and, consequently, smaller
amounts of aMT6S are produced.
AFMK appears to be a central metabolite of melato-
nin oxidation, especially in nonhepatic tissues [5,47,49].
It should be noted that the kynuric pathway of melato-
nin metabolism includes a series of radical scaven-
gers with the possible sequence of melatonin fi cyclic
3-hydroxymelatonin fi AFMK fi AMK. In the meta-
bolic steps from melatonin to AFMK, up to four free
radicals can be consumed [47]. However, the complete
cascade should be only expected under high rates of
hydroxyl radical formation. Otherwise, melatonin forms
AFMK directly and the conversion to AMK is, accord-
ing to present knowledge, predominantly catalyzed
enzymatically. Recent studies have shown a greater
number of free radicals eliminated than predicted from
the cascade, and many previously unknown products
are now being characterized [77] (J. Rosen & R. Harde-
land, unpublished results). The potent scavenger,
AMK, consumes additional radicals in primary and sec-
ondary reactions [42,77]. Interestingly, AMK interacts
not only with reactive oxygen but also with reactive
nitrogen species [78].
Melatonin antioxidant capacity also includes the
indirect effect of up-regulating several antioxidative
enzymes and down-regulating pro-oxidant enzymes, in
particular 5- and 12-lipo-oxygenases [91–93] and nitric
oxide (NO) synthases [52,87–90] (Fig. 3). The attenu-
ation of NO formation is significant as it limits the rise
in the levels of the pro-oxidant metabolite, peroxyni-
trite, and of free radicals derived from this compound
(i.e. NO
2
, CO
À
3
and OH radicals). It also helps to
reduce the inflammatory response [5].
Inasmuch as mitochondria are the major source of
free radicals, the damage inflicted by these radicals
contributes to major mitochondria-related diseases.
Electron transfer to molecular oxygen at the matrix
site, largely at the iron–sulphur cluster N2 of complex
I, is a main source of free radicals [105]. This process
also diminishes electron flux rates and therefore the
ATP-generating potential. Melatonin increases mitoch-
ondrial respiration and ATP synthesis in conjunction
with the rise in complex I and IV activities [106–109].
The effects of melatonin on the respiratory chain
may represent new opportunities for the prevention of
radical formation, in addition to eliminating radicals
already formed. A model of radical avoidance, in
which electron leakage is reduced by single electron
exchange reactions between melatonin and the compo-
nents of the electron transport chain, was proposed by
Hardeland and his coworkers [53,110]. According to
this model, a cycle of electron donation to the respirat-
ory chain at cytochrome c should generate a melatonyl
cation radical which can compete, as an alternate elec-
tron acceptor, with molecular oxygen for electrons
leaking from N2 of complex I, thereby decreasing the
rate of O
À
2
formation. In the proposed model, not only
are electrons largely recycled to the respiratory chain,
but most of the melatonin is also regenerated in the
cycle. Inasmuch as the recycled electrons are not lost
for the respiratory chain, the potential exists for
improvements in complex IV activity, oxygen con-
sumption and ATP production.
Similarly, the highly reactive melatonin metabolite,
AMK, may undergo single-electron transfer reactions
[42]. The mitochondrial protection by AMK was pro-
posed [51] and experimentally confirmed [108]. In a
manner similar to the action attributed to melatonin,
AMK exerts its effects on electron flux through the
respiratory chain and seems to improve ATP synthesis.
Melatonin’s antioxidant action: clinical
significance
Neurodegenerative diseases are a group of chronic and
progressive diseases that are characterized by selective
and often symmetric loss of neurons in motor, sensory
and cognitive systems. Clinically relevant examples of
these disorders are Alzheimer’s disease (AD), Parkin-
son’s disease, Huntington’s chorea and amyotrophic
lateral sclerosis [111]. Although the origin of neuro-
degenerative diseases mostly remains undefined, three
major and frequently inter-related processes (glutamate
excitotoxicity, free radical-mediated nerve injury and
mitochondrial dysfunction) have been identified as
common pathophysiological mechanisms leading to
neuronal death [85]. In the context of oxidative stress,
the brain is particularly vulnerable to injury because it
is enriched with phospholipids and proteins that are
sensitive to oxidative damage and has a rather weak
antioxidative defense system [112]. In the case of AD,
the increase in b-amyloid protein- or peptide-induced
Melatonin: a versatile signal S. R. Pandi-Perumal et al.
2818 FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS
oxidative stress [113], in conjunction with decreased
neurotrophic support [114], contributes significantly to
the pathophysiology of the disease. AD has been also
related to mitochondrial dysfunction [115]. Collec-
tively, most evidence convincingly supports the notion
that the neural tissue of AD patients is subjected to an
increased oxidative stress [116,117]. Therefore, attenu-
ation or prevention of oxidative stress by administra-
tion of suitable antioxidants should be a possible basis
for the strategic treatment of AD.
Melatonin has assumed a potentially significant
therapeutic role in AD inasmuch as it has been shown
to be effective in transgenic mouse models of AD
[118,119]. To date, this has to be regarded merely as a
proof-of-concept rather than as an immediately applic-
able procedure. The brains of the AD transgenic mice
exhibit increased indices of oxidative stress, such as
accumulation of thiobarbituric acid-reactive sub-
stances, a decrease in glutathione content, as well as
the up-regulation of apoptosis-related factors such as
Bax, caspase-3 and prostate apoptosis response-4. The
mouse model for AD mimics the accumulation of
senile plaques, neuronal loss and memory impairment
found in AD patients [120]. Melatonin administration
decreased the amount of thiobarbituric acid-reactive
substances, increased glutathione levels and superoxide
dismutase activity, and counteracted the up-regulation
of Bax, caspase-3 and prostate apoptosis response-4
expression, thereby significantly reducing oxidative
stress and neuronal apoptosis [120]. Melatonin inhib-
ited fibrillogenesis both in vitro [121] and at pharmaco-
logical concentrations in the transgenic mouse model
in vivo [118]. Administration of melatonin to AD
patients has been found to improve significantly sleep
and circadian abnormality and generally to decelerate
the downward progression of the disease [122–128]. It
also slowed evolution of disease [122,123,127]. In the
absence of any other therapies dealing with the core
problem of AD, the potential value of melatonin
urgently deserves further investigation.
Oxidative stress has been suggested as a major cause
of dopaminergic neuronal cell death in Parkinson’s dis-
ease [129]. Melatonin protects neuronal cells from
neurotoxin-induced damage in a variety of neuronal
culture media that serve as experimental models for
the study of Parkinson’s disease [85,117]. In a recent
study, melatonin attenuated significantly mitochondrial
DNA damage in the substantia nigra induced by
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its
active metabolite, 1-methyl-4-phenylpyridine ion: free
radical generation was reduced; and the collapse of the
mitochondrial membrane potential and cell death were
antagonized [130]. Administration of high doses of
melatonin (50 mg per day) increased actigraphically
scored total night-time sleep in parkinsonian patients
[131].
Melatonin as an oncostatic substance
There is evidence that tumor initiation, promotion
and ⁄ or progression may be restrained by the night-
time physiological surge of melatonin in the blood or
extracellular fluid [65]. Numerous experimental studies
have now provided overwhelming support for the gen-
eral oncostatic effect of melatonin. When administered
in physiological and pharmacological concentrations,
melatonin exhibits a growth inhibitory effect in estro-
gen-positive, MCF human breast cancer cell lines. Cell
culture studies have suggested that melatonin’s effects
in this regard are mediated through increased glutathi-
one levels [65]. Melatonin also inhibits the growth of
estrogen-responsive breast cancer by modulating the
cell’s estrogen signaling pathway [132]. Melatonin can
exert its action on cell growth by modulation of estra-
diol receptor a transcriptional activity in breast cancer
cells [133]. Another antitumor effect of melatonin, also
demonstrated in hepatomas, seems to result from
MT
1
⁄ MT
2
-dependent inhibition of fatty acid uptake,
in particular, of linoleic acid, thereby preventing the
formation of its mitogenic metabolite, 13-hydroxyocta-
decadienoic acid [65].
In several studies, melatonin has demonstrated onco-
static effects against a variety of tumor cells, including
ovarian carcinoma cell lines [134], endometrial carci-
noma [135], human uveal melanoma cells [136,137],
prostate tumor cells [138] and intestinal tumors
[139,140]. The concomitant administration of melato-
nin and cisplatinium etoposide increased both the sur-
vival and quality of life in patients with metastatic
nonsmall cell lung cancer [141]. Melatonin not only
exerts objective benefits concerning tumor progression,
but also provides subjective benefits and increases the
quality of life of patients by ameliorating myelotoxicity
and lymphocytopenia associated with antitumoral
therapeutic regimens [142]. Although melatonin is
mostly anticarcinogenic and an inhibitor of tumor
growth in vivo and in vitro, in some models it may
promote tumor growth [143].
Oxidative stress has been implicated to participate in
the initiation, promotion and progression of carcino-
genesis [144]. In terms of reducing mutagenesis, the
anticarcinogenic actions of melatonin are primarily
attributed to its antioxidative and free radical scaven-
ging activity [145]. Melatonin secretion is disturbed
in patients suffering from various types of cancer
[146,147]. To what extent the variations in melatonin
S. R. Pandi-Perumal et al. Melatonin: a versatile signal
FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS 2819
concentrations in cancer patients are causally related
to the disease remains to be defined. The increased
incidence of breast cancer or colorectal cancer seen in
nurses engaged in night shift work suggests a possible
link with the diminished secretion of melatonin associ-
ated with increased exposure to light at night [148].
This hypothesis received experimental support in a
recent study [149]. Exposure of rats bearing rat
hepatomas or human breast cancer xenografts to
increasing intensities of white fluorescent light during
each 12-h dark phase resulted in a dose-dependent sup-
pression of nocturnal melatonin blood levels and a sti-
mulation of tumor growth. Blask and coworkers [149]
then took blood samples from 12 healthy, premeno-
pausal volunteers. The samples were collected under
three different conditions: during the daytime; during
the night-time following 2 h of complete darkness; and
during the night-time following 90 min of exposure to
bright fluorescent light. These blood samples were then
pumped directly through the developing tumors. The
melatonin-rich blood collected from subjects while in
total darkness severely slowed the growth of the tum-
ors. The results are the first to show that the tumor
growth response to exposure to light during darkness
is intensity dependent and that the human nocturnal,
circadian melatonin signal not only inhibits human
breast cancer growth, but that this effect is extin-
guished by short-term ocular exposure to bright white
light at night [149].
Melatonin’s immunomodulatory
function
Studies undertaken in recent years have shown that
melatonin has an immunomodulatory role. Maestroni
and his coworkers first demonstrated that inhibition of
melatonin synthesis results in the attenuation of cellu-
lar and humoral responses in mice [150]. Exogenous
melatonin has been shown to counteract immunodefi-
ciencies secondary to stress events or drug treatment
and to protect mice from lethal encephalitogenic vir-
uses [151]. Melatonin has also been shown to protect
hematopoietic precursor cells from the toxic effect of
cancer chemotherapeutic agents [152]. Melatonin
enhances the production of interleukin (IL)-2 and IL-6
by cultured mononuclear cells [153] and of IL-2 and
IL-12 in macrophages [154]. The presence of specific
melatonin-binding sites in the lymphoid cells provides
evidence for a direct effect of melatonin on the regula-
tion of the immune system [155,156]. Melatonin’s
immuno-enhancing effect depends not only upon its
ability to enhance the production of cytokines, but
also upon its antiapoptotic and antioxidant actions
[117]. Melatonin synthesized by human lymphocytes
stimulates IL-2 production in an autocrine or a para-
crine manner [15]. The nocturnal melatonin levels were
found to correlate with the rhythmicity of T-helper
cells [15]; indeed, melatonin treatment augmented the
number of CD4
+
cells in rats [157]. Correlation of
serum levels of melatonin and IL-12 in a cohort of 77
HIV-1-infected individuals has revealed that decreased
levels of serum melatonin found in HIV-1-infected
individuals can contribute to the impairment of the T
helper 1 immunoresponse [158]. Inasmuch as melato-
nin stimulates the production of intracellular glutathi-
one [81], its immuno-enhancing action may be partly a
result of its action on glutathione levels.
The immuno-enhancing actions of melatonin have
been confirmed in a variety of animal species and in
humans [61,159]. Melatonin may play a role in the
pathogenesis of autoimmune diseases, particularly in
patients with rheumatoid arthritis who exhibit higher
nocturnal serum melatonin levels than healthy controls
[160]. The increased prevalence of auto-immune dis-
eases at high latitudes during winter may be caused by
an increased immunostimulatory effect of melatonin
during the long nights [160]. It has been suggested that
melatonin provides a time-related signal to the immune
system [60]. In a recent study, melatonin implants were
found to enhance a defined T helper 2-based immune
response under in vivo conditions (i.e. the increase of
antibody titres after aluminium hydroxide), thus dem-
onstrating melatonin’s potential as a novel adjuvant
immunomodulatory agent [161].
Melatonin as a hypnotic
Melatonin promotes sleep in diurnal animals, including
healthy humans [162]. The close relationship between
the nocturnal increase of endogenous melatonin and
the timing of sleep in humans suggests that melatonin
is involved in the physiological regulation of sleep
[163–165]. The temporal relationship between the noc-
turnal increase of endogenous melatonin and the
‘opening of the sleep gate’ has prompted many investi-
gators to propose that melatonin facilitates sleep by
inhibiting the circadian wakefulness-generating mech-
anism [55,166]. MT
1
receptors present in SCN presum-
ably mediate this effect.
Ingestion of melatonin (0.1–0.3 mg) during daytime,
which increased the circulating melatonin levels close
to that observed during night, induced sleep in healthy
human subjects [167]. Administration of melatonin
(3 mg, orally) for up to 6 months to insomnia patients
as an add-on to hypnotic (benzodiazepine) treatment
augmented sleep quality and duration and decreased
Melatonin: a versatile signal S. R. Pandi-Perumal et al.
2820 FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS
sleep onset latency, as well as the number of awaken-
ing episodes in elderly insomniacs [168].
A reduced endogenous melatonin production seems
to be a prerequisite for effective exogenous melatonin
treatment of sleep disorders. A recent meta-analysis of
the effects of melatonin in sleep disturbances, including
all age groups (and presumably individuals with nor-
mal melatonin levels), failed to document significant
and clinically meaningful effects of exogenous melato-
nin on sleep quality, efficiency or latency [169]. It must
be noted that a statistically nonsignificant finding indi-
cates that the alternative hypothesis (e.g. melatonin is
effective at decreasing sleep onset latency) is not likely
to be true, rather than that the null hypothesis is true
(which in this case is that melatonin has no effect on
sleep onset latency) because of the possibility of a type
II error. By combining several studies, meta-analyses
provide better size effect estimates and reduce the
probability of a type II error, making false-negative
results less likely. Nonetheless, this seems not to be the
case in the study of Buscemi et al. [169], where sample
size was constituted by less than 300 subjects. More-
over, reviewed papers showed significant variations in
the route of administration of melatonin, the dose
administered and the way in which outcomes were
measured. All of these drawbacks resulted in a signifi-
cant heterogeneity index and in a low quality size
effect estimation (shown by the wide 95% confidence
intervals reported) [169].
In contrast, another meta-analysis, undertaken by
Brzezinski et al., using 17 different studies involving
284 subjects, most of whom were older, concluded that
melatonin is effective in increasing sleep efficiency and
reducing sleep onset time [170]. Based on this meta-
analysis, the use of melatonin in the treatment of
insomnia, particularly in aged individuals with noctur-
nal melatonin deficiency, was proposed.
Melatonin as a chronobiotic molecule
Melatonin has been shown to act as an endogenous
synchronizer either in stabilizing bodily rhythms or in
reinforcing them. Hence, it is called a ‘chronobiotic’
[171] (i.e. a substance that adjusts the timing or reinfor-
ces oscillations of the central biological clock). The first
evidence that exogenous melatonin was effective in this
regard was the finding that 2 mg of melatonin was cap-
able of advancing the endogenous circadian rhythm in
humans and producing early sleepiness or fatigue [172].
Lewy et al. [173] found an alteration of the dim light
melatonin onset (i.e. the first significant rise of plasma
melatonin during the evening, after oral administration
of melatonin for four consecutive days). Since then,
many studies have confirmed that exogenous melatonin
administration changes the timing of bodily rhythms,
including sleep, core body temperature, endogenous
melatonin or cortisol [174]. Intake of 5 mg of fast-
release melatonin, for instance, has been found to
advance the timing of the internal clock up by % 1.5 h
[175]. In a recent study, daily administration of a ‘surge
sustained’ release preparation of 1.5 mg of melatonin
phase-advanced the timing of sleep without altering the
total sleep time [176], thereby showing that melatonin
acts in this context on the timing mechanisms of sleep,
rather than as a hypnotic.
The phase shifting effect of melatonin depends upon
its time of administration. When given during the
evening and the first half of the night, it phase-advan-
ces the circadian clock, whereas circadian rhythms dur-
ing the second half of the night or at early daytime are
phase delayed. The melatonin dose for producing these
effects varies from 0.5 to 10 mg [173]. The magnitude
of phase advance or phase delay depends on the dose
[175]. Melatonin can entrain free-running rhythms,
both in normal individuals and in blind people. As
melatonin crosses the placenta, it may play an active
role in synchronizing the fetal biological clock [6].
Phase-shifting by melatonin is attributed to its
action on MT
2
receptors present in the SCN [177].
Melatonin’s chronobiotic effect is caused by its direct
influence on the electrical and metabolic activity of the
SCN, a finding which has been confirmed both in vivo
and in vitro [178]. The application of melatonin
directly to the SCN significantly increases the ampli-
tude of the melatonin peak, thereby suggesting that in
addition to its phase-shifting effect, melatonin acts
directly on the amplitude of the oscillations [178].
However, amplitude modulation seems to be unrelated
to clock gene expression in the SCN [179].
Implications of melatonin’s
chronobiotic actions in CRSD
A major CRSD is shift-work disorder. Human health is
adversely affected by the disruption and desynchroniza-
tion of circadian rhythms encountered in this condition
[180,181]. The sleep loss and fatigue seen in night shift
workers has also been found to be the primary risk fac-
tor for industrial accidents and injuries. Permanent
night shift workers exhibit altered melatonin produc-
tion and sleep patterns [182]. However, a number of
studies indicate that many shift-workers retain the typ-
ical circadian pattern of melatonin production [183].
Shifting the phase of the endogenous circadian pace-
maker to coincide with the altered work schedules
of shift-workers has been proposed for improving
S. R. Pandi-Perumal et al. Melatonin: a versatile signal
FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS 2821
daytime sleep and night-time alertness. It has been
found that night shift nurses who had the ability to
shift the onset of nocturnal production to the new time
schedule exhibited improved shift-work tolerance [184].
Research studies have suggested that melatonin monit-
oring and wrist actigraphy could be useful in resolving
issues related to circadian adaptation to night shift
work.
A number of studies have investigated melatonin’s
potential for alleviating the symptoms of jet lag,
another CRSD. Melatonin has been found to be effect-
ive in 11 placebo-controlled studies for reducing the
subjective symptoms of jet lag, such as sleepiness and
impaired alertness [185]. The most severe health effects
of jet lag occur following eastbound flights, because
this requires a phase advancement of the biological
clock. In a recent study, phase advancement after
melatonin administration (3-mg doses just before bed-
time) occurred in all 11 subjects traveling from Tokyo
to Los Angeles as well as faster resynchronization
compared with controls. Melatonin increased the phase
shift from % 1.1–1.4 h per day, causing complete
entrainment of 7–8 h after 5 days of melatonin intake
[186]. Melatonin has been found to be useful in caus-
ing 50% reduction in subjective assessment of jet lag
symptoms in 474 subjects taking 5 mg of fast-release
tablets [185]. Therefore, with few exceptions, a compel-
ling amount of evidence indicates that melatonin is
useful for ameliorating ‘jet-lag’ symptoms in air trave-
lers (see the meta-analysis in the Cochrane database)
[187].
One of us examined the timely use of three factors
(melatonin treatment, exposure to light, physical exer-
cise) to hasten the resynchronization in a group of elite
sports competitors after a transmeridian flight across 12
time zones [188]. Outdoor light exposure and physical
exercise were used to cover symmetrically the phase
delay and the phase advance portions of the phase-
response curve. Melatonin taken at local bedtime
helped to resynchronize the circadian oscillator to the
new time environment. Individual actograms performed
from sleep log data showed that all subjects became
synchronized in their sleep to the local time in 24–48 h,
well in advance of what would be expected in the
absence of any treatment [188]. More recently, a retro-
spective analysis of the data obtained from 134 normal
volunteers flying the Buenos Aires to Sydney trans-
polar route in the last 9 years was published [189]. The
mean resynchronization rate was 2.27 ± 1.1 days for
eastbound flights and 2.54 ± 1.3 days for westbound
flights. These findings confirm that melatonin is benefi-
cial in situations in which re-alignment of the circadian
clock to a new environment or to impose work–sleep
schedules in inverted light ⁄ dark schedules is needed
[181,190].
A number of clinical studies have now successfully
made use of melatonin’s phase-advancing capabilities
for treating delayed sleep phase syndrome. Melatonin,
in a 5-mg dose, has been found to be very beneficial in
advancing the sleep-onset time and wake time in sub-
jects with delayed sleep phase syndrome [191–193].
Melatonin was found to be effective when given 5 h
before melatonin onset or 7 h before sleep onset.
Circadian rhythmicity is disrupted with ageing at
various levels of biological organization [165,194].
Age-related changes in the circadian system result in a
decreased amplitude of the circadian rhythm of sleep
and waking in a 12 h light ⁄ 12 h dark cycle, and phase
advancement of several circadian rhythms. Melatonin
administration in various doses (0.5–6.0 mg) has been
found to be beneficial in improving subjective and
objective sleep parameters [195]. The beneficial effects
of melatonin could be a result of either its soporific or
phase-shifting effects, or both. The efficacy of melato-
nin to entrain ‘free running’ circadian rhythms in blind
people has also been demonstrated [196,197].
One seldom-considered possibility, concerning mela-
tonin’s mechanism of action, relates to its immuno-
modulatory properties. The linkage between sleep
deprivation and susceptibility to illness has been com-
monly noted. Conversely, many infections cause
increased somnolence. Whether the increased sleep
associated with infections is just an epiphenomenon or
is the result of the enhanced immune response is uncer-
tain. Epidemiological studies have shown an associ-
ation between increased mortality rates and sleep
durations that are either longer or shorter than those
seen in normals [198]. It seems now rather clear that
cytokines released by activated immunocompetent cells
during infections may affect sleep duration. Cytokines,
including tumor necrosis factor, IL-1, IL-6 and inter-
ferons, may act as sleep inducers, while the anti-
inflammatory cytokines tend to inhibit sleep [199].
Besides, the increased somnolence associated with
acute infections seems to depend on cytokines, such as
IL-1 and IL-6, that are also important for the physio-
logical regulation of sleep. Thus, both the ability of
melatonin to stimulate the production of inflammatory
cytokines and to entrain circadian rhythms might be
related somewhat to its sleep-facilitating properties.
Melatonin in depression
A number of studies have shown altered melatonin
levels in depressed patients. Melatonin studies in
relation to patients with mood disorders have been
Melatonin: a versatile signal S. R. Pandi-Perumal et al.
2822 FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS
reported in numerous investigations [200]. In many of
those studies, low melatonin levels occurred in patients
with major depressive disorder, although increases in
melatonin have also been documented [201,202].
Phase-shift of melatonin is a major feature of major
depressive disorder, and low melatonin levels have
been described as a ‘trait marker’ for depression [203].
Reduced amplitude of melatonin secretion was found
in a group of bipolar depressive patients during the
recovery phase [204]. Indeed, the amplitude of melato-
nin secretion has been suggested as ‘state dependent’ in
bipolar patients [205]. It is interesting that male and
female MT
1
knockout (MT
1
– ⁄ –) mice tested in the
acoustic startle ⁄ prepulse inhibition, open field and
Porsolt forced swim tests displayed dramatically
impaired prepulse inhibition in the acoustic startle
response [206]. Both male and female MT
1
– ⁄ – mice
significantly increased the time spent immobile in the
forced swim test, an indication of depressed-like be-
havior. Therefore, the lifetime lack of MT
1
signaling
contributes to behavioral abnormalities, including
impairments in sensorimotor gating and increases in
depressive-like behaviors. MT
1
receptor signaling may
be important for normal brain and behavioral function
[206].
Treatment of patients with major depressive disorder
with antidepressants indicates that plasma melatonin
levels and urinary aMT6S excretion increase with
improvement of the clinical state [207–209]. As melato-
nin has been used successfully in the treatment of
CRSD [181], it has the potential value of being used
as a therapeutic agent in the treatment of mood
disorders. Melatonin treatment (3 mg) significantly
improved sleep, but did not improve the clinical state
of depressive disorders [210]. Agomelatine, an
MT
1
⁄ MT
2
melatonin agonist and selective antagonist
of 5-HT
2C
receptors, has been demonstrated to be
active in several animal models of depression. In a
double-blind, randomized multicenter multinational
placebo-controlled study, including 711 patients suffer-
ing from major depressive disorder, agomelatine
(25 mg) was significantly more effective (61.5%) than
placebo (46.3%) in the treatment of major depression
disease [211]. Recently, this finding has been confirmed
by two more studies. The efficacy of agomelatine
compared with placebo was noted after 6 weeks of
treatment (at a dose of 25 mg per day) in patients with
major depressive disorder who met Diagnostic and
Statistical Manual of Mental Disorders, version IV
(DSM-IV) criteria [212]. In another clinical study,
agomelatine, at a dose of 25 mg per day, was found to
be significantly better than placebo in treating not only
depressive symptomatology but also in treating anxiety
symptoms [213]. From these studies, it is evident that
agomelatine has emerged as a novel melatonergic anti-
depressant and may have value for the treatment of
depression.
Melatonin in meditation
Apart from the regulatory effects of melatonin on the
photoperiod, other less well-studied effects involve
melatonin’s influence on mental states. Romijn’s sug-
gestion that the pineal should be recognized as a
‘tranquilizing organ’ [214] is consistent with the well-
documented sedating effects of melatonin. Two studies
have demonstrated increases in overnight samples of
urinary aMT6S [215] and in night-time plasma melato-
nin [216] following meditative practice. Psychosocial
interventions may not only modulate melatonin levels,
but may also be mediated by the hormone. In this con-
text, the pineal can be understood as a psychosensitive
organ. Meditation is considered to be an effective
relaxation technique that has a greater benefit than
other relaxation procedures [217]. The fact that the
reported effects on various bodily symptoms of medi-
tation and melatonin are similar prompted investiga-
tors to suggest that meditation exerts its beneficial
effects by increasing melatonin secretion [215,216]. As
psychosocial factors play a significant role in stress
and stress-related health problems, influences of medi-
tation on stress management, including benefits to the
immune system and, perhaps, consequences for aging,
and the development of cancer may be related to mela-
tonin. The common effect of relaxation exerted by
both meditation and melatonin is consistent with stress
reduction observed after either intervention.
The link between meditation and increased melato-
nin secretion is not without controversy. No changes
in melatonin levels were noted in a group of breast
cancer and prostate cancer patients following medi-
tation practice [218]. In other subjects, meditation
decreased circulating melatonin (e.g. plasma melatonin
was significantly reduced 3 h after morning meditation)
[219]. The discrepancies found can be in part attrib-
uted to the time of melatonin measurement, in other
words night [215,216] or morning [219] melatonin lev-
els. This should be seen as a chronobiological effect,
reflecting, perhaps, an increased circadian amplitude.
Further studies are needed to substantiate the role of
melatonin at the interface between psyche and soma.
Clinical significance of GI melatonin
It is now known that melatonin is not only present
[220], but also synthesized in the enterochromaffin cells
S. R. Pandi-Perumal et al. Melatonin: a versatile signal
FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS 2823
of the GI tract and can be released to the circulation,
especially in response to food intake [12]. As noted
above, the presence of melatonin in the GI tract is
greater by orders of magnitude than in the pineal gland
or in the circulation. In the intestine, melatonin has been
demonstrated to increase duodenal mucosal secretion of
bicarbonate through its action on the MT
2
receptor
[221], this alkaline secretion being an important mechan-
ism for duodenal protection against gastric acid. An
inverse relationship between melatonin and the inci-
dence of stomach ulcers has been observed in the stom-
ach tissue and plasma of pigs [222]. Exacerbation of
duodenal ulcers in human patients is correlated with low
urinary melatonin levels [223]. The antioxidant action of
melatonin has also been hypothesized to be one of the
primary reasons for its gastroprotective efficacy [224].
Moreover, melatonin inhibits contraction of the smooth
muscles of the stomach, ileum and colon [12]. Melatonin
has also been detected at a high concentration in the bile
(1000 times higher than its daytime concentrations in
the blood); it has been hypothesized that melatonin in
the bile prevents oxidative damage to the intestinal epi-
thelium caused by bile acids [224].
Melatonin in cardiovascular diseases
Studies undertaken in humans suggest that melatonin
influences autonomic cardiovascular regulation [225–
227]. Decreases in nocturnal serum melatonin concen-
tration or in urinary aMT6S levels have been reported
in patients with coronary heart disease [228–230] or
cardiac failure [231]. Melatonin administration increa-
ses the cardiac vagal tone and decreases circulating NE
levels [225,226].
Melatonin is effective at reducing blood pressure in
hypertensive patients. In a double-blind, placebo-con-
trolled study conducted on 14 normal healthy men, it
was noted that the administration of 1 mg of melato-
nin reduced systolic, diastolic and mean blood pres-
sure; NE levels also decreased following melatonin
administration [226]. In another double-blind, placebo-
controlled study, melatonin given orally (2.5 mg per
day) for 3 weeks to patients with essential hypertension
reduced significantly both systolic and diastolic blood
pressure [58].
The hypotensive action of melatonin may involve
either peripheral or central mechanisms. Melatonin’s
vasodilating action is supported by a decrease of
the internal artery pulsatile index, which reflects the
downstream vasomotor state and resistance [226]. In
fact, vasoregulatory actions of melatonin are complex
insofar as vasodilation is mediated via MT
2
receptors,
whereas MT
1
-dependent signaling leads to vasocon-
striction [97]. The local balance between these receptors
is obviously different, and constriction prevails in the
cerebral vessels investigated to date. However, this
effect is accompanied by a considerably enhanced
dilatory response to hypercapnia [232]. The findings
demonstrated that melatonin attenuates diurnal fluctua-
tions in cerebral blood flow and diminishes the risk of
hypoperfusion. The overall effect of melatonin on arter-
ial blood pressure could be mediated centrally by mech-
anisms controlling the autonomic nervous system [227].
It has been suggested that the reduction of nocturnal
blood pressure by repeated melatonin intake at night is
attributable to its effect on amplification of the circa-
dian output of the SCN [58]. The normalization of cir-
cadian pacemaker function in the regulation of blood
pressure by melatonin treatment has been proposed as
a potential strategy for the treatment of essential hyper-
tension [233].
Melatonin effects on bone
A direct osseous effect of melatonin has been demon-
strated by the finding that it inhibits in vitro the
increased calcium uptake in bone samples of rats trea-
ted with pharmacologic amounts of corticosterone
[234]. A direct activity of melatonin was demonstrated
in rat pre-osteoblast and osteoblast-like osteosarcoma
cell lines [235]. In the presence of nanomolar concen-
trations of melatonin, pre-osteoblast cells underwent
cell differentiation. After melatonin exposure, both cell
lines showed an increased gene expression of bone
matrix sialoprotein as well as other bone marker pro-
teins, such as alkaline phosphatase, osteopontin and
osteocalcin. In another study on human bone cells and
osteoblastic cell lines exposed to melatonin, meth-
oxyindole increased cell proliferation in a dose-
dependent manner. In these cells, melatonin increased
procollagen type Ic-peptide production without modi-
fying alkaline phosphatase or osteocalcin [236]. Mela-
tonin seems to cause inhibition of bone resorption and
augmentation of bone mass by down-regulating recep-
tor activator of nuclear factor jB-mediated osteoclast
activation [237].
Osteoclasts generate high levels of superoxide anions
during bone resorption and this may contribute to the
degradative process. In view of the very strong antioxi-
dative efficiency of melatonin and its metabolites for
free radical scavenging, the effect of melatonin in pre-
venting osteoclast activity in bone may depend, in
part, on its antioxidant properties. The first indication
that melatonin administration was effective for
decreasing bone loss in vivo was obtained in ovariec-
tomized rats [238]. In rats receiving melatonin in the
Melatonin: a versatile signal S. R. Pandi-Perumal et al.
2824 FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS
drinking water (25 lgÆmL
)1
water), a reduction in
urinary deoxypyridinoline increase after ovariectomy
(an index of bone resorption) was seen within 30 days
after surgery, indicating a possible effect of melatonin
in delaying bone resorption after ovariectomy. Subse-
quent studies corroborated the in vivo preventive effect
of melatonin on bone loss [237,239–241].
The effect of melatonin on bone metabolism in ovar-
iectomized rats receiving estradiol replacement therapy
was also assessed [242]. Ovariectomy augmented, and
melatonin or estradiol lowered, urinary deoxypyridino-
line excretion. Moreover, the efficacy of estradiol to
counteract ovariectomy-induced bone resorption was
increased by melatonin. Therefore, postovariectomy
disruption of bone remodeling could be prevented in
rats by administering a pharmacological amount of
melatonin (in terms of circulating melatonin levels),
providing that appropriate levels of circulating estra-
diol were present [242].
Another line of evidence for a melatonin effect on
the skeleton derived from studies on experimental
scoliosis in animals. Scoliosis developed in pinealec-
tomized chickens [243], with anatomical characteristics
similar to those of human idiopathic scoliosis [244].
Pinealectomy induced malformation of the spine and
reduced the mechanical strength of vertebrae in Atlan-
tic salmon [245]. The possibility that melatonin and its
receptors could be involved in hereditary lordoscoliosis
in rabbits was also entertained [246]. Interestingly,
serum melatonin levels in adolescents with idiopathic
scoliosis were significantly lower than in controls [247].
Glucocorticoids (GC) are among the hormones that
significantly affect bone remodeling. Prolonged expo-
sure to GC at pharmacological concentrations induces
osteoporosis associated with an increased risk of bone
fracture [248–250]. The adverse effects of GC excess
on the skeleton may be mediated by direct actions on
bone cells, actions on extraskeletal tissues, or both
[251]. While high doses or long-term GC therapy cause
bone resorption and decrease bone mineral density
[252,253], other studies demonstrated that GC treat-
ment increased bone mass by a relatively greater sup-
pression of bone resorption than of bone formation
[254–256]. Thus, differences in steroid formulation,
doses and duration of administration, as well as in the
age and strain of the animals, may affect the final out-
come of the treatments. In a recent study, the effect of
melatonin (25 lgÆmL
)1
of drinking water, % 500 lg per
day) on a 10-week-long treatment of male rats with a
low dose of methylprednisolone (5 mgÆ kg
)1
subcutane-
ously, 5 days per week) was examined [257].
Bone densitometry and mechanical properties, cal-
cemia, phosphatemia, serum bone alkaline phosphatase
activity and C-telopeptide fragments of collagen type I
were measured. Most densitometric parameters aug-
mented after methylprednisolone or melatonin adminis-
tration and, in many cases, the combination of
corticoid and melatonin resulted in the highest values
observed. Rats receiving the combined treatment
showed the highest values of work to failure in femoral
biomechanical testing. Circulating levels of C-telopep-
tide fragments of collagen type I, an index of bone
resorption, decreased after melatonin or methyl-
prednisolone, both treatments summating to achieve
the lowest values observed [257]. The results were com-
patible with the view that low doses of methylpredniso-
lone or melatonin decrease bone resorption and have a
bone protecting effect.
Melatonin’s role in energy expenditure
and body mass regulation
Melatonin is known to play a role in energy expendi-
ture and body mass regulation in mammals [258]. Vis-
ceral fat levels increase with age, whereas melatonin
secretion declines [125,229,259–263]. Daily melatonin
supplementation to middle-aged rats has been shown
to restore melatonin levels to those observed in young
rats and to suppress the age-related gain in visceral fat
[264,265]. In one of our laboratories, melatonin treat-
ment prevented the increase in body fat caused by
ovariectomy in rats [242]. In a study on melatonin or
methylprednisolone, both treatments were effective at
decreasing body weight in middle-aged rats through
effects that summated when melatonin and methyl-
prednisolone were conjointly administered. Melatonin’s
effects are partly mediated through MT
2
receptors pre-
sent in adipose tissue [266].
In human adults, obesity is not accompanied by sig-
nificant modifications of melatonin secretion [267]. In
childhood and adolescence, significant changes in body
composition take place. The possible correlation of
obesity in prepubertal children and adolescents with
melatonin secretion was recently examined by measur-
ing diurnal, nocturnal and total melatonin secretion in
50 obese children and adolescents and 44 normal con-
trols matched on age, gender and maturational stage
[268]. Secretion of melatonin was assessed by measur-
ing the 24 h urinary output of the predominant mela-
tonin metabolite, aMT6S. A factorial anova indicated
that nocturnal aMT6S excretion and amplitude were
significantly higher in the obese individuals. A signifi-
cant interaction of weight and age was detected (i.e.
the effect of weight was significant in the pubertal
group only). Total nocturnal and diurnal aMT6S
excretion was significantly higher in girls. Further
S. R. Pandi-Perumal et al. Melatonin: a versatile signal
FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS 2825
statistical analysis segregated by gender indicated that
the increase in total and nocturnal aMT6S excretion
and amplitude found in obesity occurred only in boys
and at the pubertal age. Therefore, obese pubertal
males have a greater urinary excretion of aMT6S and
therefore a greater secretion of melatonin. The increase
in melatonin in pubertal obese males might be one of
the possible mechanisms accounting for delayed pub-
erty in many of these subjects [268].
Melatonin in reproduction and sexual
maturation
Available evidence indicates that melatonin regulates
the reproductive function in seasonal mammals by its
inhibitory action at various levels of the hypothalam-
ic–pituitary–gonadal axis. The pulsatile secretion of
gonadotropin-releasing hormone (GnRH), from a
small number of neurons in the hypothalamus, control
luteinizing hormone and follicle-stimulating hormone
secretion that, in turn, regulates the functional activity
of gonads [269,270]. Melatonin has been shown to
down-regulate GnRH gene expression in a cyclical pat-
tern over a 24-h period [271]. Exposure of GT1-7 neu-
rons of the hypothalamus to melatonin resulted in the
down-regulation of GnRH mRNA levels, 12 h after
exposure. Melatonin exerts its inhibitory effect by act-
ing on G-protein coupled melatonin receptors MT
1
and MT
2
and nuclear orphan receptors RORa and
RZRb [271].
Earlier studies have concluded that neurons found
in the pre-optic area and ⁄ or the mediobasal hypothala-
mus and pituitary [272,273] are the main sites through
which melatonin exerts its reproductive actions. Mela-
tonin micro-implants in the area of pre-optic and
mediobasal hypothalamus of mice caused complete
gonadal involution [269]. MT
1
and MT
2
receptors are
expressed in the pituitary gland where melatonin inhib-
its GnRH-induced calcium signaling and gonadotro-
phin secretion mainly in neonatal pituitary cells [274].
In women, an influence of melatonin on reproductive
function can be inferred from the studies indicating high
melatonin levels in hypothalamic amenorrhea, which
would support a casual relationship between high
melatonin concentration and hypothalamic–pituitary–
gonadal hypofunction [275]. Normal melatonin rhythms
are closely related to those of reproductive hormones
during infancy and reciprocally correlated during pub-
erty. The demonstration of melatonin receptors in
reproductive organs [276,277], and the localization of
sex hormone receptors in the pineal gland [278–281],
further support the inference that melatonin plays an
important role in these inter-relationships.
In seasonal breeders, reproductive performance is
timed by variations in the photoperiod [282], effects
that are mediated by corresponding changes in melato-
nin [283,284]. Whether melatonin suppresses gonadal
functions, as in many rodents, or stimulates them,
depends on the species-specific season of reproduction.
In sheep and ewes, gonadal activity is initiated during
the fall and is inhibited during summer. Melatonin
exerts a stimulatory effect on the reproductive axis in
this species [285]. It mediates the influence of photo-
period on luteinizing hormone pulsatile secretion.
Removal of the pineal gland disrupts the photoperiod-
induced reproductive responses to seasonal changes in
the duration of night and day [286]. Insertion of mela-
tonin implants in the form of slow-release capsules has
been shown to be effective at increasing sheep produc-
tion and in promoting fur growth. Administration of
melatonin induces the same effects as photoperiodic
changes on seasonal reproduction. In ewes, the summer
melatonin pattern entrains the circannual reproductive
rhythm, whereas the winter pattern does not [287].
Melatonin may mediate the moderate seasonal fluc-
tuations observed in the human reproductive function
[288,289]. The increased conception rate seen in nor-
thern countries during the summer season has been
reported to be caused by changes in luteinizing hor-
mone and melatonin secretion in these individuals. The
nocturnal plasma melatonin concentration on day 10
of the menstrual cycle has been found to be higher in
winter than in summer, whereas plasma luteinizing
hormone levels are higher in summer than in winter
[290]. Although humans are not seasonal breeders, sea-
sonal changes in reproductive performance do occur
and melatonin secretion may be involved.
Melatonin has been implicated in sexual maturation.
Melatonin exerts an inhibitory role on the hypothala-
mus and on pubertal maturation. The decline of serum
melatonin below a threshold value (% 115 pgÆ mL
)1
)
may constitute the activating signal for the hypotha-
lamic pulsatile secretion of GnRH and subsequent
onset of pubertal changes [291]. The hypothalamic–
pituitary–gonadal axis, which is already active during
fetal life, remains quiescent until the age of % 10 years
and is reactivated again at this time with the increase
in the amplitude and frequency of GnRH pulses. Sti-
mulating the pulsatile secretion of luteinizing hormone
and follicle-stimulating hormone is crucial for pubertal
changes and therefore the decline in melatonin concen-
tration below the threshold value is very important for
the initiation of puberty. Support for this has been
obtained from clinical studies. Children with preco-
cious puberty have lower nocturnal serum melatonin
levels [292]. On the other hand, children with delayed
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2826 FEBS Journal 273 (2006) 2813–2838 ª 2006 The Authors Journal compilation ª 2006 FEBS