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melatonin and septic shock - some recent concepts

Melatonin in septic shock: Some recent concepts
Venkataramanujan Srinivasan PhD
, Seithikurippu R. Pandi-Perumal MSc
D. Warren Spence BA
, Hisanori Kato PhD
, Daniel P. Cardinali MD PhD
Sri Sathya Sai Medical Educational and Research Foundation, Prsanthi Nilayam, Plot-40 Kovai Thirunagar,
Coimbatore-641014, India
Somnogen Inc, New York, NY 11418, USA
Canadian Sleep Institute, Toronto, ON, Canada M3H 3V6
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo,
Bunkyo-ku, Tokyo 113-8657, Japan
Departmento de Docencia e Investigación, Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina,
C1107AFD Buenos Aires, Argentina
Septic shock;
Nitric oxide
Abstract Melatonin is a versatile molecule, synthesized not only in the pineal gland, but also in many
other organs. Melatonin plays an important physiologic role in sleep and circadian rhythm regulation,
immunoregulation, antioxidant and mitochondrial-protective functions, reproductive control, and
regulation of mood. Melatonin has also been reported as effective in combating various bacterial and
viral infections. Melatonin is an effective anti-inflammatory agent in various animal models of
inflammation and sepsis, and its anti-inflammatory action has been attributed to inhibition of nitric oxide
synthase with consequent reduction of peroxynitrite formation, to the stimulation of various antioxidant
enzymes thus contributing to enhance the antioxidant defense, and to protective effects on mitochondrial
function and in preventing apoptosis. In a number of animal models of septic shock, as well as in
patients with septic disease, melatonin reportedly exerts beneficial effects to arrest cellular damage and
multiorgan failure. The significance of these actions in septic shock and its potential usefulness in the
treatment of multiorgan failure are discussed.
© 2010 Elsevier Inc. All rights reserved.
1. Introduction
Melatonin is a major secretory product of the pineal gland
released every day at night. In all mammals, circulating
melatonin is synthesized primarily in the pineal gland. In
addition, melatonin is also locally found in various cells,
tissues, and organs including lymphocytes, human and murine
bone marrow, the thymus, the gastrointestinal tract, skin, and
the eyes where it plays either an autocrine or paracrine role
[1,2]. Both in animals and in human beings, melatonin
participates in diverse physiologic functions, not only signaling
Disclosure: SR Pandi-Perumal is a stockholder and the President and
Chief Executive Office of Somnogen Inc, a New York corporation. He
declared no competing interests that might be perceived to influence the
content of this article. All remaining authors declare that they have no
proprietary, financial, professional, or any other personal interest of any
nature or kind in any product or services and/or company that could be
construed or considered a potential conflict of interest that might have
influenced the views expressed in this manuscript.
Corresponding author. Faculty of Medical Sciences, Department of
Teaching & Research, Pontificia Universidad Católica Argentina, 1107
Buenos Aires, Argentina. Tel.: +54 11 43490200x2310.
E-mail addresses:, (D.P. Cardinali).
0883-9441/$ see front matter © 2010 Elsevier Inc. All rights reserved.
Journal of Critical Care (2010) 25, 656.e1656.e6
the length of the night (and thus the time of the day or the season
of the year) but also enhancing free radical scavenging, the
immune response, and cytoprotective processes.
In several animal models, melatonin has been identified to
protect against bacterial, viral, and parasitic infections
presumably by acting through a variety of mechanisms, like
immunomodulation or direct or indirect antioxidant activity
[3]. Melatonin is a powerful antioxidant that scavenges
superoxide radicals as well as other radical oxygen species
(ROS) and radical nitrogen species and that gives rise to a
cascade of metabolites that share its antioxidant properties.
Melatonin also acts indirectly to promote gene expression of
antioxidant enzymes and to inhibit gene expression of
prooxidant enzymes [2].
Septic shock, the most severe problem of sepsis, is a lethal
condition caused by a pathogen-induced long chain of
sequential intracellular events occurring in immune cells,
epithelium, endothelium, and the neuroendocrine system [4].
The lethal effects of septic shock are associated with the
production and release of numerous proinflammatory
biochemical mediators like cytokines, nitric oxide (NO),
ROS, and radical nitrogen species radicals, together with
development of massive apoptosis.
Melatonin has been shown to be beneficial for reversing
symptoms of septic shock [5]. Melatonin had significant anti-
inflammatory properties presumably by decreasing the
synthesis of proinflammatory cytokines like tumor necrosis
factor (TNF)αand by suppressing inducible NO synthase
(iNOS) gene expression. Melatonin also exerts a strong
antiapototic effect [2]. This review article is focused on the
significance of melatonin in septic shock and its potential
utility to treat multiorgan failure. Published studies on animal
models of inflammation and sepsis are summarized in
Supplemental Tables 1 and 2.
In the next sections, we will review some of those studies
with the aim of exemplifying the potential therapeutic use of
melatonin in inflammation and septic shock.
2. Melatonin in lipopolysaccharide-induced
The first evidence for melatonin in controlling lipopoly-
saccharide (LPS)-induced damage was provided by Sew-
erynek and coworkers [6] in rats. They reported a reduction
in LPS-induced oxidative insult after melatonin administra-
tion, as evidenced by decreased hepatic malondialdehyde
(MDA) and 4-hydroxyalkenal (4-HDA) [6].
Melatonin prevents LPS-induced endotoxemia presum-
ably by reducing circulating TNF-αlevels, superoxide
production in the aorta, and iNOS in the liver [7].
Melatonin (10-60 mg/kg) administered intraperitoneally
(IP) to rats before and/or after LPS significantly decreased
lung lipid peroxidation and counteracted the LPS-induced
increase of NO levels in lungs and liver in a dose-
dependent manner [8]. It also prevented LPS-induced
metabolic alterations.
The activation of mitochondrial NOS can be a crucial
trigger for initiation of the chain of events leading to septic
shock [9]. The mitochondria express constitutive and
inducible forms of NOS, the latter causing mitochondrial
respiratory inhibition and failure. The protective role of
melatonin against the enhancing effects of LPS on
mitochondrial iNOS and the activity of respiratory com-
plexes in liver and lung mitochondria were evaluated in
young and old rats [10]. Melatonin administration (60 mg/kg,
IP) effectively counteracted LPS-induced inhibition of
complexes I and IV of the electron transport chain and
decreased mitochondrial NOS activity and NO production,
thereby preventing LPS toxicity [10]. The survival rate of
LPS-injected mice improved from 0% in controls to 48% and
86% after melatonin administration (2 mg/kg) 3 and 6h later,
respectively [11].
The effect of melatonin in preventing septic shock is
complex. Apart from acting on the local sites of inflamma-
tion, melatonin also exerts its beneficial actions through a
multifactorial pathway including its effects as immunomod-
ulator, antioxidant, and antiapoptotic agent. This is exem-
plified by the study performed by Carrillo-Vico et al [12] in
mice. It was reported that IP administered melatonin (10 mg/
kg) 30 minutes before and 1 hour after LPS injection
markedly protected the mice from the lethal effects of LPS
with 90% survival rates for melatonin vs 20% in LPS-
injected mice after 72 hours. Lipopolysaccharide induced the
increase of nitrite/nitrate and lipid peroxidation levels in
brain and liver. Melatonin administration increased the levels
of the anti-inflammatory cytokine interleukin (IL)-10 and
decreased the concentration of proinflammatory mediators
like TNF-α, IL-12, and interferon-γin the local site of LPS
injection [12]. Morphologic evaluation of the apoptotic
process showed that melatonin decreased the LPS-induced
programmed cell death in spleen [12]. Melatonin's anti-
apoptotic action was attributed to its stimulatory effect on IL-
10 levels because IL-10 antiapoptotic action had already
been demonstrated.
The effect of senescence on LPS-induced multiorgan
failure and the efficacy of melatonin treatment to modify this
condition were evaluated in rats [13]. Inducible NOS
expression and activity, nitrite content, lipoperoxidation
levels, and serum markers of liver, renal, and metabolic
dysfunction were measured. An age-dependent increase in
iNOS activity, NO content, and lipoperoxidation levels was
observed; and these changes were augmented further by LPS
[13]. Melatonin decreased the expression and activity of
iNOS, reducing NO and lipoperoxidation levels to basal
values in both LPS-treated groups. Liver, kidney, and
metabolic dysfunctions were also significantly higher in
aged rats and further increased by LPS. Melatonin treatment
counteracted all these alterations in young and aged rats [13].
These findings are significant because the susceptibility of
elderly patients to septic shock and multiorgan failure is
656.e2 V. Srinivasan et al.
much greater than in young individuals. The alteration of the
sleep/wake cycle may be one of the factors explaining this
susceptibility in old individuals. Relevant to this, melatonin
(5 mg/kg IP) attenuated the alveolar damage caused by
LPS and counteracted the reduced levels of Bcl-XL and
procaspase-3 seen in sleep-deprived mice [14]. Melatonin also
prevented the increase of cell death and reduced the elevated
higher levels of MDA in lungs of sleep-deprived mice [14].
It is well known that, during sepsis, ileus and mucosal cell
barrier dysfunction occurs as one of its most frequent
complications. Ileus, by promoting intestinal stasis, bacterial
overgrowth, and bacterial translocation, may cause second-
ary infections and multiple organ failure. By using the LPS
model, the beneficial effects of melatonin in preventing
gastrointestinal disturbances were studied in mice [15]. Mice
treated with LPS exhibited reduced gastric emptying of solid
beads and altered distribution of glass beads throughout the
gastrointestinal tract. Melatonin (10 mg/kg IP) reversed LPS-
induced motility disturbances. Melatonin also normalized the
altered lipid peroxidation, p38 mitogen-activated protein
kinase activation, nuclear factorκB activation, iNOS
transcription and expression, and nitrite production in
intestinal tissue from septic mice [15]. Melatonin is thus a
molecule with therapeutic potential for the treatment of
systemic inflammation because it interferes at the earliest
step of activation of the oxidative and proinflammatory
cascade. Melatonin and its metabolites may function as
modulatory agents during the inflammatory process and have
the potential to be a new class of anti-inflammatory agents
with specificity for cyclooxygenase-2 and iNOS enzymes
[16]. Melatonin treatment also reduced myeloperoxidase
activity and MDA levels [17].
The possible protective effect of melatonin in LPS-
induced pulmonary inflammation and lung injury was
evaluated in rats [18]. Melatonin (10 mg/kg, IP) given 30
minutes before LPS prevented the decrease in PaO
and the
lung injury caused by the endotoxin. Melatonin decreased
pulmonary edema, the elevated lung myeloperoxidase
(MPO) activity, and lipid peroxidation after LPS. The
increase of the proinflammatory cytokine TNF-αlevels in
pulmonary tissue given by LPS was also prevented by
melatonin, whereas the levels of the anti-inflammatory
cytokine IL-10 were augmented. The decrease in LPS-
induced pulmonary edema, lipid peroxidation, and the
infiltration of neutrophils in lung tissue was interpreted in
terms of the TNF-αinhibition and IL-10 stimulation brought
about by melatonin [18].
Severe infection in diabetic patients often leads to
multiorgan failure. In a study conducted to assess the
protective effects of melatonin in LPS-injected rats turned
diabetic by streptozotocin administration, LPS significantly
increased the serum levels of TNF-αand IL-6 in normal and
diabetic rats and augmented plasma corticotropin-releasing
hormone, ACTH, and corticosterone [19]. Both 0.1- and
1-mg/kg melatonin doses significantly decreased serum
levels of TNF-αand IL-6 in LPS-treated rats. Significant
inhibitory effects of melatonin (1 mg/kg) were also
observed on the hypothalamic-pituitary-adrenal axis [19].
Previous studies in diabetic rats indicated that melatonin
was effective to restore normal vascular responses [20].
Therefore, melatonin treatment may help to prevent the
vicious cycle of hyperglycemia and stress factors such as
severe infection in diabetic patients.
3. Melatonin in non-LPS animals models of
septic shock
Short-term melatonin administration (10 mg/kg IP) after
hemorrhage significantly improved survival in animals
subjected to a subsequent septic challenge by the cecal
ligation and puncture (CLP) procedure [21]. In these mice,
melatonin administration increased the survival rate by 28%
as compared with vehicle-treated animals.
In another experimental model for septic shock, that is,
the systemic administration of zymosan A that causes a
massive release of proinflammatory mediators like TNF-α,
IL-6, prostaglandins, NO, and ROS, a 100% mortality was
observed, whereas the simultaneous administration of
zymosan and melatonin (0.8 mg/kg) resulted in only 27%
mortality rate [22].
The CLP model of sepsis was used to further understand
the possible involvement of mitochondrial NOS and
melatonin in the pathophysiology of sepsis by examining
the changes in mitochondrial constitutive and iNOS activity
and mitochondrial function in skeletal muscles of wild-type
) and iNOS knockout mice (iNOS
)[23]. When 4
doses of melatonin (30 mg/kg) were injected IP in iNOS
mice, but not in iNOS
mice, sepsis increased mitochon-
drial NOS activity. Melatonin administration counteracted
sepsis-induced mitochondrial iNOS activity in iNOS
mice, but did not affect mitochondrial constitutive NOS
activity in either type of mice [23]. Mitochondrial nitrite
significantly increased in iNOS
mice after sepsis, whereas
melatonin treatment reduced nitrite levels to control values.
Lipid peroxidation, which was increased in septic iNOS
mice, decreased significantly after melatonin administration.
Sepsis significantly reduced the mitochondrial content of
total glutathione (GSH) in iNOS
mice and increased the
oxidized glutathione to GSH ratio, indicating a loss of
reduced GSH. These changes in mitochondrial GSH pool
during sepsis were counteracted by melatonin administration
[23]. As far as the electron transport chain, complex I, II, II,
and IV activities were significantly reduced in septic NOS
mice by about half; and the administration of melatonin not
only prevented the inhibition of complex activities induced
by sepsis but also increased their activities above their basal
values [23].
Although extensively studied, the pathophysiology of
sepsis-associated multiorgan failure remains undefined
[4,24]. It has been proposed that a key defect in sepsis is
656.e3Melatonin in septic shock: Some recent concepts
the disruption of oxidative phosphorylation within mito-
chondria [25]. The result is an inability of the cell to use
molecular oxygen for adenosine triphosphate production,
despite adequate oxygen availability. Melatonin normalized
the production of adenosine triphosphate in iNOS
mice, without affecting iNOS
animals [26].
The efficacy of melatonin to prevent intraperitoneal sepsis
and the associated multiple organ dysfunction syndrome was
evaluated in rats subjected to the CLP procedure [27].
Melatonin was administered 3, 6, and 12 hours after CLP. The
pressor response to norepinephrine was assessed at 0, 3, 9,
and 18 hours after CLP surgery. Animals that received CLP
alone showed a significantly progressive decrease in mean
arterial blood pressure from 9 to 18 hours (ie, from about 120
to 70 mm Hg). In the animals that received CLP plus
melatonin (0.3 mg/kg intravenously at 3 and 9 hours after
CLP), the delayed fall in blood pressure was prevented [27].
The administration of melatonin completely restored the
norepinephrine-induced vasomotor response back to normal.
With regard to biochemical indexes of liver dysfunction, the
rise in plasma glutamate-pyruvate transaminase and gluta-
mate-oxaloacetate transaminase caused by CLP was pre-
vented by melatonin treatment, as was the increase in
creatinine, blood urea nitrogen, and lactate dehydrogenase
(indicators of renal failure and cellular damage) in response to
CLP [27].
Several cytokines released during sepsis, especially IL-1β,
directly act on blood vessels, inducing vasodilatation through
rapid production of platelet-activating factor and NO. In CLP
rats, melatonin treatment diminished plasma NO and IL-1β
concentrations, aortic superoxide levels, and the infiltration
of polymorphonuclear neutrophils in lung and liver [27].
Therefore, Wu et al [27] attributed the beneficial effects of
melatonin in the CLP septic model to inhibition of IL-βand
NO production, O
formation, and polymorphonuclear
infiltration in organs. In a previous study, it had been
observed that melatonin (10 mg/kg, IP) 30 minutes before
and 6 hours after CLP counteracted the inhibition of in vitro
ileal and bladder contractility caused by sepsis [28].
Considering that micromolar melatonin concentrations
could be locally achieved through production by activated
immune competent cells, extrapineal melatonin could have a
protective effect against tissue injury in multiple organ
dysfunction syndrome [29].
4. Melatonin studies in septic patients
Several studies have measured melatonin levels in
critically ill patients to find out a possible correlation
between melatonin and intensity of septic shock. In one of
those studies carried out in intensive care unit (ICU) patients,
17 septic ICU patients, 7 ICU nonseptic patients, and 21
controls were examined [30]. 6-Sulfatoxymelatonin was
determined in urine samples taken at 4-hour intervals over a
total period of 24 hours. Urinary 6-sulfatoxymelatonin
exhibited significant circadian periodicity in only 1 of 17
septic patients vs 6 of 7 in nonseptic patients and 18 of 23 in
normal controls. The phase amplitude (an index of the
maximal levels attained at peak concentrations) was
significantly lower in septic patients. In sepsis survivors, 6-
sulfatoxymelatonin excretion profiles tended to normalize,
but still lacked a significant circadian rhythm at ICU
discharge [30].
In another study, melatonin levels in blood and urine were
studied over 3 consecutive days in 8 critically ill patients
during deep sedation and mechanical ventilation at the ICU
[31]. The circadian rhythm of melatonin release was
abolished in all but one patient, who recovered much more
quickly than the others [31].
Biochemical markers for the circadian rhythm were
studied in 16 patients treated at the ICU of 2 regional
hospitals in Sweden [32]. All urine excreted between 7:00
AM and 10:00 PM (day) and between 10:00 PM and 7:00 AM
(night) was collected and sampled throughout the entire ICU
period (median, 10 days) for the excretion of 6-sulfatox-
ymelatonin and free cortisol. Overall excretion of 6-
sulfatoxymelatonin was lower and cortisol excretion was
higher than reported for healthy reference populations [32].
Mechanical ventilation was associated with a markedly
lower 6-sulfatoxymelatonin excretion (median, 198 ng/h)
compared with periods without such help (555 ng/h),
whereas infusion of adrenergic drugs increased 6-sulfatox-
ymelatonin excretion significantly. Five patients (31%)
showed a virtually absent melatonin excretion for 24 hours
or more. The diurnal rhythms were consistently or
periodically disturbed in 65% and 75% of the patients [32].
Perras et al [33] measured serum melatonin concentra-
tions at 2:00 AM in the first night in hospital in 302 patients
consecutively admitted to the ICU. Correlations between
illness severity (Acute Physiology and Chronic Health
Evaluation II score and Therapeutic Intervention Scoring
System) and melatonin levels were assessed. Overall
analysis for the whole group of patients revealed no or
very weak correlation between nocturnal serum melatonin
levels and illness severity. In contrast, analysis of subgroups
indicated that, in the 14 patients with severe sepsis, Acute
Physiology and Chronic Health Evaluation and Therapeutic
Intervention Scoring System scores were correlated nega-
tively with nocturnal melatonin concentrations. In contrast,
melatonin levels and illness severity were not correlated in
patients admitted for coronary syndrome, intoxication,
gastrointestinal bleeding, pneumonia, or stroke [33].
The alteration of the sleep-wake cycle, the augmented
oxidative/nitrosative stress, and the altered inflammatory
reaction seen in patients with septic shock render them
suitable for melatonin therapy [34]. To assess in critically ill
patients receiving mechanical ventilation the effect of
exogenous melatonin on nocturnal sleep quantity, a
randomized, double-blind, placebo-controlled trial including
24 patients who had undergone a tracheostomy was
656.e4 V. Srinivasan et al.
performed [35]. Oral melatonin (10 mg) or placebo was
administered at 9:00 PM for 4 nights. Nocturnal sleep was
evaluated using the bispectral index (a signal-processing
electroencephalographic technique). Actigraphy and subjec-
tive assessment of sleep were also used. Nocturnal sleep time
was 2.5 hours in the placebo group, and melatonin use was
associated with a 1-hour increase in nocturnal sleep [35].
Based on the supraphysiologic melatonin levels detected in
plasma at the end of the night, the authors concluded that a
lower amount of melatonin (1-2 mg) would probably be
enough to improve sleep. However, amounts of melatonin in
the 10-mg range or higher should be needed to warrant the
effect on reduction of ischemic reperfusion injury, preven-
tion of multiorgan failure, or treatment of sepsis.
From a different perspective, namely, to curtail oxidative
stress, a number of clinical studies performed by Gitto and
coworkers [36] have shown that melatonin reduces oxidative
stress in newborns with sepsis, distress, or other conditions
where there is excessive ROS production. In the first of these
studies, a product of lipid peroxidation, MDA, and the nitrite/
nitrate levels were measured in the serum of 20 asphyxiated
newborns before and after treatment with melatonin given
within the first 6 hours of life. Ten asphyxiated newborns
received a total of 80 mg of melatonin (8 doses of 10 mg each
separated by 2-hour intervals) orally. One blood sample was
collected before melatonin administration, and 2 additional
blood samples (at 12 and 24 hours) were collected after
giving melatonin. Serum MDA and nitrite/nitrate concentra-
tions in newborns with asphyxia before treatment were
significantly higher than those in infants without asphyxia. In
the asphyxiated newborns given melatonin, there were
significant reductions in MDA and nitrite/nitrate levels.
Three of the 10 asphyxiated children not given melatonin
died within 72 hours after birth; none of the 10 asphyxiated
newborns given melatonin died [36].
In a second study, a total of 20 mg melatonin was
administered orally in 2 doses of 10 mg each with a 1-hour
interval. The changes in the clinical status and the serum
levels of the lipid peroxidation products MDA and 4-HDA
were recorded in 10 septic newborns treated with the
antioxidant melatonin given within the first 12 hours after
diagnosis. Ten other septic newborns in a comparable state
were used as septiccontrols, whereas 10 healthy newborns
served as normal controls. Serum MDA + 4-HDA concen-
trations in newborns with sepsis were significantly higher
than those in healthy infants without sepsis, and they were
significantly reduced by melatonin. Melatonin also improved
the clinical outcome of the septic newborns as judged by
measurement of sepsis-related serum parameters after 24 and
48 hours [36].
Gitto et al also examined whether melatonin treatment
would lower IL-6, IL-8, TNF-α, and nitrite/nitrate levels in
24 newborns with respiratory distress syndrome grade III or
IV diagnosed within the first 6 hours of life. Compared with
the melatonin-treated respiratory distress syndrome
newborns, in the untreated infants, the concentrations of
IL-6, IL-8, and TNF-αwere significantly higher at 24 hours,
72 hours, and 7 days after onset of the study. In addition,
nitrite/nitrate levels at all time points were higher in the
untreated respiratory distress syndrome newborns than in the
melatonin-treated babies. After melatonin administration,
nitrite/nitrate levels decreased significantly, whereas they
remained high and increased further in the respiratory
distress syndrome infants not given melatonin.
Proinflammatory cytokines (IL-6, IL-8, and TNF-α) and
the clinical status were examined in 110 preterm newborns
with respiratory distress syndrome ventilated before and after
treatment with melatonin. When comparing serum levels of
IL-6, IL-8, and TNF-αfor 2 groups, melatonin treatment
clearly had anti-inflammatory effects [36]. In conclusion,
these studies indicate that melatonin lowers IL-IL-6, IL-8,
TNF-α, and nitrite/nitrate levels and modifies serum
inflammatory parameters in surgical neonates, improving
their clinical course.
5. Conclusion
Active research continues to define the principal altera-
tions in sepsis, although significant challenges remain before
this devastating process is understood and conquered.
Melatonin has entered this arena because it has a promise
as an appropriate add-on pharmacologic tool in sepsis.
Although understanding of melatonin's action in the
pathogenesis of septic shock is yet to be achieved, studies
so far point out that melatonin, through its immunomodu-
latory, antioxidant, and antiapoptotic actions, may exert
beneficial effects in septic shock and multiorgan failure.
However, larger randomized controlled clinical trials are
necessary to confirm the potential benefits of melatonin
therapy before it can be routinely used in the postoperative or
critically ill patients [37].
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.jcrc.2010.03.006.
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656.e6 V. Srinivasan et al.
... Much research has considered melatonin as an anti-inflammatory agent, and here, we will mention some cases that are important for evaluating the immune-pineal axis [66,67]. In septic shock induced by LPS, melatonin reduces TNF, IL-12, and IFN-γ at the site of injection, and increased IL-10 both at the site of injection and in the plasma [68]. ...
... Its receptor-dependent actions are mediated by the G-protein coupled receptors MT1 and MT2 as well as the putative receptor MT3, which has been identified as the enzyme quinone reductase 2141516. Up to now, the protective effects of MLT during sepsis or endotoxaemia have primarily been attributed to its antiinflammatory and antioxidative action [17]. Only one clinical trial with septic newborns has studied the beneficial effect of MLT treatment in humans, but the emphasis was on survival rate and antioxidative efficacy [18]. ...
Introduction: Inhibitory effects of exogenous melatonin (MLT) on plasma coagulation and platelet aggregation have already been observed in vivo and in vitro under normal conditions. Here, we studied whether MLT also diminishes the lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) during subacute endotoxaemia. Materials and methods: Subacute endotoxaemia was induced in male Wistar rats by an intravenous infusion of LPS over a period of 300min (0.5mg LPS/kg×h). MLT was administered intravenously 15min before and 120min and 240min after starting of the LPS infusion (3×3mg MLT/kg×15min). The kinetic of clot formation was analysed by thromboelastometry. Results: Infusion of LPS led initially to a significant reduction of clotting time (120min, LPS: 150±21s vs. SHAM: 292±36s), and finally a significant increase of clotting time (300min, LPS: 2768±853s vs. SHAM: 299±67s) and a slight increase of clot formation time (300min, LPS: 1038±657s vs. SHAM: 98±14s) as well as a significant decrease of alpha-angle (300min, LPS: 35±15° vs. SHAM: 72±3°), maximum clot firmness (300min, LPS: 22±6mm vs. SHAM: 68±3mm), and area under the curve (300min, LPS: 1657±552mm×100 vs. SHAM: 6849±307mm×100). Simultaneously, a decrease of platelet count (300min, LPS: 55±8 vs. SHAM: 180±55) and a release of cell-free haemoglobin (240min, LPS: 46±5μmol/L vs. SHAM: 16±2μmol/L) could be observed in the course of subacute endotoxaemia. The additional administration of MLT did not reduce the LPS-induced alterations in parameters of thromboelastometry, but significantly reduced the LPS-induced decrease of platelet count (300min, LPS+MLT: 130±10) and release of cell-free haemoglobin (240min, LPS+MLT: 29±3μmol/L). Conclusion: Melatonin does not affect DIC but diminishes thrombocytopenia and haemolysis during endotoxaemia.
... These include various cases in which there is no reason to assume dysfunction of the SCN. In particular, such reductions have been found to accompany several stressful or painful conditions, such as Menièreʼs disease [374], fibromyalgia and neuralgia [375], migraines [376,377], heart diseases378379380381382383384, critical illness [109,385,386] and cases of cancer [387,388], in which the contribution of stress and pain has remained unclear, as well as in some metabolic diseases, such as acute intermittent porphyria [389,390], and notably, diabetes type 2 [391,392]. In some neurological disorders, decreases in melatonin are only observed in subpopulations of affected individuals or in a very limited number of subjects studied [364]. ...
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Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.
... These findings suggest that the development of modulators of the antioxidant/oxidant state could be used as a new class of drugs for the treatment of severe sepsis; however, more research is necessary to demonstrate these potential benefits. On the other hand, melatonin has been found to play an important role in various functions of the body, including immunoregulation, free radical scavenging, as well as having antioxidant and anti-apoptotic effects2728293031 . It is, therefore, not possible to conclude whether the potential benefits of melatonin are due to its antioxidant effect or due to the combination of all its effects. ...
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There is a hyperoxidative state in sepsis. The objective of this study was to determine serum malondialdehyde (MDA) levels during the first week of follow up, whether such levels are associated with severity during the first week and whether non-surviving patients showed higher MDA levels than survivors during the first week. We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in 328 patients (215 survivors and 113 non-survivors) with severe sepsis at days one, four and eight of diagnosis, and in 100 healthy controls. The primary endpoint was 30-day mortality and the secondary endpoint was six-month mortality. The association between continuous variables was carried out using Spearman's rank correlation coefficient. Cox regression analysis was applied to determine the independent contribution of serum MDA levels on the prediction of 30-day and 6-month mortality. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated as measures of the clinical impact of the predictor variables. We found higher serum MDA in septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001) of diagnosis than in healthy controls. Serum MDA was higher in surviving than non-surviving septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001). Serum MDA levels were positively correlated with lactic acid and SOFA during the first week. Finally, serum MDA levels were associated with 30-day mortality (HR = 1.05; 95% CI = 1.02-1.09; p = 0.005) and six-month mortality (hazard ratio (HR) = 1.05; 95% CI = 1.02-1.09; p = 0.003) after controlling for lactic acid levels, acute physiology and chronic health evaluation (APACHE)-II, diabetes mellitus, bloodstream infection and chronic renal failure. To our knowledge, this is the largest series providing data on the oxidative state in septic patients to date. The novel finding is that high serum MDA levels sustained throughout the first week of follow up were associated with severity and mortality in septic patients.
Background We assessed the potential impact of a high dose of melatonin treatment in patients with early septic shock.Methods Forty patients with early septic shock were randomly allocated to the melatonin or placebo groups. Besides standard-of-care treatment, melatonin and placebo were administered at a dose of 50 mg for five consecutive nights. The efficacy outcomes were severity of organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score, the number of patients requiring mechanical ventilation and ventilator-free days, the mean required vasopressor dose and vasopressor-free days, and 28 days all-cause mortality.ResultsAfter 5-day treatment, the mean SOFA scores decreased 4.05 ± 4.75 score in the melatonin group and 2.25 ± 4.87 in the placebo group. On day 28, 60% of the melatonin-treated patients and 35% of the placebo-treated patients had a SOFA score below six. Thirteen cases in the placebo group and nine cases in the melatonin group required mechanical ventilation; however, there was no statistically significant difference between the groups regarding these outcomes. The melatonin-treated patients had more ventilator-free days than placebo-treated patients over the 28-day (16.90 ± 9.24 vs. 10.00 ± 10.94; p value = 0.035). The mean reduction in the required dose of vasopressor was 6.2 ± 5.12 in the melatonin-treated patients compared to 3.20 ± 3.95 in the placebo-treated patients (p value = 0.045). Vasopressor-free days in the melatonin-treated group were also significantly more than the placebo-treated group (12.75 ± 7.43 days vs. 10.15 ± 6.12 days; p value = 0.046).Conclusions Our pilot study supported the potential benefits of melatonin in treating septic shock. Further clinical evidence is required for expanding and confirming these findings.Trial registrationThe trial was registered at (ID code: IRCT20120215009014N296). Registration date: 15/09/2019.
Melatonin is involved in regulation of a variety of physiologic functions, including circadian rhythm, reproduction, mood, and immune function. Exogenous melatonin has demonstrated many clinical effects. Numerous clinical studies have documented improved sleep quality following administration of exogenous melatonin. Recent studies also demonstrate the analgesic, anxiolytic, antiinflammatory, and antioxidative effects of melatonin. This article reviews the principal properties of melatonin and how these could find clinical applications in care of the critically ill patients.
Melatonin (N-acetyl-5-methoxytryptamine) is an endogenously produced indoleamine secreted by pineal gland. Melatonin has the ability to scavenge free radicals and chelate metals, and antioxidant property. This chapter discusses the utility of melatonin in pediatric practice, with an emphasis on (1) the structure and function of melatonin; (2) the ability of melatonin against oxidative stress; (3) current use of melatonin in different pediatric disorders; and (4) current problems and new perspectives in melatonin uses in pediatric medicine.
Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30–45 min and a t ½elimination of 45 min are well established. Several questions relate to what constitutes a clinically effective plasma concentration, the choice of ideal administration route, and the optimal method of analysis. Furthermore, investigations of melatonin metabolites in humans are urgently needed in order to characterize their biological functions and the metabolic fates of these derivatives. Finally, pharmacokinetics in patients should be investigated further in order to reduce the risk of potential adverse effects, such as daytime sleepiness or unintended sedation.
Melatonin has been demonstrated to improve survival after experimental sepsis via antioxidant effects. Yet, recent evidence suggests that this protective capacity may also rely on melatonin receptor activation. Therefore, the present study was designed to investigate whether selective melatonin receptor-agonist ramelteon may influence survival and immune response in a model of polymicrobial sepsis in rats, wild-type and melatonin receptor MT1/MT2 double knockout mice. Prospective, randomized, controlled study. University research laboratory. Male Sprague-Dawley rats (200-250 g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20-22 g). Animals underwent cecal ligation and incision and remained anesthetized for evaluation of survival for 12 hours (rats: n = 15 per group) or 15 hours (mice: n = 10 per group). Analysis of immune response by means of enzyme-linked immunosorbent assay was performed before and 5 hours after cecal ligation and incision (rats only; n = 5 per group). After induction of sepsis, animals were treated IV with vehicle, different doses of melatonin (rats: 0.01/0.1/1.0/10 mg/kg; mice: 1.0 mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0 mg/kg). Sham controls underwent laparotomy but not cecal ligation and incision. Compared with vehicle, administration of ramelteon or melatonin significantly improved median survival time in rats (sepsis/melatonin [0.1 mg/kg], 554 min, [1.0 mg/kg] 570 min, [10 mg/kg] 579 min; sepsis/ramelteon, 468 min; each p < 0.001 vs sepsis/vehicle, 303 min) and wild-type mice (sepsis/melatonin, 781 min; sepsis/ramelteon, 701 min; both p < 0.001 vs sepsis/vehicle, 435 min). This effect was completely antagonized by coadministration of luzindole in all groups. Melatonin, ramelteon, or luzindole had no significant effect on survival time in knockout mice. Significantly elevated concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-10 were observed 5 hours after cecal ligation and incision in rats (p < 0.05 vs baseline and corresponding sham); neither ramelteon nor melatonin treatment significantly affected immune response. Melatonin receptors mediate improvements of survival after polymicrobial sepsis in rats and mice; this effect appears to be independent from major alterations of cytokine release.
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The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.
The pineal secretory product melatonin was found to exert protective effects in septic shock. In a host infected by bacterial lipopolysaccharide (LPS), the expression and release of proinflammatory tumor necrosis factor-alpha (TNF-alpha) is rapidly increased, suggesting that TNF-alpha is associated with the etiology of endotoxic shock. Recent reports show that the expression of NO synthase (NOS) II and the production of superoxide anion (O2*-) also contribute to the pathophysiology of septic shock. In the present study we demonstrate that melatonin prevents circulatory failure in rats with endotoxemia and improves survival in mice treated with a lethal dose of LPS. The beneficial hemodynamic effects of melatonin in the endotoxemic animal appear to be associated with the inhibition of (i) the release of TNF-alpha in plasma, (ii) the expression of NOS II in liver, and (iii) the production of O2*- in aortae. In addition, the infiltration of polymorphonuclear neutrophils into the liver from the surviving LPS mice treated with melatonin was reduced. Thus, our results support the clinical use of melatonin in endotoxemia.
Sepsis is a major cause of mortality in critically ill patients and develops as a result of the host response to infection. In recent years, important advances have been made in understanding the pathophysiology and treatment of sepsis. Mitochondria play a central role in the intracellular events associated with inflammation and septic shock. One of the current hypotheses for the molecular mechanisms of sepsis is that the enhanced nitric oxide (NO) production by mitochondrial nitric oxide synthase (mtNOS) leads to excessive peroxynitrite (ONOO−) production and protein nitration, impairing mitochondrial function. Despite the advances in understanding of its pathophysiology, therapy for septic shock remains largely symptomatic and supportive. Melatonin has well documented protective effects against the symptoms of severe sepsis/shock in both animals and in humans; its use for this condition significantly improves survival. Melatonin administration counteracts mtNOS induction and respiratory chain failure, restores cellular and mitochondrial redox status, and reduces proinflammatory cytokines. Melatonin clearly prevents multiple organ failure, circulatory failure, and mitochondrial damage in experimental sepsis, and reduces lipid peroxidation, indices of inflammation and mortality in septic human newborns. Considering these effects of melatonin and its virtual absence of toxicity, the use of melatonin (along with conventional therapy) to preserve mitochondrial bioenergetics as well as to limit inflammatory responses and oxidative damage should be seriously considered as a treatment option in both septic newborn and adult patients. This review summarizes the data that provides a rationale for using melatonin in septic shock patients.
The aim of the present study was to investigate the protective effect of the pineal hormone melatonin in a model of acute local inflammation (zymosan-activated plasma-induced paw oedema), in which oxyradicals, nitric oxide (NO) and peroxynitrite are known to play a crucial role in the inflammatory process. The intraplantar injection of zymosan-activated plasma elicited an inflammatory response that was characterized by a time-dependent increase in paw oedema, neutrophil infiltration and increased levels of nitrite/nitrate in the paw exudate. The maximal increase in paw volume was observed at 3 h after administration (maximal in paw volume: 1.34±0.09 ml). At this time point, myeloperoxidase activity and lipid peroxidation were markedly increased in the zymosan-activated plasma-treated paw (226±10.2 mU/100 mg wet tissue, 31±2.1 mM/mg wet tissue, respectively). However, zymosan-activated plasma-induced paw oedema was significantly reduced in a dose-dependent manner by treatment with melatonin (given at 62.5 and 125 μg/paw) at 1, 2, 3, 4 h after injection of zymosan-activated plasma. Melatonin treatment also caused a significant reduction of the myeloperoxidase activity and lipid peroxidation and inhibited nitrite/nitrate levels in the paw exudate. The paw tissues were also examined immunohistochemically for the presence of nitrotyrosine (a marker of peroxynitrite formation). At 3 h following injection of zymosan-activated plasma, staining for nitrotyrosine was also found to be localised in the inflamed paw tissue. Treatment with melatonin (125 μg/paw) reduced the appearance of nitrotyrosine in the tissues. Our findings support the view that melatonin exerts anti-inflammatory effects.
Several research papers published in Critical Care throughout 2007 examined the pathogenesis, diagnosis, treatment and prognosis of sepsis and multiorgan failure. The present review summarizes the findings and implications of the papers published on sepsis and multiorgan failure and places the research in the context of other work in the field.
Malaria, which infects more than 300 million people annually, is a serious disease. Epidemiological surveys indicate that of those who are affected, malaria will claim the lives of more than one million individuals, mostly children. There is evidence that the synchronous maturation of Plasmodium falciparum, the parasite that causes a severe form of malaria in humans and Plasmodium chabaudi, responsible for rodent malaria, could be linked to circadian changes in melatonin concentration. In vitro melatonin stimulates the growth and development of P. falciparum through the activation of specific melatonin receptors coupled to phospholipase-C activation and the concomitant increase of intracellular Ca2+. The Ca2+ signaling pathway is important to stimulate parasite transition from the trophozoite to the schizont stage, the final stage of intraerythrocytic cycle, thus promoting the rise of parasitemia. Either pinealectomy or the administration of the melatonin receptor blocking agent luzindole desynchronizes the parasitic cell cycle. Therefore, the use of melatonin antagonists could be a novel therapeutic approach for controlling the disease. On the other hand, the complexity of melatonin's action in malaria is underscored by the demonstration that treatment with high doses of melatonin is actually beneficial for inhibiting apoptosis and liver damage resulting from the oxidative stress in malaria. The possibility that the coordinated administration of melatonin antagonists (to impair the melatonin signal that synchronizes P. falciparum) and of melatonin in doses high enough to decrease oxidative damage could be a novel approach in malaria treatment is discussed.
The term 'multiorgan failure' (MOF) carries the negative connotation of major homeostatic breakdown and severe malfunction. However, this traditional paradigm may not be necessarily accurate. This review will investigate the rationale for no longer considering MOF to be simply a 'failed' pathophysiological state. Multiorgan failure is characterized by a hypometabolic, immunodepressed state with clinical and biochemical evidence of decreased functioning of the body's organ systems. Notwithstanding these findings, evidence for cell death is scarce and organ recovery is frequently the rule in surviving patients without pre-existing organ disease. Decreased mitochondrial activity appears to play a key role in the processes underlying MOF, both as a victim and a player. Reduced ATP production will compromise normal metabolic functioning. To protect itself from dying, the cell may adapt by decreasing its metabolic rate, and this is clinically manifest as organ dysfunction. Mitochondrial modulation may thus represent an important therapeutic target. The concept of MOF could be revisited as a transient state of metabolic shutdown analogous to hibernation. Avoiding the detrimental effects of inappropriate and counter-adaptive iatrogenic interventions is an important cornerstone of therapeutic management.
Treatment with melatonin significantly reduces lung injury induced by bleomycin, paraquat and ischemia reperfusion. In the present study, we investigated the possible protective roles of melatonin in pulmonary inflammation and lung injury during acute endotoxemia. Thirty-two male Sprague-Dawley rats were randomly assigned to four groups: vehicle + saline group, melatonin + saline group, vehicle + lipopolysaccharide group, melatonin + lipopolysaccharide group. The rats were treated with melatonin (10 mg/kg, intraperitoneal injection (i.p.)) or vehicle (1% ethanol saline), 30 minutes prior to lipopolysaccharide administration (6 mg/kg, intravenous injection). Four hours after lipopolysaccharide injection, samples of pulmonary tissue were collected. Blood gas analysis was carried out. Optical microscopy was performed to examine pathological changes in lungs and lung injury score was assessed. Wet/dry ratios (W/D), myeloperoxidase activity, malondialdehyde concentrations and tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels in lungs were measured. The pulmonary expression of nuclear factor-kappa B (NF-kappaB) p65 was evaluated by Western blotting. PaO(2) in the vehicle + lipopolysaccharide group decreased compared with that in the vehicle + saline group. This decrease was significantly reduced in the melatonin + lipopolysaccharide group. The lung tissues from the saline + lipopolysaccharide group were significantly damaged, which were less pronounced in the melatonin + lipopolysaccharide group. The W/D ratio increased significantly in the vehicle + lipopolysaccharide group (6.1 +/- 0.18) as compared with that in the vehicle + saline group (3.61 +/- 0.3) (P < 0.01), which was significantly reduced in the melatonin + lipopolysaccharide group (4.8 +/- 0.25) (P < 0.01). Myeloperoxidase activity and malondialdehyde levels increased significantly in the vehicle + lipopolysaccharide group compared with that in the vehicle + saline group, which was reduced in the melatonin + lipopolysaccharide group. The TNF-alpha level of pulmonary tissue increased significantly in the vehicle + lipopolysaccharide group ((8.7 +/- 0.91) pg/mg protein) compared with that in the vehicle + saline group ((4.3 +/- 0.62) pg/mg protein, P < 0.01). However, the increase of TNF-alpha level of pulmonary tissue was significantly reduced in the melatonin + lipopolysaccharide group ((5.9 +/- 0.56) pg/mg protein, P < 0.01). Pulmonary IL-10 levels were elevated markedly in the vehicle + lipopolysaccharide group in contrast to that in the vehicle + saline group, whereas the elevation was augmented in the melatonin + lipopolysaccharide group. The nuclear localization of p65 increased markedly in the vehicle + lipopolysaccharide group and this enhancement of nuclear p65 expression was much less in the melatonin + lipopolysaccharide group. Melatonin reduces acute lung injury in endotoxemic rats by attenuating pulmonary inflammation and inhibiting NF-kappaB activation.