Melatonin in septic shock: Some recent concepts☆
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 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)–α and 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.
Section snippets
Melatonin in lipopolysaccharide-induced inflammation
The first evidence for melatonin in controlling lipopolysaccharide (LPS)-induced damage was provided by Sewerynek and coworkers [6] in rats. They reported a reduction in LPS-induced oxidative insult after melatonin administration, as evidenced by decreased hepatic malondialdehyde (MDA) and 4-hydroxyalkenal (4-HDA) [6].
Melatonin prevents LPS-induced endotoxemia presumably by reducing circulating TNF-α levels, superoxide production in the aorta, and iNOS in the liver [7]. Melatonin (10-60 mg/kg)
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,
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
Conclusion
Active research continues to define the principal alterations 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 immunomodulatory, antioxidant, and antiapoptotic
References (37)
- et al.
Lipopolysaccharide-induced hepatotoxicity is inhibited by the antioxidant melatonin
Eur J Pharmacol
(1995) - et al.
Age-dependent lipopolysaccharide-induced iNOS expression and multiorgan failure in rats: effects of melatonin treatment
Exp Gerontol
(2006) - et al.
Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages
J Neuroimmunol
(2005) - et al.
Protective effects of melatonin in zymosan-activated plasma-induced paw inflammation
Eur J Pharmacol
(1998) - et al.
Melatonin administration following hemorrhagic shock decreases mortality from subsequent septic challenge
J Surg Res
(1996) - et al.
The pineal gland hormone melatonin improves survival in a rat model of sepsis/shock induced by zymosan A
Surgery
(2003) - et al.
Nitric oxide, complex I, and the modulation of mitochondrial reactive species in biology and disease
Mol Aspects Med
(2004) - et al.
Melatonin treatment protects against diabetes-induced functional and biochemical changes in rat aorta and corpus cavernosum
Eur J Pharmacol
(2004) - et al.
Oxidative stress in relation to surgery: is there a role for the antioxidant melatonin?
J Surg Res
(2009) - et al.
Melatonin: nature's most versatile biological signal?
FEBS J
(2006)
Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin
Crit Rev Biochem Mol Biol
Malaria: therapeutic implications of melatonin
J Pineal Res
Is MOF an outcome parameter or a transient, adaptive state in critical illness?
Curr Opin Crit Care
Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence
J Pharm Pharmacol
Melatonin prevents endotoxin-induced circulatory failure in rats
J Pineal Res
Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats
FASEB J
Alterations of mitochondrial function in sepsis and critical illness
Curr Opin Anaesthesiol
Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats
FASEB J
Cited by (84)
Mitochondrial dysfunction in sepsis
2021, Mitochondrial Dysfunction and Nanotherapeutics: Aging, Diseases, and Nanotechnology-Related Strategies in Mitochondrial MedicineMitochondria and Critical Illness
2020, ChestCitation Excerpt :Melatonin has significant effects on inflammation, including an action to act as a scavenger for oxygen and nitrogen-derived reactive species (eg, superoxide, nitric oxide).115,118,119 In animal studies of sepsis (LPS and cecal ligation puncture induced), melatonin prevented mitochondrial structural damage, prevented mitochondrial complex I and IV inhibition, and improved mitochondrial generation of ATP.120,121 In another study, melatonin administration to newborns with sepsis produced lower concentrations of lipid peroxidation products.122
Melatonin in Critical Care
2019, Critical Care ClinicsCitation Excerpt :It is unknown whether physiologic levels of melatonin have sufficient direct antioxidant activity to attenuate the development or severity of sepsis; however, in vitro models show that melatonin and its major hydroxylated metabolite, 6-hydroxymelatonin, are both effective at reducing the levels of key inflammatory cytokines, oxidative stress, and mitochondrial dysfunction in sepsis.48 In animal models, melatonin has been identified as protective against bacterial, viral, and parasitic infections, presumably through a variety of immunomodulatory and antioxidant mechanisms.49 Melatonin is a powerful antioxidant that scavenges superoxide radicals, as well as other radical oxygen species (ROS) and radical nitrogen species, which gives rise to a cascade of metabolites that share its antioxidant properties.
Serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality
2018, Enfermedades Infecciosas y Microbiologia ClinicaCitation Excerpt :Melatonin is synthesized by the pineal gland (with a circadian rhythm with low values during the day and high values during the night); and also by other organs without circadian rhythm as thymus, retina, bone marrow, gastrointestinal tract, and lymphocytes.1 Melatonin has different effects as sleep regulation,2 and also antioxidant and anti-inflammatory effects, and preservation of mitochondrial function.3–11 Melatonin produces the upregulation of several antioxidant enzymes and is a potent scavenger of reactive oxygen species (ROS).
Exploring the role of antioxidants in sepsis-associated oxidative stress: a comprehensive review
2024, Frontiers in Cellular and Infection Microbiology
- ☆
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.