Elsevier

Journal of Critical Care

Volume 25, Issue 4, December 2010, Pages 656.e1-656.e6
Journal of Critical Care

Melatonin in septic shock: Some recent concepts

https://doi.org/10.1016/j.jcrc.2010.03.006Get rights and content

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.

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

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    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.

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