Maria D. Maldonado

The role of melatonin in the cells of the innate immunity: a review.

Melatonin is the major secretory product synthesized and secreted by the pineal gland and shows both a wide distribution within phylogenetically distant organisms from bacteria to humans and a great functional versatility. In recent years, a considerable amount of experimental evidence has accumulated showing a relationship between the nervous, endocrine, and immune systems. The molecular basis of the communication between these systems is the use of a common chemical language. In this framework, currently melatonin is considered one of the members of the neuroendocrine–immunological network. A number of in vivo and in vitro studies have documented that melatonin plays a fundamental role in neuroimmunomodulation. Based on the information published, it is clear that the majority of the present data in the literature relate to lymphocytes; thus, they have been rather thoroughly investigated, and several reviews have been published related to the mechanisms of action and the effects of melatonin on lymphocytes. However, few studies concerning the effects of melatonin on cells belonging to the innate immunity have been reported. Innate immunity provides the early line of defense against microbes and consists of both cellular and biochemical mechanisms. In this review, we have focused on the role of melatonin in the innate immunity. More specifically, we summarize the effects and action mechanisms of melatonin in the different cells that belong to or participate in the innate immunity, such as monocytes–macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, and natural killer cells.

The potential of melatonin in reducing morbidity-mortality after craniocerebral trauma

Abstract:  Craniocerebral trauma (CCT) is the most frequent cause of morbidity–mortality as a result of an accident. The probable origins and etiologies are multifactorial and include free radical formation and oxidative stress, the suppression of nonspecific resistance, lymphocytopenia (disorder in the adhesion and activation of cells), opportunistic infections, regional macro and microcirculatory alterations, disruptive sleep–wake cycles and toxicity caused by therapeutic agents. These pathogenic factors contribute to the unfavorable development of clinical symptoms as the disease progresses. Melatonin (N‐acetyl‐5‐methoxytryptamine) is an indoleamine endogenously produced in the pineal gland and in other organs and it is protective agent against damage following CCT. Some of the actions of melatonin that support its pharmacological use after CCT include its role as a scavenger of both oxygen and nitrogen‐based reactants, stimulation of the activities of a variety of antioxidative enzymes (e.g. superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase), inhibition of pro‐inflammatory cytokines and activation–adhesion molecules which consequently reduces lymphocytopenia and infections by opportunistic organisms. The chronobiotic capacity of melatonin may also reset the natural circadian rhythm of sleep and wakefulness. Melatonin reduces the toxicity of the drugs used in the treatment of CCT and increases their efficacy. Finally, melatonin crosses the blood–brain barrier and reduces contusion volume and stabilizes cellular membranes preventing vasospasm and apoptosis of endothelial cells that occurs as a result of CCT.

Melatonin as an antioxidant: Physiology versus pharmacology

Despite more than 1000 scientific publications (more than 50% of which were performed in vivo) documenting that melatonin reduces free radical damage, in the last decade there are small number of reports that claim that melatonin is not an antioxidant because it must be given in what is referred to as pharmacological doses to abate the molecular destruction associated with toxic reactants. A recent paper from Wurtman [1] argued this point. Making this statement indicates that the author either is unfamiliar with or ignored the published literature. In fact, even under extremely intensive oxidative stress conditions, surgical removal of the pineal gland, which reduces physiological circulating melatonin levels and renders animals somewhat melatonin deficient, exaggerates the degree of free radicalmediated molecular destruction and tissue loss. Furthermore, there is also evidence that endogenous concentrations of melatonin limit the amount of molecular destruction that occurs [2, 3]. Thus, even physiological levels of melatonin normally combat some free radical damage [4–6]. So the statement that physiological levels of melatonin are inconsequential in resisting oxidative damage may be erroneous. Wurtman [1] goes on to claim that for exogenously administered melatonin to have antioxidative actions, it must be given in doses that increase blood concentrations up to 100,000-fold above physiological levels. While the amounts of melatonin often given unquestionably cause much higher than physiological levels in blood, these values may not be as exaggerated relative to melatonin levels in some bodily fluids or within cells [7]. By claiming the doses used cause such high levels, the author implies that melatonin concentrations throughout the body are in equilibrium and equivalent to those in blood. Maximal blood concentrations are normally in the low nanomolar range. In some bodily fluids, e.g. bile [8] and cerebrospinal fluid (CSF) [9], measured melatonin concentrations are orders of magnitude greater than in the circulation; this may also be true for some other bodily fluids. Furthermore, melatonin concentrations within cells (especially those that produce melatonin for their own use, e.g. gut, retina, skin, some bone marrow cells, etc.), are also very likely significantly greater than in blood. Until melatonin concentrations are, in fact, known for all bodily fluids and subcellular organelles [7], the statement that melatonin doses >0.3 mg cause pharmacological elevations in humans may be wrong when referring these levels to those in the CSF and bile (and subcellular organelles). Admittedly, the amounts of melatonin given do normally cause melatonin levels to exceed physiological concentrations in blood; however, for other fluids, cells and subcellular organelles this statement may be invalid. Finally, the expectation that physiological concentrations of melatonin (or any antioxidant) could overcome the massive free radical destruction that occurs under severe oxidative stress conditions, e.g. during ischaemia/reperfusion injury, is naı̈ve. The reason that so much molecular damage and cellular death occurs under these extreme conditions is that all physiological antioxidants combined, i.e. b-carotene, vitamin E, vitamin C, melatonin, glutathione, uric acid, antioxidative enzymes, etc. are incapable of resisting the tissue destruction that accompanies these damaging episodes. Thus, any antioxidant used to effectively reduce free radical damage under such severe conditions must be administered in pharmacological doses. Wurtman [1] also states that melatonin’s efficacy as an antioxidant has not been satisfactorily compared with vitamin C or E in terms of their relative antioxidative capacities. Melatonin has been compared in a number of reports to the classic vitamin antioxidants, and in virtually all these studies it was either equivalently effective and, in many reports, more effective in subduing free radical-based molecular damage [10–12]. Considering the low toxicity of melatonin and the fact that it has been effectively used to reduce free radical damage and prevent death in human newborns with high free radical-related conditions [13, 14], should make it of extreme clinical interest. Many conditions under which massive free radical damage is conspicuous are of short duration, e.g. stroke, heart attack, septic shock, etc. so the interval of melatonin administration would also be of short duration and the presumptive long-term effects, if there are any, of its use would not be a consideration. In summary, melatonin has antioxidant capability at both physiological and pharmacological levels and it should not be overlooked as a protective agent against free radical damage. As a matter of semantics, an author may dispute the specific term antioxidant when applied to melatonin, but cannot deny its ability to reduce free radical damage. Total length limitations of this article prevented the authors from citing all of the germane literature; further published reports can be found by doing the appropriate searches.

Protective effects of melatonin in experimental free radical-related ocular diseases

Abstract:  Melatonin (N‐acetyl‐5‐methoxytryptamine) is an indoleamine with a range of antioxidative properties. Melatonin is endogenously produced in the eye and in other organs. Current evidence suggests that melatonin may act as a protective agent in ocular conditions such as photo‐keratitis, cataract, glaucoma, retinopathy of prematurity and ischemia/reperfusion injury. These diseases are sight‐threatening and they currently remain, for the most part, untreatable. The pathogenesis of these conditions is not entirely clear but oxidative stress has been proposed as one of the causative factors. Elevated levels of various reactive oxygen and nitrogen species have been identified in diseased ocular structures. These reactants damage the structure and deplete the eye of natural defense systems, such as the antioxidant, reduced glutathione, and the antioxidant enzyme superoxide dismutase. Oxidative damage in the eye leads to apoptotic degeneration of retinal neurons and fluid accumulation. Retinal degeneration decreases visual sensitivity and even a small change in the fluid content of the cornea and crystalline lens is sufficient to disrupt ocular transparency. In the eye, melatonin is produced in the retina and in the ciliary body. Continuous regeneration of melatonin in the eye offers a frontier antioxidative defense for both the anterior and posterior eye. However, melatonin production is minimal in newborns and its production gradually wanes in aging individuals as indicated by the large drop in circulating blood concentrations of the indoleamine. These individuals are possibly at risk of contracting degenerative eye diseases that are free radical‐based. Supplementation with melatonin, a potent antioxidant, in especially the aged population should be considered as a prophylaxis to preserve visual functions. It may benefit many individuals worldwide, especially in countries where access to medical facilities is limited.

Pharmacological utility of melatonin in the treatment of septic shock: Experimental and clinical evidence

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.

Melatonin present in beer contributes to increase the levels of melatonin and antioxidant capacity of the human serum.

BACKGROUND & AIM Melatonin is a molecule with antioxidative properties including direct free radical scavenging and indirect stimulatory actions on a variety of antioxidative enzymes which further promote its ability to reduce the toxicity of radicals and their associated reactants. Beer is an integral element of the diet of numerous people and is rich in antioxidants. We analyzed if melatonin is present in beer and if so, at what concentration. It further determines whether the moderate consumption of beer has an effect on the total antioxidant status (TAS) of human serum. METHODS We analyzed 18 brands of beer with different percentage of alcohol content in order to determine the concentration of melatonin. Serum samples were collected from 7 healthy volunteers. These samples were used to measure melatonin and TAS on basal conditions and after drinking beer. RESULTS Showed that all the beer analyzed did indeed contain melatonin and the more they have got, the greater was its degree of alcohol. Both melatonin and TAS in human serum increased after drinking beer. CONCLUSIONS Melatonin present in the beer does contribute to the total antioxidative capability of human serum and moderate beer consumption can protect organism from overall oxidative stress.

Chronic melatonin treatment prevents age-dependent cardiac mitochondrial dysfunction in senescence-accelerated mice

Heart mitochondria from female senescence-accelerated (SAMP8) and senescence-resistant (SAMR1) mice of 5 or 10 months of age, were studied. Mitochondrial oxidative stress was determined by measuring the levels of lipid peroxidation, glutathione and glutathione disulfide and glutathione peroxidase and reductase activities. Mitochondrial function was assessed by measuring the activity of the respiratory chain complexes and ATP content. The results show that the age-dependent mitochondrial oxidative damage in the heart of SAMP8 mice was accompanied by a reduction in the electron transport chain complex activities and in ATP levels. Chronic melatonin administration between 1 and 10 months of age normalized the redox and the bioenergetic status of the mitochondria and increased ATP levels. The results support the presence of significant mitochondrial oxidative stress in SAM mice at 10 months of age, and they suggest a beneficial effect of chronic pharmacological intervention with melatonin, which reduces the deteriorative and functional oxidative changes in cardiac mitochondria with age.

Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation

Mast cells take part of armamentarium immunologic for host defense against parasitic and bacterial infections. They are derived from bone marrow progenitors and can be activated by immunological and chemical stimuli in order to get its degranulation. The activation of mast cells generates a signalling cascade leaded to the rapid release of vasoactives and pro-inflammatory mediators. Melatonin (N-acetyl-5-methoxytryptamine) is a molecule with antioxidant, cytoprotective and immunomodulatory actions. It was initially known to be produced exclusively in the pineal gland but melatonin synthesis has been found in different sites of the organism, and a major source of extrapineal melatonin is the immune system. The aim of the present study was to prove if the rat mast cell line (RBL-2H3) synthesizes and releases melatonin, also to explain its possible mechanism of action. We report that both resting and stimulated mast cells synthesize and release melatonin. We also report that the necessary machinery to synthesize melatonin is present in mast cells and that these cells showed the presence of MT1 and MT2 melatonin membrane receptors. Those results indicated that the melatonin would be able to exert a regulatory effect on inflammatory reactions mediated by mast cells.

Melatonin as pharmacologic support in burn patients: A proposed solution to thermal injury-related lymphocytopenia and oxidative damage

Objective:To review the data that support the clinical use of melatonin in the treatment of burn patients, with special emphasis on the stimulation of the oxidative defense system, the immune system, circadian rhythm of sleep/wakefulness, and the reduction in the toxicity of therapeutic agents used in the treatment of burn victims. Data Source:A MEDLINE/PubMed search from 1975 to July 2006 was conducted. Study Selection:The screening of the literature was examined using the key words: burn patients, lymphocytopenia, skin oxidative stress, antioxidant, melatonin, and free radicals. Data Extraction and Synthesis:Thermal injury often causes damage to multiple organs remote from the original burn wound and may lead to multiple organ failure. Animal models and burn patients exhibit elevated free radical generation that may be causative in the local wound response and in the development of burn shock and distant organ injury. The suppression of nonspecific resistance and the disturbance in the adaptive immune system makes burn patients vulnerable to infections. Moreover, there is loss of sleep and the toxicity produced by drugs habitually used in the clinic for burn patients. Melatonin is a powerful antioxidant and is a potent protective agent against damage after experimental thermal injury. Some actions of melatonin as a potential supportive pharmacologic agent in burn patients include its: role as a scavenger of both oxygen and nitrogen-based reactants, stimulation of the activities of a variety of antioxidative enzymes, reduction in proinflammatory cytokines, inhibition of adhesion molecules, chronobiotic effects, and reduction in the toxicity of the drugs used in protocols to treat thermal injury patients. Conclusions:These combined actions of melatonin, along with its low toxicity and its ability to penetrate all morphophysiologic membranes, could make it a ubiquitously acting and highly beneficial molecule in burn patients.

Melatonin as a potential therapeutic agent in psychiatric illness

The aim of this review was to summarize the potential use of melatonin in the treatment of mental disorders, specifically bipolar disorders, depression, and schizophrenia. To date, melatonin has been most commonly used in psychiatry because of its hypnotic, rhythm resynchronizing, and antioxidant actions. Here, we examine other properties of the melatonin including its anti‐inflammatory, antinociceptive, anxiolytic, and drug detoxification actions as well as its protective effects against neural loss. The brain is an intricate sensory and motor organ which receives information from both the external and internal environments. It transduces information into complex chemical and electrical signals which are transmitted throughout the central nervous system (CNS) and the organism. The pathogenesis of mental disorders remains ambiguous and neuroinflammation has been proposed as a causative agent. We consider the potential contributions of melatonin as therapeutic agent in CNS and during neuroinflammation in mental disorders. Copyright