MELATONIN

Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels.

This chapter reviews the neural connections between the retinas and the pineal gland and summarizes the role of the light:dark cycle and the biological clock, i.e. the suprachiasmatic nuclei, in regulating pineal melatonin synthesis and secretion. The cellular mechanisms governing the nocturnal production of melatonin are described together with the way in which the misuse of light interferes with the circadian melatonin cycle and the total quantity of the indole generated.

Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, antiinflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5–3.2 billion years ago, was as an antioxidant.

The sleep-promoting effect of the pineal hormone melatonin in humans is known for decades. However, the mechanisms of this phenomenon remain obscure, mainly due to lack of a simple, genetically tractable, animal model. We now report that melatonin promotes sleep-like state in a diurnal lower vertebrate, zebrafish (Danio rerio), and this effect is mediated through activation of specific melatonin membrane receptors.

Clonazepam has been considered the treatment of choice for RBD. However, an alternative treatment is desirable for those with RBD refractory to clonazepam, for those who experience intolerable side-effects with clonazepam, and for those in whom clonazepam precipitates or aggravates obstructive sleep apnea (OSA). To date, there is minimal published data and limited follow-up regarding the use of melatonin for patients with RBD associated with other neurologic syndromes and disorders.

Most totally blind people have circadian rhythms that are “free-running” (i.e., that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours). This condition causes recurrent insomnia and daytime sleepiness when the rhythms drift out of phase with the normal 24-hour cycle. We investigated whether a daily dose of melatonin could entrain their circadian rhythms to a normal 24-hour cycle.

Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age. However, existing studies on the soporific efficacy of melatonin have been highly heterogeneous in regard to inclusion and exclusion criteria, measures to evaluate insomnia, doses of the medication, and routes of administration. We reviewed and analyzed (by meta-analysis) available information on effects of exogenous melatonin on sleep.

Since sleep requires neurological control, it is not surprising that disorders of the brain may be associated with severe sleep disturbance (Okawa el al. 1986). Neurologically multiply disabled children can experience chronic sleep-wake rhythm difficulties (Okawa et al. 1987, Quine 1991), which often respond poorly to strict bedtime scheduling, various psychological measures and sedatives.

The authors’ goal was to examine the hypnotic effects of slow-release melatonin during the initial 4 weeks of treatment with fluoxetine in 19 patients with major depressive disorder.

Melatonin, hormone of the pineal gland, is concerned with biological timing. It is secreted at night in all species and in ourselves is thereby associated with sleep, lowered core body temperature, and other night time events. The period of melatonin secretion has been described as ‘biological night’. Its main function in mammals is to ‘transduce’ information about the length of the night, for the organisation of daylength dependent changes, such as reproductive competence.

We describe our experience in using melatonin to treat insomnia, a common sleep concern, in children with autism spectrum disorders. One hundred seven children (2–18 years of age) with a confirmed diagnosis of autism spectrum disorders who received melatonin were identified by reviewing the electronic medical records of a single pediatrician. All parents were counseled on sleep hygiene techniques.

Previously, we reported that morning bright light therapy improved sleep time and cognitive function in Alzheimer type of dementia. We conducted a double blind study to examine the effects of melatonin on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type of dementia.

To investigate the effect of melatonin treatment on sleep, behavior, cognition, and quality of life in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia.

The treatment of prostate cancer cells with pharmacological concentrations of melatonin influences not only androgen-sensitive but also androgen-insensitive epithelial prostate cancer cells. Cell differentiation promoted by melatonin is not mediated by PKA activation although it increases, in a transitory manner, intracellular cAMP levels. Melatonin markedly influences the proliferative status of prostate cancer cells. These effects should be evaluated thoroughly since melatonin levels are diminished in aged individuals when prostate cancer typically occurs.

Exogenously administered melatonin causes a 2-fold rise in glutathione peroxidase activity within 30 min in the brain of the rat. Furthermore, brain glutathione peroxidase activity is higher at night than during the day and is correlated with high night-time tissue melatonin levels. Glutathione peroxidase is thought to be the principal enzyme eliminating peroxides in the brain.

Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson’s, Alzheimer’s, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known.

Herein, we summarize the beneŽficial effects of melatonin when combined with the following drugs: doxorubicin, cisplatin, epirubicin, cytarabine, bleomycin, gentamicin, ciclosporin, indometacin, acetylsalicylic acid, ranitidine, omeprazole, isoniazid, iron and erythropoietin, phenobarbital, carbamazepine, haloperidol, caposide-50, morphine, cyclophosphamide and L-cysteine. While the majority of these studies were conducted using animals, a number of the investigations also used man. Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the efŽficacy of these drugs, its use as a combination therapy with these agents seems important and worthy of pursuit.

The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep ‘facilitator’ in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms.

This brief review considers some of the cardiac diseases and conditions where free radicals and related reactants are believed to be causative. The report also describes the beneficial actions of melatonin against oxidative cardiovascular disorders.

Melatonin, as a new member of an expanding group of regulatory factors that control cell proliferation and loss, is the only known chronobiotic, hormonal regulator of neoplastic cell growth. At physiological circulating concentrations, this indoleamine is cytostatic and inhibits cancer cell proliferation in vitro via specific cell cycle effects. At pharmacological concentrations, melatonin exhibits cytotoxic activity in cancer cells. At both physiological and pharmacological concentrations, melatonin acts as a differentiating agent in some cancer cells and lowers their invasive and metastatic status through alterations in adhesion molecules and maintenance of gap junctional intercellular·communication.

A number of clinical trials have addressed the impact of melatonin on solid tumors; as yet, however, there is no satisfactory synthesis of the data.

In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.

Classic antioxidants, including vitamins A, C, and E, have often failed to exhibit beneficial effects in metabolic diseases and aging. Melatonin is a multifunctional indolamine that counteracts virtually all pathophysiologic steps and displays significant beneficial actions against peroxynitrite-induced cellular toxicity.

We investigated whether melatonin is present in walnuts (Juglans regia L.) and, if so, tested whether eating walnuts influences melatonin levels and the total antioxidant status of the blood.

Oxidative stress-induced mitochondrial dysfunction has been shown to play a crucial role in the pathogenesis of a wide range of diseases. Protecting mitochondrial function, therefore, is vital for cells to survive during these disease processes. In this study, we demonstrate that melatonin, a chief secretory product of the pineal gland, readily rescued mitochondria from oxidative stress-induced dysfunction and effectively prevented subsequent apoptotic events and death in rat brain astrocytes (RBA-1).

Melatonin was discovered to be a direct free radical scavenger less than 10 years ago. Besides its ability to directly neutralize a number of free radicals and reactive oxygen and nitrogen species, it stimulates several antioxidative enzymes which increase its efficiency as an antioxidant. In terms of direct free radical scavenging, melatonin interacts with the highly toxic hydroxyl radical with a rate constant equivalent to that of other highly efficient hydroxyl radical scavengers.

Melatonin was recently reported to be an eff€ective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity.

The aim of this study is to examine possible in vitro antioxidant effects of melatonin. Thus, the total in vitro antioxidant activity or melatonin was studied using a thiocyanate method. Additionally, the reducing power, the superoxide anion scavenging activity and free radical scavenging activity or melatonin were determined.

Melatonin, a molecule with antioxidant properties that is widely distributed in the animal kingdom, has now been shown to exist in the plant kingdom, including edible plants. Our findings show that melatonin is not only an endogenously produced antioxidant, but that it is also consumed in the diet.

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.

This review summarizes some of the recent findings concerning the long-held tenet that the enzyme, N-acetyltransferase, which is involved in the production of N-acetylserotonin, the immediate precursor of melatonin, may in fact not always control the quantity of melatonin generated.

The present study was undertaken in order to further elucidate additional antioxidative mechanisms responsible for melatonin-induced gastroprotection in I-R injury. Therefore the activities of certain enzymes such as XO, a producing oxidants enzyme, total glutathione levels (GSH) and the antioxidant enzymes SOD and GSSG-rd were investigated.

In the present study, oxidative stress in diabetic model and the effect of garlic oil or melatonin treatment were examined. Streptozotocin (6 0 mgykg body weight, i.p.)-induced diabetic rats, showed a significant increase of plasma glucose, total lipids, triglyceride, cholesterol, lipid peroxides, nitric oxide and uric acid. Concomitantly, significant decreases in the levels of antioxidants ceruloplasmin, albumin and total thiols were found in the plasma of diabetic rats.

Despite great advances in assisted reproductive technology, poor oocyte quality remains a profound problem for female infertility. Reactive oxygen species (ROS) are produced within the follicle, especially during the ovulatory process. It is believed that oxidative stress may be a cause of poor oocyte quality. The role of ROS and antioxidants in relation to female reproductive function has been a subject of recent research interest.

Melatonin, the main secretory product of the pineal gland, is known to collaborate against oxidative stress within cells, but its mechanism of action in terms of stimulating antioxidant enzymes remains unclear. Herein, we propose that melatonin modulates antioxidant enzyme activities via its interaction with calmodulin, which in turn inhibits downstream processes that lead to the inactivation of nuclear RORα melatonin receptor.

Melatonin (N-acetyl-5-methoxytryptamine), an indoleamine produced in many organs including the pineal gland, was initially characterized as a hormone primarily involved in circadian regulation of physiological and neuroendocrine function. Subsequent studies found that melatonin and its metabolic derivatives possess strong free radical scavenging properties.

Melatonin was found to be a potent free radical scavenger in 1993. Since then over 800 publications have directly or indirectly confirmed this observation. Melatonin scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide and peroxynitrite anion. Based on the analyses of structure-activity relationships, the indole moiety of the melatonin molecule is the reactive center of interaction with oxidants due to its high resonance stability and very low activation energy barrier towards the free radical reactions.

There may be other functions of melatonin, yet undiscovered, which enhance its ability to protect against molecular damage by oxygen and nitrogen-based toxic reactants. Numerous in vitro and in vivo studies have documented the ability of both physiological and pharmacological concentrations to melatonin to protect against free radical destruction. Furthermore, clinical tests utilizing melatonin have proven highly successful; because of the positive outcomes of these studies, melatonin’s use in disease states and processes where free radical damage is involved should be increased.

Oxidative stress has been proven to be related to the onset of a large number of health disorders. This chemical stress is triggered by an excess of free radicals, which are generated in cells because of a wide variety of exogenous and endogenous processes. Therefore, finding strategies for efficiently detoxifying free radicals has become a subject of a great interest, from both an academic and practical points of view. Melatonin is a ubiquitous and versatile molecule that exhibits most of the desirable characteristics of a good antioxidant.

A few milligrams of a novel indoleamine were initially extracted from 250,000 ovine pineal glands, and the extracted molecule was structurally identified as N-acetyl-5-methoxytryptamine in 1958. It was given the common name melatonin because it is a methoxy derivative of serotonin and, in amphibians, it has a regulatory influence on melanin dispersion in epidermal melanocytes.

A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially, superoxide and hydroxyl radical) high-energy oxidants (such as peroxynitrite) as mediators of inflammation, shock and ischemia / reperfusion injury. The aim of this review is to describe recent developments in the field of oxidative stress research.

Melatonin is the main product of the pineal gland with well documented antioxidant and immunomodulatory effects. Since the action of the indole on COX-2 has not been previously described, the goal of the present report was to test the effect of melatonin on the activities of COX-2 and inducible nitric oxide synthase (iNOS), using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as a model.

Melatonin, the secretory product of the pineal gland, is known to be neuroprotective in cerebral ischemia, which is so far mostly attributed to its antioxidant properties. Here we show that melatonin directly inhibits the mitochondrial permeability transition pore (mtPTP). mtPTP contributes to the pathology of ischemia by releasing calcium and cytochrome c (cyt c) from mitochondria.

It is generally postulated that the amyloid β protein (Aβ) plays a central role in the progressive neurodegeneration observed in Alzheimer’s disease. Important pathologic properties of this protein, such as neurotoxicity and resistance to proteolytic degradation, depend on the ability of Aβ to form β-sheet structures or amyloid fibrils.