Melatonin

Melatonin (MEL) is a hormone synthesized and secreted by the pineal gland deep within the brain in response to photoperiodic cues relayed from the retina via an endogenous circadian oscillator within the suprachiasmatic nucleus in the hypothalamus. The circadian rhythm of melatonin production and release, characterized by nocturnal activity and daytime quiescence, is an important temporal signal to the body structures that can read it. Melatonin acts through high-affinity receptors located centrally and in numerous peripheral organs. Different receptor subtypes have been cloned and characterized: MT(1) and MT(2) (transmembrane G-protein-coupled receptors), and MT(3). However, their physiological role remains unelucidated, although livestock management applications already include the control of seasonal breeding and milk production. As for potential therapeutic applications, exogenous melatonin or a melatonin agonist and selective 5-hydroxytrypiamine receptor (5-HT(2c)) antagonist, eg, S 20098, can be used to manipulate circadian processes such as the sleep-vake cycle, which are frequently disrupted in many conditions, most notably seasonal affective disorder.     

Effects of light on human melatonin production and the human circadian system

1. 1. Bright artificial light appears to have similar effects in humans as in other species.

2. 2. Bright light may therefore be used as a clinical research tool and as a therapeutic modality for treating certain biological rhythm disorders.

3. 3. Melatonin production appears to be a particularly useful “biological marker” for the human endogenous circadian pacemaker and the effects of light.

N-acetyltransferase and protein synthesis modulate melatonin production by Y79 human retinoblastoma cells

Melatonin is synthesized by the vertebrate pineal gland in a circadian fashion and is involved in numerous circadian and seasonal processes in the organism. The vertebrate retina also produces melatonin rhythmically to regulate rhythmic physiological processes in the eye. In both organs, melatonin is synthesized from serotonin by the sequential action of the enzymes, N-acethyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), and can be stimulated by increases in cyclic AMP through a mechanism requiring protein synthesis. The regulation of ocular melatonin biosynthesis in mammals and particularly humans, has not been well studied. Recently, we have shown that Y79 human retinoblastoma cells produce melatonin and that cAMP can stimulate melatonin production. Y79 cells, therefore, provide a model system in which to study melatonin synthesis in human tissue. We report that cAMP stimulates NAT, but not HIOMT activity in Y79 cells, and that stimulation of NAT activity is linearly related to melatonin release. In addition, the stimulation of NAT and melatonin requires protein synthesis. The turnover of NAT is rather rapid, with a half-life of about 20 min. These results suggest that the regulation of melatonin in Y79 retinoblastoma cells is similar to that found in the retina and pineal of other vertebrates.     

Encoding time of day and time of year by the avian circadian system

The most important zeitgeber for seasonal rhythmicity of physiology and behaviour in birds is the annual cycle of photoperiod. Regulatory mechanisms are less well understood in birds than in mammals since photic information can be perceived by photoreceptors in the retina and the pineal gland, as well as in the brain, and photoperiodic time measurement might be performed with reference to at least three autonomous circadian systems, the retina, the pineal gland and a hypothalamic oscillator. In many bird species, the pineal melatonin rhythm plays a central role in circadian organization. Durations of elevated melatonin in the blood reflect night length when animals are kept under natural photoperiodic conditions, as well as under different light/dark schedules in the laboratory. In the house sparrow, time of year is encoded in a particular melatonin signal, being short in duration and high in amplitude in long photoperiods and being long in duration and low in amplitude in short photoperiods, independent of whether the light zeitgeber is natural or artificial or varies in strength. Specific features of the melatonin signal are retained in vivo as well as in vitro when birds or isolated pineal glands are transferred to constant conditions. To regulate daily and seasonal changes of behaviour and physiology, melatonin may act at various target sites, including a complex hypothalamic oscillator that, unlike that in mammals, is not confined to a single cell group in the house sparrow. There is increasing evidence that interactions between two or more components of the songbird circadian pacemaking system are essential to encode and store biologically meaningful information about time, and thus provide the basis for photoperiodic time measurements and after effects in birds.     

Melatonin release from pineal cells of diurnal and nocturnal birds

Melatonin release from the pineal cells of chicks, pigeons and crows (diurnal birds) in vitro was compared with that from owls ( a nocturnal bird). The pineal cells of diurnal birds secreted large amounts of melatonin during the dark period, whereas oowl pineal cells released virtually no melatonin over 24 h and did not respond to exogenous stimulant agents. Histological examination revealed that the owl pineal gland is very small and has a poor vascular network. These results suggest that the pineal gland of owls may have degenerated and is not involved in the circadian clock mechanism in this species.     

Melatonin induces gene-specific effects on rhythmic mRNA expression in the pars tuberalis of the Siberian hamster (Phodopus sungorus)

In mammals, circadian and photoperiodic information is encoded in the pineal melatonin signal. The pars tuberalis (PT) of the pituitary is a melatonin target tissue, which transduces photoperiodic changes and drives seasonal changes in prolactin secretion from distal lactotroph cells. Measurement of photoperiodic time in the PT is believed to occur through melatonin dependent changes in clock gene expression, although it is unclear whether the PT should be considered a melatonin sensitive peripheral oscillator. We tested this hypothesis in the Siberian hamster (Phodopus sungorus) firstly by investigating the effects of melatonin injection, and secondly by determining whether temporal variation in gene expression within the PT persists in the absence of a rhythmic melatonin signal. Hamsters preconditioned to long days were treated with melatonin during the late light phase, to advance the timing of the nocturnal melatonin peak, or placed in constant light for one 24 h cycle, thereby suppressing endogenous melatonin secretion. Gene expression in the PT was measured by in situ hybridization. We show that melatonin rapidly induces cry1 mRNA expression without the need for a prolonged melatonin-free interval, acutely inhibits mt1 expression, advances the timing of peak rev-erb alpha expression and modulates per1 expression. With the exception of cry1, these genes continue to show temporal changes in expression over a first cycle in the absence of a melatonin signal. Our data are consistent with the hypothesis that the hamster PT contains a damped endogenous circadian oscillator, which requires a rhythmic melatonin signal for long-term synchronization.     

Potentiation effect of vasopressin on melatonin secretion as determined by trans-pineal microdialysis in the Rat

The mammalian pineal gland is known to receive a noradrenergic innervation originating from the superior cervical ganglion which corresponds to the primary regulatory input for melatonin synthesis. However, many peptidergic fibers containing peptides such as vasopressin and oxytocin have also been found in the rat pineal gland. The present study was performed to investigate the possible role of vasopressin and oxytocin on melatonin secretion in vivo. Therefore, both neuropeptides were delivered for 2 h through a trans-pineal microdialysis probe directly into the gland at different times during the nocturnal phase of the light:dark cycle. At the same time pineal dialysates were collected continuously. Melatonin concentrations were measured by radioimmunoassay. Melatonin synthesis potentiation was achieved when vasopressin was infused locally in the pineal, during the onset of nocturnal melatonin secretion. In order to assess the possible role of a physiological increase of endogenous circulating vasopressin on pineal metabolism, melatonin synthesis was recorded in the same animals before and after a prolonged dehydration period. Night time melatonin concentration was increased after the water deprivation vs control conditions. Contrary to that, oxytocin seems not to affect pineal metabolism in the rat since no significant change was observed on melatonin secretion in response to a local oxytocin infusion. These results show that vasopressin can modulate melatonin synthesis in the rat pineal whereas no effect was obtained with oxytocin, at least under the present experimental conditions.     

Melatonin in animal models

Melatonin is a hormone synthesized and secreted during the night by the pineal gland. Its production is mainly driven by the Orcadian clock, which, in mammals, is situated in the suprachiasmatic nucleus of the hypothalamus. The melatonin production and release displays characteristic daily (nocturnal) and seasonal patterns (changes in duration proportional to the length of the night) of secretion. These rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes. In mammals, the role of melatonin in the control of seasonality is well documented, and the sites and mechanisms of action involved are beginning to be identified. The exact role of the hormone in the diurnal (Orcadian) timing system remains to be determined. However, exogenous melatonin has been shown to affect the circadian clock. The molecular and cellular mechanisms involved in this well-characterized "chronobiotic" effect have also begun to be characterized. The circadian clock itself appears to be an important site for the entrapment effect of melatonin and the presence of melatonin receptors appears to be a prerequisite. A better understanding of such "chronobiotic" effects of melatonin will allow clarification of the role of endogenous melatonin in circadian organization.     

In search of novel and therapeutically significant melatoninergic ligands

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT(1) and MT(2). Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonin receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands have been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation.     

The basic physiology and pathophysiology of melatonin

Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body physiology. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas in field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlative observations, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions could depend on the melatonin signal, for instance immune, antioxidative defences, hemostasis and glucose regulation. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where the melatonin secretion can be disturbed. The resulting alteration could increase predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder.