Melatonin receptor structures shed new light on melatonin research.

The tryptophan derivative melatonin is an evolutionary old molecule that is involved in a pleiotropy of physiological functions. In humans, age-related decline of circulating melatonin levels and/or dysregulation of its circadian synthesis pattern have been associated with several disorders and disease states. Several molecular targets have been proposed for melatonin since its discovery, in 1959. Among them, melatonin MT1 and MT2 receptors are the best characterized melatonin targets, mediating melatonin effects in a variety of tissues. They belong to the superfamily of G protein-coupled receptors. Two back-to-back articles published in the "Nature" Journal earlier this year present the first crystal structures of the human MT1 and MT2 in its inactive states. Here, we will briefly outline the discovery path of melatonin receptors until their structural elucidation and discuss how these new findings will guide future research toward a better understanding of their function and rational drug design.

A critical review of melatonin assays: Past and present.

There has been increased interest in the measurement of melatonin in plasma and saliva recently either as a marker of circadian phase or to understand the physiological role of melatonin. For both situations, there is a need for a specific assay for melatonin that is sensitive enough to detect low concentrations (<2 pg/mL). Since the mid-1970s, there have been many assays developed to measure melatonin in blood and saliva. Radioimmunoassays and ELISA have predominated because of their relative simplicity and high throughput. In this review, I show that the early radioimmunoassays while providing valuable information about nocturnal melatonin levels in humans, generally produced inaccurate basal (daytime) levels. Mass spectrometry assays, however, have provided us with the target values that immunoassays need to achieve, that is, daytime plasma melatonin levels <1 pg/mL. There are now many contemporary commercial assays available utilising both RIA and ELISA technologies, but not all achieve the standards set by the mass spectrometry assays. The performance of these assays is reviewed. I conclude with recommendations on issues researchers need to consider when conducting melatonin studies, including the importance of time of day of collection, validation of assays, the potential causes of poor assay specificity at low levels, the advantages/disadvantages of using saliva vs plasma and extraction assays vs direct assays, kit manufacturers responsibilities and the reporting requirements when publishing melatonin studies.

Laudatio for centenary of the birth of Luigi Di Bella, MD, PhD.

On the centennial of the birth of Luigi Di Bella, the desire to memorialise, at least in part, his thoughts has prompted us to write this tribute, in the hope that one day his dreams may come true. Throughout his research for a treatment of cancer, he deemed it necessary to employ a complex array of substances that, by acting centripetally on neoplastic cells, could in turn be capable of affecting, either simultaneously or sequentially, the myriad of biological reactions supporting their lives. Hence, not a substance but a method (Di Bella Method, DBM). These brief hints at some aspects of Prof. Di Bella's multifaceted scientific vision are aimed not only at reasserting the truth, but also at giving a modest contribution to a novel and free direction in experimental and clinical science.

[Melatonin as a universal stabilizing factor of mental activity].

Pineal hormone melatonin stabilizes mental activity of man and animals due to its somnogenic, anxiolytic, antidepressant and nootropic properties. Melatonin effects are based on the synchronization of biological rhythms via the influence on the cerebral structures which control biological rhythms and emotions and normalize endocrine and immune state.

Axelrod, the pineal and the melatonin hypothesis: lessons of 50 years to shape chronodisruption research.

With key work in the 1950s and 1960s, the 1970 Nobel laureate Julius Axelrod made major contributions to the development of pineal science. Looking back at some of his accomplishments in and for the field, we feel that lessons can be derived for future work regarding impairments of the pineal gland's and melatonin's many functions for promoting health and preventing disease in man.

Thirty four years since the discovery of gastrointestinal melatonin.

After the discovery of melatonin in the pineal gland by Lerner and co-workers in 1958, melatonin was also detected in the retina and the human appendix. Later, melatonin was confirmed immunohistologically in all segments of the gastrointestinal tract (GIT), in the guts of bovine embryos and in the GIT of low vertebrates. Melatonin was also confirmed in the pancreas and the hepatobiliary system. Melatonin is produced in the enteroendocrine cells of the GIT mucosa. The concentrations of melatonin in the GIT are 10-100x higher than in the plasma and the total amount of melatonin in the GIT is around 400x higher than the amount of melatonin in the pineal gland. Similar to pineal melatonin, GIT melatonin is a multifunctional compound which exhibits some general as well as some specific effects, depending on the organ and the location of GIT tissue. In the GIT, melatonin exhibits endocrine, paracrine, autocrine and luminal actions. Generally, the episodic secretion of melatonin from the GIT is related to the intake and digestion of food and to the prevention of tissue damage caused by hydrochloric acid and digestive enzymes. Some actions, such as the scavenging of hydroxyl free radicals, immunoenhancement and antioxidant effects are of general nature, whereas others, such as an increase of mucosal blood flow, the reduction of peristalsis and the regulation of fecal water content, are specific to the tubular GIT. Generally, melatonin actions oppose those of serotonin. Laboratory and clinical studies indicate that the utilization of melatonin can prevent or treat pathological conditions such as esophageal and gastric ulcers, pancreatitis, colitis, irritable bowel disease, and colon cancer.

[Studying the psychotropic activity of pineal hormone melatonin: original direction of our investigations. Twentieth anniversary of the melatonin study in the pharmacology department at the Stavropol medical academy].

Results of a series of original investigations devoted to the antidepressant, anxiolytic, and nootropic activity of the pineal hormone melatonin are summarized. It is established that a decisive role in this activity belongs to the chronotropic properties of melatonin.

Julius Axelrod: 20 May 1912 - 29 December 2004.

Julie Axelrod was a laboratory technician until the age of 42, when he finally achieved his PhD and independence. He worked at the National Institutes of Health for most of his career. Among his early pioneering research achievements in applying chemical and biochemical approaches to neuroscience were the discoveries of the painkiller acetaminophen (Tylenol, Paracetamol) and the liver microsomal drug-metabolizing enzymes, and the establishment of catechol-O-methyltransferase as an important enzyme in catecholamine metabolism. He shared the Nobel Prize in Physiology or Medicine in 1970 for his discovery that the reuptake of noradrenaline (norepinephrine) into the nerve endings from which it was released represented a novel method of neurotransmitter inactivation. An important corollary was the finding that antidepressant drugs acted as inhibitors of this uptake process. Subsequent work in his laboratory on the control of melatonin biosynthesis in the pineal gland provided new insights into the way in which the nervous system controls circadian rhythms, and offered an early model system in which to study the rapid control of mammalian gene expression. Axelrod continued actively in research until shortly before his death, and trained many students who have gone on to become leaders of the new field of biochemical neuropharmacology.

[Melatonin and mental disorders. Review of neuro-endocrinologic aspects. II: Melatonin and depressive disorders]. / Melatonina y trastornos mentales. Una revisón de los aspectos neuroendocrinológicos. Parte segunda: melatonina y trastornos depresivos.

The authors have carried out a bibliography revision about the relation between Melatonin secretion in the pineal gland and mental disorders. In the introduction a revision is done of the aspects of the anatomical functions of Melatonin secretion regulation. After words they study from a chronological perspective' studies of literature with reference to mental disorders. Two stages in the evolution of knowledge about Melatonin. The first stage consists of pharmacologic studies and pharmacotherapeutic studies and pharmaco-endocrine studies. Beginning with the melatonin determinations in biological liquids during the 60's and 70's; and a second stage which began at the end of 70's up until the present date, namely Melatonin secretion endocrinal studies in mental disorders. Apart from this, the comparing of the other hormonal secretion endocrinal studies in mental disorders. Apart from this, the comparing of the other hormonal secretion rhythms such as corticoids with function tests in Hip- Hipof. axis using the Dexamethasone suppression Test (DST). The authors also compare their experimental results with previous bibliography publications. The importance of night levels of Melatonin secretions in some patients with major depressive disorders and with abnormal answers in the DST show a diminishing when compared with another depressive disorders and their normal controls. Lastly the possible pathophysiological implications of melatonin and the pineal gland in the affective disorders are discussed, such as the conceptual form and the use of future studies of chronobiological systems.

Melatonin as a hormone in humans: a history.

This article describes the history of melatonin's transformation, in the perception of the biomedical community, from a skin-lightening agent in amphibians to a hormone in mammals, which may also exert important behavioral--and physiological--effects in humans.