Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high-fat-fed rats.

Background: Melatonin is a hormone synthesized mainly by the pineal gland, and secreted only at night. Melatonin has been proposed as a modulator of glucose metabolism.

Methods: Here we studied the metabolic effects of melatonin administration alone (s.

Circadian phenotyping of obese and diabetic db/db mice.

Growing evidence links metabolic disorders to circadian alterations. Genetically obese db/db mice, lacking the long isoform of leptin receptor, are a recognized model of type 2 diabetes. In this study, we aimed at characterizing the potential circadian alterations of db/db mice in comparison to db/+ control mice.

Leptin modulates the daily rhythmicity of blood glucose.

Leptin may affect central and/or peripheral timing, in addition to its well-known regulatory effects on metabolism. Here, we investigated whether leptin can impact rhythmicity of blood glucose and lipids. For that purpose, daily variations of blood glucose and lipids were compared between mice lacking functional leptin receptor (db/db) or deficient for leptin (ob/ob) and controls (db/+ and ob/+, respectively).

Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant properties.

Agomelatine behaves both as a potent agonist at melatonin MT1 and MT2 receptors and as a neutral antagonist at 5-HT2C receptors. Accumulating evidence in a broad range of experimental procedures supports the notion that the psychotropic effects of agomelatine are due to the synergy between its melatonergic and 5-hydroxytryptaminergic effects. The recent demonstration of the existence of heteromeric complexes of MT1 and MT2 with 5-HT2C receptors at the cellular level may explain how these two properties of agomelatine translate into a synergistic action that, for example, leads to increases in hippocampal proliferation, maturation and survival through modulation of multiple cellular pathways (increase in trophic factors, synaptic remodelling, glutamate signalling) and key targets (early genes, kinases).

In vitro and in vivo antitumor activity of melatonin receptor agonists.

Melatonin has been shown to inhibit the proliferation of estrogen receptor α (ERα)-positive human breast cancer cells in vitro and suppress the growth of carcinogen-induced mammary tumors in rats. Melatonin's antiproliferative effect is mediated, at least in part, through the MT1 melatonin receptor and mechanisms involving modulation of the estrogen-signaling pathway. To develop melatonin analogs with greater therapeutic effects, we have examined the in vitro and in vivo antimitotic activity of two MT1/MT2 melatonin receptor agonists, S23219-1 and S23478-1.

Agomelatine, the first melatonergic antidepressant: discovery, characterization and development.

Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states.

Short day-length increases sucrose consumption and adiposity in rats fed a high-fat diet.

Background: Photoperiod, i.e., the relative day-length per 24h, may modulate the metabolic responses to high-fat diet (HFD) and sucrose consumption.

[Melatoninergic receptor agonists and antagonists: therapeutic perspectives].

The chronobiotic neurohormone melatonin, synthetized in the pineal gland during darkness periods governs the circadian and seasonal biological rhythms. Physiologically, melatonin regulates the sleep/activity alternance, together with the circadian cycle of body temperature and cortisol secretion, and influences various immune, endocrine and metabolic functions. Dysfunction of the endogenous melatonin secretion is associated with mood and behavioral disorders including body weight.

Increasing the fat-to-carbohydrate ratio in a high-fat diet prevents the development of obesity but not a prediabetic state in rats.

Metabolic disorders induced by high-fat feeding in rodents evoke some, if not all, of the features of human metabolic syndrome. The occurrence and severity of metabolic disorders, however, varies according to rodent species, and even strain, as well as the diet. Therefore, in the present study, we investigated the long-term obesogenic and diabetogenic effects of three high-fat diets differing by their fat/carbohydrate ratios.

[Melatoninergic receptor agonists and antagonists: pharmacological aspects and therapeutic perspective].

Melatonin, or N-acetyl 5-methoxytryptamine, a neurohormone produced in the pineal gland during periods of darkness, plays a key role in the regulation of circadian and seasonal biological rhythms. In mammals, specific MT1 and MT2 receptors are located in the central nervous system, mainly in suprachiasmatic nuclei, and also in a number of peripheral sites. Besides its chronobiotic action on light-dependant functions, such as sleep/waking alternance or seasonal depression, melatonin exerts modulatory effects on immune, endocrine and metabolic functions.

Melatonin MT(1/2) receptor stimulation reduces cortical overflow of cholecystokinin-like material in a model of anticipation of social defeat in the rat.

The involvement of cholecystokinin (CCK) in the potential anxiolytic-like effects of melatonin and of the antitumor MT(1/2) receptor agonist, S23478, was assessed by measuring the cortical outflow of CCK-like material (CCKLM) in a rat model of anticipation of social defeat. After repeated social defeats by a male Tryon Maze Dull (TMD) rat, Sprague-Dawley (SD) rats were implanted for microdialysis in the frontal cortex and placed in the same environment as for the defeated sessions, but no confrontation with the TMD rat was allowed. Anticipation of social defeat induced anxiety-like behaviors (immobility, ultrasonic vocalization, defensive postures) associated with a significant increase (approximately +90%) in cortical CCKLM outflow in SD rats.

Interactions between imidazoline binding sites and dopamine levels in the rat nucleus accumbens.

Imidazoline binding sites are present in the striatal complex and in the extended amygdala and have been implicated in mood disorders. In this report we analysed the influence of these sites on the functional activity of the mesolimbic dopaminergic transmission, one of the major brain systems involved in the regulation of motivation and reward. We studied the effects of two imidazoline ligands, S23229 and S23230 (respectively S(+) and R(-) enantiomers of the S22687 or (5-[2-methyl phenoxy methyl] 1,3-oxazolin-2-yl) amine), on extracellular dopamine in the nucleus accumbens using microdialysis in freely moving rats.

Substituted oxygenated heterocycles and thio-analogues: synthesis and biological evaluation as melatonin ligands.

A new series of substituted oxygenated heterocycles and thio-analogues were synthesized and evaluated as melatonin receptor ligands. The replacement of the indolic moiety of melatonin by heterocyclic skeleton such as 1,4-benzodioxin, 2,3-dihydro-1,4-benzodioxin, chroman, 2,3-dihydro-1,4-benzoxathiin, thiochroman, carrying the amidic chain on the aromatic ring, leads to compounds showing a weak affinity for melatonin receptors, except for the compounds 1cb and 1hb.

In vitro mechanism of action on insulin release of S-22068, a new putative antidiabetic compound.

1. The MIN6 cell line derived from in vivo immortalized insulin-secreting pancreatic beta cells was used to study the insulin-releasing capacity and the cellular mode of action of S-22068, a newly synthesized imidazoline compound known for its antidiabetic effect in vivo. 2.

Interindividual differences in the pattern of melatonin secretion of the Wistar rat.

In vivo trans-pineal microdialysis was performed in male Wistar rats maintained under a 12 hr light:12 hr dark (LD 12:12) cycle. Collected dialysates were assayed by radioimmunoassay for melatonin concentrations. A non-linear regression was fitted through the obtained datapoints to determine the time points at which a 50% increase (IT50) and decrease (DT50) of the nocturnal melatonin peak were reached.

Effects of melatonin on neophobic responses in different strains of mice.

Anxiolytic properties of melatonin in rodents had usually been examined in behavioral tests based on stressful situations, i.e., in animal models of "state" anxiety.

Effect of the new imidazoline derivative S-22068 (PMS 847) on insulin secretion in vitro and glucose turnover in vivo in rats.

We have investigated the possible mechanisms underlying the antihyperglycaemic effect of the imidazoline derivative S-22068. In vitro, in the presence of 5 mmol/l glucose, S-22068 (100 micromol/l) induced a significant and sustained increase in insulin secretion from isolated, perifused, rat islets and a marked sensitization to a subsequent glucose challenge (10 mmol/l). S-22068 (100 micromol/l was able to antagonize the stimulatory effect of diazoxide on 86Rb efflux from preloaded islets incubated in the presence of 20 mmol/l glucose.

Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 2. Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines and isosteric analogues of imidazoline.

Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines resulted in the identification of 1-methyl-4-(2', 4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of alpha2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties.

The role of the retrochiasmatic area in the control of pineal metabolism.

The aim of the present investigation was to study the effect of neurotoxic ibotenic acid lesion of the retrochiasmatic area on the daily profile of pineal N-acetylserotonin and melatonin synthesis and on the pineal metabolic reactivity to nocturnal short-term retinal photostimulation. Groups of rats were killed 6 h after lights off either in the dark of immediately after being photostimulated for 1 or 15 min. Additionally, groups of rats were sacrificed at six different time points throughout the 24-hour light-dark cycle.

Lack of melatonin effects on insulin action in normal rats.

Despite a large number of studies, the role of melatonin on glucose metabolism is still controversial. The aim of the present work was to further characterize the effect of melatonin on insulin action during: i) intravenous insulin tolerance test performed at different times of the day using melatonin, a melatonin agonist (S-20304), a melatonin antagonist (S-20928) or in pinealectomized rats. ii) euglycemic-hyperinsulinemic clamp performed in melatonin agonist-treated as well as in pinealectomized rats.

[Melatonin and regulation of the cardiovascular system].

Evidence from the last 10 years suggests that melatonin may influence the cardiovascular system. Vascular melatoninergic receptors/sites have been demonstrated and are functionally linked with vasoconstrictor or vasodilatory effects of low (10(-9)-10(-7) M) and high (10(-6)-10(-3) M) melatonin concentrations respectively. Furthermore several other properties of the neurohormone (e.

[Development of animal models for the chronobiotics of melatonin analogs].

Melatonin is a neurohormone secreted by the pineal gland (or epiphysis). It is secreted only during the night whether in man or in diurnal or nocturnal animals. Melatonin secretion is regulated by light, which inhibits or synthesizes it.

[Melatonin, a pertinent prototype for therapeutic innovation].

Melatonin fulfils most of the requirements of a typical lead compound for rational drug design. We have rationally modified each of its structural features with a view to clarifying their role in drug-receptor interactions (affinity and activity) and to obtain agonist and antagonist ligands which could be used as pharmacological tools and/or as drugs. Molecular modelling studies allow us to propose a pharmacophore model.

Effects of melatoninergic agonists on light-suppressed circadian rhythms in rats.

This study addressed the question whether light-suppressed circadian rhythms in cardiovascular parameters in rats could be restored by melatonin and a synthetic analogue. Blood pressure, heart rate, and locomotor activity were monitored by radiotelemetry in six Sprague-Dawley rats. After synchronization to a 12:12 light/dark (LD) schedule (lights on at 0700 hours, 100 lux), rats were kept in constant light (LL) of low intensity (5-10 lux) for 11 weeks.

Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands.

A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogues of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings.