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PubMedDate not supplied

Melatonin receptors in peripheral tissues: a new area of melatonin research.

Melatonin is synthesized and secreted by pineal gland, retina, harderian gland, lacrimal gland, and gut. It is a lipid-soluble molecule with ubiquitous distribution and multifarious functions. Thus, along with the better established sites of melatonin action, such as brain, retina, and pituitary, direct melatonin actions on other peripheral tissues should also be considered. The presence of melatonin receptors in peripheral tissues was rightfully hypothesized. Earlier studies on melatonin receptors had limited success. The advent of 2-[125I]iodomelatonin, a labelled melatonin agonist with a specific activity as high as 2,200 Ci/mmol, has allowed the studies of melatonin receptors with picomolar affinity and femtomolar density. Putative melatonin receptors demonstrated by autoradiography and/or radioreceptor assay in gut, kidney, lung, heart, vas deferens, and blood vessels are discussed.

Animals↗
PubMed1994

Evidence that melatonin binding sites in the pars tuberalis do not mediate the photoperiodic actions of melatonin on LH and prolactin secretion in ewes.

An experiment was designed to determine whether the pars tuberalis is the site of action of melatonin involved in the photoperiodic control of LH and prolactin secretion in sheep. In an attempt to produce a 'short-day' effect on these hormones (i.e. stimulation of LH secretion and inhibition of prolactin release), microimplants of melatonin were placed either around the pituitary stalk (n = 6) or in the third ventricle (n = 5) as a control for the efficacy of the microimplant. Two sham-operated groups were treated with empty microimplants around the pituitary stalk (n = 4) or in the third ventricle (n = 3). A further two control groups were given either no melatonin (n = 5) or a melatonin implant s.c. (n = 6). Administration of a melatonin implant s.c. is known to stimulate LH secretion and inhibit prolactin release in photoperiodically inhibited ewes. During the experiment (over 75 days), there was no significant increase in LH concentrations for the ewes receiving melatonin around the pituitary stalk. A similar lack of response was noted in the untreated or sham-treated ewes. In contrast, LH concentrations increased in ewes treated with the melatonin microimplant in the third ventricle on day 37 (+/- 4) and remained high until day 62 (+/- 4). Similarly, in the ewes given an implant s.c., LH concentrations rose on day 39 (+/- 4) and remained high until the end of the study. Furthermore, melatonin caused an inhibition of prolactin secretion relative to controls only when delivered to these sites (i.e. s.c. and into the third ventricle, but not around the pituitary stalk).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Effect of continuous melatonin infusions on steady-state plasma melatonin levels, metabolic fate and tissue retention in rats under near physiological conditions.

The fate and disposition of melatonin released into the circulation is still poorly understood, and almost all current knowledge is derived from measurements made after one single, often very large dose of labeled melatonin. In continuous infusion experiments in freely moving rats, 500 ng melatonin/mL hr had to be infused in order to elevate the circulating hormone from low daytime levels to the 10-fold higher nocturnal steady state concentrations. To study the fate and tissue accumulation of the infused melatonin, tritiated melatonin was added to the infusion solution, and the retention of [3H]-melatonin and chloroform-insoluble [3H]-melatonin-metabolites were measured in almost all body tissues and their subcellular compartments immediately at the end of the infusion period and six hours later. A considerable amount of the infused melatonin was found in the gut and in all tissues, some melatonin was covalently attached to proteins.

Animals↗
PubMed1984

Acute effects of a single afternoon melatonin injection on LH, prolactin, and pineal melatonin titers in the Syrian hamster.

Young adult male Syrian hamsters maintained in an LD 14:10 photo-period (lights out at 8 p.m.) were given a single injection of 25 micrograms melatonin or ethanolic-saline at 4 p.m. Animals from each group were sacrificed at 5 p.m., 4 a.m., and 10 a.m. following the injections. Pituitary and plasma LH and prolactin as well as pineal melatonin levels were determined in all animals by RIA. Pineal melatonin levels were significantly (p greater than 0.025) reduced at 10 a.m. in the melatonin treated group. Melatonin administration also suppressed pituitary LH levels at 4 a.m. and plasma LH levels at 10 a.m. Plasma prolactin concentrations at 4 a.m. and pituitary prolactin levels at both 5 p.m. and 10 a.m. were significantly elevated in melatonin treated hamsters compared with those given ethanolic-saline. These results indicate that exogenous melatonin has immediate effects on several hormones important in the regulation of reproductive events in this species. This acute injection model may therefore aid in the elucidation of melatonin's mechanism of action in the Syrian hamster.

Animals↗
PubMed2002

Organisation of the circadian system in melatonin-proficient C3H and melatonin-deficient C57BL mice: a comparative investigation.

In all vertebrates melatonin is rhythmically synthesised in the pineal gland and functions as a hormonal message encoding for the duration of darkness. This review focuses on the role of melatonin in the circadian organisation of mammals by comparing signal transduction mechanisms in the pineal organ, the suprachiasmatic nucleus and the hypophyseal pars tuberalis in melatonin-proficient (C3H) and melatonin-deficient (C57BL) mice strains. Surprisingly, the major signal transduction cascades in the pineal organ did not differ between the two mouse strains. With regard to the suprachiasmatic nucleus, the site of the endogenous clock, it was found that melatonin at most sets the gain for clock error signals mediated via the retinohypothalamic tract, but has no effect on the rhythm generation itself or on the maintenance of the oscillation. In contrast, melatonin plays an essential role in the control of the hypophyseal pars tuberalis. Here it acts in concert with adenosine to elicit rhythms in clock gene expression. Melatonin opens a temporally restricted gate for adenosine to induce cyclic AMP (cAMP)-sensitive genes by sensitising the adenylyl cyclase. This interaction, which grants a temporally precise regulation of gene expression, may reflect the central role of melatonin, i.e. in synchronising peripheral clock cells that require unique phasing of output signals with the master clock in the brain.

Animals↗
PubMed1992

Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract.

The administration of L-tryptophan (Trp, 150-300 mg/kg) to rats and chicks causes a rapid and dose-dependent elevation of circulating melatonin. The elevation of serum melatonin was greater after oral compared to the intraperitoneal route of administration of the same dose of Trp (150 mg/kg). The Trp-induced increase of circulating melatonin was unaffected by prior pinealectomy but was almost abolished by a partial ligature of the portal vein. The Trp-induced increase of melatonin in the portal blood preceded that in the systemic circulation. The gut contains considerable amounts of melatonin and the Trp-induced elevation of melatonin was greater in the duodenum compared to the pineal or the blood. The enterochromaffin cells of the gastrointestinal tract appear to be the major source of the Trp-induced increment of circulating melatonin. The possibility is discussed that the sedating, sleep inducing effects of Trp are mediated by the Trp-induced elevation of circulating melatonin.

Administration, Oral↗
PubMed2006

A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocaRdial Infarction undergoing primary Angioplasty The Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty (MARIA) trial: study design and rationale.

BACKGROUND: Experimental studies have documented the beneficial effects of the endogenously produced antioxidant, melatonin, in reducing tissue damage and limiting cardiac pathophysiology in models of experimental ischemia-reperfusion. Melatonin confers cardioprotection against ischemia-reperfusion injury most likely through its direct free radical scavenging activities and its indirect actions in stimulating antioxidant enzymes. These actions of melatonin permit it to reduce molecular damage and limit infarct size in experimental models of transient ischemia and subsequent reperfusion. STUDY DESIGN: The Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty (MARIA) trial is an unicenter, prospective, randomized, double-blind, placebo-controlled, phase 2 study of the intravenous administration of melatonin. The primary efficacy end point of this study is to determine whether melatonin treatment reduces infarct size determined by the cumulative release of alpha-hydroxybutyrate dehydrogenase (area under the curve: 0 to 72 h). Other secondary end points will be the clinical events occurring within the first 90 days: death, sustained ventricular arrhythmias, resuscitation from cardiac arrest, cardiogenic shock, heart failure, major bleedings, stroke, need for revascularization, recurrent ischemia, re-infarctions and rehospitalization. IMPLICATIONS: The MARIA trial tests a novel pharmacologic agent, melatonin, in patients with acute myocardial infarction and the hypothesis that it will confer cardioprotection against ischemia-reperfusion injury. If successful, the finding would support the use of melatonin in therapy of ischemic-reperfusion injury of the heart.

Adult↗
PubMed2001

Circadian rhythm of melatonin release in pineal gland culture: arg-vasopressin inhibits melatonin release.

The mammalian pineal gland is known to receive a noradrenergic sympathetic efferent signal from the suprachiasmatic nucleus (SCN) via the superior cervical ganglion. Arg-vasopressin (AVP) containing neurons in the SCN is one of the output paths of circadian information to the other brain areas. AVP release from the SCN is suppressed by melatonin. In turn, we determined the direct effect of AVP on melatonin release using pineal gland explant culture. AVP (1 microM) suppressed melatonin release. Noradrenaline stimulated melatonin release was attenuated by AVP. In turn, the expression of the melatonin synthesis enzyme arylalkylamine N-acetyltransferase mRNA in the rat SCN was reported. We measured melatonin content in the SCN in rats kept under the light-dark cycle and constant dim light. Melatonin in the SCN was higher during the dark period than that in the light. A similar tendency was also observed in the SCN of animals kept under a constant dim light. It was suggested that the reciprocal regulation of melatonin release and AVP release occurs in the SCN and pineal gland.

Animals↗
PubMed1998

Can high maternal melatonin concentrations be responsible for inducing fetal pathologies, and can melatonin participate in immunohormonal homeostasis by determining prohormone convertase activity?--Hypothesis and facts.

The hypothesis proposed here presents a mechanism of melatonin action, which may explain the role of this neurohormone in the genesis of various human pathologies, including fetal abnormalities. It assumes that monomeric or dimeric forms of indoloderived compounds such as melatonin and precursors of melanin have the ability to selectively stimulate the synthesis of prohormone 1 convertase (PC1) or prohormone 2 convertase (PC2), in proportion to their concentrations in the body. Thus, the mean circadian level of melatonin, by determining the manner and rapidity of proopiomelanocortin (POMC) cleavage, would also determine the mean proopiomelanocortin (POMC) level, maintained in dynamic equilibrium as a result of the simultaneous influence of testosterone, estradiol and cortisol on the intensity of POMC mRNA synthesis. The correlative proportions between the activity of PC1 and PC2 would therefore shape the character of hormonal balance in the organism, and in particular the mean ACTH concentration that determines the level of cyclic adenosine monophosphate (cAMP) concentration in its cells. The hypothesis also suggests that melatonin, by influencing the concentration of ACTH and beta-endorphin and their relative proportion could determine the stimulation or suppression of the immune system, thereby confirming its role as an immunomodulator. A disturbance in the above model of immunohormonal equilibrium, resulting from, for example, decreased pineal efficiency, would lead to stimulation of an alternative mode of achieving homeostasis, i.e. increase in concentration of melanin monomers and dimers, with concomitant high activity of tyrosine kinase and high cyclic guanosine monophosphate (cGMP) concentration in the cells. According to the proposed hypothesis, the risk of bearing a developmentally handicapped child would be highest in a woman with a high circadian secretion of melatonin, i.e. with domination of melatonin dimers and high PC1 activity, a condition which may be additionally aggravated by the exposure of the mother to adverse environmental factors or by immunohormonal disturbances. The hypothetical break-up of maternal melatonin dimers when crossing placenta would be the cause of excessive concentration of melatonin monomers and high PC2 activity in the fetus, and thus it should be the reason for very low levels of vimentin filaments and cAMP concentration in embryonal cells, the latter being directly responsible for inducing fetal pathologies.

Adrenocorticotropic Hormone↗
PubMed1998

Time course of saliva and serum melatonin levels after ingestion of melatonin.

Salival and serum melatonin levels after melatonin ingestion were measured by gas chromatography-mass spectrometry. Ingestion of 3 mg melatonin caused a marked increase in serum melatonin (3561+/-1201 pg/mL) within 20 min, followed by a gradual decrease, but the level still remained higher than the basal level at 240 min after the ingestion. The saliva melatonin 60 min after the ingestion showed the highest level (1177+/-403 pg/mL) which was one-third of the plasma level. The saliva melatonin level was highly correlated with the serum level throughout the experimental period (r=0.82, P=0.0001). These data indicate that the measurement of saliva melatonin level may be a suitable indicator for the melatonin secretion into general circulation.

Adult↗
PubMed2005

Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin-induced oncostatic effects.

Melatonin is endowed with a growth inhibitory effect in MCF-7 breast cancer cells whose mechanism has been related to an antiestrogenic activity exerted by inhibition of binding of the estradiol-estrogen receptor complex to its DNA responsive element. Looking for downstream gene determinants of this effect, we performed a transcriptome profiling by high-density microarrays of estrogen-treated MCF-7 cells exposed or not to melatonin. We found that cyclin D1 was one of the main downregulated genes by melatonin. Validation experiments clearly confirm that in MCF-7 cells the estrogen-induced growth inhibitory activity of melatonin is consistently associated with inhibition of estrogen-elicited cyclin D1 induction. This effect is almost purely transcriptional. Reporter gene assays indicate that the same portion of the cyclin D1 promoter which confers estrogen sensitivity, encompassing a potential cAMP responsive element binding site, is repressed by melatonin. Transcriptional downregulation of cyclin D1 is the key molecular event for melatonin's antiproliferative activity, as this activity can be completely and selectively rescued by transient cyclin D1 overexpression. Finally, we provide indirect evidence that the effect of melatonin on the cyclin D1 promoter is mediated by the c-jun and ATF-2 proteins, known to bind the minimal estrogen-sensitive cyclin D1 promoter element. These findings establish for the first time a molecular link between melatonin and its effects on the cell cycle, providing at the same time a rationale for its use in adjuvant chemotherapy.

Adjuvants, Immunologic↗
PubMed2003

Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters.

Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.

Animals↗
PubMed1981

Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition.

Effects of aging and melatonin on testicular function of golden male hamsters were investigated. Young (3-4 months) and old (22-26 months) male hamsters were maintained on a long photoperiod (14 h light, 10 h dark) and injected with graded doses of 10, 25, 50 microgram melatonin or injection vehicle, at 17:00 h (3 h before lights off) for a period of 6 weeks. Old male hamsters had significantly decreased testicular weights as compared with the young counterparts, but accessory sex organ (seminal vesicles and accessory glands) weights did not differ between young and old male hamsters. All doses of melatonin suppressed testicular and accessory sex organ weights in the young as well as in the old animals. The percent decrease in testicular weight in response to melatonin treatment was significantly greater (p less than 0.01) in the old than in the young hamsters. Basal plasma prolactin concentration did not differ between young and old male hamsters. Melatonin significantly decreased plasma prolactin concentrations in both age-groups. Young hamsters had greater mean plasma luteinizing hormone concentrations than old hamsters, and melatonin suppressed luteinizing hormone equally in both groups. These results indicate that the testes of the male hamster spontaneously regress during the aging process, and this may be independent of prolactin, since there was no difference in serum prolactin concentrations between young and old hamsters. The finding that melatonin injections brought about a greater percent decrease in testicular weight in the old than in the young hamsters suggests that there is an increased sensitivity of the reproductive system to melatonin inhibition in the old male hamster.

Aging↗
PubMed1982

24-hour rhythm of hypothalamic melatonin immunofluorescence correlates with serum and retinal melatonin rhythms.

The 24-hour rhythm of retinal and hypothalamic melatonin immunofluorescence was determined in male albino rats and compared to the 24-hour rhythm of serum melatonin determined by radioimmunoassay. Under a 12-hour (0:00-12:00): 12-hour dark cycle, the 24-hour rhythm of melatonin immunocytochemical fluorescence in the retina was biomodal (crests at 1:00 and 10:00-13:00). In serum, melatonin has a single crest late in the dark period (18:00). In the hypothalamus melatonin immunofluorescence showed increments corresponding to the crests in retina (13:00) and serum (18:00). In a 2-hour light: 22-hour dark cycle, the retinal rhythm was suppressed, the serum rhythm unchanged, and the hypothalamic rhythm had a single crest corresponding to the crest of the serum melatonin rhythm. These data indicate that the 24-hour hypothalamic rhythm of melatonin immunofluorescence may be secondary to the serum and retinal 24-hour rhythms of melatonin.

Animals↗
PubMed1983

Influence of exogenous melatonin on melatonin secretion and the neuroendocrine reproductive axis of intact male rats during sexual maturation.

The influence of daily sc administration of melatonin (5-100 micrograms/day) on sexual development of prepubertal and pubertal male rats was studied in vivo. Adult animals were also studied. When melatonin was injected daily into young animals starting at day 20 of age, dose-dependent reductions in plasma testosterone, testis and seminal vesicles weights, plasma FSH and LH levels, and pituitary GnRH receptor number were observed at day 40 or 45 of age when animals were killed. In contrast, prepubertal animals (5-20 days old) showed no significant responses to similar treatment with melatonin, whereas in adult animals (70-90 days old), melatonin elicited only a small decrease in plasma testosterone concentration. Melatonin analogs such as N-acetyl-serotonin and 5-hydroxytryptophol administered daily from 20-45 days of age did not produce any effect. Chronic melatonin administration from 20-50 days of life did not alter the occurrence of the nocturnal rise of circulating plasma melatonin, but did enhance its amplitude. Our results demonstrate that exogenous melatonin can inhibit or delay sexual maturation in the male rat if administered between 20 and 40 days of age and suggest that this inhibitory action is exerted at the hypothalamic and/or pituitary level.

Animals↗
PubMed2000

Differences in gonadotropin-releasing hormone-induced calcium signaling between melatonin-sensitive and melatonin-insensitive neonatal rat gonadotrophs.

The sensitivity of GnRH-stimulated calcium signaling to melatonin, in a subpopulation of neonatal gonadotrophs, is supposed to be attributable to melatonin receptors. However, it is not yet known whether the intracellular pathway for GnRH action in melatonin-sensitive cells is the same as in melatonin-insensitive cells. By monitoring intracellular Ca2+ changes as an outward current carried through apamin-sensitive Ca2+-activated K+ channels, we compared GnRH-induced calcium responses in these two subpopulations of neonatal gonadotrophs. GnRH induced various oscillatory, as well as nonoscillatory, responses in both cell types that was not related to melatonin sensitivity. Melatonin-sensitive GnRH-induced responses could be clearly distinguished according to the pharmacological properties of their latency. The latency increased in zero extracellular Ca2+ or with the addition of nifedipine, staurosporine, and ryanodine. This effect was only rarely observed in melatonin-insensitive cells. This indicates that there are two pathways for initiation of GnRH-induced calcium signaling in neonatal gonadotrophs. The first pathway is mediated by inositol 1,4,5,-trisphosphate production, whereas the second involves extracellular calcium entry through voltage-dependent L-type Ca2+ channels, protein kinase C activation, and Ca2+ release from a ryanodine-sensitive store, which may coactivate Ca2+ release from an inositol 1,4,5,-trisphosphate-sensitive store. Only the second mechanism is accessible to inhibition by melatonin.

Animals↗
PubMed1985

Response in peripheral plasma melatonin to photoperiod change and the effects of exogenous melatonin on seasonal quiescence in the tammar, Macropus eugenii.

During the light phase of each of 3 photoperiods tested, plasma melatonin concentrations were less than 16 to 62 pg/ml and during the dark phase they were 31 to 169 pg/ml. When the photoperiod to which the tammars were exposed was altered from 15 h light:9 h dark to 12L:12D the onset of the nocturnal rise in melatonin was advanced from the first day, thereby extending its duration, and the females gave birth 32 +/- 0.4 (mean +/- s.e.m.) days later. To test whether melatonin mediated this effect of photo-period change, tammars in a second group were injected s.c. with melatonin (400 ng/kg, N = 6) or the arachis oil vehicle (N = 6), 2.5 to 2.25 h before dark during 15L:9D for 15 days before exposure to 12.5L:11.5D. The melatonin injections mimicked the endogenous melatonin profile of 12L:12D and the melatonin-injected tammars gave birth 32 +/- 0.8 days after the start of injections, which was the same as the interval from photoperiod change in Exp. 1 but was significantly different (P less than 0.005) from the interval in the control group (46.0 +/- 1.1 days). These results show that exogenous melatonin given 2.5 to 2.25 h in advance of the endogenous rise fully mimics the response of the tammar to photoperiod change.

Anestrus↗
PubMedDate not supplied

Melatonin and colon carcinogenesis. IV. Effect of melatonin on proliferative activity and expression of apoptosis-related proteins in the spleen of rats exposed to 1,2-dimethylhydrazine.

The suppression of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis by melatonin was previously demonstrated. The objective of the present work was to evaluate histologically and immunohistochemically the splenic immune response to the induced cancer and to melatonin. Spleens from rats, either untreated, injected with DMH, fed with melatonin or treated with both carcinogen and melatonin, were studied. The exposure to the carcinogen and the consequential carcinogenesis resulted in splenic changes that reflected the insufficiency of the immune response, as manifested in significant reduction of the white pulp and the simultaneous expansion of the red pulp. The effects of melatonin on most splenic components were inverse to those of DMH. The anti-carcinogenic properties of melatonin were evidenced from the reversal of the inhibitory effects of DMH, especially when the densities of lymphocytes in different parts of the spleen were compared. The combined treatment of the rats with DMH and melatonin resulted in the expansion of the splenic zones by 106% to 125%, compared to those from DMH-treated rats, and the numbers of CD8+ lymphocytes and Fas-positive cells increased sharply. Therefore we conclude that anti-carcinogenic effects of melatonin are related to activation of several elements of the host's lymphatic system.

1,2-Dimethylhydrazine↗