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PubMed1997

Melatonin cycle in the fiddler crab Uca pugilator and influence of melatonin on limb regeneration.

Melatonin was measured over 24 hr in the eyestalks of Uca pugilator by means of radioimmunoassay; crabs were acclimatized either to a LD 12:12 photoperiod or constant darkness. A significant peak occurred at 13.00 hr in the LD 12:12 crabs. A photophase peak in melatonin has only been reported in one other species, also a crustacean. In constant darkness, two melatonin peaks occurred, one at 16.00 hr and the other 12 hr later; these results suggest that the melatonin cycle is a true circadian rhythm. HPLC with ultraviolet-visible detection was used to confirm the identity of melatonin immunoactivity. The influence of melatonin on regeneration of the walking legs was also examined: eyestalks were either removed or left intact, and limb bud length was measured every other day for at least 17 days in control and melatonin-treated crabs (60 microg ml(-1) seawater). Melatonin significantly increased the rate of limb regeneration in both eyestalk-intact and eyestalk-removed groups; this is contrary to results of regeneration studies in other phyla, in which similar melatonin concentrations inhibited regeneration.

Animals↗
PubMed2006

Injury switches melatonin production source from endocrine (pineal) to paracrine (phagocytes) - melatonin in human colostrum and colostrum phagocytes.

A large number of data show that melatonin has immunomodulatory properties and is produced by immunocompetent cells; also, some evidence suggests a 'feedback' of the activated immune system on the pineal gland. In this paper, we studied immune-pineal interactions in colostrum obtained from healthy puerperae and mothers with mastitis taking into account that, (a) melatonin levels in milk reflects pineal activity and (b) colostrum quiescent mononuclear and polymorphonuclear phagocytes from healthy mothers in culture are adequate for evaluating the ability of immunocompetent cells to produce melatonin. Here we compared the diurnal and nocturnal melatonin levels in colostrum from healthy puerperae and mothers with mastitis; this is a unique noninvasive model for determining pineal activity in the proinflammatory phase of a defense response. In addition, we determined the 'in vitro' production of melatonin by colostrum immunocompetent cells stimulated by enteropathogenic Escherichia coli or zymosan. Suppression of nocturnal melatonin rise in mothers with mastitis was highly correlated with increased tumor necrosis factor-alpha (TNF-alpha) secretion. This result, interpreted taking into account the presence of the transcription factor nuclear factor kappa B in pineal gland, suggest that the proinflammatory cytokine can inhibit nocturnal pineal melatonin production. On the other hand, stimulated, but not quiescent, immunocompetent cells secreted in the colostrum produced melatonin in vitro. In addition, this production ceases after bacteria killing. These results suggest that during the response to an injury the production of melatonin can be transiently shifted from an endocrine (pineal) to a paracrine (immunocompetent cells) source.

Adolescent↗
PubMed1996

Melatonin rhythm is not shifted by lights that suppress nocturnal melatonin in humans under entrainment.

Effects of a single light exposure on the circadian rhythm in plasma melatonin were, examined in young males to obtain the threshold of light intensity for suppressing the nocturnal melatonin level on the one hand and to understand the relationship between the light-induced phase shift of melatonin rhythm and the melatonin suppression on the other hand. Eight subjects spent 3 days in an experimental living facility where light intensity was set below 200 lx and were exposed to light for 3 h in the early morning on the 2nd day. The same procedure was repeated five times in each subject with an interval of at least 3 wk, and one of five light intensities was tested in each trial. As a result, nocturnal melatonin level was not suppressed by light of 200 lx but significantly suppressed by light of intensity > or + 500 lx. On the other hand, the circadian melatonin rhythm was not shifted by any light intensity up to 10,000 lx. It is concluded that the threshold of light intensity for suppressing the melatonin level is located between 200 and 500 lx in young Japanese males, and the threshold for phase shifting the circadian melatonin rhythm was much greater than that for suppressing the nocturnal melatonin level in humans under entrained conditions.

Adult↗
PubMed1997

Salivary melatonin as a circadian phase marker: validation and comparison to plasma melatonin.

There are many situations in which it would be useful to know the phase state of the biological clock. It is recognized that measurement of melatonin levels can provide this information, but traditionally blood has been used for the analysis, and there are many problems in extending the measurements into the home or field situations. The aim of this study was to develop and validate a salivary melatonin radioimmunoassay and to compare results obtained against a plasma assay for determining the onset of melatonin secretion. The assay developed was sensitive (4.3 pM) and required only 200 microliters of sample. A rhythm in melatonin was detected in saliva, peaking at approximately 120 pM or 30% of the plasma levels. Using an objective criterion for determining the onset of secretion (mean +/- 2 standard deviations of three daytime samples), the time of onset was shown to exhibit low intraindividual variability (coefficient of variation = 1.5%-4.3%). The time of onset determined using saliva was significantly correlated with the plasma onset (r = .70, p < .05). The onsets determined were 22:30 h +/- 22 min for the saliva and 21:50 h +/- 16 min for plasma for 17 subjects. Similarly, the acrophases of the saliva and plasma melatonin rhythms were significantly correlated. Neither posture alone nor changes in posture affected the calculation of the onset of melatonin secretion using the saliva approach. Very high saliva flow rates induced by citric acid resulted in lower melatonin concentrations compared to the gentle chewing on parafin film. These results firmly establish the use of salivary melatonin measurements for phase typing of the melatonin rhythm in humans.

Adult↗
PubMed1998

Melatonin rhythm onset in the adult siberian hamster: influence of photoperiod but not 60-Hz magnetic field exposure on melatonin content in the pineal gland and in circulation.

To determine the relationship between pineal melatonin production and its appearance in circulation, the rising phase of the pineal and serum melatonin rhythm was studied in the adult Siberian hamster. Melatonin concentrations increased in the pineal gland and in serum at 1.50 and 1.75 h, respectively, relative to lights off in long days (16 h of light/day) and at 2.00 and 2.75 h, respectively, in short days (10 h of light/day). Thus, a photoperiod-dependent melatonin rise in circulation lagged production by the pineal gland by 0.50 h--a delay of 0.75 h in short-day hamsters versus 0.25 h in long-day hamsters. Following initiation of this rise, concentrations that were typical of the nighttime peak were achieved within 2 h of melatonin rhythm onset, regardless of photoperiod. To determine whether clock control of the rising phase of the melatonin rhythm, in the absence of photoperiod cues, may be disrupted by perturbations in the ambient magnetic field, hamsters in constant darkness were acutely exposed to a 1-Gauss, 60-Hz magnetic field for 15 min or were daily exposed to this treatment for 14 or 21 days. Neither the melatonin rise in pineal content or circulation during subjective night was affected by acute or chronic magnetic field exposures; testes regression similarly occurred in sham and daily magnetic field-exposed hamsters in constant darkness. These findings indicate that magnetic field exposures are unlikely to serve as a zeitgeber for the circadian mechanism that controls onset of the melatonin rhythm; rather, photoperiod is a predominant cue that may differentially regulate the rising phase of melatonin production in the pineal gland and concentration in circulation.

Animals↗
PubMed1982

Effects of melatonin implants on the circadian rhythm of plasma melatonin and prolactin in sheep.

The effects of implanting Silastic capsules containing melatonin on plasma melatonin and prolactin levels were investigated in pinealectomized (Px) and sham-operated sheep (SPx). Prior to implantation, melatonin was found in plasma samples obtained during the night period from SPx sheep (mean value 150 pg/ml), but could not be (less than 25 pg/ml) detected in plasma samples obtained during the day in SPx sheep or in any sample obtained during the night or day period in Px sheep. Following implantation, a constant basal plasma melatonin level of about 165 pg/ml was established in all sheep with a superimposed nighttime rise in SPx animals suggesting no diminution of endogenous melatonin production during the dark period. Following melatonin treatment, there was a marked depression in plasma prolactin levels in both SPx and Px sheep. These results are interpreted to indicate that 1) there is no negative feedback of melatonin upon its own synthesis and release, 2) that there is no circadian change in the rate of metabolism of melatonin and 3) that constant melatonin availability in sheep caused a depression in plasma prolactin levels similar to that found following exposure of animals to a short day.

Animals↗
PubMed1986

Effects of long-term treatment with melatonin or melatonin plus ectopic pituitary transplants on testicular LH/hCG and prolactin receptors in juvenile Syrian hamsters (Mesocricetus auratus).

Juvenile hamsters were injected daily with melatonin and some were also given transplants of 2 pituitaries under the kidney capsule. Weights of the testes and the accessory reproductive glands were reduced after 8 and after 12 weeks of melatonin treatment, but remained unaltered in animals treated with ectopic pituitary transplants. Levels of testicular LH/hCG receptors were significantly reduced by daily melatonin injections for 8 and 12 weeks. The presence of pituitary transplants in melatonin-injected hamsters prevented these reductions, and increased LH/hCG receptors above control levels. These changes in testicular LH/hCG receptors were closely related to alterations in serum prolactin concentration induced by melatonin and pituitary transplants. After 8, but not after 12 weeks of treatment, testicular prolactin receptor levels were reduced by melatonin and maintained by the presence of pituitary transplants. We conclude that: juvenile male hamsters become sensitive to the effects of daily melatonin injections when they reach maturity; daily melatonin injections can reduce the levels of testicular LH/hCG and prolactin receptors; and the effects of melatonin on LH/hCG and prolactin receptors are probably due to suppression of endogenous prolactin release.

Animals↗
PubMed1999

The effect of age and pre-light melatonin concentration on the melatonin sensitivity to dim light.

The hormone melatonin is secreted at night from the pineal gland, with light being a potent inhibitor of its secretion. Age related decreases in plasma melatonin concentrations have indicated that this may be related to pineal calcification with aging. Recently, it was shown that the melatonin sensitivity to light may be a biological marker of bipolar disorder. However, on average, patients were older than the control group in most studies, and it is not known if age has an effect on the melatonin suppression by light. To test this hypothesis, the present study investigated the effect of age on the melatonin sensitivity to dim light (200 lux). Participants were grouped into three age groups. On the testing night, they were placed in a dark room from 21.00 h to 02.30 h. Light exposure was for an hour from midnight to 01.00 h. Blood samples were collected at regular intervals for measurement of plasma melatonin. No significant differences were found in the percentage suppression of melatonin within the age groups defined in the present study (P > 0.5). No correlation was also found between age and percentage suppression of melatonin (r2 = 0.007; P > 0.1). Our results suggest that the melatonin suppression by light (200 lux) is not affected by age.

Adolescent↗
PubMed2002

Does the negative correlation found in breast cancer patients between plasma melatonin and insulin-like growth factor-I concentrations imply the existence of an additional mechanism of oncostatic melatonin influence involved in defense?

BACKGROUND: Insulin-like growth factor-I (IGF-I) is probably involved in promoting both normal and neoplastic cell growth, neoplastic transformation processes, angiogenesis, and neoplasma progression. On the other hand, one possible mechanism of the oncostatic action of melatonin is its influence on the action and/or release of the growth factors that stimulate neoplastic cell growth. Quantitative changes in melatonin and IGF-I, as well as an imbalance between melatonin and IGF-I, may affect the growth of breast cancer cells and exacerbate the disease. The aim of our research was to study the interactions between plasma melatonin and IGF-I concentrations in pre-menopausal breast cancer patients. MATERIAL/METHODS: Our research involved 24 breast cancer patients (mean age 43 +/-6) with stage II breast cancer (Bloom and Richardson classification), confirmed by histological studies, and were 4 weeks after radical mastectomy. The control group consisted of 16 healthy women volunteers (mean age 44 +/- 5). RESULTS: No statistically significant relations were found between mean plasma melatonin and IGF-I concentrations in the two study groups. In the breast cancer group the correlation coefficient between IGF-I concentration in plasma and melatonin was r = -0.392 (p = 0.058). CONCLUSIONS: The negative correlation between the plasma melatonin and IGF-I concentrations in the breast cancer patients we studied could reach statistical significance in a larger population. The presence of such a negative correlation between plasma melatonin and IGF-I concentrations in patients with neoplastic disease may imply the existence of an additional defense mechanism based on the oncostatic influence of melatonin.

Adult↗
PubMed1986

Characterization of central melatonin receptors using 125I-melatonin.

The binding of 125I-melatonin, a potent analog of melatonin, to rat brain synaptosomal preparations was investigated. 125I-melatonin bound with high affinity (Kd = 38 nM) to a single class of sites (Bmax = 81 fmol/mg protein). Kinetic studies indicated that binding was time-dependent and reversible. Specific 125I-melatonin binding was inhibited by melatonin, and was unaffected by other structurally related compounds including serotonin. Binding of 125I-melatonin was greatly reduced if the synaptosomal preparations were pretreated by heat or trypsin but was unaffected by freeze-thawing. These results suggest that 125I-melatonin may serve as a valuable probe for studying melatonin receptors.

Animals↗
PubMed2004

Recovery of experimental Parkinson's disease with the melatonin analogues ML-23 and S-20928 in a chronic, bilateral 6-OHDA model: a new mechanism involving antagonism of the melatonin receptor.

Over the past 10 years, there has been a resurgence of interest in examining the role of melatonin in health and disease. While the brunt of research in this area has portrayed melatonin in a favorable light, there is a growing body of evidence suggesting that melatonin may possess adverse effects contributing to the development of various neuropsychiatric disease states. In preclinical models of Parkinson's disease (PD), melatonin has been shown to enhance the severity of this condition while its antagonism, using constant light or pinealectomy, facilitates recovery. To test this hypothesis further, the present study employed the melatonin analogues ML-23 and S-20928 in a post-6-OHDA injection regime to determine whether they may have a favorable effect on the symptoms of this more chronic model of PD. When ML-23 was injected I.P. in a dose of 3 mg/kg twice daily for 3.5 days after 6-OHDA, significant improvement in motor function and regulatory deficits was observed. Similarly, the injection of S-20928 in a 1 mg/kg dose (I.P.), in the same regimen, facilitated modest improvement in motor function and regulatory deficits while the larger dose enhanced the severity of behavioural deficits and produced severe side effects causing deterioration in condition during the course of drug administration. ML-23 administration totally abolished the 6-OHDA-induced mortality, which accompanies dopamine (DA) degeneration, while S-20928 had no effect on this parameter. These results suggest that some melatonin analogues can aid in recovery from DA depleting lesions after DA degeneration has commenced and the recovery is not attributable to the antioxidative properties of this hormone. While the exact mechanism by which ML-23 and S-20928 are exerting their therapeutic effect is unclear, it is possible that antagonism of melatonin receptors may play some role and this should be considered when assessing the potential of melatonin analogues for treatment of human neuropsychiatric disorders.

5-Methoxytryptamine↗
PubMed1997

Identification of Mel1a melatonin receptors in the human embryonic kidney cell line HEK293: evidence of G protein-coupled melatonin receptors which do not mediate the inhibition of stimulated cyclic AMP levels.

Binding assays using 2-[125I]iodomelatonin revealed high-affinity, guanosine 5'-O-(3-thiotriphosphate) sensitive, melatonin binding sites (B(max) 1.1 fmol/mg protein) in the human embryonic kidney cell line HEK293. Competition studies using the selective melatonin receptor antagonist luzindole and RT-PCR techniques identified these sites as human Mel1a melatonin receptors. Challenge of HEK293 cells with 1 microM melatonin had no effect on forskolin stimulated cyclic AMP levels, whereas in HEK293 cells engineered to stably over-express the human Mel1a melatonin receptor (B(max) > 400 fmol/mg protein) melatonin dose-dependently inhibited stimulated cyclic AMP levels (IC50 7.7 pM). These data may indicate that certain tissues, expressing low levels of G protein-coupled melatonin receptors, do not display melatonin mediated inhibition of cAMP.

Binding, Competitive↗
PubMed2000

Selective MT(2) melatonin receptor antagonist blocks melatonin-induced antinociception in rats.

The present study was undertaken to assess the effects of intracerebroventricular (i.c.v.) luzindole (a selective MT(2) melatonin receptor antagonist) and prazosin (a selective MT(3) melatonin receptor antagonist) on melatonin-induced antinociception, so as to clarify which of melatonin receptor subtypes within the central nervous system (CNS) was mediating antinociception. The pain threshold of rats was measured by the hot water (50 degrees C) tail-flick test. It was found that intraperitoneal (i.p.) melatonin (30, 60, 120 mg/kg) resulted in a dose-dependent antinociception. Luzindole (50, 100 microgram) administered intracerebroventricularly antagonized significantly the antinociceptive effect induced by i.p. melatonin (120 mg/kg), whereas prazosin (50 microgram) did not. Neither luzindole (100 microgram, i.c.v.) nor prazosin (50 microgram, i.c.v.) affected the nociceptive threshold when given alone. The results suggest that melatonin-induced antinociception is mediated through the MT(2) melatonin receptor subtype within the CNS.

Analgesics↗
PubMed1998

Melatonin receptor ligands: synthesis of new melatonin derivatives and comprehensive comparative molecular field analysis (CoMFA) study.

The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C:N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.

Animals↗
PubMed2002

The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors.

Exposure of neuronal cells to the Alzheimer's amyloid beta protein (Abeta) results in extensive oxidative damage of bio-molecules that are profoundly harmful to neuronal homeostasis. It has been demonstrated that melatonin protects neurons against Abeta-mediated neurotoxicity, including cell death and a spectrum of oxidative lesions. We undertook the current study to determine whether melatonin membrane receptors are involved in the mechanism of neuroprotection against Abeta neurotoxicity. For this purpose, we characterized the free-radical scavenging potency of several compounds exhibiting various affinities for melatonin membrane receptors (MLT 1a and 1b). Abeta-mediated neurotoxicity was assessed in human neuroblastoma cells and in primary hippocampal neurons. In sharp contrast with melatonin, no neuroprotection against Abeta toxicity was observed when we used melatonin membrane receptor agonists that were devoid of antioxidant activity. In contrast, the cells were fully protected in parallel control experiments when either melatonin, or the structurally unrelated free-radical scavenger phenyl-N-t-butyl nitrone (PBN), were added to Abeta-containing culture media. This study demonstrates that the neuroprotective properties of melatonin against Abeta-mediated toxicity does not require binding of melatonin to a membrane receptor and is likely the result of the antioxidant and antiamyloidogenic features of the agent.

5-Methoxytryptamine↗
PubMed2004

Circadian rhythm entrainment with melatonin, melatonin receptor antagonist S22153 or their combination in mice exposed to constant light.

The ability of daily melatonin and the melatonin receptor antagonist, S22153, to entrain circadian system function was investigated in mice with atypical melatonin rhythm. B6D2F(1) mice were first synchronized to a LD 12:12 for approximately 2 wk, then exposed to continuous light (LL) until study completion. After 10-18 days of LL exposure, mice received daily subcutaneous (s.c.) melatonin at a dose of 0.1, 1 or 10 mg/kg/day (exp. 1) or daily intraperitoneal (i.p.) S22153 (20 mg/kg/day) with or without melatonin (1 mg/kg/day, exp. 2) at subjective zeitgeber time (ZT) 10 for 19 days. Then all the mice were exposed to LL for another 10 days. Spectral analysis showed that initial LL lengthened the period of both rhythms by approximately 1.5 hr as compared with LD 12:12. No entrainment of either rhythm was found in controls. Conversely, daily melatonin-only, S22153-only or their combination set the temperature and activity periods to approximately 24 hr and produced a significant increase of the circadian amplitude of both rhythms as compared with controls. However, after treatment withdrawal, the dominant period lengthened to approximately 25.5 hr in mice receiving either melatonin or S22153. On the contrary, the period remained close to 24 hr for the 10 days following withdrawal of combined S22153 and melatonin. Such sustained pharmacological resetting of circadian function could display therapeutic potential against external resynchronization resulting from defective photoperiodic entrainment.

Animals↗
PubMedDate not supplied

Modulation of blood glucose by melatonin: a direct action on melatonin receptors in mouse hepatocytes.

Melatonin receptors were studied in isolated mouse hepatocytes using the 2[(125)I]iodomelatonin binding assay. The binding of 2[(125)I]iodomelatonin to hepatocytes isolated from the mouse using collagenase was stable, saturable, reversible and of high affinity. The equilibrium dissociation constant (K(d)) obtained from saturation studies was 10.0 +/- 0.4 pmol/l (n = 16), which was comparable to the K(d) obtained from kinetics studies (6.9 +/- 1.2 pmol/l, n = 3), and the maximum number of binding sites (B(max)) was 2.9 +/- 0.4 fmol/mg protein (n = 16). The relative order of potency of indoles in competing for 2[(125)I]iodomelatonin binding was 2-iodomelatonin > 2-phenylmelatonin > 6-chloromelatonin > melatonin > 6-hydroxymelatonin > N-acetylserotonin, indicating that the binding was mediated by the ML(1) receptor subtype. The linear Rosenthal plots, the close proximity of the Hill coefficient to unity and the monophasic competition curves suggest that a single class of 2[(125)I]iodomelatonin binding sites is present in the mouse hepatocytes. Guanosine 5'-O-(3-thiotriphosphate) dose-dependently inhibited 2[(125)I]iodomelatonin by lowering the affinity of binding, while no inhibitory effects of adenosine nucleotides were observed, suggesting that the binding sites are G-protein linked. Western immunoblotting was used to identify the melatonin receptor subtype in mouse hepatocytes using anti-Mel(1a) and anti-Mel(1b). Hepatocyte membrane extract reacted with anti-Mel(1b) but not anti-Mel(1a) giving a peptide-blockable band of 36 kD, supporting the hypothesis that the melatonin receptors in mouse hepatocytes are of the Mel(1b) subtype. Melatonin injection and a high plasma glucose level affected 2[(125)I]iodomelatonin binding in the whole mouse liver homogenates. Plasma glucose was elevated by mid-light intraperitoneal injection of melatonin (4 and 40 mg/kg body weight) in a dose-dependent manner with maximum elevation achieved 1 h after injection. 2[(125)I]Iodomelatonin binding at this time showed increased K(d) with no changes in B(max). When the plasma glucose returned to normal within 2 h, the binding remained lowered with increased K(d) but no changes in B(max). Elevation of plasma glucose by 2-deoxyglucose injection (500 mg/kg), on the other hand, decreased the binding by decreasing the B(max) without affecting the K(d). Suppression of plasma glucose by insulin injection (3 IU/kg) did not change the binding. Thus, melatonin may act directly on the liver to elevate the plasma glucose level, and changes in plasma glucose level itself may in turn affect hepatic melatonin binding.

Adenine Nucleotides↗