Relationship between post-awakening salivary cortisol and melatonin secretion in healthy participants

We report the relationship between patterns of post-awakening salivary melatonin and cortisol secretion in healthy participants (n=51; mean age 21.6 ±5.0 years). Saliva samples were collected within the domestic setting, at 0-, 15-, 30-, and 45-min post-awakening on 2 consecutive typical weekdays. Analyses were undertaken on data with electronically verified sample timing accuracy (55-min delay between awakening and the start of saliva sampling). Melatonin secretion declined linearly by an average of 29% within the first 45-min post-awakening. In contrast, there was a marked 112% surge in cortisol, characteristic of the cortisol awakening response. No day differences in melatonin or cortisol secretion were observed but melatonin concentrations were lower with later awakening. Despite contrasting post-awakening changes in these hormones, there was a lack of relationship between overall levels or patterns of melatonin and cortisol during this period.

Urinary 6-Sulphatoxymelatonin Levels Are Depressed in Chronic Migraine and Several Comorbidities

Objective.- To assess urinary 6-sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. Background.- Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders. Methods.- Urine samples were collected into a single plastic container over a 12-hour period from 8:00 pm to 8:00 am of the next day, and 6-sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory. Results.- A total of 220 subjects were evaluated - 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6-sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6-sulphatoxymelatonin levels and depression, anxiety, and fatigue. Conclusions.- To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.

Establishment and persistence of photoperiodic memory in hamsters

Long summer days unequivocally stimulate, and short winter days inhibit reproduction in Siberian hamsters. By contrast, intermediate-duration day lengths (12.5–14 h long) either accelerate reproductive development or initiate regression of the reproductive apparatus. Which of these outcomes transpires depends on an animal's photoperiodic history, suggesting that hamsters must encode a representation of prior photoperiods. The duration of nocturnal melatonin secretion is the endocrine representation of day length, but nothing is known about how long it takes to establish photoperiodic histories or how long they endure. Hamsters exposed for 2 or more weeks to long summer day lengths acquired a long-day photoperiodic history that determined subsequent reproductive responses to intermediate-duration day lengths and melatonin signals. The memory for long-day lengths persisted in pinealectomized hamsters for 6.5 weeks, faded significantly after 13 weeks, and was functionally absent after 20 weeks. These findings indicate that hamsters are influenced only by relatively recent day lengths and melatonin signals and ignore earlier ones that might cause them to misinterpret the salience of current day lengths.

Local Corticosterone Infusion Enhances Nocturnal Pineal Melatonin Production In Vivo

Melatonin, an important marker of the endogenous rhythmicity in mammals, also plays a role in the body defence against pathogens and injuries. In vitro experiments have shown that either pro- or anti-inflammatory agents, acting directly in the organ, are able to change noradrenaline-induced pineal indoleamine production. Whereas corticosterone potentiates melatonin production, incubation of the gland with tumour necrosis factor-alpha decreases pineal hormonal production. In the present study, we show that nocturnal melatonin production measured by intra-pineal microdialysis is enhanced in pineals perfused with corticosterone at concentrations similar to those measured in inflamed animals. In vitro experiments suggest that this enhancement may be due to an increase in the activity of the two enzymes that convert serotonin to N-acetylserotonin (NAS) and NAS to melatonin. The present results support the hypothesis that the pineal gland is a sensor of inflammation mediators and that it plays a central role in the control of the inflammatory response.

Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase

To examine the immediate phase-shifting effects of high-intensity exercise of a practical duration (1 h) on human circadian phase, five groups of healthy men 20-30 yr of age participated in studies involving no exercise or exposure to morning, afternoon, evening, or nocturnal exercise. Except during scheduled sleep/dark and exercise periods, subjects remained under modified constant routine conditions allowing a sleep period and including constant posture, knowledge of clock time, and exposure to dim light intensities averaging (±SD) 42 ± 19 lx. The nocturnal onset of plasma melatonin secretion was used as a marker of circadian phase. A phase response curve was used to summarize the phase-shifting effects of exercise as a function of the timing of exercise. A significant effect of time of day on circadian phase shifts was observed (P < 0.004). Over the interval from the melatonin onset before exercise to the first onset after exercise, circadian phase was significantly advanced in the evening exercise group by 30 ± 15 min (SE) compared with the phase delays observed in the no-exercise group (-25 ± 14 min, P < 0.05). Phase shifts in response to evening exercise exposure were attenuated on the second day after exercise exposure and no longer significantly different from phase shifts observed in the absence of exercise. Unanticipated transient elevations of melatonin levels were observed in response to nocturnal exercise and in some evening exercise subjects. Taken together with the results from previous studies in humans and diurnal rodents, the current results suggest that 1) a longer duration of exercise exposure and/or repeated daily exposure to exercise may be necessary for reliable phase-shifting of the human circadian system and that 2) early evening exercise of high intensity may induce phase advances relevant for nonphotic entrainment of the human circadian system.

Interplay among nocturnal activity, melatonin, corticosterone and performance in the invasive cane toad (Rhinella marinus)

Most animals conduct daily activities exclusively either during the day or at night. Here, hormones such as melatonin and corticosterone, greatly influence the synchronization or regulation of physiological and behavioral cycles needed for daily activity. How then do species that exhibit more flexible daily activity patterns, responses to ecological, environmental or life-history processes, regulate daily hormone profiles important to daily performance? This study examined the consequences of (1) nocturnal activity on diel profiles of melatonin and corticosterone and (2) the effects of experimentally increased acute melatonin levels on physiological and metabolic performance in the cane toad (Rhinella marinus). Unlike inactive captive toads that had a distinct nocturnal melatonin profile, nocturnally active toads sampled under field and captive conditions, exhibited decreased nocturnal melatonin profiles with no evidence for any phase shift. Nocturnal corticosterone levels were significantly higher in field active toads than captive toads. In toads with experimentally increased melatonin levels, plasma lactate and glucose responses following recovery post exercise were significantly different from control toads. However, exogenously increased melatonin did not affect resting metabolism in toads. These results suggest that toads could adjust daily hormone profiles to match nocturnal activity requirements, thereby avoiding performance costs induced by high nocturnal melatonin levels. The ability of toads to exhibit plasticity in daily hormone cycles, could have broad implications for how they and other animals utilize behavioral flexibility to optimize daily activities in response to natural and increasingly human mediated environmental variation.

Annual pattern of plasma melatonin and progesterone concentrations in hair and wool ewe lambs kept under natural photoperiod at lower latitudes in the southern hemisphere

To study the annual pattern of plasma melatonin and progesterone concentrations in hair [Santa Ines (SI)] and wool [Romney Marsh (RM) and Suffolk (SU)] ewe lambs kept under natural photoperiods at 21 degrees 59'S, 12 ewe lambs (four/breed) were used. For melatonin, blood samples were collected monthly throughout the year at the onset (17:00, 19:00 and 21:00 hr) and end (04:00, 06:00 and 08:00 hr) of the night, and for progesterone the samples were collected in the morning, two to three times a week throughout the year. Plasma melatonin concentrations at different times of the day changed according to the season. In diurnal periods (17:00 and 8:00 hr) no seasonal differences were observed but they became evident in the nocturnal intervals (21:00 and 4:00 hr) and transitional night-day (6:00 hr) times. The patterns of melatonin secretion were higher in winter and autumn than in spring and summer. The patterns of plasma progesterone secretion were affected by interaction between breed and season. There was no seasonal variation in plasma progesterone concentrations for SI females. The progesterone pattern for RM and SU females varied with season. The plasma levels were higher in autumn and winter than in spring and summer. At 21 degrees 59'S hair and wool ewe lambs showed the same annual pattern of plasma melatonin concentration while the annual progesterone profiles were quite different. For SI females this pattern was constant along all seasons and for RM and SU females this pattern was higher during autumn and winter than spring and summer.

Melatonin inhibits LPS-induced NO production in rat endothelial cells

Endothelial cells produce NO by activation of constitutive nitric oxide synthase (NOS) and transcription of inducible NOS (iNOS). We have previously shown that melatonin, in the nanomolar range, inhibits activation of constitutive NOS, and in the present paper, we evaluated whether it could interfere with the expression of iNOS, which is activated by lipopolysaccharide (LPS), a major component of gram-negative bacteria cell walls. Primary cultures of rat endothelial cells were loaded with fluorescent probe for NO detection. Nuclear factor kappa B (NF-kappa B) translocation in endothelial cells elicited by LPS was measured by electromobility shift assay, and the vasodilation of aortic rings was accessed by recording isometric contraction. Melatonin in a micromolar but not in a nanomolar range inhibits the NO production induced by LPS. This effect is not dependent on the activation of G protein-coupled melatonin receptors. The nuclear NF-kappa B translocation is a process necessary for iNOS transcription, and melatonin also inhibits its translocation. LPS induced vasodilation only in endothelium-intact aortic rings, and melatonin (10 mu m) inhibits the vasodilation. Here, we show that concentrations compatible with nocturnal melatonin surge (nm) did not interfere with the activity of iNOS. Considering that micromolar melatonin concentrations could be locally achieved through production by activated immune competent cells, extra-pineal melatonin could have a protective effect against tissue injury. We propose that melatonin blocked the LPS-induced vasodilation by inhibiting the NF-kappa B pathway. Finally, we propose that the effect of melatonin on vascular reactivity is one of the mechanisms that underlies the protective effect of this indolamine against LPS.

Melatonin and the circadian entrainment of metabolic and hormonal activities in primary isolated adipocytes

The aim of this work was to investigate the effect of the in vitro circadian-like exposure to melatonin [in the presence or absence of insulin (Ins)] on the metabolism and clock gene expression in adipocytes. To simulate the cyclic characteristics of the daily melatonin profile, isolated rat adipocytes were exposed in a circadian-like pattern to melatonin added to the incubating medium for 12 hr (mimicking the night), followed by an equal period without melatonin (mimicking the day) combined or not with Ins. This intermittent incubation was interrupted when four and a half 24-hr cycles were fulfilled. At the end, either during the induced night (melatonin present) or the induced day (melatonin absent), the rates of lipolysis and D-[U-(14)C]-glucose incorporation into lipids were estimated, in addition to the determination of lipogenic [glucose-6-phosphate dehydrogenase and fatty acid synthase (FAS)] and lipolytic (hormone sensitive lipase) enzymes and clock gene (Bmal-1b, Clock, Per-1 and Cry-1) mRNA expression. The leptin release was also measured. During the induced night, the following effects were observed: an increase in the mRNA expression of Clock, Per-1 and FAS; a rise in lipogenic response and leptin secretion; and a decrease in the lipolytic activity. The intermittent exposure of adipocytes to melatonin temporally and rhythmically synchronized their metabolic and hormonal function in a circadian fashion, mimicking what is observed in vivo in animals during the daily light-dark cycle. Therefore, this work helps to clarify the physiological relevance of the circadian pattern of melatonin secretion and its interactions with Ins, contributing to a better understanding of the adipocyte biology.

Effect of antidepressants on melatonin metabolite in depressed patients

Antidepressants increase melatonin levels, but it is still unclear whether this effect is related to the improvement of depressive symptoms or to unrelated pharmacological action of antidepressants. To answer this question, the effect of antidepressants on 6-sulphatoxymelatonin (aMT6s), the main melatonin urinary metabolite, was examined in drug-free depressed patients - most of them antidepressant-naive. aMT6s was evaluated in 34 depressed patients, before and after 8 weeks of placebo (n = 12) or antidepressant (n = 22; fluoxetine, duloxetine or Hypericum perforatum). Both groups showed an improvement of depressive symptoms after treatment compared to baseline (Hamilton Depression scores): 17.0 +/- 1.4 vs. 9.0 +/- 2.8, P = 0.007 for placebo, and 18.6 +/- 1.1 vs. 11.8 +/- 1.6, P < 0.001 for antidepressants). After treatment, aMT6s levels increased after antidepressants (P < 0.01), but not after placebo (P > 0.05). As depressive symptoms improved both in patients taking antidepressant and in those taking placebo, but an effect of antidepressants could only be seen in those taking antidepressants, we suggest that melatonin changes after antidepressants are more likely due to a pharmacological action of these drugs on melatonin secretion.

Daily rhythm of salivary IL-1 beta, cortisol and melatonin in day and night workers

Shiftwork-induced sleep deprivation and circadian disruption probably leads to an increase in the production of cytokines and dysregulation of innate immune system, respectively. This project aims evaluating changes in salivary IL-1 beta, cortisol, and melatonin in night workers. Method. Two day and three night healthy workers participated in this study. Sleep was evaluated by actimetry and activity protocols. Saliva was collected at waking and bedtime the last workday and the following two days-off and was analyzed by ELISA. Results. Neither sleep duration nor efficiency showed any association with salivary IL-1beta. IL-1beta levels were higher at waking than at bedtime during working days for all workers, but only one day and one night-worker maintained this pattern and hormone rhythms during days off. For this night worker, melatonin levels were shifted to daytime. A second one presented clear alterations in IL-1beta and hormone rhythms on days-off. Conclusions. Our preliminary results suggest that night work can disturb the variation pattern of salivary IL-1beta. No association of this variation with sleep was observed. It seems that disruption in hormone rhythms interfere with salivary IL-1beta production. IL-1beta production pattern seems to be maintained when rhythms are present, in spite of a shift in melatonin secretion.

Seasonal variations of melatonin in ram seminal plasma are correlated to those of testosterone and antioxidant enzymes

Abstract Background Some breeds of sheep are highly seasonal in terms of reproductive capability, and these changes are regulated by photoperiod and melatonin secretion. These changes affect the reproductive performance of rams, impairing semen quality and modifying hormonal profiles. Also, the antioxidant defence systems seem to be modulated by melatonin secretion, and shows seasonal variations. The aim of this study was to investigate the presence of melatonin and testosterone in ram seminal plasma and their variations between the breeding and non-breeding seasons. In addition, we analyzed the possible correlations between these hormones and the antioxidant enzyme defence system activity. Methods Seminal plasma from nine Rasa Aragonesa rams were collected for one year, and their levels of melatonin, testosterone, superoxide dismutase (SOD), glutathione reductase (GRD), glutathione peroxidase (GPX) and catalase (CAT) were measured. Results All samples presented measurable quantities of hormones and antioxidant enzymes. Both hormones showed monthly variations, with a decrease after the winter solstice and a rise after the summer solstice that reached the maximum levels in October-November, and a marked seasonal variation (P < 0.01) with higher levels in the breeding season. The yearly pattern of GRD and catalase was close to that of melatonin, and GRD showed a significant seasonal variation (P < 0.01) with a higher activity during the breeding season. Linear regression analysis between the studied hormones and antioxidant enzymes showed a significant correlation between melatonin and testosterone, GRD, SOD and catalase. Conclusions These results show the presence of melatonin and testosterone in ram seminal plasma, and that both hormones have seasonal variations, and support the idea that seasonal variations of fertility in the ram involve interplay between melatonin and the antioxidant defence system.

Norepinephrine activates NF-κB transcription factor in cultured rat pineal gland

AIMS: The circadian rhythm in mammalian pineal melatonin secretion is modulated by norepinephrine (NE) released at night. NE interaction with β1-adrenoceptors activates PKA that phosphorylates the transcription factor CREB, leading to the transcription and translation of the arylalkylamine-N-acetyltransferase (AANAT) enzyme. Several studies have reported the interplay between CREB and the nuclear factor-κB (NF-κB) and a circadian rhythm for this transcription factor was recently described in the rat pineal gland. In this work we studied a direct effect of NE on NF-κB activation and the role played by this factor on melatonin synthesis and Aanat transcription and activity. MAIN METHODS: Cultured rat pineal glands were incubated in the presence of two different NF-κB inhibitors, pyrrolidine-dithiocarbamate or sodium salicylate, and stimulated with NE. Melatonin content was quantified by HPLC with electrochemical detection. AANAT activity was measured by a radiometric assay and the expression of Aanat mRNA was analyzed by real-time PCR. Gel shift assay was performed to study the NF-κB activation in cultured rat pineal glands stimulated by NE. KEY FINDINGS: Our results showed that the p50/p50 homodimer of NF-κB is activated by NE and that it has a role in melatonin synthesis, acting on Aanat transcription and activity. SIGNIFICANCE: Here we present evidence that NF-κB is an important transcription factor that acts, directly or indirectly, on Aanat transcription and activity leading to a modulation of melatonin synthesis. NE plays a role in the translocation of NF-κB p50/p50 homodimer to the nucleus of pinealocytes, thus probably influencing the nocturnal pineal melatonin synthesis

Melatonin for cardioprotection in ST elevation myocardial infarction: Are we ready for the challenge?

Melatonin, an endocrine product of the pineal gland, is formed predominantly during the nighttime. Light has an inhibitory effect on pineal melatonin secretion. Pineal melatonin release is synchronised by this daily light-dark cycle via a multisynaptic pathway between the eyes and the pineal gland. Light stimulates the retina to modulate the activity of the suprachiasmatic nucleus, the master biological clock.1 The suprachiasmatic nucleus controls pineal melatonin synthesis and the concentrations of melatonin in the sera of healthy subjects, which reach values of 10−10 to 10−9 mol/L during the night, with much lower concentrations being present during the day. Many publications have shown that melatonin has an important role in a variety of cardiovascular pathophysiologic processes: the indoleamine has anti-inflammatory, antioxidant, antihypertensive, antithrombotic and antilipaemic properties.

Variations circadiennes du syndrome d’impatiences musculaires de l’éveil (SIME ou RLS – restless legs syndrome)

La sécrétion de mélatonine chez des patients atteints du syndrome d’impatience musculaire de l’éveil (SIME) débute approximativement 2 heures avant l’aggravation des symptômes en soirée (Michaud et al., 2004). Le but de ce projet était de préciser le rôle de la mélatonine dans l’augmentation de la sévérité des symptômes en soirée. Huit sujets atteints de SIME primaire ont été étudiés dans trois conditions : contrôle, avec administration de mélatonine, avec exposition à la lumière vive. La sévérité des symptômes a été évaluée par l’administration de tests d’immobilisation suggérée (TIS). Les résultats ont démontré une augmentation significative des mouvements périodiques des jambes durant l’éveil (MPJE) lorsque de la mélatonine avait été administrée comparativement à la condition contrôle et celle où les sujets étaient exposés à la lumière vive. La lumière vive n’a pas eu d’effet significatif sur les symptômes moteurs comparativement à la condition contrôle mais elle a amélioré significativement les symptômes sensoriels comparativement à la condition contrôle. Ainsi, bien que la mélatonine exogène ait un effet aggravant sur les symptômes moteurs du SIME, l’augmentation de la sécrétion endogène au cours de la soirée ne saurait expliquer à elle seule les variations de la sévérité des symptômes du SIME.