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Sample records for alters melatonin secretion

  1. Altered melatonin secretion in hypogonadal men: clinical evidence.

    PubMed

    Kumanov, Philip; Tomova, Analia; Isidori, Aldo; Nordio, Maurizio

    2005-08-01

    The pineal gland, through the rhythmic production of melatonin, seems to play an important role in the control of the reproductive function of many vertebrate species. In contrast, the effects of the pineal gland in humans and the relationship between gonadotropins and melatonin secretion are not yet clarified. On the basis of these considerations, the aim of the present study was to clarify whether melatonin serum concentrations were altered in males with different hypothalamo-pituitary-gonadal disturbances, in comparison to normal individuals. We have studied 36 individuals divided into three groups according to their gonadotropin status: normals, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. They were submitted to blood sample withdrawal at 03.00, 11.00 and 19.00 h for melatonin determination according to a radioimmunological method, without extraction of the sample. The results obtained in the present study suggest the existence of an interaction between the pituitary and the pineal gland. In fact, in the case of hypersecretion of gonadotropins, nocturnal melatonin release is reduced, while night melatonin secretion is increased in the opposite situation (hypogonadotropic hypogonadism). Both these endocrine pathologies are characterized by a reduced sexual steroid secretion; for that reason, this reduction cannot be regarded as responsible for the two opposite dysfunctions of melatonin release. In conclusion, our study shows that darkness-dependent release of melatonin in males with hypogonadotropic hypogonadism is significantly higher in comparison with the healthy men, while it is significantly reduced in patients with hypergonadotropic hypogonadism. A strong significant negative correlation is also found between gonadotropins and melatonin release.

  2. No Pattern Alteration in Single Nocturnal Melatonin Secretion in Patients With Hypnic Headache: A Case-Control Study.

    PubMed

    Naegel, Steffen; Huhn, Jana-Isabel; Gaul, Charly; Diener, Hans-Christoph; Obermann, Mark; Holle, Dagny

    2017-04-01

    To investigate headache-related serum melatonin levels and melatonin excretion rhythmicity in patients with hypnic headache (HH). Strict sleep dependency of headache attacks is a pathognomonic feature of HH. Changes in melatonin levels, a marker for circadian rhythm, are assumed to play a pivotal role in the pathophysiology of HH. Serum melatonin levels were acquired in nine patients with HH and nine age- and gender-matched healthy controls over a 20-hour time period (12 pm, 4 pm, 7 pm, 10 pm, time of headache, and 8 am). No significant changes of melatonin levels could be detected comparing HH patients and healthy controls. Melatonin excretion rhythmicity was not significantly altered in patients with HH (Mean melatonin level in ng/mL ± SD, patients vs controls at 12 pm: 21.5 ± 9.5 vs 13.6 ± 6.3 [P = .077], 4 pm: 18.4 ± 8.4 vs 14.0 ± 4.7 [P = .222], 7 pm: 19.4 ± 5.1 vs 15.1 ± 4.5 [P = .094], 10 pm: 59.5 ± 45.0 vs 29.4 ± 12.7 [P =.136], headache time: 96.9 ± 68.3 vs 49.1 ± 22.8 [P = .94], and 8 am: 31.6 ± 18.3 vs 26.7 ± 15.6 [P = .489]). This study is not able to confirm a significant role of melatonin concentration changes in the pathophysiology of HH and vetoes that melatonin deficiency plays a major role in the pathophysiology of the disorder. © 2016 American Headache Society.

  3. Nocturnal cortisol and melatonin secretion in primary insomnia.

    PubMed

    Riemann, Dieter; Klein, Torsten; Rodenbeck, Andrea; Feige, Bernd; Horny, Andrea; Hummel, Ruth; Weske, Gesa; Al-Shajlawi, Anam; Voderholzer, Ulrich

    2002-12-15

    The present study investigated evening and nocturnal serum cortisol and melatonin concentrations in patients with primary insomnia to test if this clinical condition is accompanied by an increase of cortisol secretion and a simultaneous decrease of nocturnal melatonin production. Ten drug-free patients (4 males, 6 females) with primary insomnia (mean age+/-S.D.: 39.2+/-9.1 years) and 10 age- and gender-matched healthy controls participated in the study. All subjects spent three consecutive nights in the sleep laboratory with polysomnography. Measurement of cortisol and melatonin (from 19:00 h to 09:00 h) was performed prior to and during the last laboratory night. Contrary to expectation, cortisol secretion did not differ between healthy controls and insomniac patients. On the other hand, nocturnal melatonin production was significantly diminished in insomniac patients. Polysomnographically determined sleep patterns, in contrast to subjective ratings of sleep, demonstrated only minor alterations of sleep in the insomniac group. The lack of increased cortisol secretion in the patients with primary insomnia indicates that results from studies on the biological consequences of experimental sleep loss in healthy subjects cannot be applied to primary insomnia in general, especially if there are only minor objective sleep alterations. In spite of the negligible objective sleep disturbances in the present sample, nocturnal melatonin production was reduced, which tentatively suggests a role for this hormone in primary insomniacs. The pathophysiological significance of this finding is, however, still a matter of debate.

  4. Seasonal fluctuation in the secretion of the antioxidant melatonin is not associated with alterations in sperm DNA damage

    PubMed Central

    Malm, Gunilla; Haugen, Trine B; Rylander, Lars; Giwercman, Aleksander

    2017-01-01

    A high sperm DNA fragmentation index (DFI) is associated with reduced fertility. DFI is influenced by the balance between reactive oxygen species and antioxidants. A circannual variation in melatonin, an antioxidant and free radical scavenger, could thus impact semen quality and fertility. The association between the major melatonin metabolite, urine 6-sulfatoxymelatonin (aMT6s), and DFI was analyzed in 110 Oslo men (south of the Arctic Circle) and 86 Tromsoe men (north of the Arctic Circle). Two semen analyses, summer and winter, and four urine samples (early/late summer; early/late winter), were analyzed. The associations between aMT6s in urine and DFI were characterized in a cross-sectional and longitudinal manner using correlation analysis and linear regression. Regardless of season and location, no significant correlations between aMT6s and DFI were observed. The correlation coefficients for associations between changes over time (early winter–early summer) in aMT6s and DFI were for the total cohort: rho = −0.08 (P = 0.322), for the Oslo cohort: rho = −0.07 (P = 0.485), and for the Tromsoe cohort: rho = −0.14 (P = 0.273), respectively. Similar results were seen when comparing late winter and late summer. There was no any statistically significant correlation between changes over time in aMT6s and DFI for men with DFI below and above the median value (10%), respectively. The seasonal variation in melatonin excretion seems not to have any impact on DFI. PMID:27748316

  5. Melatonin in Epilepsy: A New Mathematical Model of Diurnal Secretion

    PubMed Central

    Kijonka, Marek; Pęcka, Marcin; Sokół, Maria

    2016-01-01

    Purpose. The main objective of the study was to create a mathematical model that describes the melatonin circadian secretion and, then the functionality of the model was tested by a comparison of the melatonin secretions in children with and without epilepsy. Material and Methods. The patients were divided into the epilepsy group (EG, n = 52) and the comparison group (CG, n = 30). The melatonin level was assessed by a radioimmunoassay method. The diurnal melatonin secretion was described using a nonlinear least squares method. Spearman's rank correlation coefficient was chosen to estimate the dependence of the acquired data. The model reproduces blood concentration profiles and its parameters were statistically analyzed using the Mann-Whitney-Wilcoxon test and logistic regression. Results. The correlation analysis performed for the EG and CG groups showed moderate correlations between age and the melatonin secretion model parameters. Patients with epilepsy are characterized by an increased phase shift of melatonin release. PMID:27478439

  6. Melatonin effects on prolactin secretion in pituitary-grafted male rats.

    PubMed

    Villanua, M A; Agrasal, C; Tresguerres, J A; Vaughan, M K; Esquifino, A I

    1989-01-01

    Melatonin influences prolactin (PRL) secretion through unknown mechanisms. This work was undertaken to study the effects of melatonin administration on PRL secretion in pituitary-grafted male rats. Melatonin administration 5 hours before dark resulted in a marked decrease of previously high basal plasma PRL levels in pituitary-grafted rats, whereas a marked increase was detected in sham-operated animals. Vehicle treatment did not modify basal PRL values in grafted or sham-operated animals. Luteinizing hormone-releasing hormone (LHRH) administration resulted in a marked decrease of plasma PRL levels in vehicle-treated, sham-operated or grafted rats, as well as in melatonin-treated sham-operated rats. An increase in PRL levels was shown in grafted rats treated with melatonin. Estradiol benzoate (EB) administration resulted in an increase in plasma PRL levels both in sham-operated and grafted vehicle-treated rats. No PRL response could be detected in sham-operated, melatonin-treated animals after EB administration. In pituitary-grafted animals given melatonin, PRL response to EB administration was slight and delayed. From these data, melatonin appears to modify PRL secretion through multiple complex mechanisms that may depend on the physiological status (hormonal and neurotransmitter) of the animals. A direct effect at the pituitary level altering lactotroph sensitivity seems to be one plausible explanation for the current findings, although an hypothalamic site of action cannot be excluded.

  7. Central Interleukin-1β Suppresses the Nocturnal Secretion of Melatonin

    PubMed Central

    Herman, A. P.; Bochenek, J.; Król, K.; Krawczyńska, A.; Antushevich, H.; Pawlina, B.; Herman, A.; Romanowicz, K.; Tomaszewska-Zaremba, D.

    2016-01-01

    In vertebrates, numerous processes occur in a rhythmic manner. The hormonal signal reliably reflecting the environmental light conditions is melatonin. Nocturnal melatonin secretion patterns could be disturbed in pathophysiological states, including inflammation, Alzheimer's disease, and depression. All of these states share common elements in their aetiology, including the overexpression of interleukin- (IL-) 1β in the central nervous system. Therefore, the present study was designed to determine the effect of the central injection of exogenous IL-1β on melatonin release and on the expression of the enzymes of the melatonin biosynthetic pathway in the pineal gland of ewe. It was found that intracerebroventricular injections of IL-1β (50 µg/animal) suppressed (P < 0.05) nocturnal melatonin secretion in sheep regardless of the photoperiod. This may have resulted from decreased (P < 0.05) synthesis of the melatonin intermediate serotonin, which may have resulted, at least partially, from a reduced expression of tryptophan hydroxylase. IL-1β also inhibited (P < 0.05) the expression of the melatonin rhythm enzyme arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase. However, the ability of IL-1β to affect the expression of these enzymes was dependent upon the photoperiod. Our study may shed new light on the role of central IL-1β in the aetiology of disruptions in melatonin secretion. PMID:27212805

  8. Seasonal alterations in circadian melatonin rhythms of the European wild boar and domestic gilt.

    PubMed

    Tast, A; Hälli, O; Ahlström, S; Andersson, H; Love, R J; Peltoniemi, O A

    2001-01-01

    The aims of the present study were: 1) to determine if the European wild boar exhibits a circadian pattern of melatonin secretion under its natural light environment; 2) to compare this pattern with the pattern in domestic pigs reared under the light environment typical for domesticity; and 3) to determine if there are seasonal alterations in melatonin rhythms. Four to six young, pure-bred, European wild boars and four to six cross-bred (Yorkshire x Finnish Landrace) domestic gilts were sampled at 2-hr intervals for 48 hr at the spring/autumn equinoxes and summer/winter solstices. Samples were obtained via saphenous arterial catheters from the wild boars and via ear vein catheters from the domestic gilts. The ambient light intensity was recorded simultaneously with sampling both outdoors and indoors. Following ether extraction, the serum samples were assayed for melatonin using a commercial RIA (Bühlman). All the experimental animals exhibited a distinct circadian pattern in melatonin secretion, with high concentrations occurring during the scotophase. There was no difference in scotophase melatonin response between the wild boars and domestic gilts in any season in terms of mean melatonin concentration or peak value. The mean duration of increased melatonin secretion (more than two standard deviations over a mean photophase concentration) in 24 hr in the wild boars in spring, summer, autumn and winter, was 10, 6, 11 and 17 hr, respectively, and in the domestic gilts, 9, 8, 12 and 11 hr, respectively. These results demonstrate the existence of circadian rhythm in melatonin secretion in both the European wild boar and domestic pig. In both groups, the duration of secretion is subject to seasonal alterations. The results suggest no difference in photoperiodic-melatonin transduction between the European wild boar and domestic pig whether due to altered genotype or reduced light environment.

  9. Melatonin modifies basal and stimulated insulin secretion via NADPH oxidase.

    PubMed

    Simões, Daniel; Riva, Patrícia; Peliciari-Garcia, Rodrigo Antonio; Cruzat, Vinicius Fernandes; Graciano, Maria Fernanda; Munhoz, Ana Claudia; Taneda, Marco; Cipolla-Neto, José; Carpinelli, Angelo Rafael

    2016-12-01

    Melatonin is a hormone synthesized in the pineal gland, which modulates several functions within the organism, including the synchronization of glucose metabolism and glucose-stimulated insulin secretion (GSIS). Melatonin can mediate different signaling pathways in pancreatic islets through two membrane receptors and via antioxidant or pro-oxidant enzymes modulation. NADPH oxidase (NOX) is a pro-oxidant enzyme responsible for the production of the reactive oxygen specie (ROS) superoxide, generated from molecular oxygen. In pancreatic islets, NOX-derived ROS can modulate glucose metabolism and regulate insulin secretion. Considering the roles of both melatonin and NOX in islets, the aim of this study was to evaluate the association of NOX and ROS production on glucose metabolism, basal and GSIS in pinealectomized rats (PINX) and in melatonin-treated isolated pancreatic islets. Our results showed that ROS content derived from NOX activity was increased in PINX at baseline (2.8 mM glucose), which was followed by a reduction in glucose metabolism and basal insulin secretion in this group. Under 16.7 mM glucose, an increase in both glucose metabolism and GSIS was observed in PINX islets, without changes in ROS content. In isolated pancreatic islets from control animals incubated with 2.8 mM glucose, melatonin treatment reduced ROS content, whereas in 16.7 mM glucose, melatonin reduced ROS and GSIS. In conclusion, our results demonstrate that both basal and stimulated insulin secretion can be regulated by melatonin through the maintenance of ROS homeostasis in pancreatic islets. © 2016 Society for Endocrinology.

  10. Melatonin and Female Hormone Secretion in Postmenopausal Overweight Women

    PubMed Central

    Walecka-Kapica, Ewa; Chojnacki, Jan; Stępień, Agnieszka; Wachowska-Kelly, Patrycja; Klupińska, Grażyna; Chojnacki, Cezary

    2015-01-01

    Estrogen deficiency is considered to be the main cause of increased appetite and increased weight in postmenopausal women. In this period, reduced secretion of melatonin (MEL) was also observed. The aim of the study was to evaluate the secretion of melatonin, 17-β estradiol and follicle-stimulating hormone (FSH) in relation to body mass index (BMI) in pre- and postmenopausal women. The study included 90 women divided into three equal groups: group I (control)—women without menstrual disorders, group II—postmenopausal women without change in appetite and body weight, group III—postmenopausal women experiencing increased appetite and weight gain. In each patient, serum melatonin, 17-β-estradiol, FSH and urine a 6-sulfatoxymelatonin (aMT6s) were determined. Compared to the control group, the level of melatonin and estradiol was statistically lower. The FSH level was higher than in the groups of postmenopausal women. No significant correlation was found in all groups between the level of melatonin and the levels of estradiol and FSH. A negative correlation was found between aMT6s excretion and BMI, and a positive correlation between the level of FSH and BMI, mainly in overweight women. The obtained results indicate a significant effect of melatonin deficiency on the process of weight gain in postmenopausal women and justify its use in treatment of these disorders. PMID:25569084

  11. Does hypercalcaemia or calcium antagonism affect human melatonin secretion or renal excretion?

    PubMed

    Wikner, J; Wetterberg, L; Röjdmark, S

    1997-05-01

    Patients with primary hyperparathyroidism have higher serum melatonin concentrations during active disease than after surgical cure. Whether this is caused by hypercalcaemia per se, increased parathyroid hormone secretion or other mechanisms is unknown. We decided to elucidate whether exogenous hypercalcaemia influences melatonin secretion. For this purpose, eight healthy volunteers were infused with calcium and saline on separate days and in random order (experiment A). Hypercalcaemia inhibited nocturnal melatonin secretion by 20% but left urinary melatonin excretion unaffected. If exogenous hypercalcaemia inhibits melatonin secretion, it is reasonable to assume that calcium channel blockers such as verapamil might have the opposite effect. This was investigated in experiment B, in which eight healthy subjects were treated on separate occasions with oral verapamil and placebo. Verapamil did not affect nocturnal melatonin secretion but increased melatonin excretion by 145%. As 6-sulphatoxy-melatonin is the main melatonin metabolite excreted by the kidneys, it was considered important to find out whether verapamil would also influence the excretion of 6-sulphatoxy-melatonin. This was investigated in experiment C, in which eight healthy volunteers were treated, on separate occasions, with oral verapamil and placebo. In this experiment also, verapamil increased urinary melatonin excretion significantly (by 67%), but left excretion of 6-sulphatoxy-melatonin unaffected. These findings imply that verapamil influences the renal and/or hepatic handling of melatonin.

  12. The effects of coffee consumption on sleep and melatonin secretion.

    PubMed

    Shilo, Lotan; Sabbah, Hussam; Hadari, Ruth; Kovatz, Susy; Weinberg, Uzi; Dolev, Sara; Dagan, Yaron; Shenkman, Louis

    2002-05-01

    In this study we examined the effects of caffeine on sleep quality and melatonin secretion. Melatonin is the principal hormone responsible for synchronization of sleep. Melatonin secretion is controlled by neurotransmitters that can be affected by caffeine. In the first part of the study, six volunteers drank either decaffeinated or regular coffee in a double-blind fashion on one day, and the alternate beverage 7 days later. Sleep parameters were assessed by actigraphy. In the second part of the study, the subjects again drank either decaffeinated or regular coffee, and they then collected urine every 3h for quantitation of 6-sulphoxymelatonin (6-SMT), the main metabolite of melatonin in the urine. We found that drinking regular caffeinated coffee, compared to decaffeinated coffee, caused a decrease in the total amount of sleep and quality of sleep, and an increase in the length of time of sleep induction. Caffeinated coffee caused a decrease in 6-SMT excretion throughout the following night. The results of our study confirm the widely held belief that coffee consumption interferes with sleep quantity and quality. In addition, we found that the consumption of caffeine decreases 6-SMT excretion. Individuals who suffer from sleep abnormalities should avoid caffeinated coffee during the evening hours.

  13. Dietary melatonin alters uterine artery hemodynamics in pregnant Holstein heifers.

    PubMed

    Brockus, K E; Hart, C G; Gilfeather, C L; Fleming, B O; Lemley, C O

    2016-04-01

    The objective was to examine uterine artery hemodynamics and maternal serum profiles in pregnant heifers supplemented with dietary melatonin (MEL) or no supplementation (CON). In addition, melatonin receptor-mediated responses in steroid metabolism were examined using a bovine endometrial epithelial culture system. Twenty singleton pregnant Holstein heifers were supplemented with 20 mg of melatonin (n = 10) or no melatonin supplementation (control; n = 10) from days 190 to 262 of gestation. Maternal measurements were recorded on days 180 (baseline), 210, 240, and 262 of gestation. Total uterine blood flow was increased by 25% in the MEL-treated heifers compared with the CON. Concentrations of progesterone were decreased in MEL vs CON heifers. Total serum antioxidant capacity was increased by 43% in MEL-treated heifers when compared with CON. Activity of cytochrome P450 1A, 2C, and superoxide dismutase was increased in bovine endometrial epithelial cells treated with melatonin, whereas the melatonin receptor antagonist, luzindole, negated the increase in cytochrome P450 2C activity. Moreover, estradiol or progesterone treatment altered bovine uterine melatonin receptor expression, which could potentiate the melatonin-mediated responses during late gestation. The observed increase in total uterine blood flow during melatonin supplementation could be related to its antioxidant properties. Compromised pregnancies are typically accompanied by increased oxidative stress; therefore, melatonin could serve as a therapeutic supplementation strategy. This could lead to further fetal programming implications in conjunction with offspring growth and development postnatally.

  14. Acute melatonin treatment alters dendritic morphology and circadian clock gene expression in the hippocampus of Siberian hamsters.

    PubMed

    Ikeno, Tomoko; Nelson, Randy J

    2015-02-01

    In the hippocampus of Siberian hamsters, dendritic length and dendritic complexity increase in the CA1 region whereas dendritic spine density decreases in the dentate gyrus region at night. However, the underlying mechanism of the diurnal rhythmicity in hippocampal neuronal remodeling is unknown. In mammals, most daily rhythms in physiology and behaviors are regulated by a network of circadian clocks. The central clock, located in the hypothalamus, controls melatonin secretion at night and melatonin modifies peripheral clocks by altering expression of circadian clock genes. In this study, we examined the effects of acute melatonin treatment on the circadian clock system as well as on morphological changes of hippocampal neurons. Male Siberian hamsters were injected with melatonin in the afternoon; 4 h later, mRNA levels of hypothalamic and hippocampal circadian clock genes and hippocampal neuron dendritic morphology were assessed. In the hypothalamus, melatonin treatment did not alter Period1 and Bmal1 expression. However, melatonin treatment increased both Period1 and Bmal1 expression in the hippocampus, suggesting that melatonin affected molecular oscillations in the hippocampus. Melatonin treatment also induced rapid remodeling of hippocampal neurons; melatonin increased apical dendritic length and dendritic complexity in the CA1 region and reduced the dendritic spine density in the dentate gyrus region. These data suggest that structural changes in hippocampal neurons are regulated by a circadian clock and that melatonin functions as a nighttime signal to coordinate the diurnal rhythm in neuronal remodeling. © 2014 Wiley Periodicals, Inc.

  15. Melatonin Administration Alters Nicotine Preference Consumption via Signaling Through High-Affinity Melatonin Receptors

    PubMed Central

    Horton, William J.; Gissel, Hannah J.; Saboy, Jennifer E.; Wright, Kenneth P.; Stitzel, Jerry A.

    2015-01-01

    Rationale While it is known that tobacco use varies across the 24-hour day, the time-of-day effects are poorly understood. Findings from several previous studies indicate a potential role for melatonin in these time-of-day effects; however the specific underlying mechanisms have not been well characterized. Understanding of these mechanisms may lead to potential novel smoking cessation treatments. Objective Examine the role of melatonin and melatonin receptors in nicotine free choice consumption Methods A two-bottle oral nicotine choice paradigm was utilized with melatonin supplementation in melatonin deficient mice (C57BL/6J) or without melatonin supplementation in mice proficient at melatonin synthesis (C3H/Ibg) compared to melatonin proficient mice lacking both or one of the high affinity melatonin receptors (MT1 and MT2; double null mutant DM, or MT1 or MT2). Preference for bitter and sweet tastants also was assessed in wild type and MT1 and MT2 DM mice. Finally, home cage locomotor monitoring was performed to determine the effect of melatonin administration on activity patterns. Results Supplemental melatonin in drinking water significantly reduced free-choice nicotine consumption in C57BL/6J mice, which do not produce endogenous melatonin, while not altering activity patterns. Independently, genetic deletion of both MT1 and MT2 receptors in a melatonin proficient mouse strain (C3H) resulted in significantly more nicotine consumption than controls. However single genetic deletion of either the MT1 or MT2 receptor alone did not result in increased nicotine consumption. Deletion of MT1 and MT2 did not impact taste preference. Conclusions This study demonstrates that nicotine consumption can be affected by exogenous or endogenous melatonin and requires at least one of the high-affinity melatonin receptors. The fact that expression of either the MT1 or MT2 melatonin receptor is sufficient to maintain lower nicotine consumption suggests functional overlap and

  16. Melatonin secretion and puberty in female lambs exposed to environmental electric and magnetic fields

    SciTech Connect

    Lee, J.M. Jr.; Stormshak, F.; Thompson, J.M.; Thinesen, P.; Painter, L.J.; Olenchek, E.G.; Hess, D.L.; Forbes, R.; Foster, D.L. )

    1993-10-01

    This study determined whether chronic exposure of female lambs to the electric and magnetic fields (EMF) of a high voltage transmission line can alter pineal secretion of melatonin and the normal occurrence of puberty. Twenty female Suffolk lambs were assigned randomly in equal numbers to a control and a treatment group. Treatment from 2 to 10 mo of age consisted of continuous exposure within the electrical environment of a 500-kV transmission line (mean electric field 6 kV/m, mean magnetic field 40 mG). Treated lambs were penned directly beneath the transmission line; control lambs were maintained in a pen of similar construction 229 m from the line where EMF were at ambient levels (mean electric field < 10 V/m, mean magnetic field < 0.3 mG). Melatonin was analyzed by RIA in serum of blood samples collected at 0.5-3-h intervals over eight 48-h periods. To assess attainment of puberty, serum concentrations of progesterone were determined by RIA from blood samples collected twice weekly beginning at 19 wk of age. Concentrations of circulating melatonin in control and treated lambs were low during daylight hours and increased during nighttime hours. The characteristic pattern of melatonin secretion during nighttime (amplitude, phase, and duration) did not differ between control and treatment groups. Age at puberty and number of subsequent estrous cycles also did not differ between groups. These data suggest that chronic exposure of developing female sheep to 60-Hz environmental EMF does not affect the mechanisms underlying the generation of the circadian pattern of melatonin secretion or the mechanisms involved in the onset of reproductive activity.

  17. Abnormally Increased Secretion in Olfactory Neuronal Precursors from a Case of Schizophrenia Is Modulated by Melatonin: A Pilot Study

    PubMed Central

    Cercós, Montserrat G.; Galván-Arrieta, Tania; Valdés-Tovar, Marcela; Argueta, Jesús; Benítez-King, Gloria; Trueta, Citlali

    2017-01-01

    The alterations that underlie the pathophysiology of schizophrenia (SCZ) include the dysregulation of structural and functional properties of neurons. Among these, the secretion of neurotransmitters and hormones, which plays a key role for neuronal communication and development, is altered. Neuronal precursors from the human olfactory epithelium have been recently characterized as a reliable model for studying the etiopathogenesis of neuropsychiatric diseases. Our previous work has shown that melatonin enhances the development of morphological and functional features of cloned olfactory neuronal precursors (ONPs) from a healthy subject. In this work we found that primary cultures of ONPs obtained from a schizophrenic patient display an increased potassium-evoked secretion, when compared with ONPs from an age- and gender-matched healthy control subject (HCS). Secretion was evaluated by FM1-43 fluorescence cumulative changes in response to depolarization. Interestingly, a 12 h-melatonin treatment modulated the abnormally increased secretion in SCZ ONPs and brought it to levels similar to those found in the HCS ONPs. Our results suggest that the actin cytoskeleton might be a target for melatonin effects, since it induces the thickening of actin microfilament bundles. Further research will address the mechanisms by which melatonin modulates neurochemical secretion from ONPs. PMID:28703738

  18. Abnormally Increased Secretion in Olfactory Neuronal Precursors from a Case of Schizophrenia Is Modulated by Melatonin: A Pilot Study.

    PubMed

    Cercós, Montserrat G; Galván-Arrieta, Tania; Valdés-Tovar, Marcela; Solís-Chagoyán, Héctor; Argueta, Jesús; Benítez-King, Gloria; Trueta, Citlali

    2017-07-13

    The alterations that underlie the pathophysiology of schizophrenia (SCZ) include the dysregulation of structural and functional properties of neurons. Among these, the secretion of neurotransmitters and hormones, which plays a key role for neuronal communication and development, is altered. Neuronal precursors from the human olfactory epithelium have been recently characterized as a reliable model for studying the etiopathogenesis of neuropsychiatric diseases. Our previous work has shown that melatonin enhances the development of morphological and functional features of cloned olfactory neuronal precursors (ONPs) from a healthy subject. In this work we found that primary cultures of ONPs obtained from a schizophrenic patient display an increased potassium-evoked secretion, when compared with ONPs from an age- and gender-matched healthy control subject (HCS). Secretion was evaluated by FM1-43 fluorescence cumulative changes in response to depolarization. Interestingly, a 12 h-melatonin treatment modulated the abnormally increased secretion in SCZ ONPs and brought it to levels similar to those found in the HCS ONPs. Our results suggest that the actin cytoskeleton might be a target for melatonin effects, since it induces the thickening of actin microfilament bundles. Further research will address the mechanisms by which melatonin modulates neurochemical secretion from ONPs.

  19. The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans.

    PubMed

    Matsumoto, M; Sack, R L; Blood, M L; Lewy, A J

    1997-01-01

    A physiological dose of melatonin (0.5 mg) or placebo was given at bedtime to night shift workers (n = 21) for seven days, and endogenous melatonin profiles were measured on the eighth day. The amplitude of endogenous melatonin secretion was unchanged by treatment. Also, a melatonin treatment trial using a 50 mg daily bedtime dose for 37 days to a blind subject resulted in no change in the endogenous melatonin profile. We conclude that circulating melatonin can shift the phase, but does not alter the amplitude, of pineal melatonin secretion.

  20. Melatonin secretion is impaired in women with preeclampsia and an abnormal circadian blood pressure rhythm.

    PubMed

    Bouchlariotou, Sofia; Liakopoulos, Vassilios; Giannopoulou, Myrto; Arampatzis, Spyridon; Eleftheriadis, Theodoros; Mertens, Peter R; Zintzaras, Elias; Messinis, Ioannis E; Stefanidis, Ioannis

    2014-08-01

    Non-dipping circadian blood pressure (BP) is a common finding in preeclampsia, accompanied by adverse outcomes. Melatonin plays pivotal role in biological circadian rhythms. This study investigated the relationship between melatonin secretion and circadian BP rhythm in preeclampsia. Cases were women with preeclampsia treated between January 2006 and June 2007 in the University Hospital of Larissa. Volunteers with normal pregnancy, matched for chronological and gestational age, served as controls. Twenty-four hour ambulatory BP monitoring was applied. Serum melatonin and urine 6-sulfatoxymelatonin levels were determined in day and night time samples by enzyme-linked immunoassays. Measurements were repeated 2 months after delivery. Thirty-one women with preeclampsia and 20 controls were included. Twenty-one of the 31 women with preeclampsia were non-dippers. Compared to normal pregnancy, in preeclampsia there were significantly lower night time melatonin (48.4 ± 24.7 vs. 85.4 ± 26.9 pg/mL, p<0.001) levels. Adjustment for circadian BP rhythm status ascribed this finding exclusively to non-dippers (p<0.01). Two months after delivery, in 11 of the 21 non-dippers both circadian BP and melatonin secretion rhythm reappeared. In contrast, in cases with retained non-dipping status (n=10) melatonin secretion rhythm remained impaired: daytime versus night time melatonin (33.5 ± 13.0 vs. 28.0 ± 13.8 pg/mL, p=0.386). Urinary 6-sulfatoxymelatonin levels were, overall, similar to serum melatonin. Circadian BP and melatonin secretion rhythm follow parallel course in preeclampsia, both during pregnancy and, at least 2 months after delivery. Our findings may be not sufficient to implicate a putative therapeutic effect of melatonin, however, they clearly emphasize that its involvement in the pathogenesis of a non-dipping BP in preeclampsia needs intensive further investigation.

  1. Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women.

    PubMed

    McMullan, Ciaran J; Curhan, Gary C; Schernhammer, Eva S; Forman, John P

    2013-07-15

    Exogenous melatonin ameliorates insulin resistance in animals, while among humans, polymorphisms in the melatonin receptor gene are associated with insulin resistance. We aimed to investigate the association of endogenous nocturnal melatonin secretion with insulin resistance in humans. We analyzed the association between endogenous nocturnal melatonin secretion, estimated by measuring the main melatonin metabolite, 6-sulfatoxymelatonin, from the first morning urinary void, and the prevalence of insulin resistance based on fasting blood samples collected in a cross-sectional study of 1,075 US women (1997-1999) without diabetes, hypertension, or malignancy. Urinary 6-sulfatoxymelatonin level was standardized to urinary creatinine level; insulin resistance was defined as an insulin sensitivity index value (using the McAuley formula) less than 7.85. Logistic regression models included adjustment for age, body mass index, smoking, physical activity, alcohol intake, dietary glycemic index, family history of diabetes mellitus, blood pressure, plasma total cholesterol, uric acid, and estimated glomerular filtration rate. Higher nocturnal melatonin secretion was inversely associated with insulin levels and insulin resistance. In fully adjusted models, the odds ratio for insulin resistance was 0.45 (95% confidence interval: 0.28, 0.74) among women in the highest quartile of urinary 6-sulfatoxymelatonin:creatinine ratio compared with women in the lowest quartile. Nocturnal melatonin secretion is independently and inversely associated with insulin resistance.

  2. Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis

    PubMed Central

    Jaworek, Jolanta; Leja-Szpak, Anna; Nawrot-Porąbka, Katarzyna; Szklarczyk, Joanna; Kot, Michalina; Pierzchalski, Piotr; Góralska, Marta; Ceranowicz, Piotr; Warzecha, Zygmunt; Dembinski, Artur; Bonior, Joanna

    2017-01-01

    Melatonin is an indoleamine produced from the amino acid l-tryptophan, whereas metabolites of melatonin are known as kynuramines. One of the best-known kynuramines is N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK). Melatonin has attracted scientific attention as a potent antioxidant and protector of tissue against oxidative stress. l-Tryptophan and kynuramines share common beneficial features with melatonin. Melatonin was originally discovered as a pineal product, has been detected in the gastrointestinal tract, and its receptors have been identified in the pancreas. The role of melatonin in the pancreatic gland is not explained, however several arguments support the opinion that melatonin is probably implicated in the physiology and pathophysiology of the pancreas. (1) Melatonin stimulates pancreatic enzyme secretion through the activation of entero-pancreatic reflex and cholecystokinin (CCK) release. l-Tryptophan and AFMK are less effective than melatonin in the stimulation of pancreatic exocrine function; (2) Melatonin is a successful pancreatic protector, which prevents the pancreas from developing of acute pancreatitis and reduces pancreatic damage. This effect is related to its direct and indirect antioxidant action, to the strengthening of immune defense, and to the modulation of apoptosis. Like melatonin, its precursor and AFMK are able to mimic its protective effect, and it is commonly accepted that all these substances create an antioxidant cascade to intensify the pancreatic protection and acinar cells viability; (3) In pancreatic cancer cells, melatonin and AFMK activated a signal transduction pathway for apoptosis and stimulated heat shock proteins. The role of melatonin and AFMK in pancreatic tumorigenesis remains to be elucidated. PMID:28481310

  3. Inhibition of melatonin secretion by ethanol in man.

    PubMed

    Röjdmark, S; Wikner, J; Adner, N; Andersson, D E; Wetterberg, L

    1993-08-01

    To determine whether ethanol inhibits nocturnal melatonin (MT) secretion, three experiments (A, B, and C) were performed in seven normal subjects. In A, ethanol at a dose of 0.34 g/kg was administered orally at 6:00, 8:00, and 10:00 PM. Each dose was increased to 0.52 g/kg in B. In C, water was substituted for ethanol. Blood samples for determination of serum MT levels were drawn every second hour between 6:00 PM and 8:00 AM. Urinary excretion of MT during the night was also determined. In A, serum ethanol reached a maximal level of 13 +/- 1 mmol/L at 12 midnight. In B, the corresponding maximum was 25 +/- 1 mmol/L. The higher alcohol dose inhibited nocturnal MT secretion by 20% +/- 5% (P < .01), whereas the lower dose lacked such effect. Urinary excretion of MT was left unaffected by alcohol at both doses. Five additional normal subjects were given alcohol as described above at a dose of 0.52 g/kg (experiment D). This induced mild nocturnal hypoglycemia as evidenced by a glucose decremental area (5.9 +/- 1.8 mmol/L.h) that differed significantly from zero (P < .05). To determine whether a reduced glucose delivery to pinealocytes might contribute to the decreased MT secretion in alcohol-intoxicated subjects, two experiments (E and F) were performed in eight healthy individuals. In E, ethanol was given orally as in B; three small oral doses of glucose were also given at 8:00 PM, 10:00 PM, and 12 midnight. In F, water was substituted for ethanol and glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. The influence of vasopressin deficiency and acute desmopressin administration on melatonin secretion in patients with central diabetes insipidus.

    PubMed

    Catrina, S B; Rotarus, R; Wivall, I-L; Coculescu, M; Brismar, K

    2004-01-01

    Melatonin secretion is modulated by the light-dark schedule, mainly through a sympathetic input to the pineal gland. Besides this, arginine vasopressin (AVP) has been found in the pineal glands of several animal species and there is experimental evidence that AVP modulates melatonin secretion in animals. However, the interaction between vasopressin and melatonin secretion in humans has not been systematically investigated. We proposed to study the nocturnal melatonin pattern in patients with central diabetes insipidus (CDI) who lack endogenous secretion of AVP, and the effect on their melatonin secretion of the agonist for V2 type receptors: desmopressin (1-Desamino [8-D Arginine] vasopressin). Plasma melatonin levels were measured in 14 patients with CDI, every 2 h starting from 22:00 h until 06:00 h, following iv injection of saline (day 1) and 3 microg desmopressin (day 2) at 20:00 h. The lights were turned off at 22:30 h and the samples were taken in a dim light. The plasma melatonin secretion pattern was normal in patients with CDI. Desmopressin at a dose 3 times higher than the antidiuretic one did not modify the melatonin levels or the time of the peak secretion. In conclusion melatonin secretion is not modulated by AVP in humans.

  5. Melatonin secretion during postnatal development in wild and domestic female lambs.

    PubMed

    Gómez-Brunet, A; Santiago-Moreno, J; Chemineau, P; Malpaux, B; López-Sebastián, A

    2010-05-01

    This study examines the patterns of melatonin secretion during postnatal development in wild (mouflon; n = 7) and domestic (Spanish Merino; n = 6) female lambs under their natural photoperiod conditions. The aim was to determine whether these types of sheep which differ in the timing of puberty, also differ in the establishment of daily melatonin secretory rhythms and/or in the nocturnal plasma melatonin secretion. In addition, the time when the lambs first reached nocturnal levels of melatonin similar to adults was also evaluated. For this purpose, the melatonin secretion in lambs was compared with those of their mothers. A day/night (D/N) difference in plasma melatonin concentration was noticed as early as 1 day after birth in the Merino female lambs (D: 5.9 +/- 1.0 pg/ml compared to N: 22.0 +/- 3.3 pg/ml; p < 0.05), and by 1 week after birth in the mouflon female lambs (D: 4.9 +/- 0.3 pg/ml compared to N: 56.9 +/- 15.3 pg/ml; p < 0.05). An effect of the genotype (p < 0.05) and age (p < 0.01) was detected on mean nocturnal plasma melatonin concentrations, which were lower in the Merino than in the mouflon lambs. Night-time plasma concentration of melatonin was also high in mouflon than in Merino mothers (p < 0.05). No differences were detected between the wild genotype and the domestic one in the time when the lambs first reached nocturnal levels of melatonin similar to those of their mothers.

  6. Melatonin and cortisol secretion profile in patients with pineal cyst before and after pineal cyst resection.

    PubMed

    Májovský, Martin; Řezáčová, Lenka; Sumová, Alena; Pospíšilová, Lenka; Netuka, David; Bradáč, Ondřej; Beneš, Vladimír

    2017-05-01

    A pineal cyst is a benign affection of the human pineal gland on the borderline between pathology and normality. Only a small percentage of patients present with symptoms and a surgical treatment is indicated in highly selected cases. A melatonin secretion in patients with a pineal cyst before and after a pineal cyst resection has not been studied yet and the effect of surgery on human metabolism is unknown. The present study examined melatonin, cortisol and blood glucose secretion profiles perioperatively in a surgical group of 4 patients. The control group was represented by 3 asymptomatic patients with a pineal cyst. For each patient, 24-h circadian secretion curves of melatonin, cortisol and glycemia were acquired. An analysis of melatonin profiles showed an expected diurnal pattern with the night peak in patients before the surgery and in the control group. In contrast, melatonin levels in patients after the surgery were at their minimum throughout the whole 24-h period. The cortisol secretion was substantially increased in patients after the surgery. Blood glucose sampling showed no statistically significant differences. Clinical results demonstrated statistically significant headache relief measured by Visual Analogue Scale in patients after the surgery. Despite the small number of examined patients, we can conclude that patients with a pineal cyst preserved the physiological secretion of the hormone melatonin while patients who underwent the pineal cyst resection experienced a loss of endogenous pineal melatonin production, which equated with pinealectomy. Surprisingly, cortisol secretion substantially increased in patients after the surgery. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Can tryptophan supplement intake at breakfast enhance melatonin secretion at night?

    PubMed

    Nagashima, Shunsuke; Yamashita, Makoto; Tojo, Chiaki; Kondo, Masayuki; Morita, Takeshi; Wakamura, Tomoko

    2017-02-28

    Tryptophan (TRP) is an essential amino acid, and it has been suggested that TRP intake at breakfast combined with daytime bright light exposure can increase nocturnal melatonin secretion. However, the mechanisms involved are not yet clear. The aim of this study was to examine the effect of TRP supplement intake at breakfast on nocturnal melatonin secretion under different daytime light intensities in humans. Twelve subjects (aged 21.3 ± 3.0 years, mean ± standard deviation) participated in a random order in experimental sessions lasting 3 days under four conditions in a laboratory setting. The four conditions were TRP*Bright, Placebo*Bright, TRP*Dim, and Placebo*Dim. A TRP capsule (1000 mg) or a placebo starch capsule (1000 mg) were taken at breakfast. In addition, during the daytime (07:00-18:00), the subjects were asked to stay under different light intensities: >5000 lx (bright) or <50 lx (dim). Saliva samples were collected for measuring the concentration of melatonin. The time courses of melatonin concentration and dim light melatonin onset (DLMO) were compared among the four conditions using repeated measurements analysis of variance (ANOVA). Nocturnal melatonin concentrations in the bright light condition tended to be higher than in the dim light condition (main effect of light: p = .099). Moreover, in the bright light condition, the change in DLMO between baseline and after the intervention was significantly higher than that in the dim light condition (main effect of light: p <.001). However, the ANOVA results indicated no significant effect of TRP intake on melatonin secretion. Our findings indicated that intake of 1000 mg of TRP at breakfast on 1 day did not change nocturnal melatonin secretion, even though TRP is the precursor of melatonin. In contrast, daytime bright light exposure increased nocturnal melatonin secretion and advanced the phase of melatonin onset. Therefore, TRP supplementation, unlike exposure to daytime bright

  8. Melatonin administration reverses the alteration of amyloid precursor protein-cleaving secretases expression in aged mouse hippocampus.

    PubMed

    Mukda, Sujira; Panmanee, Jiraporn; Boontem, Parichart; Govitrapong, Piyarat

    2016-05-16

    Beta-amyloid (Aβ) peptide is the pathological hallmark of Alzheimer's disease (AD). Interestingly, Aβ is normally synthesized in the brain of healthy people; however, during advanced aging, the level of Aβ peptides increases. As a result, the aggregation of Aβ peptides leads to trafficking problems, synaptic loss, inflammation, and cell death. Melatonin, the hormone primarily synthesized and secreted from the pineal gland, is decreased with progressing age, particularly in Alzheimer's disease patients. The loss of melatonin levels and the abnormal accumulation of some proteins, such as Aβ peptides in the brains of AD patients are considered important factors in the initiation of the cognitive symptoms of dementia. A previous study in mice reported that increased brain melatonin levels remarkably diminished the potentially toxic Aβ peptide levels. The present study showed that aged mice significantly impaired spatial memory in the Morris Water Maze task. We also showed that α-, β-, and γ-secretases, which are type-I membrane protein proteases responsible for Aβ production, showed alterations in both mRNA and protein expression in the hippocampus of aged mice. The long-term administration of melatonin, mice had shorter escape latencies and remained in the target quadrant longer compared to the aged group. Melatonin attenuated the reduction of α-secretase and inhibited the increase of β- and γ-secretases. Moreover, melatonin attenuated the upregulation of pNFkB and the reduction of sirtuin1 in the hippocampus of aged mice. These results suggested that melatonin protected against Aβ peptide production in aged mice. Hence, melatonin loss in aging could be recompensed through dietary supplementation as a beneficial therapeutic strategy for AD prevention and progression.

  9. The role of somatostatin (octreotide) in the regulation of melatonin secretion in healthy volunteers and in patients with primary hypothyroidism.

    PubMed

    Wikner, J; Wetterberg, L; Röjdmark, S

    1999-01-01

    Somatostatin has been found in the pineal gland of several animal species, which suggests that it may be involved in the regulation of melatonin secretion. Whether somatostatin has regulatory influence on melatonin secretion in man has never been unequivocally shown. We studied the nocturnal melatonin secretion in 8 healthy volunteers, and 6 women with untreated primary hypothyroidism, a disease state that is associated with increased nocturnal secretion of melatonin. The participants were given subcutaneous injections at 18:00 h and 23:00 h of either saline or octreotide (Sandostatin; each injection 50 microg). During the nights when the healthy volunteers were given octreotide, melatonin secretion was similar to that recorded during administration of saline. Also the urinary excretion of melatonin was of similar magnitude at these two occasions. By contrast, the GH secretion was significantly lower the nights the healthy controls were given octreotide (GH AUC 22.6+/-5.4 mU/l x h during octreotide and 126.6+/-21.9 mU/l x h during saline; p<0.01). The patients with hypothyroidism also showed similar nocturnal melatonin secretion during octreotide and saline. Urinary excretion of melatonin also remained unchanged, as did GH secretion. The total nocturnal secretion of TSH was, however, significantly reduced by octreotide (TSH AUC 562+/-136 mU/l x h during octreotide and 851+/-185 mU/l x h during saline; p<0.05), thus suggesting that 100 microg of octreotide should be sufficient to inhibit also the pinealocytes if their function were regulated by somatostatin. Since exogenous somatostatin--in the form of octreotide--fails to influence nocturnal secretion and urinary excretion of melatonin in normal subjects and in patients with primary hypothyroidism, it is reasonable to assume that endogenous somatostatin may not be an important regulator of melatonin secretion in man.

  10. Modulation of Ca2+ oscillation and melatonin secretion by BKCa channel activity in rat pinealocytes.

    PubMed

    Mizutani, Hiroya; Yamamura, Hisao; Muramatsu, Makoto; Hagihara, Yumiko; Suzuki, Yoshiaki; Imaizumi, Yuji

    2016-05-01

    The pineal glands regulate circadian rhythm through the synthesis and secretion of melatonin. The stimulation of nicotinic acetylcholine receptor due to parasympathetic nerve activity causes an increase in intracellular Ca(2+) concentration and eventually downregulates melatonin production. Our previous report shows that rat pinealocytes have spontaneous and nicotine-induced Ca(2+) oscillations that are evoked by membrane depolarization followed by Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs). These Ca(2+) oscillations are supposed to contribute to the inhibitory mechanism of melatonin secretion. Here we examined the involvement of large-conductance Ca(2+)-activated K(+) (BKCa) channel conductance on the regulation of Ca(2+) oscillation and melatonin production in rat pinealocytes. Spontaneous Ca(2+) oscillations were markedly enhanced by BKCa channel blockers (1 μM paxilline or 100 nM iberiotoxin). Nicotine (100 μM)-induced Ca(2+) oscillations were also augmented by paxilline. In contrast, spontaneous Ca(2+) oscillations were abolished by BKCa channel opener [3 μM 12,14-dichlorodehydroabietic acid (diCl-DHAA)]. Under whole cell voltage-clamp configurations, depolarization-elicited outward currents were significantly activated by diCl-DHAA and blocked by paxilline. Expression analyses revealed that the α and β3 subunits of BKCa channel were highly expressed in rat pinealocytes. Importantly, the activity of BKCa channels modulated melatonin secretion from whole pineal gland of the rat. Taken together, BKCa channel activation attenuates these Ca(2+) oscillations due to depolarization-synchronized Ca(2+) influx through VDCCs and results in a recovery of reduced melatonin secretion during parasympathetic nerve activity. BKCa channels may play a physiological role for melatonin production via a negative-feedback mechanism.

  11. Pineal melatonin synthesis is altered in Period1 deficient mice.

    PubMed

    Christ, E; Pfeffer, M; Korf, H W; von Gall, C

    2010-12-01

    Melatonin is an important endocrine signal for darkness in mammals. Transcriptional activation of the arylalkylamine-N-acetyltransferase gene encoding for the penultimate enzyme in melatonin synthesis drives the daily rhythm of the hormone in the pineal gland of rodents. Rhythmic arylalkylamine-N-acetyltransferase expression is controlled by the cAMP-signal transduction pathway and involves the activation of β-adrenergic receptors and the inducible cAMP early repressor. In addition, the rat arylalkylamine-N-acetyltransferase promoter contains an E-box element which can interact with clock proteins. Moreover, the pineal gland of mice shows a circadian rhythm in clock proteins such as the transcriptional repressor Period1, which has been shown to control rhythmic gene expression in a variety of tissues. However, the role of Period1 in the regulation of pineal melatonin synthesis is still unknown. Therefore, circadian rhythms in arylalkylamine-N-acetyltransferase, β-adrenergic receptor, and inducible cAMP early repressor mRNA levels (real time PCR), arylalkylamine-N-acetyltransferase enzyme activity (radiometric assay) and melatonin concentration radio immuno assay (RIA) were analyzed in the pineal gland of mice with a targeted deletion of the Period1 gene (Per1-/-) and the corresponding wildtype. In Per1-/- the amplitude in arylalkylamine-N-acetyltransferase expression was significantly elevated as compared to wildtype. In contrast, β-adrenergic receptor and inducible cAMP early repressor mRNA levels were not affected by the Period1-deficiency. This indicates that the molecular clockwork alters the amplitude of arylalkylamine-N-acetyltransferase expression. In vitro, pineal glands of Per1-/- mice showed a day night difference in arylalkylamine-N-acetyltransferase expression with high levels at night. This suggests that a deficient in Period1 elicits similar effects as the activation of the cAMP-signal transduction pathway in wildtype mice.

  12. Geomagnetic activity influences the melatonin secretion at latitude 70 degrees N.

    PubMed

    Weydahl, A; Sothern, R B; Cornélissen, G; Wetterberg, L

    2001-01-01

    Factors other than light may affect variations in melatonin, including disturbances in the geomagnetic field. Such a possibility was tested in Alta, Norway, located at latitude 70 degrees N, where the aurora borealis is a result of large changes in the horizontal component (H) of the geomagnetic field. Geomagnetic disturbances are felt more strongly closer to the pole than at lower latitudes. Also noteworthy in Alta is the fact that the sun does not rise above the horizon for several weeks during the winter. To examine whether changes in geomagnetic activity influence the secretion of melatonin, saliva was collected from 25 healthy subjects in Alta several times during the day-night and at different times of the year. Single cosinor analyses yielded individual estimates of.the circadian amplitude and MESOR of melatonin. A 3-hour mean value for the local geomagnetic activity index, K, was used for approximately the same 24-hour span. A circadian rhythm was found to characterize both melatonin and K, the peak in K (23:24) preceding that of melatonin (06:08). During the span of investigation, a circannual variation also characterized both variables. Correlation analyses suggest that changes in geomagnetic activity had to be of a certain magnitude to affect the circadian amplitude of melatonin. If large enough (> 80 nT/3 h), changes in geomagnetic activity also significantly decreased salivary melatonin concentration.

  13. Role of melatonin in the control of growth and growth hormone secretion in poultry.

    PubMed

    Zeman, M; Buyse, J; Lamosová, D; Herichová, I; Decuypere, E

    1999-10-01

    The pineal hormone melatonin controls reproduction of photoperiodic mammals and is an integral part of the circadian organization in birds. Recent findings indicate an involvement of this hormone also in more basic physiological processes, including growth, development, and aging. Melatonin may modulate growth in poultry through interaction with transcriptional factors, through interaction with hormones involved in growth control, and by modulation of energy metabolism and decreasing physical activity. Our studies showed that a single melatonin injection increased plasma growth hormone (GH) concentrations in the Japanese quail. Specific serotonin receptor blocker ketanserin did not preclude a stimulatory action of melatonin on GH synthesis. Serotonin agonist quipazine increased GH levels but failed to enhance the stimulatory effect of melatonin. Pretreatment with melatonin in drinking water did not affect the magnitude of the GH response to subcutaneous (s.c.) administration of thyrotropin releasing hormone (TRH) that considerably stimulated GH secretion. Present data suggest that melatonin modulates rather central neural pathways involved in the control of GH synthesis at the hypothalamic level than the sensitivity of the pituitary gland.

  14. Exosomes from Melatonin Treated Hepatocellularcarcinoma Cells Alter the Immunosupression Status through STAT3 Pathway in Macrophages

    PubMed Central

    Cheng, Liang; Liu, Jiatao; Liu, Qingqing; Liu, Yu; Fan, Lulu; Wang, Fang; Yu, Hanqing; Li, Yuhuan; Bu, Lijia; Li, Xiaoqiu; Wei, Wei; Wang, Hua; Sun, Guoping

    2017-01-01

    Immunosuppression is a significant factor in the progression of tumor invasion and metastasis. Melatonin, a well-known hormone, has certain cytotoxic and immune regulatory effects to inhibit tumor function. Exosomes are small membrane vesicles released by many kinds of cells, which contain different macromolecules, such as mRNAs and microRNAs (miRNAs), and proteins that can mediate communications between cells. Tumor-derived exosomes may cause immunosuppression, however, it is unknown whether melatonin can attenuate an immunosuppressive status by altering the function of tumor-derived exosomes. In the present study, we evaluated the effects of hepatocellularcarcinoma-derived exosomes (Exo-con) and exosomes derived from hepatocellularcarcinoma cells treated with 0.1 mM melatonin (Exo-MT), on the expression of inflammatory factors and programmed death ligand 1(PD-L1) by co-culturing Exo-con and Exo-MT, respectively, with macrophages differentiated from THP-1 cells or RAW264.7 cells. Our in vitro results indicate that Exo-MT can downregulate the expression of PD-L1 on macrophages while Exo-con can upregulate the expression of PD-L1 through flow cytometry and immunofluorescence analysis. In addition, Exo-con upregulates the secretion of cytokines, such as IL-6, IL-10, IL-1β, and TNF-α in macrophages. Accordingly, Exo-MT could attenuate the high expression of these inflammatory cytokines. Furthermore, in vivo experiments confirmed the results found in vitro. PD-L1 expression and cytokine secretion were lower in the Exo-MT group compared with those in the Exo-con group. Working to identify a specific mechanism, our research shows that Exo-MT decreases STAT3 activation compared to the Exo-con group. In summary, we found exosomes from melatonin treated hepatocellularcarcinoma cells alters the immunosupression status through STAT3 pathway in macrophages. Our study may provide a new avenue to investigate the mechanisms of melatonin in regulating an immunosuppressive status

  15. A preliminary study on the relationships between diurnal melatonin secretion profile and sleep variables in patients emergently admitted to the coronary care unit.

    PubMed

    Takaesu, Yoshikazu; Futenma, Kunihiro; Kobayashi, Mina; Komada, Yoko; Tanaka, Nobuhiro; Yamashina, Akira; Inoue, Yuichi

    2015-01-01

    To clarify the significance of melatonin secretion under intensive care conditions, we investigated melatonin secretion profiles and sleep parameters of 23 patients just after admission to the coronary care unit (CCU) and 19 age-matched controls. Sleep parameters were evaluated by actigraphy, and melatonin secretion was assessed by measuring the urinary 6-sulphatoxy melatonin (6-SMT). 6-SMT secretion was lower and nocturnal sleep parameters were less satisfactory in the subjects than those in the controls, and there were positive correlations between these variables, particularly in the subject patients. The lowered melatonin secretion might be involved in the mechanism of insomnia in CCU patients.

  16. Low testosterone levels and unimpaired melatonin secretion in young males with metabolic syndrome.

    PubMed

    Robeva, R; Kirilov, G; Tomova, A; Kumanov, P

    2006-12-01

    The interrelations between testosterone, insulin and melatonin levels in males with metabolic syndrome (MS) are still not clarified, especially in young age groups. The aim of the present study was to compare the testosterone serum levels in young men with MS to those in healthy controls, and to determine the possible changes in their melatonin rhythm, as well as the relation between melatonin, insulin and lipid profile. Fasting insulin and testosterone concentrations were measured in 10 healthy nonobese and 10 MS patients. Blood samples for melatonin, insulin and luteinizing hormone (LH) were collected at 19.00, 03.00 and 11.00 hours. A significant difference was found between the testosterone levels in controls and patients. Luteinizing hormone levels in both groups were similar, however, higher night LH levels in MS patients were observed. No changes in the melatonin concentrations of the two groups were found. In conclusion, total testosterone levels were significantly lower in young men with MS compared with healthy age-matched controls. Mild hypoandrogenia in hyperinsulinaemic patients was not related with changes in their melatonin levels. No alterations in the endogenous melatonin rhythm of the MS patients were found.

  17. Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment.

    PubMed

    De Leersnyder, Hélène

    2006-09-01

    Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features and congenital anomalies ascribed to an interstitial deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptative daytime behavior have been linked to an abnormal circadian secretion pattern of melatonin, with a diurnal instead of nocturnal secretion of this hormone. SMS provides a demonstration of a biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate the generation of the circadian rhythm, haploinsufficiency for a circadian system gene, mapping to chromosome 17p11.2 might cause the inversion of the melatonin circadian rhythm in SMS. The disorder of circadian timing in SMS might also affect the entrainment pathway (retinohypothalamic tract), pacemaker functions (suprachiasmatic nucleus) or synthesis and release of melatonin by the pineal gland. Elucidating pathophysiological mechanisms of behavioral phenotypes in genetic disease can provide an original therapeutic approach in SMS: blockade of endogenous melatonin production during the day combined with exogenous melatonin administration in the evening.

  18. Effect of calcium on melatonin secretion in chick pineal gland I.

    PubMed

    Pablos, M I; Agapito, M T; Gutierrez-Baraja, R; Reiter, R J; Recio, J M

    1996-10-18

    Melatonin is the neurohormone which is synthesized by the pineal gland and secreted rhythmically. The role of calcium in the activation of melatonin production remains unknown. In this study, we demonstrated that calcium input participates in the regulation of chick pineal gland. Pineal glands from Gallus domesticus were perifuse with Krebs medium (controls) or with Krebs medium plus drugs (ethylene glycol tetraacetic acid (EGTA) or calcium ionophore A23187). When EGTA was added to the perifusion medium, free extracellular calcium concentrations were dramatically decreased and melatonin synthesis was decreased. On the other hand, when the calcium ionophore A23187 was added to the perifusion medium, chick pineal glands exhibited a marked increase in secretion of melatonin. No effects were observed when chick pineal glands were treated with drugs during or after the time of the natural peak levels. We propose that calcium input from extracellular medium and output from intracellular calcium reserves are primary mechanisms in the activation of melatonin synthesis in the chick pineal gland.

  19. Transcutaneous Auricular Vagus Nerve Stimulation Triggers Melatonin Secretion and Is Antidepressive in Zucker Diabetic Fatty Rats

    PubMed Central

    Rong, Peijing; McCabe, Michael F.; Zhao, Jingjun; Ben, Hui; Wang, Xing; Wang, Shuxing

    2014-01-01

    Decreased circulating melatonin is implicated in depression. We recently found that Zucker diabetic fatty rats (ZDF, fa/fa) develop depression-like behaviors and that transcutaneous auricular vagus nerve stimulation (taVNS) is antidepressive in ZDF rats. Here we studied whether the ZDF rats could be used as a depression rodent model and whether the antidepressive effect of taVNS is mediated through modulation of melatonin secretion. Adult male ZDF and Zucker lean (ZL, fa/+) littermates were used. 30 min-taVNS procedures (2/15 Hz, 2 mA) were administered once daily under anesthesia for 34 consecutive days in pineal intact ZDF (n = 8) and ZL (n = 6) rats, as well as in pinealectomized ZDF rats (n = 8). Forced swimming test (FST) was used to determine depression-like behavior and ELISA to detect plasma melatonin concentration on day 35. We found that naïve ZDF rats had a longer immobility time in FST and that long-term (34 days) taVNS treatment ameliorated the depression-like behavior. In both pineal intact and pinealectomized ZDF rats, taVNS induced acute melatonin secretion, both during and after the taVNS session. A low melatonin level is related to the poor FST performance in ZDF rats (R = −0.544) in contrast to ZL rats (R = 0.247). In conclusion, our results show that ZDF rats are ideal candidates of innate depression and that taVNS is antidepressive through triggering melatonin secretion and increasing its production. PMID:25347185

  20. The effect of light on melatonin secretion in the cultured pineal glands of Anolis lizards.

    PubMed

    Moore, Ashli F; Menaker, Michael

    2011-10-01

    Melatonin, a hormone produced by the pineal gland, is important for regulating circadian rhythms in many animals. Light at night causes an acute suppression of melatonin in nearly all vertebrate species. A previous study found that light failed to suppress melatonin in the lizard Anolis carolinensis. This is a surprising result given that the Anolis pineal gland is intrinsically photosensitive, is a key pacemaker controlling locomotor activity, and can be directly entrained to a light-dark cycle. To find out if the lack of photic suppression is widespread in the Anolis genus, we investigated the acute effects of light on melatonin secretion in five different species of Anolis using flow-through tissue culture. We administered a two-hour pulse of bright light to isolated pineal glands during the night. The results show photic suppression of melatonin in all five Anolis species, but the suppression is weak relative to that seen in other vertebrates. Moreover, Anolis species differ in the magnitude of the effect. These findings are discussed in the context of vertebrate pineal evolution and the ecology of Anolis lizards. Given their extensive phylogenetic and ecological divergence, Anolis lizards provide a promising system for investigating the ecology and evolution of circadian organization.

  1. Melatonin in Aging and Disease —Multiple Consequences of Reduced Secretion, Options and Limits of Treatment

    PubMed Central

    Hardeland, Rüdiger

    2012-01-01

    Melatonin is a pleiotropically acting regulator molecule, which influences numerous physiological functions. Its secretion by the pineal gland progressively declines by age. Strong reductions of circulating melatonin are also observed in numerous disorders and diseases, including Alzheimer’s disease, various other neurological and stressful conditions, pain, cardiovascular diseases, cases of cancer, endocrine and metabolic disorders, in particular diabetes type 2. The significance of melatonergic signaling is also evident from melatonin receptor polymorphisms associated with several of these pathologies. The article outlines the mutual relationship between circadian oscillators and melatonin secretion, the possibilities for readjustment of rhythms by melatonin and its synthetic analogs, the consequences for circadian rhythm-dependent disorders concerning sleep and mood, and limits of treatment. The necessity of distinguishing between short-acting melatonergic effects, which are successful in sleep initiation and phase adjustments, and attempts of replacement strategies is emphasized. Properties of approved and some investigational melatonergic agonists are compared. PMID:22724080

  2. Spectral modulation of light wavelengths using optical filters: effect on melatonin secretion.

    PubMed

    Casper, Robert F; Rahman, Shadab

    2014-08-01

    Shiftwork has been identified as a risk factor for various medical problems, such as cancer, heart disease, metabolic disturbances, depression, and anxiety disorders, and as reviewed this month, adverse reproductive function. Shiftwork misaligns physiological rhythms with respect to each other and to external environmental rhythms such as the 24-hour light/dark cycle. Light is the strongest time cue for entraining circadian rhythms in mammals, and aberrant light exposure patterns during shiftwork is one of the key factors that induce circadian misalignment. We have recently demonstrated, in both animal and clinical models, that filtering short wavelengths (below 480 nm) from nocturnal lighting can attenuate alterations in hormone secretion (melatonin and glucocorticoids) and in central and peripheral clock gene expression induced by nighttime light exposure. We also demonstrated that the use of optical filters led to an improvement in mood and in cognitive performance under controlled laboratory conditions and during field-based shiftwork studies. Moreover, there was an increase in sleep duration and quality on nights immediately following night shifts. We believe it is likely that optical filters incorporated into glasses or as coverings for light bulbs could be used as a method to improve or prevent many of the medical problems associated with circadian misalignment and rotating shiftwork.

  3. Effects of orexigenic peptides and leptin on melatonin secretion during different photoperiods in seasonal breeding ewes: an in vitro study.

    PubMed

    Zieba, D A; Kirsz, K; Molik, E; Romanowicz, K; Wojtowicz, A K

    2011-04-01

    The pineal gland (PG) acts as a neuroendocrine transducer of daily and seasonal time through the nocturnal release of melatonin. Here, we examined the interaction of season, orexin, ghrelin, and leptin on melatonin secretion by pineal explants in short-term culture. Glands were collected after sunset from 12 ewes during long days (LD; April and May) and from an additional 12 ewes during short days (SD; October and November). Glands were transected sagittally into strips, with each equilibrated in 2.5 mL of Dulbecco's modified Eagle's medium for 60 min, followed by a 2-h incubation in control medium or medium containing orexin B (10 and 100 ng/mL), ghrelin (10 and 100 ng/mL), or 50 ng/mL of leptin. After a 3-h incubation, some PG explants treated previously with lower doses of orexin or ghrelin were challenged with 50 ng/mL of leptin and those treated with both doses of orexin were challenged with 300 nM of the β-agonist isoproterenol. One milliliter of medium was harvested and replaced from each well every 30 min. Treatment with the low dose of orexin during LD increased melatonin secretion about 110% (P<0.01); treatment with a high dose increased melatonin secretion about 47% (P<0.001). During the SD period, leptin stimulated (P < 0.05) melatonin secretion slightly compared with mean melatonin concentration in controls. However, together, orexin and leptin depressed (P<0.01) melatonin secretion. Both doses of ghrelin reduced (P < 0.01) melatonin concentration during the SD season compared with control culture. Addition of ghrelin and leptin to culture medium increased (P<0.01) melatonin concentration compared with ghrelin-treated culture and decreased melatonin concentration (P<0.01) compared with leptin-treated culture during SD. Isoproterenol stimulated (P<0.01) melatonin secretion compared with values observed during the pretreatment period. We conclude that orexigenic peptides (orexin B and ghrelin) and an anorectic peptide (leptin) affect PG directly. The

  4. Dietary melatonin alters uterine artery hemodynamics in pregnant holstein heifers

    USDA-ARS?s Scientific Manuscript database

    The objective was to examine uterine artery hemodynamics and maternal serum profiles in pregnant heifers supplemented with dietary melatonin (MEL) or no supplementation (CON). In addition, melatonin receptor–mediated responses in steroid metabolism were examined using a bovine endometrial epithelial...

  5. Melatonin influences somatostatin secretion from human pancreatic δ-cells via MT1 and MT2 receptors.

    PubMed

    Zibolka, Juliane; Mühlbauer, Eckhard; Peschke, Elmar

    2015-03-01

    Melatonin is an effector of the diurnal clock on pancreatic islets. The membrane receptor-transmitted inhibitory influence of melatonin on insulin secretion is well established and contrasts with the reported stimulation of glucagon release from α-cells. Virtually, nothing is known concerning the melatonin-mediated effects on islet δ-cells. Analysis of a human pancreatic δ-cell model, the cell line QGP-1, and the use of a somatostatin-specific radioimmunoassay showed that melatonin primarily has an inhibitory effect on somatostatin secretion in the physiological concentration range. In the pharmacological range, melatonin elicited slightly increased somatostatin release from δ-cells. Cyclic adenosine monophosphate (cAMP) is the major second messenger dose-dependently stimulating somatostatin secretion, in experiments employing the membrane-permeable 8-Br-cAMP. 8-Br-cyclic guanosine monophosphate proved to be of only minor relevance to somatostatin release. As the inhibitory effect of 1 nm melatonin was reversed after incubation of QGP-1 cells with the nonselective melatonin receptor antagonist luzindole, but not with the MT2-selective antagonist 4-P-PDOT (4-phenyl-2-propionamidotetraline), an involvement of the MT1 receptor can be assumed. Somatostatin release from the δ-cells at low glucose concentrations was significantly inhibited during co-incubation with 1 nm melatonin, an effect which was less pronounced at higher glucose levels. Transient expression experiments, overexpressing MT1, MT2, or a deletion variant as a control, indicated that the MT1 and not the MT2 receptor was the major transmitter of the inhibitory melatonin effect. These data point to a significant influence of melatonin on pancreatic δ-cells and on somatostatin release.

  6. Evidence for a seasonal variation in the ability of exogenous melatonin to suppress prolactin secretion in the mare.

    PubMed

    Fitzgerald, B P; Davison, L A; McManus, C J

    2000-05-01

    In seasonally breeding species photoperiodic information is thought to be conveyed to the reproductive and prolactin axis via changes in circulating concentrations of melatonin. For some species, a constant melatonin stimulus is perceived as a short day, whereas in others no photoperiodic information is provided. In the mare, a preliminary study demonstrated that constant administration of melatonin did not modify prolactin secretion, suggesting that this treatment regimen failed to provide photoperiodic information. To further investigate this proposal and to investigate an alternative explanation, namely a seasonal variation in response to melatonin, 4 experiments were performed. In experiments 1-3, the effects of constant administration of melatonin on prolactin secretion were investigated. In each study the time of treatment initiation varied beginning before the summer solstice, (May 9; Exp. 1), at the autumnal equinox (Sept. 21; Exp. 2) or the winter solstice (Dec. 21; Exp. 3). In Experiment 4, melatonin was administered as a timed daily injection (5 PM) for 6 months, beginning at the summer solstice (June 21). Constantly elevated physiological concentrations of melatonin (expts. 1-3) and an extended nighttime elevation of melatonin (exp. 4) suppressed prolactin concentrations only during the spring and early summer months (April-August). At other times during the year prolactin concentrations were similar to untreated mares. In the presence of a continuous melatonin implant the circannual rhythm of prolactin secretion was not disturbed. The results suggest that the prolactin axis of the mare is sensitive to an inhibitory melatonin signal during a restricted period of time and that at other times is refractory to this signal.

  7. What is known about melatonin, chemotherapy and altered gene expression in breast cancer

    PubMed Central

    Martínez-Campa, Carlos; Menéndez-Menéndez, Javier; Alonso-González, Carolina; González, Alicia; Álvarez-García, Virginia; Cos, Samuel

    2017-01-01

    Melatonin, synthesized in and released from the pineal gland, has been demonstrated by multiple in vivo and in vitro studies to have an oncostatic role in hormone-dependent tumors. Furthermore, several clinical trials point to melatonin as a promising adjuvant molecule to be considered for cancer treatment. In the past few years, evidence of a broader spectrum of action of melatonin as an antitumor agent has arisen; thus, melatonin appears to also have therapeutic effects in several types of hormone-independent cancer, including ovarian, leukemic, pancreatic, gastric and non-small cell lung carcinoma. In the present study, the latest findings regarding melatonin molecular actions when concomitantly administered with either radiotherapy or chemotherapy in cancer were reviewed, with a particular focus on hormone-dependent breast cancer. Finally, the present study discusses which direction should be followed in the next years to definitely clarify whether or not melatonin administration could protect against non-desirable effects (such as altered gene expression and post-translational protein modifications) caused by chemotherapy or radiotherapy treatments. As treatments move towards personalized medicine, comparative gene expression profiling with and without melatonin may be a powerful tool to better understand the antitumor effects of melatonin, the pineal gland hormone. PMID:28454355

  8. Melatonin: Physiological effects in humans.

    PubMed

    Claustrat, B; Leston, J

    2015-01-01

    Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal light/dark conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be evaluated by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body structures. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas under field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlations between clinical observations and melatonin secretion, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions depend also on the melatonin signal, for instance immune, antioxidant defences, haemostasis and glucose regulation. The difference between physiological and pharmacological effects of melatonin is not always clear but is based upon consideration of dose and not of duration of the hormone message. It is admitted that a "physiological" dose provides plasma melatonin levels in the same order of magnitude as a nocturnal peak. Since the regulating system of melatonin secretion

  9. Differential melatonin alterations in cerebrospinal fluid and serum of patients with major depressive disorder and bipolar disorder.

    PubMed

    Bumb, J M; Enning, F; Mueller, J K; van der List, Till; Rohleder, C; Findeisen, P; Noelte, I; Schwarz, E; Leweke, F M

    2016-07-01

    Melatonin, which plays an important role for regulation of circadian rhythms and the sleep/wake cycle has been linked to the pathophysiology of major depressive and bipolar disorder. Here we investigated melatonin levels in cerebrospinal fluid (CSF) and serum of depression and bipolar patients to elucidate potential differences and commonalities in melatonin alterations across the two disorders. Using enzyme-linked immunosorbent assays, CSF and serum melatonin levels were measured in 108 subjects (27 healthy volunteers, 44 depressed and 37 bipolar patients). Covariate adjusted multiple regression analysis was used to investigate group differences in melatonin levels. In CSF, melatonin levels were significantly decreased in bipolar (P<0.001), but not major depressive disorder. In serum, we observed a significant melatonin decrease in major depressive (P=0.003), but not bipolar disorder. No associations were found between serum and CSF melatonin levels or between melatonin and measures of symptom severity or sleep disruptions in either condition. This study suggests the presence of differential, body fluid specific alterations of melatonin levels in bipolar and major depressive disorder. Further, longitudinal studies are required to explore the disease phase dependency of melatonin alterations and to mechanistically explore the causes and consequences of site-specific alterations. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Effects of tryptophan-rich breakfast and light exposure during the daytime on melatonin secretion at night.

    PubMed

    Fukushige, Haruna; Fukuda, Yumi; Tanaka, Mizuho; Inami, Kaoru; Wada, Kai; Tsumura, Yuki; Kondo, Masayuki; Harada, Tetsuo; Wakamura, Tomoko; Morita, Takeshi

    2014-11-19

    The purpose of the present study is to investigate effects of tryptophan intake and light exposure on melatonin secretion and sleep by modifying tryptophan ingestion at breakfast and light exposure during the daytime, and measuring sleep quality (by using actigraphy and the OSA sleep inventory) and melatonin secretion at night. Thirty three male University students (mean ± SD age: 22 ± 3.1 years) completed the experiments lasting 5 days and 4 nights. The subjects were randomly divided into four groups: Poor*Dim (n = 10), meaning a tryptophan-poor breakfast (55 mg/meal) in the morning and dim light environment (<50 lx) during the daytime; Rich*Dim (n = 7), tryptophan-rich breakfast (476 mg/meal) and dim light environment; Poor*Bright (n = 9), tryptophan-poor breakfast and bright light environment (>5,000 lx); and Rich*Bright (n = 7), tryptophan-rich breakfast and bright light. Saliva melatonin concentrations on the fourth day were significantly lower than on the first day in the Poor*Dim group, whereas they were higher on the fourth day in the Rich*Bright group. Creatinine-adjusted melatonin in urine showed the same direction as saliva melatonin concentrations. These results indicate that the combination of a tryptophan-rich breakfast and bright light exposure during the daytime could promote melatonin secretion at night; further, the observations that the Rich*Bright group had higher melatonin concentrations than the Rich*Dim group, despite no significant differences being observed between the Poor*Dim and Rich*Dim groups nor the Poor*Bright and Rich*Bright groups, suggest that bright light exposure in the daytime is an important contributor to raised melatonin levels in the evening. This study is the first to report the quantitative effects of changed tryptophan intake at breakfast combined with daytime light exposure on melatonin secretion and sleep quality. Evening saliva melatonin secretion changed significantly and indicated that a tryptophan

  11. Low ambient temperature accelerates short-day responses in Siberian hamsters by altering responsiveness to melatonin.

    PubMed

    Larkin, J E; Freeman, D A; Zucker, I

    2001-02-01

    Exposure to low ambient temperatures (Ta) accelerates appearance of the winter phenotype in Siberian hamsters transferred from long to short day lengths. Because melatonin transduces the effects of day length on the neuroendocrine axis, the authors assessed whether low Ta promotes the transition to winterlike traits by accelerating the onset of increased nocturnal melatonin secretion or by enhancing responsiveness to melatonin in short day lengths. Male hamsters were transferred from 16L (16 h light/day) to 8L (8 h light/day) photoperiods and held at 5 degrees C or 22 degrees C. Locomotor activity was recorded continuously, and body mass, testis size, and pelage color were determined biweekly for 8 weeks. The duration of nocturnal locomotion (alpha), a reliable indicator of the duration of nocturnal melatonin secretion, lengthened significantly earlier in hamsters exposed to a Ta of 5 degrees C than 22 degrees C. Cold exposure increased the proportion of hamsters that were photoresponsive: gonadal regression in short days increased from 44% at 22 degrees C to 81% at 5 degrees C (p < 0.05); low Ta did not, however, accelerate testicular regression in animals that were photoresponsive. Nonphotoresponsive animals at 5 degrees C temporarily had longer alphas during the first 4 weeks in short days and significant decreases in body mass and testicular size that were reversed during the ensuing weeks when alpha decreased. In a 2nd experiment, pinealectomized male hamsters infused for 10 h/day with melatonin for 2 weeks had significantly lower body and testes masses when maintained at 5 degrees C but not 22 degrees C. Low-ambient temperature appears to accelerate the appearance of the winter phenotype primarily by increasing target tissue responsiveness to melatonin and to a lesser extent by augmenting the rate at which the duration of nocturnal melatonin secretion increases in short day lengths.

  12. [The circadian system in man: From the internal clock to melatonin secretion].

    PubMed

    Touitou, Y

    2016-09-01

    The internal or biological clock which is located in the suprachiasmatic nuclei of the anterior hypothalamus is controlled by clock genes and environmental factors which are able to synchronize the clock to 24h. Rhythm desynchronization (shiftwork and nightwork, transmeridian flights, aging, some psychiatric diseases, blindness, intake of some drugs…) occurs when the internal clock does no longer work in harmony with the astronomical time i.e. our watch. The circadian system consists of three major elements, which are the clock, the retinohypothalamic tract and melatonin which is secreted by the pineal gland and considered as the arrow of the clock. Both light and melatonin present a phase response curve useful for the treatment of sleep circadian disorders. Copyright © 2016 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

  13. Melatonin in pathogenesis and therapy of cancer.

    PubMed

    Ravindra, T; Lakshmi, N K; Ahuja, Y R

    2006-12-01

    Melatonin is a neuroendocrine hormone secreted by the pineal gland to transduce the body's circadian rhythms. An internal 24 hour time keeping system (biological clock) regulated by melatonin, controls the sleep-wake cycle. Melatonin production is a highly conserved evolutionary phenomenon. The indole hormone is synthesized in the pinealocytes derived from photoreceptors. Altered patterns and/or levels of melatonin secretion have been reported to coincide with sleep disorders, jetlag, depression, stress, reproductive activities, some forms of cancer and immunological disorders. Lately, the physiological and pathological role of melatonin has become a priority area of investigation, particularly in breast cancer, melanoma, colon cancer, lung cancer and leukemia. According to the 'melatonin hypothesis' of cancer, the exposure to light at night (LAN) and anthropogenic electric and magnetic fields (EMFs) is related to the increased incidence of breast cancer and childhood leukaemia via melatonin disruption. Melatonin's hypothermic, antioxidant and free radical scavenging properties, attribute it to an immunomodulator and an oncostatic agent as well. Many clinical studies have envisaged the potential therapeutic role of melatonin in various pathophysiological disorders, particularly cancer. A substantial reduction in risk of death and low adverse effects were reported from various randomized controlled trials of melatonin treatment in cancer patients. This review summarizes the physiological significance of melatonin and its potential role in cancer therapy. Furthermore, the article focuses on melatonin hypothesis to represent the cause-effect relationship of the three aspects: EMF, LAN and cancer.

  14. Melatonin Alters the Mechanical and Thermal Hyperalgesia Induced by Orofacial Pain Model in Rats.

    PubMed

    Scarabelot, Vanessa Leal; Medeiros, Liciane Fernandes; de Oliveira, Carla; Adachi, Lauren Naomi Spezia; de Macedo, Isabel Cristina; Cioato, Stefania Giotti; de Freitas, Joice S; de Souza, Andressa; Quevedo, Alexandre; Caumo, Wolnei; Torres, Iraci Lucena da Silva

    2016-10-01

    Melatonin is a neuroendocrine hormone that presents a wide range of physiological functions including regulating circadian rhythms and sleep, enhancing immune function, sleep improvement, and antioxidant effects. In addition, melatonin has received special attention in pain treatment since it is effective and presents few adverse effects. In this study, we evaluated the effect of acute dose of melatonin upon hyperalgesia induced by complete Freund's adjuvant in a chronic orofacial pain model in Sprague-Dawley rats. Nociceptive behavior was assessed by facial Von Frey and the hot plate tests at baseline and thereafter 30, 60, and 120 min, 24 h, and 7 days after melatonin treatment. We demonstrated that acute melatonin administration alters mechanical and thermal hyperalgesia induced by an orofacial pain model (TMD), highlighting that the melatonin effect upon mechanical hyperalgesia remained until 7 days after its administration. Besides, we observed specific tissue profiles of neuroimmunomodulators linked to pain conditions and/or melatonin effect (brain-derived neurotrophic factor, nerve growth factor, and interleukins 6 and 10) in the brainstem levels, and its effects were state-dependent of the baseline of these animals.

  15. Role of tachykinin receptors and melatonin in oxitocin secretion from isolated rat hypothalmo-neurohypophysial system.

    PubMed

    Juszczak, M; Furykiewicz-Nykiś, K; Stempniak, B

    2004-12-01

    Present investigations were undertaken to study the influence of peptide NK-1 and NK-2 receptor agonists and antagonists as well as substance P and neurokinin A (the natural ligands for these tachykinin receptors) on oxytocin (OT) release from isolated rat hypothalamo-neurohypophysial (H-N) system as well as to determine whether the tachykinin NK-1 and/or NK-2 receptors contribute to the response of oxytocinergic neurons to melatonin. The results show, for the first time, that highly selective NK-1 receptor agonist, i.e., [Sar(9),Met(O(2))(11)]-Substance P, enhances while the NK-1 receptor antagonist (Tyr(6),D-Phe(7),D-His(9))-Substance P (6-11) - sendide - diminishes significantly OT secretion; the latter peptide was also found to antagonize the substance P-induced hormone release from isolated rat H-N system, when used at the concentration of 10(-7) M/L. Melatonin significantly inhibited basal and substance P-stimulated OT secretion. Neurokinin A and the NK-2 receptor selective agonist (beta-Ala(8))-Neurokinin A (4-10) as well as the NK-2 receptor antagonist (Tyr(5),D-Trp(6,8,9),Lys-NH(2)(10))-Neurokinin A (4-10) were essentially inactive in modifying OT release from the rat H-N system in vitro. The present data indicate a distinct role for tachykinin NK-1 (rather than NK-2) receptor in tachykinin-mediated regulation of OT secretion from the rat H-N system. Under present experimental conditions, however, a role of respective tachykinin receptors in the response of oxytocinergic neurons to melatonin has not been found.

  16. Sleep Deprivation Aggravates Median Nerve Injury-Induced Neuropathic Pain and Enhances Microglial Activation by Suppressing Melatonin Secretion

    PubMed Central

    Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

    2014-01-01

    deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion. SLEEP 2014;37(9):1513-1523. PMID:25142572

  17. Interleukin-1 β Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study.

    PubMed

    Herman, A P; Bochenek, J; Skipor, J; Król, K; Krawczyńska, A; Antushevich, H; Pawlina, B; Marciniak, E; Tomaszewska-Zaremba, D

    2015-01-01

    The study was designed to determine the effect of proinflammatory cytokine, interleukin- (IL-) 1β, on melatonin release and expression enzymes essential for this hormone synthesis: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) in ovine pineal gland, taking into account the immune status of animals before sacrificing. Ewes were injected by lipopolysaccharide (LPS; 400 ng/kg) or saline, two hours after sunset during short day period (December). Animals were euthanized three hours after the injection. Next, the pineal glands were collected and divided into four explants. The explants were incubated with (1) medium 199 (control explants), (2) norepinephrine (NE; 10 µM), (3) IL-1β (75 pg/mL), or (4) NE + IL-1β. It was found that IL-1β abolished (P < 0.05) NE-induced increase in melatonin release. Treatment with IL-1β also reduced (P < 0.05) expression of AA-NAT enzyme compared to NE-treated explants. There was no effect of NE or IL-1β treatment on gene expression of HIOMT; however, the pineal fragments isolated from LPS-treated animals were characterized by elevated (P < 0.05) expression of HIOMT mRNA and protein compared to the explants from saline-treated ewes. Our study proves that IL-1β suppresses melatonin secretion and its action seems to be targeted on the reduction of pineal AA-NAT protein expression.

  18. Evidence of the receptor-mediated influence of melatonin on pancreatic glucagon secretion via the Gαq protein-coupled and PI3K signaling pathways.

    PubMed

    Bähr, Ina; Mühlbauer, Eckhard; Albrecht, Elke; Peschke, Elmar

    2012-11-01

    Melatonin has been shown to modulate glucose metabolism by influencing insulin secretion. Recent investigations have also indicated a regulatory function of melatonin on the pancreatic α-cells. The present in vitro and in vivo studies evaluated whether melatonin mediates its effects via melatonin receptors and which signaling cascade is involved. Incubation experiments using the glucagon-producing mouse pancreatic α-cell line αTC1 clone 9 (αTC1.9) as well as isolated pancreatic islets of rats and mice revealed that melatonin increases glucagon secretion. Preincubation of αTC1.9 cells with the melatonin receptor antagonists luzindole and 4P-PDOT abolished the glucagon-stimulatory effect of melatonin. In addition, glucagon secretion was lower in the pancreatic islets of melatonin receptor knockout mice than in the islets of the wild-type (WT) control animals. Investigations of melatonin receptor knockout mice revealed decreased plasma glucagon concentrations and elevated mRNA expression levels of the hepatic glucagon receptor when compared to WT mice. Furthermore, studies using pertussis toxin, as well as measurements of cAMP concentrations, ruled out the involvement of Gαi- and Gαs-coupled signaling cascades in mediating the glucagon increase induced by melatonin. In contrast, inhibition of phospholipase C in αTC1.9 cells prevented the melatonin-induced effect, indicating the physiological relevance of the Gαq-coupled pathway. Our data point to the involvement of the phosphatidylinositol 3-kinase signaling cascade in mediating melatonin effects in pancreatic α-cells. In conclusion, these findings provide evidence that the glucagon-stimulatory effect of melatonin in pancreatic α-cells is melatonin receptor mediated, thus supporting the concept of melatonin-modulated and diurnal glucagon release.

  19. The effect of nutrition on the neural mechanisms potentially involved in melatonin-stimulated LH secretion in female Mediterranean goats.

    PubMed

    Zarazaga, Luis A; Celi, Irma; Guzmán, José Luis; Malpaux, Benoît

    2011-12-01

    This research examines which neural mechanisms among the endogenous opioid, dopaminergic, serotonergic and excitatory amino acid systems are involved in the stimulation of LH secretion by melatonin implantation and their modulation by nutritional level. Female goats were distributed to two experimental groups that received either 1.1 (group H; n=24) or 0.7 (group L; n=24) times their nutritional maintenance requirements. Half of each group was implanted with melatonin after a long-day period. Plasma LH concentrations were measured twice per week. The effects of i.v. injections of naloxone, pimozide, cyproheptadine and N-methyl-d,l-aspartate (NMDA) on LH secretion were assessed the day before melatonin implantation and again on days 30 and 45. The functioning of all but the dopaminergic systems was clearly modified by the level of nutrition, melatonin implantation and time elapsed since implantation. Thirty days after implantation, naloxone increased LH concentrations irrespective of the level of nutrition (P<0.05), similar to NMDA in the melatonin-implanted H goats (HM; P<0.01). On day 45, naloxone increased LH concentrations in the HM animals (P<0.05), similar to cyproheptadine in both the non-implanted H (HC) and the HM animals (P<0.01). Finally, at 45 days, NMDA increased the LH concentration in all subgroups (P<0.01). These results provide evidence that the effects of different neural systems on LH secretion are modified by nutritional level and melatonin implantation. Endogenous opioids seem to be most strongly involved in the inhibition of LH secretion on days 30 and 45 after melatonin implantation. However, the serotonergic mechanism appears to be most influenced by nutritional level.

  20. The role of melatonin membrane receptors in melatonin-dependent oxytocin secretion from the rat hypothalamo-neurohypophysial system - an in vitro and in vivo approach.

    PubMed

    Juszczak, Marlena; Wolak, Monika; Bojanowska, Ewa; Piera, Lucyna; Roszczyk, Magdalena

    2016-01-01

    Melatonin exerts its biological role acting mainly via G protein-coupled membrane MT1 and MT2 receptors. To determine whether a response of oxytocinergic neurons to different concentrations of melatonin is mediated through membrane MT1 and/or MT2 receptors, the effect of melatonin receptors antagonists, i.e. luzindole (a non-selective antagonist of both MT1 and MT2 receptors) and 4-phenyl-2-propionamidotetralin (4-P-PDOT - a selective antagonist of MT2 receptor), on melatonin-dependent oxytocin (OT) secretion from the rat hypothalamo-neurohypophysial (H-N) system, has been studied both in vitro and in vivo. For in vitro experiment, male rats served as donors of the H-N explants, which were placed in 1 ml of normal Krebs-Ringer fluid (nKRF) heated to 37oC. The H-N explants were incubated successively in nKRF {fluid B1} and incubation fluid as B1 enriched with appropriate concentration of melatonin, i.e. 10-9 M, 10-7 M, or 10-3 M and luzindole or 4-P-PDOT, or their vehicles (0.1% ethanol or DMSO) {fluid B2}. After 20 minutes of incubation in fluid B1 and then B2, the media were collected and immediately frozen before OT estimation by the RIA. The OT secretion was determined by using the B2/B1 ratio for each H-N explant. During in vivo experiment, rats were given an intracerebroventricular (i.c.v.) infusion of 5 mL luzindole or 4-P-PDOT, or their solvent (0.1% DMSO) and 10 minutes later the next i.c.v. infusion of 5 mL of either melatonin solution (10-7 M) or its vehicle (0.1 % ethanol in 0.9% sodium chloride). Melatonin at a concentration of 10-3 M significantly stimulated, while at a concentration of 10-9 M had no effect on, oxytocin secretion from the rat H-N system in vitro, also when luzindole or 4-P-PDOT was present in a medium. On the other hand, melatonin at a concentration of 10-7 M diminished this neurohormone output from an isolated H-N system and into the blood. Luzindole significantly suppressed such melatonin action, while 4-P-PDOT did not change the

  1. Older poor-sleeping women display a smaller evening increase in melatonin secretion and lower values of melatonin and core body temperature than good sleepers.

    PubMed

    Olbrich, Denise; Dittmar, Manuela

    2011-10-01

    h) and older (19:57 h) good-sleeping women, but was delayed ∼50 min in older poor-sleeping women (20:47 h). Older poor sleepers showed a shorter phase angle between DLMO and sleep onset, but a longer phase angle between CBT peak and sleep onset than young good sleepers, whereas older good sleepers had intermediate phase angles (insignificant). Regression analysis showed that the DLMO was a significant predictor of SOL in the older women (R(2) = 0.64, p < .001), but not in the younger women. This indicates that melatonin production started later in those older women who needed more time to fall asleep. In conclusion, changes in melatonin level and CBT were intact in older poor sleepers in that evening melatonin increased and CBT decreased. However, poor sleepers showed a weaker evening increase in melatonin level, and their DLMO was delayed compared with good sleepers, suggesting that it is not primarily the absolute level of endogenous melatonin, but rather the timing of the circadian rhythm in evening melatonin secretion that might be related to disturbances in the sleep-wake cycle in older people.

  2. Peripheral autonomic nerves of human pineal organ terminate on vessels, their supposed role in the periodic secretion of pineal melatonin.

    PubMed

    Manzano E Silva, Maria Joao; Singh, Royana; Haldar, Chandana; Vigh, Béla; Szél, Ágoston

    2012-08-01

    Nonvisual pineal and retinal photoreceptors are synchronizing circadian and circannual periodicity to the environmental light periods in the function of various organs. Melatonin of the pineal organ is secreted at night and represents an important factor of this periodic regulation. Night illumination suppressing melatonin secretion may result in pathological events like breast and colorectal cancer. Experimental works demonstrated the role of autonomic nerves in the pineal melatonin secretion. It was supposed that mammalian pineals have lost their photoreceptor capacity that is present in submammalians, and sympathetic fibers would mediate light information from the retina to regulate melatonin secretion. Retinal afferentation may reach the organ by central nerve fibers via the pineal habenulae as well. In our earlier works we have found that the pineal organ developing from lobular evaginations of the epithalamus differs from peripheral endocrine glands and is composed of a retina-like central nervous tissue that is comprised of cone-like pinealocytes, secondary pineal neurons and glial cells. Their autonomic nerves in submammalians as well as in mammalian animals do not terminate on pineal cells, rather, they run in the meningeal septa among pineal lobules and form vasomotor nerve endings. Concerning the adult human pineal there are no detailed fine structural data about the termination of autonomic fibers, therefore, in the present work we investigated the ultrastructure of the human pineal peripheral autonomic nerve fibers. It was found, that similarly to other parts of the brain, autonomic nerves do not enter the human pineal nervous tissue itself but separated by glial limiting membranes take their course in the meningeal septa of the organ and terminate on vessels by vasomotor endings. We suppose that these autonomic vasomotor nerves serve the regulation of the pineal blood supply according to the circadian and circannual changes of the metabolic activity

  3. Melatonin secretion and excretion in patients with obstructive sleep apnea syndrome.

    PubMed

    Wikner, J; Svanborg, E; Wetterberg, L; Röjdmark, S

    1997-11-01

    Melatonin (MT) secretion and excretion were investigated in patients with obstructive sleep apnea syndrome (OSAS). Nine men, mean age 55.1 years, mean body mass index 31.2, with a previously confirmed diagnosis of moderate to severe OSAS, were tested on two occasions: immediately before initiation of continuous positive airway pressure (CPAP) treatment and again after at least 4 weeks of continuous nocturnal use of CPAP. Serum MT concentrations were determined every second hour between 2000 and 0800 hours. Urine was collected between 2200 and 0700 hours for determination of urinary MT excretion. Sleep apnea recordings included ear oximetry, respiration and body movements, body position, and breathing sounds. Nine healthy male controls were tested on one occasion. We found that the MT secretion, as reflected by the area under the curve (AUC), among the OSAS patients did not differ from that found in healthy controls (MT AUC 1.68 vs. 1.92 nmol/l x h). Sleep apnea recordings were normalized during CPAP treatment. Moreover, the excessive daytime sleepiness disappeared in all patients. Neither MT secretion (MT AUC 1.68 vs. 1.56 nmol/l x h) nor urinary excretion of MT (0.122 vs. 0.108 nmol/9 h) changed significantly as a result of the CPAP treatment.

  4. Estimation of frequently sampled nocturnal melatonin production in humans by deconvolution analysis: evidence for episodic or ultradian secretion.

    PubMed

    Geoffriau, M; Claustrat, B; Veldhuis, J

    1999-10-01

    In order to investigate nocturnal melatonin production and clearance rates, we applied deconvolution analysis to plasma melatonin concentration time series obtained every 20 min for 12 hr from 20:00 h to 08:00 h in two groups of healthy subjects at rest (group 1, 12 male subjects, 22-26 yr; group 2, ten female subjects, 31-42 yr). The estimated melatonin production rate from group 1 (0.55 +/- 0.21 microg/kg/night) was significantly higher than that of group 2 (0.26 +/- 0.19 microg/kg/night), as well as the mass of melatonin released per burst (275 +/- 110 vs. 145 +/- 130 pg/mL for groups 1 and 2, respectively), the amplitude of secretory bursts (7.8 +/- 3.2 vs. 4.7 +/- 3.5 pg/mL/min), and the pulsatile melatonin production rate (2.76 +/- 1.14 vs. 1.27 +/- 0.97 ng/mL/night). These differences could reflect alterations related to age and or gender. No differences were observed between the two groups in the secretory burst half-duration and frequency and the interburst interval. Melatonin production rates, as estimated by deconvolution analysis, are in agreement with other independent estimates, especially the isotopic method, and disclose an ultradian rhythmicity.

  5. Growth hormone and melatonin prevent age-related alteration in apoptosis processes in the dentate gyrus of male rats.

    PubMed

    Kireev, R A; Vara, E; Tresguerres, J A F

    2013-08-01

    It has been suggested that the age-related decrease in the number of neurons in the hippocampus that leads to alterations in brain function, may be associated with an increase in apoptosis due to the reduced secretion of growth hormone (GH) and/or melatonin in old animals. In order to investigate this possibility, male Wistar rats of 22 months of age were divided into three groups. One group remained untreated and acted as the control group. The second was treated with growth hormone (hGH) for 10 weeks (2 mg/kg/d sc) and the third was subjected to melatonin treatment (1 mg/kg/d) in the drinking water for the same time. A group of 2-months-old male rats was used as young controls. All rats were killed by decapitation at more than 24 month of age and dentate gyri of the hippocampi were collected. Aging in the dentate gyrus was associated with an increase in apoptosis promoting markers (Bax, Bad and AIF) and with the reduction of some anti-apoptotic ones (XIAP, NIAP, Mcl-1). Expressions of sirtuin 1 and 2 (SIRT1 and 2) as well as levels of HSP 70 were decreased in the dentate gyrus of old rats. GH treatment was able to reduce the pro/anti-apoptotic ratio to levels observed in young animals and also to increase SIRT2. Melatonin reduced also expression of pro-apoptotic genes and proteins (Bax, Bad and AIF), and increased levels of myeloid cell leukemia-1 proteins and SIRT1. Both treatments were able to reduce apoptosis and to enhance survival markers in this part of the hippocampus.

  6. Transcutaneous vagus nerve stimulation induces tidal melatonin secretion and has an antidiabetic effect in Zucker fatty rats.

    PubMed

    Wang, Shuxing; Zhai, Xu; Li, Shaoyuan; McCabe, Michael F; Wang, Xing; Rong, Peijing

    2015-01-01

    Melatonin plays a protective role in type 2 diabetes (T2D) through regulation of glucose metabolism. Whether transcutaneous vagus nerve stimulation (taVNS) is antidiabetic and whether a modulated melatonin production is involved in the antidiabetic mechanism of taVNS is unknown. In this study, once daily 30 min noninvasive taVNS was administered in Zucker diabetic fatty (ZDF, fa/fa) and Zucker lean (ZL, +/fa) littermates under anesthesia for 5 consecutive weeks. The acute and chronic influences of taVNS on the secretion of melatonin were studied as well as the effects of taVNS on blood glucose metabolism. We found that naïve ZDF rats develop hyperglycemia naturally with age. Each taVNS session would trigger a tidal secretion of melatonin both during and after the taVNS procedure and induce an acute two-phase glycemic change, a steep increase followed by a gradual decrease. Once daily taVNS sessions eventually reduced the glucose concentration to a normal level in seven days and effectively maintained the normal glycemic and plasma glycosylated hemoglobin (HbAlc) levels when applied for five consecutive weeks. These beneficial effects of taVNS also exist in pinealectomized rats, which otherwise would show overt and continuous hyperglycemia, hyperinsulinemia, and high HbAlc levels. We concluded that multiple taVNS sessions are antidiabetic in T2D through triggering of tidal secretion of melatonin. This finding may have potential importance in developing new approaches to the treatment of T2D, which is highly prevalent, incurable with any current approaches, and very costly to the world.

  7. Experimental models of melatonin-deficient hypertension.

    PubMed

    Simko, Fedor; Reiter, Russel J; Pechanova, Olga; Paulis, Ludovit

    2013-01-01

    Melatonin secreted by the pineal gland plays an important role in the regulation of blood pressure (BP) and its administration reduces hypertension both in animals and humans. There are two experimental models of melatonin-deficient hypertension: one induced by pinealectomy and another by continuous 24 hour exposure to light. Both models cause melatonin deficiency and prevent darkness-mediated nocturnal melatonin secretion and are associated with increased BP and myocardial, vascular and renal dysfunction. These models also lead to neurohumoral activation of the renin-angiotensin system, sympathetic nervous system, adrenocorticotrophin-glucocorticoid axis and cause insulin resistance. Together, these alterations contribute to rise in blood pressure by vasoconstrictive or circulatory fluid volume overload. The light induced hypertension model mimics the melatonin deficiency in patients with insufficient nocturnal BP decline, in those who have night shift or who are exposed to environmental light pollution. For this reason, this model is useful in development of anti-hypertensive drugs.

  8. Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion.

    PubMed

    Boudreau, Eilis A; Johnson, Kyle P; Jackman, Angela R; Blancato, Jan; Huizing, Marjan; Bendavid, Claude; Jones, Marypat; Chandrasekharappa, Settara C; Lewy, Alfred J; Smith, Ann C M; Magenis, R Ellen

    2009-07-01

    Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body's signal for nighttime darkness. Published reports of 24-hr melatonin secretion patterns in two independent SMS cohorts (US and France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion ( approximately 6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.2p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern.

  9. Circadian phase typing in idiopathic generalized epilepsy: Dim light melatonin onset and patterns of melatonin secretion-Semicurve findings in adult patients.

    PubMed

    Manni, Raffaele; De Icco, Roberto; Cremascoli, Riccardo; Ferrera, Giulia; Furia, Francesca; Zambrelli, Elena; Canevini, Maria Paola; Terzaghi, Michele

    2016-08-01

    It has been debated in the literature whether patients with idiopathic generalized epilepsy (IGE) have a distinctive, evening-oriented chronotype. The few questionnaire-based studies that are available in the literature have conflicting results. The aim of our study was to define chronotype in patients with IGE by determining dim light melatonin onset (DLMO). Twenty adults diagnosed with IGE (grand mal on awakening [GM] in 7 cases and juvenile myoclonic epilepsy in 13 cases) were investigated by means of a face-to-face semistructured sleep interview, Morningness-Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality Index (PSQI) questionnaire, and a melatonin salivary test with DLMO determination. Eighteen healthy subjects (HC) and 28 patients affected with cryptogenic focal epilepsy (FE) served as controls. The mean MEQ score was significantly lower in patients with IGE than that in patients with FE (49.1±5.9 versus 56.1±8.7 P<0.01) but not significantly lower than that in HC (49.1±5.9 versus 49.3±8.6). Midsleep on free days corrected for sleep duration did not differ significantly between the three subject groups (04:59±01:21h, 04:37±01:17h, 04:29±00:52h). The mean DLMO time in patients with IGE (22:13±01:34h) occurred 49min later than that in HC (21.24±1h), and the melatonin surge within the 30-minute time interval after DLMO in patients with IGE was significantly lower than that in HC (1.51±2.7 versus 3.8±3.6pg/mL P=0.045). Subjective measures of chronotype do not indicate a definite evening-oriented chronotype in patients with IGE. However, the data concerning endogenous melatonin secretion indicate that patients with IGE tend to have a late circadian phase. Further studies are warranted in order to better define the late pattern of endogenous melatonin secretion in patients with IGE and to ascertain the role of this pattern in influencing behavioral chronotype in these subjects. Copyright © 2016. Published by Elsevier Inc.

  10. Beneficial effects of melatonin on cardiological alterations in a murine model of accelerated aging.

    PubMed

    Forman, Katherine; Vara, Elena; García, Cruz; Kireev, Roman; Cuesta, Sara; Acuña-Castroviejo, Darío; Tresguerres, J A F

    2010-10-01

    This study investigated the effect of aging-related parameters such as inflammation, oxidative stress and cell death in the heart in an animal model of accelerated senescence and analyzed the effects of chronic administration of melatonin on these markers. Thirty male mice of senescence-accelerated prone (SAMP8) and 30 senescence-accelerated-resistant mice (SAMR1) at 2 and 10 months of age were used. Animals were divided into eight experimental groups, four from each strain: two young control groups, two old untreated control groups, and four melatonin-treated groups. Melatonin was provided at two different dosages (1 and 10 mg/kg/day) in the drinking water. After 30 days of treatment, the expression of inflammatory mediators (tumor necrosis factor-alpha, interleukin 1 and 10, NFkBp50 and NFkBp52), apoptosis markers (BAD, BAX and Bcl2) and parameters related to oxidative stress (heme oxygenases 1 and 2, endothelial and inducible nitric oxide synthases) were determined in the heart by real-time reverse transcription polymerase chain reaction (RT-PCR). Inflammation, as well as, oxidative stress and apoptosis markers was increased in old SAMP8 males, when compared to its young controls. SAMR1 mice showed significantly lower basal levels of the measured parameters and smaller increases with age or no increases at all. After treatment with melatonin, these age-altered parameters were partially reversed, especially in SAMP8 mice. The results suggest that oxidative stress and inflammation increase with aging and that chronic treatment with melatonin, a potent antioxidant, reduces these parameters. The effects were more marked in the SAMP8 animals. © 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S.

  11. Plasma melatonin is reduced in Huntington's disease.

    PubMed

    Kalliolia, Eirini; Silajdžić, Edina; Nambron, Rajasree; Hill, Nathan R; Doshi, Anisha; Frost, Chris; Watt, Hilary; Hindmarsh, Peter; Björkqvist, Maria; Warner, Thomas T

    2014-10-01

    This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24-hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease.

  12. Seasonal Patterns of Melatonin, Cortisol, and Progesterone Secretion in Female Lambs Raised Beneath a 500-KV Transmission Line

    NASA Astrophysics Data System (ADS)

    Lee, Jack Monroe, Jr.

    There is ongoing controversy about the possibility of adverse biological effects from environmental exposures to electric and magnetic fields. These fields are produced by all electrical equipment and appliances including electrical transmission lines. The objective of this environmental science study was to investigate the possible effects of a high voltage transmission line on domestic sheep (Ovis aries L.), a species that can often be found near such lines. The study was primarily designed to determine whether a specific effect of electric and magnetic fields found in laboratory animals also occurs in livestock under natural environmental conditions. The effect is the ability of fields, at levels found in the environment, to significantly depress the normally high nocturnal concentrations of the pineal hormone-melatonin. Ten female Suffolk lambs were penned for 10 months directly beneath a 500-kV transmission line near Estacada, Oregon. Ten other lambs of the same type were penned in a control area away from the transmission line where electric and magnetic fields were at ambient levels. Serum melatonin was analyzed by radioimmunoassay (RIA) from 6618 blood samples collected at 0.5 to 3-hour intervals over eight 48-hour periods. Serum progesterone was analyzed by RIA from blood samples collected twice weekly. Serum cortisol was also assayed by RIA from the blood samples collected during the 48-hour samples. Results showed that lambs in both the control and line groups had the typical pattern of melatonin secretion consisting of low daytime and high nighttime serum concentrations. There were no statistically significant differences between groups in melatonin levels, or in the phase or duration of the nighttime melatonin elevation. Age at puberty and number of reproductive cycles also did not differ between groups. Serum cortisol showed a circadian rhythm with highest concentrations during the day. There were, however, no differences in cortisol concentrations

  13. Melatonin pretreatment prevented the effect of dexamethasone negative alterations on behavior and hippocampal neurogenesis in the mouse brain.

    PubMed

    Ruksee, Nootchanart; Tongjaroenbuangam, Walaiporn; Mahanam, Thanutchaporn; Govitrapong, Piyarat

    2014-09-01

    Glucocorticoids play various physiological functions via the glucocorticoid receptor (GR). Glucocorticoid is associated with the pathophysiology of depression. Dexamethasone (DEX), a synthetic GR agonist, has a greater affinity for GR than the mineralocorticoid receptor (MR) in the hippocampus of pigs and may mimic the effects of GR possession. DEX decreases neurogenesis and induces damage to hippocampal neurons that is associated with depressive-like behavior. Melatonin, a hormone mainly synthesized in the pineal gland, is a potent free radical scavenger and antioxidant. Melatonin alters noradrenergic transmission in depressed patients. It may be interesting to further explore the mechanism of melatonin that is associated with the role of stress as a key factor to precipitate depression and as a factor altering neurogenesis. In this study, we assessed the capability of melatonin to protect the hippocampus of mouse brains to counteract the effects of chronic DEX treatment for 21 days on depressive-like behavior and neurogenesis. Our results revealed that chronic administration of DEX induced depressive-like behavior and that this could be reversed by pretreatment with melatonin. Moreover, the number of 5-bromo-2-deoxyuridine (BrdU)-immunopositive cells and doublecortin (DCX; the neuronal-specific marker) protein levels were significantly reduced in the DEX-treated mice. Pretreatment with melatonin was found to renew BrdU and DCX expression in the dentate gyrus. Furthermore, pretreatment with melatonin prevented DEX-induced reductions in GR and an extracellular-signal-regulated kinase (ERK1/2) in the hippocampal area. Melatonin may protect hippocampal neurons from damage and reverse neurogenesis after chronic DEX by activating brain-derived neurotrophic (BDNF) and ERK1/2 cascades. These results revealed that melatonin pretreatment prevented the reduction of cell proliferation, immature neuron precursor cells, and GR and ERK1/2 expression. This finding indicates that

  14. Melatonin prevents hypochlorous acid-induced alterations in microtubule and chromosomal structure in metaphase-II mouse oocytes.

    PubMed

    Banerjee, Jashoman; Maitra, Dhiman; Diamond, Michael P; Abu-Soud, Husam M

    2012-09-01

    Hypochlorous acid (HOCl) is generated by myeloperoxidase, using chloride and hydrogen peroxide as substrates. Here we demonstrate that HOCl alters metaphase-II mouse oocyte microtubules and chromosomal (CH) alignment which can be prevented by melatonin. Metaphase-II mouse oocytes, obtained commercially, were grouped as: control, melatonin (150, 200nmol/mL), HOCl (10, 20, 50, and 100nmol/mL), and HOCl (50nmol/mL) pretreated with 150 and 200 nmol/mL of melatonin. Microtubule and CH alignment was studied utilizing an indirect immunofluorescence technique and scored by two observers. Pearson chi-square test and Fisher's exact test were used to compare outcomes between controls and treated groups and also among each group. Poor scores for the spindle and chromosomes increased significantly at 50nmol/mL of HOCl (P<0.001). Oocytes treated with melatonin only at 150 and 200 nmol/mL showed no changes; significant differences (P<0.001) were observed when oocytes exposed to 50nmol/mL of HOCl were compared to oocytes pretreated with 200 nmol/mL melatonin. Fifty percent of the oocytes demonstrated good scores, both in microtubule and CH alterations, when pretreated with melatonin at 150 nmol/mL compared to 0% in the HOCl-only group. HOCl alters the metaphase-II mouse oocyte spindle and CH alignment in a dose-dependant manner, which might be a potential cause of poor oocyte quality (e.g., in patients with endometriosis). Melatonin prevented the HOCl-mediated spindle and CH damage, and therefore, may be an attractive therapeutic option to prevent oocyte damage in endometriosis or inflammatory diseases where HOCl levels are known to be elevated. © 2012 John Wiley & Sons A/S.

  15. Evaluation of anxiety, salivary cortisol and melatonin secretion following reflexology treatment: a pilot study in healthy individuals.

    PubMed

    McVicar, A J; Greenwood, C R; Fewell, F; D'Arcy, V; Chandrasekharan, S; Alldridge, L C

    2007-08-01

    This pilot study sought to identify an appropriate methodology to investigate the impact of reflexology in healthcare settings. The study involved healthy volunteers to prevent unnecessary intervention to individuals who may already be experiencing health related trauma. Thirty participants underwent either reflexology or no treatment (control), in a cross-over experimental design. Self-reported anxiety (Spielberger STAI), cardiovascular parameters (BP and pulse rate) and salivary cortisol and melatonin concentrations were assessed before and after reflexology. Control data were obtained at the same time points in identical settings. Reflexology had a powerful anxiety-reduction effect ('state'; P<0.001) but no significant effect on underlying anxiety ('trait'). Cardiovascular parameters decreased (P<0.001). Baseline salivary cortisol and melatonin were not significantly correlated with STAI scores and did not change significantly following reflexology. Reflexology reduced 'state' anxiety and cardiovascular activity within healthy individuals, consistent with stress-reduction. Considering the connection between stress/anxiety and well being, the effects of reflexology may have beneficial outcomes for patients. These findings will be transferred to a study involving breast cancer patients where effects may be more pronounced particularly since cancer patients display disregulation of cortisol and melatonin secretion.

  16. Changes in melatonin secretion in tourists after rapid movement to another lighting zone without transition of time zone.

    PubMed

    Wieczorek, Joanna; Blazejczyk, Krzysztof; Morita, Takeshi

    2016-01-01

    Most of the research in the field of Chronobiology is focused on the problem of the circadian rhythms (CR) desynchronization. In travelers, it results mostly from the changes of surrounding: photoperiod, local climate conditions (radiation and thermal load) and behavior (e.g. type and place of tourism and activity level). Until now, it was not documented whether the changes in melatonin (MLT) secretion occur in effect of mid-distance transparallel travels (TpT), without complications arising due to time-zone transitions (e.g. jet-lag syndrome). To cope with this problem, a special field experiment was carried out. In the experiment, MLT characteristics were examined twice a year in real conditions through a group of young tourists (23-26 years old) at their place of habitual residence (Warsaw, Poland), and at their tourist destination (Tromso, Norway). Transition to circumpolar zone in summer has resulted in insignificant reduction in melatonin peak value (MPV) compared to preflight control (2 days before travel) and the melatonin peak time (MPT) was delayed. However, after traveling southward on the returning flight, MPV was lower compared to control and MPT was advanced. In winter, MPV was insignificantly higher in comparison to preflight control and MPT was almost unchanged. While changes in MPV do not depend on season, flight direction and day of stay after flight than MPT was differentiated seasonally and due to direction of flight. MPV and MPT were significantly modified by characteristics of individual light exposure during daytime and evening. The experiment showed also that in real conditions activity level is an important factor affected melatonin peak in tourists. In winter, greater daytime activity significantly influenced earlier MPT occurrence, both after northward and southward flights.

  17. Melatonin and 6-methoxy-2-benzoxazolinone (6-MBOA) alter the response of the male Syrian hamster to natural photoperiod

    NASA Astrophysics Data System (ADS)

    Vaughan, M. K.; Little, J. C.; Powell, D. C.; Puig-Domingo, M.; Reiter, R. J.

    1988-06-01

    Adult male hamsters bearing either a blank beeswax, 6-methoxy-2-benzoxazolinone (6-MBOA), or melatonin pellet were exposed to 8 weeks (Oct. 6 Dec. 6) of natural autumn decreasing photoperiod (<11 h light) and temperature conditions (mean 10°C for last 4 weeks) or to a 14 h light/10 h dark (14L∶10D) photoperiod and controlled temperature (20°C). Melatonin but not 6-MBOA pellets partially prevented the combined effects of short photoperiod and cold temperatures on the testes and accessory organs. However, both 6-MBOA-and melatonin-treated hamsters maintained outdoors had significantly higher pituitary follicle stimulating hormone (FSH) values compared to their respective indoor-treated controls or to the animals kept outdoors and treated with a blank beeswax pellet. When one compares the various effects of 6-MBOA and melatonin (2 mg/month) on the reproductive system of the male hamster, 6-MBOA is not as effective as melatonin in altering reproductive responses to short photoperiod and cool temperatures at the dose administered.

  18. Abnormal secretion of melatonin and cortisol in relation to sleep disturbances in children with Williams syndrome.

    PubMed

    Sniecinska-Cooper, Anna Maria; Iles, Ray Kruse; Butler, Stephen Andrew; Jones, Huw; Bayford, Richard; Dimitriou, Dagmara

    2015-01-01

    A high rate of sleep disturbances has been reported in individuals with Williams syndrome (WS) but the underlying aetiology has yet to be identified. Melatonin and cortisol levels display circadian rhythmicity and are known to affect and regulate sleep/wake patterns. The current study examined the levels of these two endocrine markers and explored a possible relationship with sleep patterns in children with WS. Twenty-five children with WS and 27 typically developing age- and gender-matched comparison children were recruited. Saliva was collected from each child at three time points: 4-6 pm, before natural bedtime, and after awakening. The levels of salivary melatonin and cortisol were analysed by specific enzyme-linked immunoassays. Sleep patterns were examined using actigraphy and the Children's Sleep Habit Questionnaire. The WS group had shallower drops in cortisol and less pronounced increase in melatonin at bedtime compared to the controls. Furthermore, they also had significantly higher levels of cortisol before bedtime. Increased bedtime cortisol and less pronounced rise in melatonin levels before sleep may play a role in the occurrence of sleep disturbances, such as delayed sleep onset, observed in children with WS. As both markers play a significant role in our circadian rhythm and sleep/wake cycle, it is necessary to examine sleep using multi-system analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. TRPV4 Stimulation Induced Melatonin Secretion by Increasing Arylalkymine N-acetyltransferase (AANAT) Protein Level.

    PubMed

    Alkozi, Hanan Awad; Perez de Lara, Maria J; Sánchez-Naves, Juan; Pintor, Jesús

    2017-04-01

    Melatonin is a molecule which has gained a great deal of interest in many areas of science; its synthesis was classically known to be in the pineal gland. However, many organs synthesize melatonin, such as several ocular structures. Melatonin is known to participate in many functions apart from its main action regulating the circadian rhythm. It is synthesized from serotonin in two steps, with a rate-limiting step carried out by arylalkymine N-acetyltransferase (AANAT). In this report, the role of TRPV4 channel present in human ciliary body epithelial cells in AANAT production was studied. Several experiments were undertaken to verify the adequate time to reach the maximal effect by using the TRPV4 agonist GSK1016790A, together with a dose-response study. An increase of 2.4 folds in AANAT was seen after 18 h of incubation with 10 nM of GSK1016790A (p < 0.001, n = 6). This increment was verified by antagonist assays. In summary, AANAT levels and therefore melatonin synthesis change after TRPV4 channel stimulation. Using this cell model together with human ciliary body tissue it is possible to suggest that AANAT plays an important role in pathologies related to intraocular pressure.

  20. A common variant in the melatonin receptor gene (MTNR1B) is associated with increased risk of future type 2 diabetes and impaired early insulin secretion

    PubMed Central

    Lyssenko, Valeriya; Nagorny, Cecilia L.F.; Erdos, Michael R.; Wierup, Nils; Jonsson, Anna; Spégel, Peter; Bugliani, Marco; Saxena, Richa; Fex, Malin; Pulizzi, Nicolo; Isomaa, Bo; Tuomi, Tiinamaija; Nilsson, Peter; Kuusisto, Johanna; Tuomilehto, Jaakko; Boehnke, Michael; Altshuler, David; Sundler, Frank; Eriksson, Johan G.; Jackson, Anne U.; Laakso, Markku; Marchetti, Piero; Watanabe, Richard M.; Mulder, Hindrik; Groop, Leif

    2013-01-01

    Genome wide association studies revealed that variation in the Melatonin Receptor 1B gene (MTNR1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the Melatonin Receptor 1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in β-cells in islets. Non-diabetic individuals carrying the risk allele and patients with T2D showed increased expression of the receptor in islets. Insulin release from clonal β-cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of Melatonin Receptor 1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on β-cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D. PMID:19060908

  1. The influence of long-term exposure of mice to randomly varied power frequency magnetic fields on their nocturnal melatonin secretion patterns.

    PubMed

    de Bruyn, L; de Jager, L; Kuyl, J M

    2001-02-01

    Disruption of the normal melatonin rhythm has many implications in health and disease. Exposure to magnetic fields is alleged to suppress nocturnal melatonin production, which could implicate magnetic fields in the development of, for example, breast cancer. Magnetic fields of overhead powerlines allegedly pose a risk in the development of childhood leukemia, and the question arises whether changed pineal function could play a role here. In this study two strains of mice were exposed to a rms 50-Hz magnetic field which varied randomly between 0.5 and 77 microT with an average of 2.75 microT and compared to sham-exposed groups. The male mice were exposed for 24 h per day from conception until adult age. Nighttime plasma melatonin values were determined using radioimmunoassay (n=9 for each time point). Statistical comparison was done by nonparametric 95% confidence intervals for median differences to determine nocturnal elevated melatonin values. Although a shortcoming of the study was the small sample size, no statistically significant difference in the nocturnal median elevated melatonin values between exposed and sham-exposed groups could be demonstrated. Long-term and continuous exposure to simulated powerline magnetic fields did not result in a decreased nocturnal melatonin secretion in mice. Copyright 2001 Academic Press.

  2. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics

    PubMed Central

    Gorenz, Annika; Shaikh, Maliha; Desai, Vishal; Forsyth, Christopher; Fogg, Louis; Burgess, Helen J.; Keshavarzian, Ali

    2015-01-01

    Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = −0.39, P = 0.03; urinary sucralose, r = −0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. PMID:25907689

  3. Secretion of melatonin and 6-sulfatoxymelatonin urinary excretion in functional dyspepsia

    PubMed Central

    Chojnacki, Cezary; Poplawski, Tomasz; Klupinska, Grażyna; Blasiak, Janusz; Chojnacki, Jan; Reiter, Russel J

    2011-01-01

    AIM: To evaluate blood concentration of melatonin and urinary excretion of its metabolite, 6-sulfatoxymelatonin (6-OHMS), in functional dyspepsia (FD). METHODS: Ninety individuals were enrolled in the study: 30 in each study group: patients with postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and controls. Blood samples were drawn at 02:00 and 09:00 h and 24-h urine collection was performed. Serum melatonin and urinary 6-OHMS concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: Serum melatonin concentration at night and in the morning was significantly (P < 0.001) higher in PDS patients [at 02:00 h-93.3 pg/mL, quartile range (QR): 79.8-116.2; at 09.00 h-14.3 pg/mL, QR: 7.06-19.0] than in EPS (57.2 pg/mL, QR: 42.6-73.1; 8.1 pg/mL, QR: 4.1-9.3) and control patients (57.7 pg/mL, QR: 51.2-62.5; 8.1 pg/mL, QR: 5.4-10.3). A similar relationship was observed for urinary 6-OHMS excretion. Patients with severe PDS symptoms had a higher melatonin concentration than these with moderate syndromes, whereas patients with severe EPS had a lower urinary 6-OHMS excretion than patients with moderate symptoms. CONCLUSION: Evaluation of melatonin serum concentrations and 24-h urinary 6-OHMS excretion are useful methods for differential diagnosis of various clinical forms of FD. PMID:21677834

  4. Day or night administration of ketamine and pentobarbital differentially affect circadian rhythms of pineal melatonin secretion and locomotor activity in rats.

    PubMed

    Mihara, Takahiro; Kikuchi, Tatsuaki; Kamiya, Yoshinori; Koga, Motokazu; Uchimoto, Kazuhiro; Kurahashi, Kiyoyasu; Goto, Takahisa

    2012-10-01

    Surgery with general anesthesia disturbs circadian rhythms, which may lead to postoperative sleep disorders and delirium in patients. However, it is unclear how circadian rhythms are affected by different anesthetics administered at different times during the rest-activity cycle. We hypothesized that pentobarbital (an agonist at the γ-aminobutyric acid A receptors) and ketamine (an antagonist at the N-methyl-d-aspartate receptors) would have differential effects on circadian rhythms, and these effects would also be influenced by the time of their administration (the active versus resting phase). Rats were divided into 4 groups according to the anesthetic administered (pentobarbital or ketamine) and the timing of intraperitoneal administration (active/night phase or resting/day phase). Using online pineal microdialysis, we analyzed pineal melatonin secretion and locomotor activity rhythms in rats under a light/dark (12/12-hour) cycle for 5 days after anesthesia and microdialysis catheter implantation. The data were analyzed for rhythmicity by cosinor analysis. Ketamine administered during the resting phase produced 65- and 153-minute phase advances, respectively, in melatonin secretion and locomotor activity rhythms on the first day after anesthesia. In contrast, ketamine administered during the active phase produced 43- and 235-minute phase delays. Pentobarbital had no effect on the phase of either melatonin secretion or locomotor activity, irrespective of the timing of administration. When administered during the active phase, both anesthetics decreased the amplitude of melatonin secretion on the day after anesthesia; when administered during the resting phase, however, neither anesthetic affected the amplitude. The amplitude of locomotor activity decreased in all animals for 3 days after anesthesia. Ketamine has opposite phase-shifting effects on circadian rhythms according to the time of administration, whereas pentobarbital has no effect. Furthermore, both

  5. Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: Health impacts and mechanisms of circadian disruption.

    PubMed

    Touitou, Yvan; Reinberg, Alain; Touitou, David

    2017-03-15

    Exposure to Artificial Light At Night (ALAN) results in a disruption of the circadian system, which is deleterious to health. In industrialized countries, 75% of the total workforce is estimated to have been involved in shift work and night work. Epidemiologic studies, mainly of nurses, have revealed an association between sustained night work and a 50-100% higher incidence of breast cancer. The potential and multifactorial mechanisms of the effects include the suppression of melatonin secretion by ALAN, sleep deprivation, and circadian disruption. Shift and/or night work generally decreases the time spent sleeping, and it disrupts the circadian time structure. In the long run, this desynchronization is detrimental to health, as underscored by a large number of epidemiological studies that have uncovered elevated rates of several diseases, including cancer, diabetes, cardiovascular risks, obesity, mood disorders and age-related macular degeneration. It amounts to a public health issue in the light of the very substantial number of individuals involved. The IARC has classified shift work in group 2A of "probable carcinogens to humans" since "they involve a circadian disorganization". Countermeasures to the effects of ALAN, such as melatonin, bright light, or psychotropic drugs, have been proposed as a means to combat circadian clock disruption and improve adaptation to shift and night work. We review the evidence for the ALAN impacts on health. Furthermore, we highlight the importance of an in-depth mechanistic understanding to combat the detrimental properties of exposure to ALAN and develop strategies of prevention.

  6. Daylight effect on melatonin secretion in adult female guanacos (Lama guanicoe).

    PubMed

    Riveros, J L; Correa, L M; Schuler, G

    2017-07-21

    The wild South American camelids developed a strategy of seasonal reproduction during spring and summer with singleton birth. The photoperiod is one of the factors that may modulate this seasonality where light would be translated into a hormonal signal. This study evaluated the influence of changes in daily light intensity on melatonin concentration in captive guanacos under a long-day photoperiod (16 hr light/8 hr dark; 33 '28'S). Mean melatonin concentration was 28.3 ± 20.3 pg/ml, with a maximum of 52.14 ± 17.19 pg/ml at 23:30 and minimum of 14.29 ± 6.64 pg/ml at 08:30 (p < .001). There was a negative association between light intensity and melatonin concentration (r = -0.57; p < .001). The results indicate that guanacos respond to variation in daily environmental light with a hormonal response and point to a circannual rhythm as a function of the photoperiod. © 2017 Blackwell Verlag GmbH.

  7. [Melatonin receptor agonist].

    PubMed

    Uchiyama, Makoto

    2015-06-01

    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics.

  8. Melatonin: potential functions in the oral cavity.

    PubMed

    Cutando, Antonio; Gómez-Moreno, Gerardo; Arana, Carlos; Acuña-Castroviejo, Darío; Reiter, Russel J

    2007-06-01

    Melatonin is synthesized and secreted by the pineal gland and other organs. The pattern of melatonin secretion is controlled by an endogenous circadian timing system and conveys information about the light-dark cycle to the organism, thereby organizing its seasonal and circadian rhythms. Melatonin has powerful antioxidant effects, functions in an immunomodulatory role, may protect against certain cancers, delays some age-related processes, stimulates the synthesis of type I collagen fibers, and promotes bone formation. An extensive review was made (e.g., using PubMed, Science Direct, and Web of Knowledge) of the literature. Melatonin, which is released into the saliva, may have important implications for dental disorders, especially in periodontal disease. Diseases of the periodontium are known to be aggravated by free radicals and by alterations in the immune response to microorganisms that are present in plaque. In response to periodontal inflammation, the blood and salivary levels of melatonin may increase. Melatonin may play a role in protecting the oral cavity from tissue damage that is due to oxidative stress, and it may contribute to the regeneration of alveolar bone through the stimulation of type I collagen fiber production and the modulation of osteoblastic and osteoclastic activity.

  9. Melatonin alters amino acid metabolism and inflammatory responses in colitis mice.

    PubMed

    Liu, Gang; Jiang, Qian; Chen, Shuai; Fang, Jun; Ren, Wenkai; Yin, Jie; Yao, Kang; Yin, Yulong

    2017-09-19

    Inflammatory bowel disease is a chronic inflammatory dysfunction of the gastrointestinal tract. This study explored the hypothesis that melatonin has beneficial functions in the mouse model of colitis induced by dextran sodium sulfate (DSS), with a specific focus on the expression of intestinal inflammatory cytokines and the serum levels of amino acids. The results revealed that mice with melatonin supplementation had a reduction in weight loss and disease index induced by DSS treatment. Melatonin stifled the expression of colonic IL-17 in mice with DSS-induced colitis. Melatonin also lowered the serum levels of Asp, Ser, Met, and Leu (p < 0.05), but increased those of Glu and Cys (p < 0.05). Thus, melatonin treatment is promising and may function as a potential adjuvant therapy to alleviate the clinical symptoms of patients with inflammatory bowel disease.

  10. Effect of constant-release melatonin implants and prolonged exposure to a long day photoperiod on prolactin secretion and hair growth in mouflon (Ovis gmelini musimon).

    PubMed

    Santiago-Moreno, J; López-Sebastián, A; del Campo, A; González-Bulnes, A; Picazo, R; Gómez-Brunet, A

    2004-05-01

    The aims of this study were to examine whether mouflons exposed to constant long and short day photoperiods are able to exhibit an annual cycle of hair growth and moult, and prolactin (PRL) secretion. Mouflon ewes were assigned to three groups of treatment. Ewes were maintained, either under natural photoperiod (control, n = 9), or received a series of subcutaneous melatonin implants from December to April (n = 8), or were exposed to a constant long day photoperiod (16-h light:8-h dark; 16L:8D) during 18 months (n = 7). Blood was collected weekly to determine PRL concentrations, and hair samples were clipped weekly from the base of the neck to measure the length of predominant hair. Under constant long days and with melatonin implants, mouflons expressed an annual rhythm of PRL secretion, even though these treatments modified the times of rise or falling of PRL concentrations throughout the year. Hair growth initiation was almost coincident with the summer solstice in both control and melatonin-implanted mouflons but occurred two months earlier in long day hold mouflons (P < 0.001). Long day hold mouflons had a lower hair growth rate than control and melatonin-implanted mouflons (P < 0.001), and at the end of the experiment, a shorter hair length (3.4 +/- 0.24 cm; P < 0.01) than control (4.3 +/- 0.17 cm), and melatonin-implanted mouflons (4.2 +/- 0.12 cm). Our data support the conclusion that in mouflon, an endogenous circannual rhythm of PRL secretion exists, and that the seasonal cycle of hair growth and moult appears to depend, at least in part, on circulating levels of PRL.

  11. Placental melatonin production and melatonin receptor expression are altered in preeclampsia: new insights into the role of this hormone in pregnancy.

    PubMed

    Lanoix, Dave; Guérin, Pascale; Vaillancourt, Cathy

    2012-11-01

    The melatonin system in preeclamptic pregnancies has been largely overlooked, especially in the placenta. We have previously documented melatonin production and expression of its receptors in normal human placentas. In addition, we and others have shown a beneficial role of melatonin in placental and fetal functions. In line with this, decreased maternal blood levels of melatonin are found in preeclamptic compared with normotensive pregnancies. However, melatonin production and expression of its receptors in preeclamptic compared with normotensive pregnancy placentas has never been examined. This study compares (i) melatonin-synthesizing enzyme expression and activity, (ii) melatonin and serotonin, melatonin's immediate precursor, levels and (iii) expression of MT1 and MT2 melatonin receptors in placentas from preeclamptic and normotensive pregnancies. Protein and mRNA expression of aralkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT), the melatonin-synthesizing enzymes, as well as MT1 and MT2 receptors were determined by RT-qPCR and Western blot, respectively. The activities of melatonin-synthesizing enzymes were assessed by radiometric assays while melatonin levels were determined by LC-MS/MS. There is a significant inhibition of AANAT, melatonin's rate-limiting enzyme, expression and activity in preeclamptic placentas, correlating with decreased melatonin levels. Likewise, MT1 and MT2 expression is significantly reduced in preeclamptic compared with normotensive pregnancy placentas. We propose that reduced maternal plasma melatonin levels may be an early diagnostic tool to identify pregnancies complicated by preeclampsia. This study indicates a clinical utility of melatonin as a potential treatment for preeclampsia in women where reduced maternal plasma levels have been identified.

  12. Loss of melatonin signalling and its impact on circadian rhythms in mouse organs regulating blood glucose.

    PubMed

    Mühlbauer, Eckhard; Gross, Elena; Labucay, Karin; Wolgast, Sabine; Peschke, Elmar

    2009-03-15

    The transmission of circadian rhythms is mediated by specific promoter sequences binding a particular circadian clock factor. The pineal hormone melatonin acts via G-protein-coupled receptors to synchronise these clock-generated circadian rhythms. The study was aimed to elucidate the possible role of melatonin as a zeitgeber for peripheral clocks in pancreas and liver. Reverse transcription polymerase chain reaction (RT-PCR) provided evidence of the simultaneous expression of the melatonin receptors MT(1) and MT(2) in mouse pancreas, liver and hypothalamus. Melatonin receptor knockout mice were analysed with respect to the clock gene- or clock-output transcripts PER1, DBP and RevErbalpha in pancreas and liver, and both the occurrence of phase shifts and amplitude changes were detected. Circadian PER1 protein expression was found to be retained in melatonin receptor double knockout mice with an increased amplitude as measured by semiquantitative Western blot analysis. Moreover, an impact of melatonin receptor deficiency on insulin transcripts, and altered regulation of insulin secretion and glucose homeostasis were monitored in the knockout animals. Insulin secretion from isolated islets of melatonin receptor MT(1), MT(2) or MT(1) and MT(2) double melatonin receptor-knockout animals was found to be increased relative to the wild type. These data support the idea that melatonin synchronises the functions of the major organs involved in blood glucose regulation and negatively acts on the insulin secretion.

  13. Melatonin modulates monochromatic light-induced GHRH expression in the hypothalamus and GH secretion in chicks.

    PubMed

    Zhang, Liwei; Cao, Jing; Wang, Zixu; Dong, Yulan; Chen, Yaoxing

    2016-04-01

    To study the mechanism by which monochromatic lights affect the growth of broilers, a total of 192 newly hatched broilers, including the intact, sham-operated and pinealectomy groups, were exposed to white light (WL), red light (RL), green light (GL) and blue light (BL) using a light-emitting diode (LED) system for 2 weeks. The results showed that the GHRH-ir neurons were distributed in the infundibular nucleus (IN) of the chick hypothalamus. The mRNA and protein levels of GHRH in the hypothalamus and the plasma GH concentrations in the chicks exposed to GL were increased by 6.83-31.36%, 8.71-34.52% and 6.76-9.19% compared to those in the chicks exposed to WL (P=0.022-0.001), RL (P=0.002-0.000) and BL (P=0.290-0.017) in the intact group, respectively. The plasma melatonin concentrations showed a positive correlation with the expression of GHRH (r=0.960) and the plasma GH concentrations (r=0.993) after the various monochromatic light treatments. After pinealectomy, however, these parameters decreased and there were no significant differences between GL and the other monochromatic light treatments. These findings suggest that melatonin plays a critical role in GL illumination-enhanced GHRH expression in the hypothalamus and plasma GH concentrations in young broilers. Copyright © 2016 Elsevier GmbH. All rights reserved.

  14. Nocturnal activity in the green sea turtle alters daily profiles of melatonin and corticosterone.

    PubMed

    Jessop, Tim S; Limpus, Colin J; Whittier, Joan M

    2002-06-01

    In nature, green turtles (Chelonia mydas) can exhibit nocturnal activity in addition to their typically diurnal activity cycle. We examined whether nocturnal activity in captive and free-living green turtles altered daily plasma profiles of melatonin (MEL) and corticosterone (CORT). In captivity, diurnally active green turtles expressed distinct diel cycles in MEL and CORT; a nocturnal rise was observed in MEL and a diurnal rise was observed in CORT. However, when induced to perform both low- and high-intensity nocturnal activity, captive green turtles exhibited a significant decrease in MEL, compared to inactive controls. In contrast, plasma CORT increased significantly with nocturnal activity, and further, the relative increase in CORT was correlated with the intensity of the nocturnal behavior. In free-living green turtles that performed nocturnal activity including: nesting, mate searching, and feeding/swimming behaviors, plasma profiles in MEL and CORT exhibited relatively little, or no, daily fluctuation. Our findings demonstrate that nocturnal activity in green turtles is often associated with MEL and CORT profiles that resemble those measured during the day. We speculate that these conspicuous changes in MEL and CORT during nocturnal activity could either support or promote behaviors that enable acquisition of transient resources important to the survival and reproductive success of green turtles. (c) 2002 Elsevier Science (USA).

  15. Investigation of the effects of magnetic field exposure on human melatonin. Interim report

    SciTech Connect

    Graham, C.; Cook, M.R.; Cohen, H.D.

    1994-08-01

    Several rodent studies have suggested that magnetic field exposure may alter the daily pattern of melatonin secretion. This study investigated melatonin levels in mean exposed overnight to magnetic fields of 10 mG and 200 mG. The study also assessed the potential effects of exposure on a number of performance and self-reported endpoints in the subjects. Investigation of this area is important, as altered diurnal melatonin cycles have been linked to a variety of endpoints, including reproductive outcome, neurobehavioral function, and carcinogenesis. The results of this investigation did not support the a priori hypothesis that exposure to 60-Hz magnetic fields of 10 mG and 200 mG alters nighttime melatonin levels in a population of adult males. However, the data suggested the possibility of differential sensitivity to magnetic fields based on an individual`s baseline melatonin level.

  16. Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

    PubMed

    Ishigaki, Sayaka; Ohashi, Naro; Isobe, Shinsuke; Tsuji, Naoko; Iwakura, Takamasa; Ono, Masafumi; Sakao, Yukitoshi; Tsuji, Takayuki; Kato, Akihiko; Miyajima, Hiroaki; Yasuda, Hideo

    2016-12-01

    Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (β = -0.31, p = 0.044) and U-Alb (β = -0.25, p = 0.025) only at night. Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

  17. Continuous light after a long-day treatment is equivalent to melatonin implants to stimulate testosterone secretion in Alpine male goats.

    PubMed

    Delgadillo, J A; Vélez, L I; Flores, J A

    2016-04-01

    In rams, artificial long days followed by continuous light stimulate testosterone secretion during the non-breeding season. The objective of this study was to determine whether artificial long days followed by continuous light could stimulate testosterone secretion in Alpine bucks as well as in those exposed to long days followed by a melatonin treatment. All bucks were kept in shaded open pens. Control males were exposed to natural photoperiod conditions (n=5). Males of the two experimental groups were exposed to 2.5 months of long days from 1 December (n=5 each). On 16 February, one group of males was exposed to 24 h of light per day until 30 June; the other group was exposed to natural variations of photoperiod and received two s.c. melatonin implants. Testicular weight was determined every 2 weeks, and the plasma testosterone concentrations once a week. In the control and the two photoperiodic-treated groups, a treatment×time interaction was detected for testicular weight and plasma testosterone concentrations (P<0.001). In control bucks, testicular weight increased from January and peaked in June, whereas in both photoperiodic-treated groups, this variable increased from January, but peaked in April, when the values were higher than in controls (P<0.05). In the control group, plasma testosterone concentrations remained low from January to June, whereas in both photoperiodic-treated groups, this variable remained low from January to March; thereafter, these levels increased in both photoperiodic-treated groups, and were higher than controls in April and May (P<0.05). We conclude that continuous light after a long-day treatment stimulate testosterone secretion in Alpine male goats during the non-breeding season as well as the long days followed by a melatonin treatment. Therefore, continuous light could replace the implants of melatonin.

  18. Alterations in Lipid Levels of Mitochondrial Membranes Induced by Amyloid-β: A Protective Role of Melatonin

    PubMed Central

    Rosales-Corral, Sergio A.; Lopez-Armas, Gabriela; Cruz-Ramos, Jose; Melnikov, Valery G.; Tan, Dun-Xian; Manchester, Lucien C.; Munoz, Ruben; Reiter, Russel J.

    2012-01-01

    Alzheimer pathogenesis involves mitochondrial dysfunction, which is closely related to amyloid-β (Aβ) generation, abnormal tau phosphorylation, oxidative stress, and apoptosis. Alterations in membranal components, including cholesterol and fatty acids, their characteristics, disposition, and distribution along the membranes, have been studied as evidence of cell membrane alterations in AD brain. The majority of these studies have been focused on the cytoplasmic membrane; meanwhile the mitochondrial membranes have been less explored. In this work, we studied lipids and mitochondrial membranes in vivo, following intracerebral injection of fibrillar amyloid-β (Aβ). The purpose was to determine how Aβ may be responsible for beginning of a vicious cycle where oxidative stress and alterations in cholesterol, lipids and fatty acids, feed back on each other to cause mitochondrial dysfunction. We observed changes in mitochondrial membrane lipids, and fatty acids, following intracerebral injection of fibrillar Aβ in aged Wistar rats. Melatonin, a well-known antioxidant and neuroimmunomodulator indoleamine, reversed some of these alterations and protected mitochondrial membranes from obvious damage. Additionally, melatonin increased the levels of linolenic and n-3 eicosapentaenoic acid, in the same site where amyloid β was injected, favoring an endogenous anti-inflammatory pathway. PMID:22666620

  19. Melatonin in Alzheimer's disease and other neurodegenerative disorders

    PubMed Central

    Srinivasan, V; Pandi-Perumal, SR; Cardinali, DP; Poeggeler, B; Hardeland, R

    2006-01-01

    Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric

  20. Melatonin in Alzheimer's disease and other neurodegenerative disorders.

    PubMed

    Srinivasan, V; Pandi-Perumal, S R; Cardinali, D P; Poeggeler, B; Hardeland, R

    2006-05-04

    Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-beta toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and

  1. Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8).

    PubMed

    Cuesta, Sara; Kireev, Roman; García, Cruz; Rancan, Lisa; Vara, Elena; Tresguerres, Jesús A F

    2013-06-01

    The aim of the present study was to investigate the effect of aging on several parameters related to glucose homeostasis and insulin resistance in pancreas and how melatonin administration could affect these parameters. Pancreas samples were obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant mice (SAMR1). Insulin levels in plasma were increased with aging in both SAMP8 and SAMR1 mice, whereas insulin content in pancreas was decreased with aging in SAMP8 and increased in SAMR1 mice. Expressions of glucagon and GLUT2 messenger RNAs (mRNAs) were increased with aging in SAMP8 mice, and no differences were observed in somatostatin and insulin mRNA expressions. Furthermore, aging decreased also the expressions of Pdx-1, FoxO 1, FoxO 3A and Sirt1 in pancreatic SAMP8 samples. Pdx-1 was decreased in SAMR1 mice, but no differences were observed in the rest of parameters on these mice strains. Treatment with melatonin was able to decrease plasma insulin levels and to increase its pancreatic content in SAMP8 mice. In SAMR1, insulin pancreatic content and plasma levels were decreased. HOMA-IR was decreased with melatonin treatment in both strains of animals. On the other hand, in SAMP8 mice, treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin mRNA. Furthermore, it was also able to increase the expression of Sirt1, Pdx-1 and FoxO 3A. According to these results, aging is associated with significant alterations in the relative expression of pancreatic genes associated to glucose metabolism. This has been especially observed in SAMP8 mice. Melatonin administration was able to improve pancreatic function in old SAMP8 mice and to reduce HOMA-IR improving their insulin physiology and glucose metabolism.

  2. Adrenergic activation of melatonin secretion in ovine pineal explants in short-term superfusion culture occurs via protein synthesis independent and dependent phenomena.

    PubMed

    Lewczuk, Bogdan; Ziółkowska, Natalia; Prusik, Magdalena; Przybylska-Gornowicz, Barbara

    2014-01-01

    The ovine pineal is generally considered as an interesting model for the study on adrenergic regulation of melatonin secretion due to some functional similarities with this gland in the human. The present investigations, performed in the superfusion culture of pineal explants, demonstrated that the norepinephrine-induced elevation of melatonin secretion in ovine pinealocytes comprised of two subsequent periods: a rapid increase phase and a slow increase phase. The first one included the quick rise in release of N-acetylserotonin and melatonin, occurring parallel to elevation of NE concentration in the medium surrounding explants. This rapid increase phase was not affected by inhibition of translation. The second, slow increase phase began after NE level had reached the maximum concentration in the culture medium and lasted about two hours. It was completely abolished by the treatment with translation inhibitors. The obtained results showed for the first time that the regulation of N-acetylserotonin synthesis in pinealocytes of some species like the sheep involves the on/off mechanism, which is completely independent of protein synthesis and works very fast. They provided strong evidence pointing to the need of revision of the current opinion that arylalkylamines N-acetyltransferase activity in pinealocytes is controlled exclusively by changes in enzyme abundance.

  3. Melatonin: functions and ligands.

    PubMed

    Singh, Mahaveer; Jadhav, Hemant R

    2014-09-01

    Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the 'hormone of darkness'. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands.

  4. Aging-dependent changes in the effect of daily melatonin supplementation on rat metabolic and behavioral responses.

    PubMed

    Rasmussen, D D; Mitton, D R; Larsen, S A; Yellon, S M

    2001-08-01

    Pineal melatonin secretion has been reported to commonly decrease with aging, whereas intra-abdominal adiposity, plasma insulin and plasma leptin levels tend to increase. We recently demonstrated that daily melatonin administration starting at middle age suppressed male rat intra-abdominal fat, plasma leptin and plasma insulin to youthful levels, suggesting that aging-related changes in pineal melatonin secretion and in energy regulation may be functionally related. Accordingly, we have now investigated the effects of daily melatonin treatment on energy regulation in young versus middle-aged male Sprague Dawley rats. Addition of melatonin to the drinking water (0.2 microg/mL) produced nocturnal and diurnal plasma melatonin concentrations in middle-aged rats (12 months) equivalent to those of young adult (5 months) rats. Administration of this melatonin dosage every day for 10 wk starting at 10 months of age suppressed (P < 0.01) relative intra-abdominal fat, non-fasted plasma insulin and plasma leptin by 27, 39, and 51%, respectively (vs. vehicle-treated controls). In contrast, administration of melatonin for 10 wk starting at 3 months of age did not significantly alter (P> 0.10) any of these parameters. The melatonin administration stimulated (102%, P < 0.001) behavioral responsiveness of the middle-aged rats in a test of response to novelty, restoring youthful levels, but did not significantly alter behavioral responsiveness of the young rats. These results suggest that suppression of intra-abdominal adiposity and plasma leptin and insulin levels and stimulation of behavioral responsiveness in response to daily exogenous melatonin begins at middle age, coincident with and likely dependent upon the aging-associated decline in endogenous pineal melatonin secretion. These results further suggest that appropriate melatonin supplementation may potentially provide therapy or prophylaxis not only for the insulin resistance, increased intra-abdominal fat and resulting

  5. Effects of light and melatonin treatment on body temperature and melatonin secretion daily rhythms in a diurnal rodent, the fat sand rat.

    PubMed

    Schwimmer, Hagit; Mursu, Netta; Haim, Abraham

    2010-08-01

    Many mammals display predictable daily rhythmicity in both neuroendocrine function and behavior. The basic rest-activity cycles are usually consistent for a given species and vary from night-active (nocturnal), those mostly active at dawn and dusk (i.e., crepuscular), and to day-active (diurnal) species. A number of daily rhythms are oppositely phased with respect to the light/dark (LD) cycle in diurnal compared with nocturnal mammals, whereas others are equally phased with respect to the LD cycle, regardless of diurnality/nocturnality. Pineal produced melatonin (MLT) perfectly matches this phase-locked feature in that its production and secretion always occurs during the night in both diurnal and nocturnal mammals. As most rodents studied to date in the field of chronobiology are nocturnal, the aim in this study was to evaluate the effect of light manipulations and different photoperiods on a diurnal rodent, the fat sand rat, Psammomys obesus. The authors studied its daily rhythms of body temperature (T(b)) and 6-sulphatoxymelatonin (6-SMT) under various photoperiodic regimes and light manipulations (acute and chronic exposures) while maintaining a constant ambient temperature of 30 degrees C +/- 1 degrees C. The following protocols were used: (A) Control (CON) conditions 12L:12D; (A1) exposure to one light interference (LI) of CON-acclimated individuals for 30 min, 5 h after lights-off; (A2) short photoperiod (SP) acclimation (8L:16D) for 3 wks; (A3) 3 wks of SP acclimation with chronic LI of 15 min, three times a night at 4-h intervals; (A4) chronic exposure to constant dim blue light (470 nm, 30 lux) for 24 h for 3 wks (LL). (B) The response to exogenous MLT administration, provided in drinking water, was measured under the following protocols: (B1) After chronic exposure to SP with LI, MLT was provided once, starting 1 h before the end of photophase; (B2) after a continuous exposure to dim blue light, MLT was provided at 15:00 h for 2 h for 2 wks; (B3) to CON

  6. Melatonin in Chronic Pain Syndromes.

    PubMed

    Danilov, Andrei; Kurganova, Julia

    2016-06-01

    Melatonin is a neurohormone secreted by epiphysis and extrapineal structures. It performs several functions including chronobiotic, antioxidant, oncostatic, immune modulating, normothermal, and anxiolytic functions. Melatonin affects the cardiovascular system and gastrointestinal tract, participates in reproduction and metabolism, and body mass regulation. Moreover, recent studies have demonstrated melatonin efficacy in relation to pain syndromes. The present paper reviews the studies on melatonin use in fibromyalgia, headaches, irritable bowel syndrome, chronic back pain, and rheumatoid arthritis. The paper discusses the possible mechanisms of melatonin analgesic properties. On one hand, circadian rhythms normalization results in sleep improvement, which is inevitably disordered in chronic pain syndromes, and activation of melatonin adaptive capabilities. On the other hand, there is evidence of melatonin-independent analgesic effect involving melatonin receptors and several neurotransmitter systems.

  7. Effect of melatonin on the vasopressin secretion as influenced by tachykinin NK-1 receptor agonist and antagonist: in vivo and in vitro studies.

    PubMed

    Juszczak, M; Boczek-Leszczyk, E; Stempniak, B

    2007-12-01

    The aim of the present study was to investigate the influence of melatonin on vasopressin (AVP) release from the rat hypothalamo-neurohypophysial (H-NH) system, both in vivo and in vitro, possibly modified by the peptide NK-1 and/or NK-2 receptor agonists and antagonists. Highly selective NK-1 receptor agonist, i.e., [Sar(9),Met(O(2))(11)]-Substance P, has been shown to enhance the AVP release from isolated rat H-NH system in vitro, while the NK-1 receptor antagonist--(Tyr(6),DPhe(7),D-His(9))-Substance P (6-11) as well as the NK-2 receptor selective agonist--(beta-Ala(8))-Neurokinin A (4-10) and antagonist--(Tyr(5),D-Trp(6,8,9),Lys-NH(2)(10))-Neurokinin A (4-10) were essentially inactive in modifying AVP secretion. Melatonin inhibited basal release of AVP but was not able to reduce significantly the in vitro response of vasopressinergic neurones to NK-1 receptor agonist. After intracerebroventricular (icv) administration, substance P (SP), neurokinin A (NKA) and the NK-1 receptor agonist (all at the concentration of 10(-7) M/L) significantly enhanced plasma AVP concentration. Such stimulatory effect of the latter peptide on AVP output from the eurohypophysis was reduced by an intravenous (iv) injection of melatonin, which itself (at a concentration of 5 ng/ml) caused a significant decrease in AVP release 10 min after injection. The inhibitory influence of melatonin on the AVP secretion was absent in rats injected icv with both tachykinin receptors antagonists, the NK-2 receptor agonist or NKA. The present data indicate a distinct role for NK-1 receptor in NKA/SP-mediated regulation of AVP release from the rat H-NH system. They have also shown that, under present experimental conditions, the stimulatory effect of NK-1 receptor activation on AVP secretion into the blood is sensitive to inhibitory influence of melatonin.

  8. Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion.

    PubMed

    Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

    2014-09-01

    Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. © 2014 Associated Professional Sleep Societies, LLC.

  9. Physiology and Endocrinology Symposium: Alterations in uteroplacental hemodynamics during melatonin supplementation in sheep and cattle

    USDA-ARS?s Scientific Manuscript database

    The efficiency of the placenta in transferring nutrients and wastes among the maternal and fetal circulations is vital to ensuring proper fetal development. This articles summarizes previous research from our laboratory examining umbilical and uterine blood flow during dietary melatonin supplementat...

  10. Melatonin treatment alters glucosensing capacity and mRNA expression levels of peptides related to food intake control in rainbow trout hypothalamus.

    PubMed

    Conde-Sieira, Marta; Librán-Pérez, Marta; López Patiño, Marcos A; Soengas, José L; Míguez, Jesús M

    2012-08-01

    As demonstrated in previous studies, the functioning of brain glucosensing systems in rainbow trout is altered under stress conditions in a way that they are unable to respond properly to changes in glucose levels. Melatonin has been postulated as necessary for homeostatic control of energy metabolism in several vertebrate groups, and in fish it has been suggested as an anti-stress molecule. To evaluate the possible effects of melatonin on glucosensing, we have incubated hypothalamus and hindbrains of rainbow trout at different glucose concentrations in the presence of increased doses (0.01, 1, and 100nM) of melatonin assessing whether or not the responses to changes in glucose levels of parameters related to glucosensing (glucose, glycogen and glucose 6-phosphate levels, activities of GK, GSase and PK, and mRNA content of GK, GLUT2, Kir6.x-like, and SUR-like) are modified in the presence of melatonin. While no effects of melatonin were observed in hindbrain, in hypothalamus melatonin treatment up-regulated glucosensing parameters, especially under hypo- and normo-glycaemic conditions. The effects of melatonin in hypothalamus occurred apparently through MT(1) receptors since most effects were counteracted by the presence of luzindole but not by the presence of 4-P-PDOT. Moreover, melatonin treatment induced in hypothalamus increased mRNA expression levels of NPY and decreased mRNA levels of POMC, CART, and CRF. A role of the hormone in daily re-adjustment of hypothalamic glucosensor machinery is discussed. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Melatonin counteracts alterations in oxidative metabolism and cell viability induced by intracellular calcium overload in human leucocytes: changes with age.

    PubMed

    Espino, Javier; Bejarano, Ignacio; Paredes, Sergio D; González, David; Barriga, Carmen; Reiter, Russel J; Pariente, José A; Rodríguez, Ana B

    2010-07-01

    Ageing is associated with an increased production of free radicals and alterations in the mechanisms of adaptation to oxidative stress. In fact, the free radical theory of ageing proposes that deleterious actions of free radicals are responsible for the functional deterioration associated with ageing. Moreover, a close relationship exists between calcium homeostasis and oxidative stress. The current work was aimed at proving that intracellular calcium overload induced by N-formyl-methionyl-leucyl-phenylalanine (FMLP) and/or thapsigargin leads to oxidative stress. We additionally examined the effect of melatonin on the levels of reactive oxygen species (ROS) and cell viability in human leucocytes collected from young (20-30-year-old) and elderly (65-75-year-old) individuals under both basal and oxidative stress-induced conditions. Treatments with 10 nM FMLP and/or 1 microM thapsigargin induced a transient increase in cytosolic free-calcium concentration ([Ca(2 + )](c)) in human leucocytes due to calcium release from internal stores, and led in turn to oxidative stress, as assessed by intracellular ROS measurement. Non-treated leucocytes from aged individuals exhibited higher ROS levels and lower rates of cell survival when compared to leucocytes from young individuals. Similar results were obtained in FMLP and/or thapsigargin-treated leucocytes from elderly individuals when compared to those from the young individuals. Melatonin treatment significantly reduced both hydrogen peroxide (H(2)O(2)) and superoxide anion levels, likely due to its free-radical scavenging properties, and enhanced leucocyte viability in both age groups. Therefore, melatonin may be a useful tool for the treatment of disease states and processes where an excessive production of oxidative damage occurs.

  12. Antioxidant properties of melatonin--an emerging mystery.

    PubMed

    Beyer, C E; Steketee, J D; Saphier, D

    1998-11-15

    Over three centuries ago, the French philosopher René Descartes described the pineal gland as "the seat of the soul." However, it was not until the late 1950s that the chemical identity and biosynthesis of melatonin, the principal hormone secreted by the pineal body, were revealed. Melatonin, named from the Greek melanos, meaning black, and tonos, meaning color, is a biogenic amine with structural similarities to serotonin. The mechanisms mediating the synthesis of melatonin are transcriptionally regulated by the photoperiodic environment. Once synthesized, the neurohormone is a biologic modulator of mood, sleep, sexual behavior, reproductive alterations, immunologic function, and circadian rhythms. Moreover, melatonin exerts its regulatory roles through high-affinity, pertussis toxin-sensitive, G-protein (or guanine nucleotide binding protein) coupled receptors that reside primarily in the eye, kidney, gastrointestinal tract, blood vessels, and brain. Additional evidence also indicates a role for melatonin in aging and age-related diseases, probably related to its efficient free radical scavenger (or antioxidant) activity. The potential clinical benefit of melatonin as an antioxidant is remarkable, suggesting that it may be of use in the treatment of many pathophysiological disease states including various cancers, hypertension, pulmonary diseases, and a variety of neurodegenerative diseases such as Alzheimer's disease. This review summarizes the biosynthesis of melatonin and its many endocrine and physiological functions, including its therapeutic potential in human disease states. Emphasis is placed on the recent speculations indicating that this pineal hormone serves as an endogenous antioxidant agent with proficient free radical scavenging activity.

  13. Altered MT1 and MT2 melatonin receptors expression in the hippocampus of pilocarpine-induced epileptic rats.

    PubMed

    Rocha, Anna Karynna Alves de Alencar; de Lima, Eliangela; Amaral, Fernanda; Peres, Rafael; Cipolla-Neto, José; Amado, Débora

    2017-06-01

    Clinical and experimental findings show that melatonin may be used as an adjuvant to the treatment of epilepsy-related complications by alleviates sleep disturbances, circadian alterations and attenuates seizures alone or in combination with AEDs. In addition, it has been observed that there is a circadian component on seizures, which cause changes in circadian system and in melatonin production. Nevertheless, the dynamic changes of the melatoninergic system, especially with regard to its membrane receptors (MT1 and MT2) in the natural course of TLE remain largely unknown. The aim of this study was to evaluate the 24-hour profile of MT1 and MT2 mRNA and protein expression in the hippocampus of rats submitted to the pilocarpine-induced epilepsy model analyzing the influence of the circadian rhythm in the expression pattern during the acute, silent, and chronic phases. Melatonin receptor MT1 and MT2 mRNA expression levels were increased in the hippocampus of rats few hours after SE, with MT1 returning to normal levels and MT2 reducing during the silent phase. During the chronic phase, mRNA expression levels of both receptors return to levels close to control, however, presenting a different daily profile, showing that there is a circadian change during the chronic phase. Also, during the acute and silent phase it was possible to verify MT1 label only in CA2 hippocampal region with an increased expression only in the dark period of the acute phase. The MT2 receptor was present in all hippocampal regions, however, it was reduced in the acute phase and it was found in astrocytes. In chronic animals, there is a reduction in the presence of both receptors especially in regions where there is a typical damage derived from epilepsy. Therefore, we conclude that SE induced by pilocarpine is able to change melatonin receptor MT1 and MT2 protein and mRNA expression levels in the hippocampus of rats few hours after SE as well as in silent and chronic phases. Copyright © 2017

  14. Seasonal Patterns of Melatonin, Cortisol, and Progesterone Secretion in Female Lambs Raised Beneath a 500-kV Transmission Line.

    SciTech Connect

    Lee, Jack M.

    1992-06-01

    Although several kinds of biological effects of electric and magnetic fields have been reported from laboratory studies, few have been independently replicated. When this study was being planned, the suppression of nighttime melatonin in rodents was thought to represent one of the strongest known effects of these fields. The effect had been replicated by a single laboratory for 60-Hz electric fields, and by multiple laboratories for d-c magnetic fields. The primary objective of this study was to determine whether the effect of electric and magnetic fields on melatonin would also occur in sheep exposed to a high voltage transmission line. The specific hypothesis tested by this experiment was as follows: The electrical environment produced by a 60-Hz, 500-kV transmission line causes a depression in nocturnal melatonin in chronically exposed female lambs. This may mimic effects of pinealectomy or constant long-day photoperiods, thus delaying the onset of reproductive cycles. Results of the study do not provide evidence to support the hypothesis. Melatonin concentrations in the sheep exposed to the transmission line showed the normal pattern of low daytime and high nighttime serum levels. As compared to the control group, there were no statistically significant group differences in the mean amplitude, phase, or duration of the nighttime melatonin elevation.

  15. Evidence of melatonin secretion in cetaceans: plasma concentration and extrapineal HIOMT-like presence in the bottlenose dolphin Tursiops truncatus.

    PubMed

    Panin, Mattìa; Gabai, Gianfranco; Ballarin, Cristina; Peruffo, Antonella; Cozzi, Bruno

    2012-06-01

    The pineal gland is generally believed to be absent in cetaceans, although few and subsequently unconfirmed reports described the organ in some species. The recent description of a complete and photographed pineal body in a bottlenose dolphin (Tursiops truncatus) prompted us to examine a series of 29 brains of the same species, but no gland was found. We then decided to investigate if the main product of the gland, melatonin, was nevertheless produced and present in the plasma of this species. We collected plasma and serum samples from a series of captive bottlenose dolphins for a period of 7 months spanning from winter to summer and we determined the indoleamine concentration by radio-immunoassay (RIA). The results demonstrated for the first time a quantitative assessment of melatonin production in the blood of a cetacean. Melatonin levels were comparable to those of terrestrial mammals (5.15-27.74 pg/ml daylight concentration), with indications of both seasonal and daily variation although the presence of a circadian rhythm remains uncertain. Immunohistochemical analyses using as a marker hydroxyindole-O-methyl-transferase (HIOMT, the key enzyme involved in the biosynthesis of the hormone), suggested extrapineal melatonin production by the retina, the Harderian gland and the gut. The enzyme was unequivocally localized in all the three tissues, and, specifically, ganglion cells in the retina showed a very strong HIOMT-immunoreactivity. Our results suggest that further research might reveal unexplored aspects of melatonin production in cetaceans and deserves special attention and further efforts.

  16. Melatonin and male reproduction.

    PubMed

    Li, Chunjin; Zhou, Xu

    2015-06-15

    Melatonin is a neurohormone secreted by the pineal gland whose concentrations in the body are regulated by both the dark-light and seasonal cycles. The reproductive function of seasonal breeding animals is clearly influenced by the circadian variation in melatonin levels. Moreover, a growing body of evidence indicates that melatonin has important effects in the reproduction of some non-seasonal breeding animals. In males, melatonin affects reproductive regulation in three main ways. First, it regulates the secretion of two key neurohormones, GnRH and LH. Second, it regulates testosterone synthesis and testicular maturation. Third, as a potent free radical scavenger that is both lipophilic and hydrophilic, it prevents testicular damage caused by environmental toxins or inflammation. This review summarizes the existing data on the possible biological roles of melatonin in male reproduction. Overall, the literature data indicate that melatonin affects the secretion of both gonadotropins and testosterone while also improving sperm quality. This implies that it has important effects on the regulation of testicular development and male reproduction.

  17. [Melatonin production in patients with duodenal ulcer at different stages of disease].

    PubMed

    Komarov, F I; Rapoport, S I; Malinovskaia, N K; Voznesenskaia, L A; Sharov, A A; Vetterberg, L

    1998-01-01

    Melatonin secretion was measured in patients with duodenal ulcer in exacerbation and remission. Melatonin production was found abnormal both in duodenal ulcer remission and exacerbation. It is suggested that melatonin may participate in pathogenesis of duodenal ulcer.

  18. Electrophysiological effects of melatonin on mouse Per1 and non-Per1 suprachiasmatic nuclei neurones in vitro.

    PubMed

    Scott, F F; Belle, M D C; Delagrange, P; Piggins, H D

    2010-11-01

    The master circadian pacemaker in the suprachiasmatic nuclei (SCN) regulates the nocturnal secretion of the pineal hormone melatonin. Melatonin, in turn, has feedback effects on SCN neuronal activity rhythms via high affinity G protein-coupled receptors (MT(1) and MT(2) ). However, the precise effects of melatonin on the electrical properties of individual SCN neurones are unclear. In the present study, we investigated the acute effects of exogenous melatonin on SCN neurones using whole-cell patch-clamp recordings in brain slices prepared from Per1::d2EGFP-expressing transgenic mice. In current-clamp mode, bath applied melatonin, at near-physiological concentrations (1 nM), hyperpolarised the majority (63.7%) of SCN neurones tested at all times of the projected light/dark cycle. In addition, melatonin depolarised a small proportion of cells (11.0%). No differences were observed for the effects of melatonin between Per1::GFP or non-Per1::GFP SCN neurones. Melatonin-induced effects were blocked by the MT(1)/MT(2) antagonist, luzindole (1 μM) and the proportion of SCN neurones responsive to melatonin was greatly reduced in the presence of either tetrodotoxin (200 or 500 nM) or gabazine (20 μM). In voltage-clamp recordings, 1 nM melatonin increased the frequency of GABA-mediated currents. These findings indicate, for the first time, that exogenous melatonin can alter neuronal excitability in the majority of SCN neurones, regardless of whether or not they overtly express the core clock gene Per1. The results also suggest that melatonin acts mainly by modulating inhibitory GABAergic transmission within the SCN. This may explain why exogenous application of melatonin has heterogenous effects on individual SCN neurones. © 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.

  19. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels.

    PubMed

    Rasmussen, D D; Boldt, B M; Wilkinson, C W; Yellon, S M; Matsumoto, A M

    1999-02-01

    Human and rat pineal melatonin secretion decline with aging, whereas visceral fat and plasma insulin levels increase. Melatonin modulates fat metabolism in some mammalian species, so these aging-associated melatonin, fat and insulin changes could be functionally related. Accordingly, we investigated the effects of daily melatonin supplementation to male Sprague-Dawley rats, starting at middle age (10 months) and continuing into old age (22 months). Melatonin was added to the drinking water (92% of which was consumed at night) at a dosage (4 microg/ml) previously reported to attenuate the aging-associated decrease in survival rate in male rats, as well as at a 10-fold lower dosage. The higher dosage produced nocturnal plasma melatonin levels in middle-aged rats which were 15-fold higher than in young (4 months) rats; nocturnal plasma melatonin levels in middle-aged rats receiving the lower dosage were not significantly different from young or middle-aged controls. Relative (% of body wt) retroperitoneal and epididymal fat, as well as plasma insulin and leptin levels, were all significantly increased at middle age when compared to young rats. All were restored within 10 weeks to youthful (4 month) levels in response to both dosages of melatonin. Continued treatment until old age maintained suppression of visceral (retroperitoneal + epididymal) fat levels. Plasma corticosterone and total thyroxine (T4) levels were not significantly altered by aging or melatonin treatment. Plasma testosterone, insulin-like growth factor I (IGF-I) and total triiodothyronine (T3) decreased by middle age; these aging-associated decreases were not significantly altered by melatonin treatment. Thus, visceral fat, insulin and leptin responses to melatonin administration may be independent of marked changes in gonadal, thyroid, adrenal or somatotropin regulation. Since increased visceral fat is associated with increased insulin resistance, diabetes, and cardiovascular disease, these results

  20. Toxicology of melatonin.

    PubMed

    Guardiola-Lemaître, B

    1997-12-01

    Despite the fact that melatonin has been released for public use in the United States by the Food and Drug Administration and is available over the counter nationwide, there currently is a total lack of information on the toxicology of melatonin. In Europe, melatonin has a completely different status in that it is considered a "neurohormone" and cannot be sold over the counter. Even though administration of melatonin in humans, as well as in animals (even at supraphysiological doses), has not shown evidence of toxicological effects (i.e., no deaths), a drug toxicological file still would need to be prepared and approved by the regulatory authorities. Several features that are specific to this neurohormone need to be taken into consideration. Whatever the species concerned, melatonin is secreted during the night; it is the "hormone of darkness." It presents a circadian rhythm and a circannual rhythm (in photoperiodic species). The duration of these secretions could have an impact on the reproductive system, for example, showing the importance of the pharmacodynamics of melatonin. An inappropriate time schedule of melatonin administration could induce supraphysiological concentrations of the neurohormone and a desensitization of melatonin receptors. A long duration of exposure to melatonin also could mimic an "artificial darkness" condition when a circadian rhythm with a basal zero level during the day needs to be conserved for a physiological function. Furthermore, administration of large doses of melatonin could induce high concentrations of melatonin and of different metabolites that could have deleterious effects per se. Numerous books, magazines, and articles have praised melatonin as a "miraculous cure-all" for ailments ranging from sleeplessness, to aging, without any clinical evidence of efficacy (with the exception of its chronobiotic and resynchronizing effect). Very little attention has been paid to the possible side effects of melatonin. Nightmares

  1. Neuroprotective effects of melatonin as evidenced by abrogation of oxaliplatin induced behavioral alterations, mitochondrial dysfunction and neurotoxicity in rat brain.

    PubMed

    Waseem, Mohammad; Tabassum, Heena; Parvez, Suhel

    2016-09-01

    Neurotoxicity is a burdensome consequence of platinum-based chemotherapy that neutralizes the administration of effective dosage and often prompts treatment withdrawal. Oxaliplatin (Oxa), a third-era platinum analogue that is active against both early-organize and progressed colorectal growth, produces critical neurotoxicity. It has been reported that the Melatonin (Mel) is a pineal hormone its metabolites display important antioxidant properties in nervous system. There is dearth of literature involving the role of mitochondria and cytosolic compartments mediated Oxa-induced neurotoxicity and its underlying mechanisms are still debatable. Rats were pre-treated with Mel (10mg/kg b.wt., i.p.) and treated with Oxa (4mg/kg b.wt. i.p.) for 5 consecutive days. For neurobehavioral performances, decreased locomotor activity and muscular strength were observed in rats. Treatment with Mel in Oxa treated rats could protect the Oxa induced alterations in motor activity and muscular strength. For painful neuropathy, thermal hyperalgesia/nociceptive tests were evaluated. In addition, pre-treatment of Mel could block or alter the inactivation of Bcl-2, caspase 3 apoptotic protein and alterations Cytochrome c (Cyt c) release in an Oxa rich environment. Pre-treatment of Mel have shown an alteration in hyperalgesia behaviour in Oxa treated rats. Oxidative stress biomarkers, levels of non-enzymatic antioxidants and mitochondrial complexes were evaluated against neurotoxicity induced by Oxa. Mel pre-treatment replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. Mel also modulated altered non-enzymatic, enzymatic antioxidants and complex enzymes of mitochondria. Futures studies are also required to identify other molecular markers involved in neurotoxicity induced by Oxa and possible action of Mel in its modulation. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  2. Melatonin and female reproduction.

    PubMed

    Tamura, Hiroshi; Takasaki, Akihisa; Taketani, Toshiaki; Tanabe, Manabu; Lee, Lifa; Tamura, Isao; Maekawa, Ryo; Aasada, Hiromi; Yamagata, Yoshiaki; Sugino, Norihiro

    2014-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by the pineal gland. After entering the circulation, melatonin acts as an endocrine factor and a chemical messenger of light and darkness. It regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It also affects the brain, immune, gastrointestinal, cardiovascular, renal, bone and endocrine functions and acts as an oncostatic and anti-aging molecule. Many of melatonin's actions are mediated through interactions with specific membrane-bound receptors expressed not only in the central nervous system, but also in peripheral tissues. Melatonin also acts through non-receptor-mediated mechanisms, for example serving as a scavenger for reactive oxygen species and reactive nitrogen species. At both physiological and pharmacological concentrations, melatonin attenuates and counteracts oxidative stress and regulates cellular metabolism. Growing scientific evidence of reproductive physiology supports the role of melatonin in human reproduction. This review was conducted to investigate the effects of melatonin on female reproduction and to summarize our findings in this field. © 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.

  3. Photoperiod Regulates Corticosterone Rhythms by Altered Adrenal Sensitivity via Melatonin-Independent Mechanisms in Fischer 344 Rats and C57BL/6J Mice

    PubMed Central

    Kawai, Misato; Togo, Yuki; Sato, Katsuyoshi; Katoh, Kazuo; Furuse, Mitsuhiro; Yasuo, Shinobu

    2012-01-01

    Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long-day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock. PMID:22720039

  4. Photoperiod regulates corticosterone rhythms by altered adrenal sensitivity via melatonin-independent mechanisms in Fischer 344 rats and C57BL/6J mice.

    PubMed

    Otsuka, Tsuyoshi; Goto, Mariko; Kawai, Misato; Togo, Yuki; Sato, Katsuyoshi; Katoh, Kazuo; Furuse, Mitsuhiro; Yasuo, Shinobu

    2012-01-01

    Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long-day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock.

  5. [Metabolic syndrome and melatonin].

    PubMed

    Rapoport, S I; Molchanov, A Iu; Golichenkov, V A; Burlakova, O V; Suprunenko, E S; Savchenko, E S

    2013-01-01

    Metabolic syndrome (MS) is characterized by the following symptoms: obesity, AH, dyslipidemia, insulin resistance. Pathophysiologically, MS is underlain by disorders of many biochemical and physiological processes, such as elevated levels of low density lipoproteins, hyperstimulation of pancreatic b-cells, increased insulin secretion, substitution of lipid metabolism for carbohydrate one, overgrowth of adipose tissue, excess production of adiponectin, leptin and other signal molecules and a rise in their local intravascular concentration, weight gain. Endogenous and exogenous melatonin inhibits these pathophysiological mechanisms, normalizes metabolism, equilibrates insulin secretion, prevents pancreatic hyperfunction, phosphorylates insulin receptors, inactivates active oxygen and nitrogen species including those produced in LDLP metabolism. Melatonin has specific MT1 and MT2 receptors localized in all body cells. Due to this, it exerts combined preventive action in patients with MS. Recently, melatonin has been reported to have therapeutic effect in MS; it may be recommended to treat this condition.

  6. Dibutyltin-induced alterations of interleukin 1beta secretion from human immune cells.

    PubMed

    Brown, Shyretha; Tehrani, Shahin; Whalen, Margaret M

    2017-02-01

    Dibutyltin (DBT) is used to stabilize polyvinyl chloride plastics (including pipes that distribute drinking water) and as a de-worming agent in poultry. DBT is found in human blood, and DBT exposures alter the secretion of tumor necrosis factor alpha and interferon gamma from lymphocytes. Interleukin (IL)-1β is a proinflammatory cytokine that regulates cellular growth, tissue restoration and immune response regulation. IL-1β plays a role in increasing invasiveness of certain tumors. This study reveals that exposures to DBT (24 h, 48 h and 6 days) modify the secretion of IL-1β from increasingly reconstituted preparations of human immune cells (highly enriched human natural killer cells, monocyte-depleted [MD] peripheral blood mononuclear cells [PBMCs], PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes). DBT altered IL-1β secretion from all cell preparations. Higher concentrations of DBT (5 and 2.5 μm) decreased the secretion of IL-1β, while lower concentrations of DBT (0.1 and 0.05 μm) increased the secretion of IL-1β. Selected signaling pathways were examined in MD-PBMCs to determine if they play a role in DBT-induced elevations of IL-1β secretion. Pathways examined were IL-1β converting enzyme (caspase 1), mitogen-activated protein kinases and nuclear factor kappa B. Caspase 1 and mitogen-activated protein kinase pathways appear to be utilized by DBT in increasing IL-1β secretion. These results indicate that DBT alters IL-1β secretion from human immune cells in an ex. vivo system utilizing several IL-1β regulating signaling pathways. Thus, DBT may have the potential to alter IL-1β secretion in an in vivo system. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Experiments on the effects of a continuous 16.7 Hz magnetic field on melatonin secretion, core body temperature, and heart rates in humans.

    PubMed

    Griefahn, B; Künemund, C; Blaszkewicz, M; Golka, K; Mehnert, P; Degen, G

    2001-12-01

    The present study investigated the hypothesis that a strong extremely low frequency magnetic field partially suppresses the synthesis of melatonin and subsequently elevates the core body temperature. Seven healthy young men (16-22 years) took part in a control and in an exposure session. Three men experienced first the control and then the exposure session, four men experienced the sessions in reverse order. Control sessions were performed as constant routines, where the participants spent 24 hour periods continuously in bed while air temperature was 18 degrees C, illumination less than 30 lux, and the sound pressure level 50 dBA. The exposure sessions differed from that protocol only between 6 pm and 2 am when a strong extremely low frequency magnetic field was continuously applied (16.7 Hz, 0.2 mT). Assuming that the participants were unable to perceive the field consciously, they were blind against the actual condition. Salivary melatonin levels were determined hourly; body core temperatures and heart rates were registered continuously throughout. Neither of these parameters revealed alterations that can be related to the influence of the magnetic field. The present results, taken together with other investigations using that particular field, lead to the hypothesis that the effects most likely, occur, only after repetitive exposures to intermittent fields.

  8. Melatonin-Based Therapeutics for Neuroprotection in Stroke

    PubMed Central

    Shinozuka, Kazutaka; Staples, Meaghan; Borlongan, Cesar V.

    2013-01-01

    The present review paper supports the approach to deliver melatonin and to target melatonin receptors for neuroprotection in stroke. We discuss laboratory evidence demonstrating neuroprotective effects of exogenous melatonin treatment and transplantation of melatonin-secreting cells in stroke. In addition, we describe a novel mechanism of action underlying the therapeutic benefits of stem cell therapy in stroke, implicating the role of melatonin receptors. As we envision the clinical entry of melatonin-based therapeutics, we discuss translational experiments that warrant consideration to reveal an optimal melatonin treatment strategy that is safe and effective for human application. PMID:23698756

  9. The foetal pig pineal gland is richly innervated by nerve fibres containing catecholamine-synthesizing enzymes, neuropeptide Y (NPY) and C-terminal flanking peptide of NPY, but it does not secrete melatonin.

    PubMed

    Bulc, Michał; Lewczuk, Bogdan; Prusik, Magdalena; Całka, Jarosław

    2013-05-01

    Innervation of the mammalian pineal gland during prenatal development is poorly recognized. Therefore, immunofluorescence studies of the pineals of 70- and 90-day-old foetuses of the domestic pig were performed using antibodies against tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DβH), neuropeptide Y (NPY) and C-terminal flanking peptide of NPY (CPON). The investigated glands were supplied by numerous nerve fibres containing TH and DβH. The density of these fibres was higher in the distal and middle parts of the gland than in the proximal one. NPY and CPON were identified in the majority of DβH-positive fibres as well as in a small population of DβH-negative fibres localized mainly in the proximal part of the pineal. The immunoreactive fibres were more numerous in 90-day-old foetuses than in 70-day-old ones. The effect of norepinephrine on melatonin secretion by the foetal pineals in the short-term organ culture was studied to determine the role of DβH-positive fibres during prenatal life. For the same purpose melatonin was measured in the blood in the umbilical cords and in the jugular vein of the mother. The pineals of both groups of foetuses did not secrete melatonin in the organ culture, independently of the presence or absence of norepinephrine in the medium. Melatonin concentrations in the blood in the umbilical cords of foetuses from the same litter and in the jugular vein of their mother were similar. The presence of adrenergic nerve fibres in the pig pineal during gestation does not seem to be associated with the control of melatonin secretion.

  10. Exogenous melatonin reproduces the effects of short day lengths on hippocampal function in male white-footed mice, Peromyscus leucopus.

    PubMed

    Walton, J C; Chen, Z; Travers, J B; Nelson, R J

    2013-09-17

    Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain the time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long-term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After 10 weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short-day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length-induced changes in the structure and function of the hippocampus in a photoperiodic rodent. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Exogenous Melatonin Reproduces the Effects of Short Day Lengths on Hippocampal Function in Male White-Footed Mice, Peromyscus leucopus

    PubMed Central

    Walton, James C.; Chen, Zhixiong; Travers, Joseph B.; Nelson, Randy J.

    2013-01-01

    Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After ten weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length induced changes in the structure and function of the hippocampus in a photoperiodic rodent. PMID:23806713

  12. Secretion of interferon gamma from human immune cells is altered by exposure to tributyltin and dibutyltin.

    PubMed

    Lawrence, Shanieek; Reid, Jacqueline; Whalen, Margaret

    2015-05-01

    Tributyltin (TBT) and dibutyltin (DBT) are widespread environmental contaminants found in food, beverages, and human blood samples. Both of these butyltins (BTs) interfere with the ability of human natural killer (NK) cells to lyse target cells and alter secretion of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells in vitro. The capacity of BTs to interfere with secretion of other pro-inflammatory cytokines has not been examined. Interferon gamma (IFNγ) is a modulator of adaptive and innate immune responses, playing an important role in overall immune competence. This study shows that both TBT and DBT alter secretion of IFNγ from human immune cells. Peripheral blood cell preparations that were increasingly reconstituted were used to determine if exposures to either TBT or DBT affected IFNγ secretion and how the makeup of the cell preparation influenced that effect. IFNγ secretion was examined after 24 h, 48 h, and 6 day exposures to TBT (200 - 2.5 nM) and DBT (5 - 0.05 µM) in highly enriched human NK cells, a monocyte-depleted preparation of PBMCs, and monocyte-containing PBMCs. Both BTs altered IFNγ secretion from immune cells at most of the conditions tested (either increasing or decreasing secretion). However, there was significant variability among donors as to the concentrations and time points that showed changes as well as the baseline secretion of IFNγ. The majority of donors showed an increase in IFNγ secretion in response to at least one concentration of TBT or DBT at a minimum of one length of exposure.

  13. Endocrine and immune effects of melatonin therapy in metastatic cancer patients.

    PubMed

    Lissoni, P; Barni, S; Crispino, S; Tancini, G; Fraschini, F

    1989-05-01

    Melatonin, the most important indole hormone produced by the pineal gland, appears to inhibit tumor growth; moreover, altered melatonin secretion has been reported in cancer patients. Despite these data, the possible use of melatonin in human neoplasms remains to be established. The aim of this clinical trial was to evaluate the therapeutic, immunological and endocrine effects of melatonin in patients with metastatic solid tumor, who did not respond to standard therapies. The study was carried out on 14 cancer patients (colon, six; lung, three; pancreas, two; liver, two; stomach, one). Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period in an oral dose of 10 mg daily in patients who had a remission, stable disease or an improvement in PS. Before and after the first 2 months of therapy, GH, somatomedin-C, beta-endorphin, melatonin blood levels and lymphocyte subpopulations were evaluated. A partial response was achieved in one case with cancer of the pancreas, with a duration of 18+ months; moreover, six patients had stable disease, while the other eight progressed. An evident improvement in PS was obtained in 8/14 patients. In patients who did not progress, T4/T8 mean ratio was significantly higher after than before melatonin therapy, while it decreased in patients who progressed. On the contrary, hormonal levels were not affected by melatonin administration. This study would suggest that melatonin may be of value in untreatable metastatic cancer patients, particularly in improving their PS and quality of life; moreover, based on its effects on the immune system, melatonin could be tested in association with other antitumor treatments.

  14. Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration.

    PubMed

    Hulleman, John D; Kaushal, Shalesh; Balch, William E; Kelly, Jeffery W

    2011-12-01

    An Arg345Trp (R345W) mutation in epidermal growth factor-containing, fibulin-like extracellular matrix protein 1 (EFEMP1) causes its inefficient secretion and the macular dystrophy malattia leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). To understand the influence of the protein homeostasis (or proteostasis) network in rescuing mutant EFEMP1 misfolding and inefficient secretion linked to ML/DHRD, we developed a convenient and sensitive cell-based luminescence assay to monitor secretion versus intracellular accumulation. Fusing EFEMP1 to Gaussia luciferase faithfully recapitulates mutant EFEMP1 secretion defects observed previously using more cumbersome methodology. To understand what governs mutant intracellular retention, we generated a series of R345 mutants. These mutants revealed that aromatic residue substitutions (i.e., Trp, Tyr, and Phe) at position 345 cause significant EFEMP1 secretion deficiencies. These secretion defects appear to be caused, in part, by reduced native disulfide bonding in domain 6 harboring the 345 position. Finally, we demonstrate that mutant EFEMP1 secretion and proper disulfide formation are enhanced by adaptation of the cellular environment by a reduced growth temperature and/or translational attenuation. This study highlights the mechanisms underlying the inefficient secretion of R345W EFEMP1 and demonstrates that alteration of the proteostasis network may provide a strategy to alleviate or delay the onset of this macular dystrophy.

  15. Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration

    PubMed Central

    Hulleman, John D.; Kaushal, Shalesh; Balch, William E.; Kelly, Jeffery W.

    2011-01-01

    An Arg345Trp (R345W) mutation in epidermal growth factor–containing, fibulin-like extracellular matrix protein 1 (EFEMP1) causes its inefficient secretion and the macular dystrophy malattia leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). To understand the influence of the protein homeostasis (or proteostasis) network in rescuing mutant EFEMP1 misfolding and inefficient secretion linked to ML/DHRD, we developed a convenient and sensitive cell-based luminescence assay to monitor secretion versus intracellular accumulation. Fusing EFEMP1 to Gaussia luciferase faithfully recapitulates mutant EFEMP1 secretion defects observed previously using more cumbersome methodology. To understand what governs mutant intracellular retention, we generated a series of R345 mutants. These mutants revealed that aromatic residue substitutions (i.e., Trp, Tyr, and Phe) at position 345 cause significant EFEMP1 secretion deficiencies. These secretion defects appear to be caused, in part, by reduced native disulfide bonding in domain 6 harboring the 345 position. Finally, we demonstrate that mutant EFEMP1 secretion and proper disulfide formation are enhanced by adaptation of the cellular environment by a reduced growth temperature and/or translational attenuation. This study highlights the mechanisms underlying the inefficient secretion of R345W EFEMP1 and demonstrates that alteration of the proteostasis network may provide a strategy to alleviate or delay the onset of this macular dystrophy. PMID:22031286

  16. Altered Myokine Secretion Is an Intrinsic Property of Skeletal Muscle in Type 2 Diabetes

    PubMed Central

    Ciaraldi, Theodore P.; Ryan, Alexander J.; Mudaliar, Sunder R.; Henry, Robert R.

    2016-01-01

    Skeletal muscle secretes factors, termed myokines. We employed differentiated human skeletal muscle cells (hSMC) cultured from Type 2 diabetic (T2D) and non-diabetic (ND) subjects to investigate the impact of T2D on myokine secretion. Following 24 hours of culture concentrations of selected myokines were determined to range over 4 orders of magnitude. T2D hSMC released increased amounts of IL6, IL8, IL15, TNFa, Growth Related Oncogene (GRO)a, monocyte chemotactic protein (MCP)-1, and follistatin compared to ND myotubes. T2D and ND hSMC secreted similar levels of IL1ß and vascular endothelial growth factor (VEGF). Treatment with the inflammatory agents lipopolysaccharide (LPS) or palmitate augmented the secretion of many myokines including: GROa, IL6, IL8, IL15, and TNFa, but did not consistently alter the protein content and/or phosphorylation of IkBa, p44/42 MAPK, p38 MAPK, c-Jun N-terminal kinase (JNK) and NF-kB, nor lead to consistent changes in basal and insulin-stimulated glucose uptake or free fatty acid oxidation. Conversely, treatment with pioglitazone or oleate resulted in modest reductions in the secretion of several myokines. Our results demonstrate that altered secretion of a number of myokines is an intrinsic property of skeletal muscle in T2D, suggesting a putative role of myokines in the response of skeletal muscle to T2D. PMID:27453994

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

    PubMed

    Shirakawa, S; Tsuchiya, S; Tsutsumi, Y; Kotorii, T; Uchimura, N; Sakamoto, T; Yamada, S

    1998-04-01

    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.

  18. Melatonin and glucose metabolism: clinical relevance.

    PubMed

    Lardone, P J; Alvarez-Sanchez, Sanchez N; Guerrero, J M; Carrillo-Vico, A

    2014-01-01

    The role of melatonin in glucose homeostasis is an active area of investigation. There is a growing body of evidence suggesting a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Furthermore, melatonin has been found to influence insulin secretion both in vivo and in vitro, and night-time melatonin levels are related to night-time insulin concentrations in patients with diabetes. In several recent studies, a single nucleotide polymorphism of the human melatonin receptor 1B has been described as being causally linked to an increased risk of developing type 2 diabetes. Taken together, these data suggest that endogenous as well as exogenous melatonin may play a role in diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species, considering pancreatic β-cells are particularly susceptible to oxidative stress because they possess only low-antioxidative capacity.

  19. Daily Socs1 rhythms alter with aging differentially in peripheral clocks in male Wistar rats: therapeutic effects of melatonin.

    PubMed

    Vinod, Ch; Jagota, Anita

    2017-03-22

    Suprachiasmatic nucleus (SCN) in synchronization with the peripheral clocks regulates the temporal oscillations leading to overt rhythms. Aging leads to attenuation of such circadian regulation, accompanied by increased inflammatory mediators prevalently the cytokines. Suppressors of cytokine signaling (SOCS) family of proteins such as SOCS 1, 3 and cytokine-inducible SH2-containing protein (CIS) negatively regulate the cytokine signaling pathway. The role of SOCS1 in aging and circadian system is obscure. We therefore studied the daily rhythms of rSocs1 mRNA expression at Zeitgeber time (ZT) -0, 6, 12 and 18 in peripheral clocks such as liver, kidney, intestine and heart of 3, 12 and 24 months (m) old male Wistar rats. Interestingly the peripheral clocks studied displayed a rhythmic rSocs1 gene expression in 3 months. In 12 months group, 12 h phase advance in liver and 12 h phase delay in kidney and heart was observed with abolition of rhythms in intestine. Aging (24 months group) resulted in a phase advance by 6 h in liver and heart with abolition of rhythms in intestine in 24 months group. Kidney was also significantly affected upon aging with significant decrease in the rSocs1 levels and abolition of rhythms. The decrease in melatonin levels with aging is associated with decreased immunity and increased oxidative stress. The exogenous administration of melatonin has been linked to play a role in re-synchronization of circadian rhythms, reducing oxidative stress and enhancing immune properties. We therefore had studied the effect of exogenous melatonin upon age induced changes in daily rSocs1 gene expression patterns. Melatonin treatment partially restored the rhythms and daily pulse (ratio of maximum:minimum levels) in liver and intestine in 12 months group. Melatonin administration resulted in a significant increase in mean 24 h rSocs1 expression in intestine and heart of 24 months group compared to that of 3 months. The melatonin administration

  20. Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells

    SciTech Connect

    Raza, Haider John, Annie; Brown, Eric M.; Benedict, Sheela; Kambal, Amr

    2008-01-15

    Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolism and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival.

  1. Membrane alteration is necessary but not sufficient for effective glutamate secretion in Corynebacterium glutamicum.

    PubMed Central

    Hoischen, C; Krämer, R

    1990-01-01

    We showed recently that secretion of glutamate in biotin-limited cells of Corynebacterium glutamicum is mediated by carrier systems in the plasma membrane (C. Hoischen and R. Krämer, Arch. Microbiol. 151:342-347, 1989). In view of the generally accepted hypothesis that glutamate efflux is directly caused by alterations of the membrane, it was necessary to examine the kind of correlation between changes in lipid content and composition of the bacterial membrane and glutamate secretion activity. Two new experimental approaches were used. (i) Changes in lipid content and composition were analyzed in glutamate-producing cells which were forced to switch to nonproducers by addition of biotin in a short-term fermentation. (ii) The time courses of both the fatty acid or phospholipid composition and the efflux activity were analyzed within the first minutes of the switch from high to low secretion activity. The following results were obtained. (i) The time course of the change in fatty acid or phospholipid content and composition was not related to the change in secretion behavior. (ii) There was no specific fatty acid or phospholipid compound which regulated glutamate efflux. (iii) High efflux activity could only be induced when the total lipid content of the membrane was reduced. (iv) Although consistently correlated to high secretion activity, membrane alteration was never a sufficient prerequisite for glutamate efflux in C. glutamicum. PMID:1971623

  2. Thyroid status alters structure of VLDL secreted by perfused rat liver.

    PubMed

    Schroeder, F; Keyes, W G; Wilcox, H G; Heimberg, M

    1982-01-01

    The interaction of thyroid status and oleic acid infusion rate on the thermal behavior of the very low density lipoprotein (VLDL) secreted by isolated perfused rat liver was examined. The livers were infused at 37 degrees C with oleate at rates of 0, 83, 166, or 332 mumoles/hr for 4 hours and VLDL was isolated from the perfusate at 12 degrees C. The lipid composition of the VLDL secreted by the perfused liver from hyperthyroid animals was dramatically different from controls at all infusion rates of oleate. Significant changes in the ratio of [phospholipid + cholesterol]/[triglyceride] and in fatty composition of secreted triglycerides occurred. Differential scanning calorimetry of the intact VLDL and extracted triglycerides secreted by euthyroid rats suggested the existence of four thermotropic endothermic transitions centered at -20.5, -14.0, -3.0, and 9.0 degrees C. Both the total enthalpies and the temperatures at which the phase alterations occurred in the triglyceride fraction from VLDL secreted by livers from euthyroid rats were highly dependent on the rate of infusion of oleate. Pretreatment of the rats with triiodothyronine and infusion of 332 mumoles oleate/hr abolished in the intact VLDL the temperature transitions centered at -20.8 and at 10.5 degrees C and decreased the total enthalpy from 8.13 to 38.5 cal/gm. Livers from rats pretreated with propylthiouracil and infused with oleate at 332 mumoles/hr secreted VLDL in which only one transition centered at -5.0 degrees C remained. The total enthalpy was unaffected. At all rates of infusion of oleate, the phase behavior of the intact VLDL or triglycerides extracted from the VLDL was altered by prior treatment of the rats with triiodothyronine or propylthiouracil. The thyroid state of the rat profoundly affected the thermal properties of the VLDL secreted by the perfused liver infused with the unsaturated fatty acid oleate.

  3. Pre- and post-natal melatonin administration partially regulates brain oxidative stress but does not improve cognitive or histological alterations in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Corrales, Andrea; Parisotto, Eduardo B; Vidal, Verónica; García-Cerro, Susana; Lantigua, Sara; Diego, Marian; Wilhem Filho, Danilo; Sanchez-Barceló, Emilio J; Martínez-Cué, Carmen; Rueda, Noemí

    2017-09-15

    Melatonin administered during adulthood induces beneficial effects on cognition and neuroprotection in the Ts65Dn (TS) mouse model of Down syndrome. Here, we investigated the effects of pre- and post-natal melatonin treatment on behavioral and cognitive abnormalities and on several neuromorphological alterations (hypocellularity, neurogenesis impairment and increased oxidative stress) that appear during the early developmental stages in TS mice. Pregnant TS females were orally treated with melatonin or vehicle from the time of conception until the weaning of the offspring, and the pups continued to receive the treatment from weaning until the age of 5 months. Melatonin administered during the pre- and post-natal periods did not improve the cognitive impairment of TS mice as measured by the Morris Water maze or fear conditioning tests. Histological alterations, such as decreased proliferation (Ki67+ cells) and hippocampal hypocellularity (DAPI+ cells), which are typical in TS mice, were not prevented by melatonin. However, melatonin partially regulated brain oxidative stress by modulating the activity of the primary antioxidant enzymes (superoxide dismutase in the cortex and catalase in the cortex and hippocampus) and slightly decreasing the levels of lipid peroxidation in the hippocampus of TS mice. These results show the inability of melatonin to prevent cognitive impairment in TS mice when it is administered at pre- and post-natal stages. Additionally, our findings suggest that to induce pro-cognitive effects in TS mice during the early stages of development, in addition to attenuating oxidative stress, therapies should aim to improve other altered processes, such as hippocampal neurogenesis and/or hypocellularity. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. The role of melatonin in diabetes: therapeutic implications.

    PubMed

    Sharma, Shweta; Singh, Hemant; Ahmad, Nabeel; Mishra, Priyanka; Tiwari, Archana

    2015-10-01

    Melatonin referred as the hormone of darkness is mainly secreted by pineal gland, its levels being elevated during night and low during the day. The effects of melatonin on insulin secretion are mediated through the melatonin receptors (MT1 and MT2). It decreases insulin secretion by inhibiting cAMP and cGMP pathways but activates the phospholipaseC/IP3 pathway, which mobilizes Ca2+from organelles and, consequently increases insulin secretion. Both in vivo and in vitro, insulin secretion by the pancreatic islets in a circadian manner, is due to the melatonin action on the melatonin receptors inducing a phase shift in the cells. Melatonin may be involved in the genesis of diabetes as a reduction in melatonin levels and a functional interrelationship between melatonin and insulin was observed in diabetic patients. Evidences from experimental studies proved that melatonin induces production of insulin growth factor and promotes insulin receptor tyrosine phosphorylation. The disturbance of internal circadian system induces glucose intolerance and insulin resistance, which could be restored by melatonin supplementation. Therefore, the presence of melatonin receptors on human pancreatic islets may have an impact on pharmacotherapy of type 2 diabetes.

  5. Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome.

    PubMed

    Miyamoto, A; Oki, J; Takahashi, S; Okuno, A

    1999-01-01

    We studied the circadian rhythm of serum melatonin levels in two patients with classical Rett syndrome having severe sleep disorders; serum melatonin levels were measured before and during melatonin treatment using radioimmunoassay. Patient 1 had a free-running rhythm of sleep-wake cycle from 3 years of age. At the age of 4 years, the peak time of melatonin was delayed 6 h compared to normal control and the peak value was at the lower limit. Patient 2 had a fragmented sleep pattern accompanied by night screaming from 1 year and 6 months of age. At the age of 10 years, the peak time of melatonin secretion was normal but the peak value was at the lower limit. These patients were given 5 mg melatonin orally prior to bedtime. Exogenous melatonin dramatically improved the sleep-wake cycle in patient 1. In patient 2, exogenous melatonin showed a hypnotic effect but early morning awakenings occurred occasionally. When melatonin treatment was stopped, the sleep disorders recurred and re-administration of 3 mg melatonin was effective in both patients. The effect was maintained over 2 years without any adverse effects. These findings suggests that sleep disorders in patients with Rett syndrome may relate with an impaired secretion of melatonin.

  6. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders.

    PubMed

    Geoffroy, Pierre Alexis; Etain, Bruno; Franchi, Jean-Arthur Micoulaud; Bellivier, Frank; Ritter, Philipp

    2015-01-01

    Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD.

  7. Melatonin, endocrine pancreas and diabetes.

    PubMed

    Peschke, Elmar

    2008-01-01

    Melatonin influences insulin secretion both in vivo and in vitro. (i) The effects are MT(1)-and MT(2)-receptor-mediated. (ii) They are specific, high-affinity, pertussis-toxin-sensitive, G(i)-protein-coupled, leading to inhibition of the cAMP-pathway and decrease of insulin release. [Correction added after online publication 4 December 2007: in the preceding sentence, 'increase of insulin release' was changed to 'decrease of insulin release'.] Furthermore, melatonin inhibits the cGMP-pathway, possibly mediated by MT(2) receptors. In this way, melatonin likely inhibits insulin release. A third system, the IP(3)-pathway, is mediated by G(q)-proteins, phospholipase C and IP(3), which mobilize Ca(2+) from intracellular stores, with a resultant increase in insulin. (iii) Insulin secretion in vivo, as well as from isolated islets, exhibits a circadian rhythm. This rhythm, which is apparently generated within the islets, is influenced by melatonin, which induces a phase shift in insulin secretion. (iv) Observation of the circadian expression of clock genes in the pancreas could possibly be an indication of the generation of circadian rhythms in the pancreatic islets themselves. (v) Melatonin influences diabetes and associated metabolic disturbances. The diabetogens, alloxan and streptozotocin, lead to selective destruction of beta-cells through their accumulation in these cells, where they induce the generation of ROS. Beta-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. Results suggest that melatonin in pharmacological doses provides protection against ROS. (vi) Finally, melatonin levels in plasma, as well as the arylalkylamine-N-acetyltransferase (AANAT) activity, are lower in diabetic than in nondiabetic rats and humans. In contrast, in the pineal gland, the AANAT mRNA is increased and the insulin receptor mRNA is decreased, which indicates a close interrelationship between insulin and melatonin.

  8. Altered folate metabolism modifies cell proliferation and progesterone secretion in human placental choriocarcinoma JEG-3 cells.

    PubMed

    Moussa, Carolyne; Ross, Nikia; Jolette, Philippe; MacFarlane, Amanda J

    2015-09-28

    Folate is an essential B vitamin required for de novo purine and thymidylate synthesis, and for the remethylation of homocysteine to form methionine. Folate deficiency has been associated with placenta-related pregnancy complications, as have SNP in genes of the folate-dependent enzymes, methionine synthase (MTR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). We aimed to determine the effect of altered folate metabolism on placental cell proliferation, viability and invasive capacity and on progesterone and human chorionic gonadotropin (hCG) secretion. Human placental choriocarcinoma (JEG-3) cells cultured in low folic acid (FA) (2 nM) demonstrated 13% (P<0.001) and 26% (P<0.001) lower proliferation, 5.5% (P=0.025) and 7.5% (P=0.004) lower invasion capacity, and 5 to 7.5% (P=0.004-0.025) lower viability compared with control (20 nM) or supplemented (100 nM) cells, respectively. FA concentration had no effect on progesterone or hCG secretion. Small interfering RNA (siRNA) knockdown of MTR gene and protein expression resulted in 17.7% (P<0.0001) lower proliferation and 61% (P=0.014) higher progesterone secretion, but had no effect on cell invasion and hCG secretion. siRNA knockdown of MTHFD1 gene expression in the absence of detectable changes in protein expression resulted in 10.3% (P=0.001) lower cell proliferation, but had no effect on cell invasion and progesterone or hCG secretion. Our data indicate that impaired folate metabolism can result in lower trophoblast proliferation, and could alter viability, invasion capacity and progesterone secretion, which may explain in part the observed associations between folate and placenta-related complications.

  9. Diel changes in plasma melatonin and corticosterone concentrations in tropical Nazca boobies (Sula granti) in relation to moon phase and age.

    PubMed

    Tarlow, Elisa M; Hau, Michaela; Anderson, David J; Wikelski, Martin

    2003-10-01

    We investigated the effects of moon phases and age on diel rhythms of plasma melatonin and corticosterone in free-living Nazca boobies (Sula granti) on the Galápagos Islands, Ecuador. Melatonin and corticosterone secretion are regulated by the circadian system and the two hormones play a role in the control of locomotor activity and foraging, which can be influenced by moon phases. These seabirds have a long life span and in many vertebrates circadian function deteriorates with age. The functioning of the circadian system under different environmental conditions and changes related to age are poorly understood and hardly studied in wild birds. Nazca boobies had generally low plasma melatonin concentrations but showed a diel variation with higher concentrations at 00:00 and 16:00h. The diel variations in melatonin concentrations disappeared during full moon, suggesting that natural light levels at night can suppress melatonin secretion in Nazca boobies. Maximal melatonin concentrations tended to decline in older birds (10-19 years). Birds showed a clear diel variation in basal plasma corticosterone with a peak in the early morning, before the active period begins, and low concentrations throughout the day. As with melatonin, there were no diel variations in corticosterone at full moon, which may be due to different activity patterns in response to food availability or changes in the circadian system. While other studies have found a relationship between corticosterone and melatonin, we found no such correlation in Nazca boobies. The lunar cycle appears to affect the hormone titers of Nazca boobies both directly and indirectly. First, melatonin rhythms can be directly affected by the light intensity associated with full moon. Second, prey availability may change foraging patterns and can therefore indirectly alter corticosterone secretion in Nazca boobies.

  10. Does evening exposure to mobile phone radiation affect subsequent melatonin production?

    PubMed

    Wood, Andrew W; Loughran, Sarah P; Stough, Con

    2006-02-01

    To test whether exposure to the emissions from a digital mobile phone handset prior to sleep alters the secretion of melatonin. In a double-blind cross-over design, 55 adult volunteers were both actively exposed or sham-exposed (in random order on successive Sunday nights) to mobile phone emissions for 30 min (0.25 W average power). Urine collection occurred immediately prior to retiring to bed and on rising the next morning. Melatonin output was estimated from principal metabolite concentrations (6-sulphatoxymelatonin (aMT6s) via radioimmunoassay), urine volumes and creatinine concentrations. Total melatonin metabolite output (concentration x urine volume) was unchanged between the two exposure conditions (active 14.1+/-1.1 microg; sham 14.6+/-1.3 microg). The pre- and post-bedtime outputs considered separately were also not significantly different, although the pre-bedtime value was less for active versus sham exposure. When melatonin metabolite output was estimated from the ratio of aMT6s to creatinine concentrations, the pre-bedtime value was significantly less (p = 0.037) for active compared to sham. Examination of individual responses is suggestive of a small group of 'responders'. Total nighttime melatonin output is unchanged by mobile phone handset emissions, but there could be an effect on melatonin onset time.

  11. Altered protein secretion of Chlamydia trachomatis in persistently infected human endocervical epithelial cells

    PubMed Central

    Wang, Jin; Frohlich, Kyla M.; Buckner, Lyndsey; Quayle, Alison J.; Luo, Miao; Feng, Xiaogeng; Beatty, Wandy; Hua, Ziyu; Rao, Xiancai; Lewis, Maria E.; Sorrells, Kelly; Santiago, Kerri; Zhong, Guangming

    2011-01-01

    Chlamydia trachomatis is the most common bacterial infection of the human reproductive tract globally; however, the mechanisms underlying the adaptation of the organism to its natural target cells, human endocervical epithelial cells, are not clearly understood. To secure its intracellular niche, C. trachomatis must modulate the host cellular machinery by secreting virulence factors into the host cytosol to facilitate bacterial growth and survival. Here we used primary human endocervical epithelial cells and HeLa cells infected with C. trachomatis to examine the secretion of bacterial proteins during productive growth and persistent growth induced by ampicillin. Specifically, we observed a decrease in secretable chlamydial protease-like activity factor (CPAF) in the cytosol of host epithelial cells exposed to ampicillin with no evident reduction of CPAF product by C. trachomatis. In contrast, the expression of CopN and Tarp was downregulated, suggesting that C. trachomatis responds to ampicillin exposure by selectively altering the expression of secretable proteins. In addition, we observed a greater accumulation of outer-membrane vesicles from C. trachomatis in persistently infected cells. Taken together, these results suggest that the regulation of both gene expression and the secretion of chlamydial virulence proteins is involved in the adaptation of the bacteria to a persistent infection state in human genital epithelial cells. PMID:21737500

  12. Bright light delights: effects of daily light exposure on emotions, rest-activity cycles, sleep and melatonin secretion in severely demented patients.

    PubMed

    Münch, Mirjam; Schmieder, Michael; Bieler, Katharina; Goldbach, Rolf; Fuhrmann, Timo; Zumstein, Naomi; Vonmoos, Petra; Scartezzini, Jean-Louis; Wirz-Justice, Anna; Cajochen, Christian

    2017-05-22

    We tested whether the effects of a dynamic lighting system are superior to conventional lighting on emotions, agitation behaviour, quality of life, melatonin secretion and circadian rest-activity cycles in severely demented patients. As a comparison, an age matched control patient group was exposed to conventional lighting. For none of the output measures, significant differences between the two lighting conditions were found during the 8 study weeks in fall/winter. Thus, we divided the patient cohort (n = 89) into two groups, solely based on the median of their daily individual light exposure. Patients with higher average daily light exposure (>417 lx) showed significantly longer emotional expressions of pleasure and alertness per daily observations than patients with lower daily light exposure. Moreover, they had a higher quality of life, spent less time in bed, went to bed later and initiated their sleep episodes later although the two groups did not differ with respect to age, severity of cognitive impairment and mobility. In general, men were more agitated, had shorter sleep with more wake episodes, had a lower circadian amplitude of relative rest-wake activity and inter-daily circadian stability than women. In particular, lower daily light exposures significantly predicted lower circadian amplitudes of rest-activity cycles in men but not in women. This may indicate sex specific susceptibility to daily light exposures for rest-activity regulation in older demented patients. Our results provide evidence that a higher daily light exposure has beneficial effects on emotions and thus improved quality of life in a severely demented patient group. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Hypothalamic gonadotropin-releasing hormone receptor activation stimulates oxytocin release from the rat hypothalamo-neurohypophysial system while melatonin inhibits this process.

    PubMed

    Juszczak, Marlena; Boczek-Leszczyk, Emilia

    2010-01-15

    The present study was undertaken to investigate the influence of gonadotropin-releasing hormone (GnRH) and its agonist and antagonist on oxytocin (OT) release from the rat hypothalamo-neurohypophysial (H-N) system. An additional aim was to determine whether the possible response of oxytocinergic neurons to these peptides could be modified by melatonin through a cAMP-dependent mechanism. The results show that the highly selective GnRH agonist (i.e., [Des-Gly(10),d-His(Bzl)(6),Pro-NHEt(9)]-LHRH; Histrelin) stimulates the secretion of OT from an isolated rat H-N system. Melatonin significantly inhibited basal and histrelin-induced release of OT in vitro, and displayed no significant influence on OT release in the presence of GnRH or its antagonist. Addition of melatonin to a medium containing forskolin resulted in significant reduction of OT secretion from the H-N system. On the other hand, addition of forskolin to a medium containing both histrelin and melatonin did not further alter the inhibitory influence of melatonin on the histrelin-dependent secretion of OT in vitro. Intracerebroventricular (icv) infusion (experiment in vivo) of a GnRH antagonist resulted in substantial inhibition of OT release, thus revealing the stimulatory action of endogenous GnRH. In melatonin-treated animals, blood plasma OT levels were not changed in comparison to the vehicle. Our present data strongly suggests that activation of the GnRH receptor in the hypothalamus is involved in stimulation of OT secretion from the rat H-N system. It has also been shown, under experimental in vitro conditions, that melatonin fully suppresses the response of oxytocinergic neurons to the GnRH agonist - histrelin. The effect of melatonin on OT release is mediated by the cAMP-dependent mechanism, although other mechanisms of action are also possible.

  14. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients

    PubMed Central

    Artemiou, Panagiotis; Bilecova-Rabajdova, Miroslava; Sabol, Frantisek; Torok, Pavol; Kolarcik, Peter; Kolesar, Adrian

    2015-01-01

    Introduction Post-cardiac surgery delirium is a severe complication. The circadian rhythm of melatonin secretion has been shown to be altered postoperatively. Aim of the study It was hypothesized that restoring normal sleeping patterns with a substance that is capable of resynchronizing circadian rhythm such as exogenous administration of melatonin may possibly reduce the incidence of postoperative delirium. Material and methods This paper represents a prospective clinical observational study. Two consecutive groups of 250 consecutive patients took part in the study. Group A was the control group and group B was the melatonin group. In group B, the patients received prophylactic melatonin treatment. The main objectives were to observe the incidence of delirium, to identify any predictors of delirium, and to compare the two groups based on the delirium incidence. Results The incidence of delirium was 8.4% in the melatonin group vs. 20.8% in the control group (p = 0.001). Predictors of delirium in the melatonin group were age (p = 0.001) and higher EuroSCORE II value (p = 0.001). In multivariate analysis, age and EuroSCORE II value (p = 0.014) were predictors of postoperative delirium. Comparing the groups, the main predictors of delirium were age (p = 0.001), EuroSCORE II value (p = 0.001), cardio-pulmonary bypass (CPB) time (p = 0.001), aortic cross-clamping (ACC) time (p = 0.008), sufentanil dose (p = 0.001) and mechanical ventilation (p = 0.033). Conclusions Administration of melatonin significantly decreases the incidence of postoperative delirium after cardiac surgery. Prophylactic treatment with melatonin should be considered in every patient scheduled for cardiac surgery. PMID:26336494

  15. The Aspergillus nidulans pyrG89 mutation alters glycosylation of secreted acid phosphatase.

    PubMed

    Justino, A; Nozawa, S R; Maccheroni, W; May, G S; Martinez-Rossi, N M; Rossi, A

    2001-03-01

    The glycosylation level of the pacA-encoded acid phosphatase secreted by Aspergillus nidulans was reduced in strains pabaA1 pyroA4and pabaA1 pyroA4 pyrG89, compared to strains carrying these mutations singly. The molecular mass of the enzyme secreted by the triple mutant grown at pH 5.0 was 105 and 45 kDa as determined by exclusion chromatography and SDS-PAGE, respectively. In contrast, the pabaA1 strain secreted acid phosphatases of 119 and 62 kDa. The enzyme also had an altered electrophoretic mobility and glycosylation had a protective effect against its heat inactivation. Thus, this combination of mutants alters glycosylation of the enzyme, leading to changes in their structural properties. In spite of this, no deviation was observed in the apparent optimum pH and Michaelis kinetics for enzymatic hydrolysis of p-nitrophenyl phosphate or alpha-naphthyl phosphate.

  16. Pharmacology and function of melatonin receptors

    SciTech Connect

    Dubocovich, M.L.

    1988-09-01

    The hormone melatonin is secreted primarily from the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone, through an action in the brain, appears to be involved in the regulation of various neural and endocrine processes that are cued by the daily change in photoperiod. This article reviews the pharmacological characteristics and function of melatonin receptors in the central nervous system, and the role of melatonin in mediating physiological functions in mammals. Melatonin and melatonin agonists, at picomolar concentrations, inhibit the release of dopamine from retina through activation of a site that is pharmacologically different from a serotonin receptor. These inhibitory effects are antagonized by the novel melatonin receptor antagonist luzindole (N-0774), which suggests that melatonin activates a presynaptic melatonin receptor. In chicken and rabbit retina, the pharmacological characteristics of the presynaptic melatonin receptor and the site labeled by 2-(125I)iodomelatonin are identical. It is proposed that 2-(125I)iodomelatonin binding sites (e.g., chicken brain) that possess the pharmacological characteristics of the retinal melatonin receptor site (order of affinities: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-di-chloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin greater than N-acetyltryptamine greater than or equal to luzindole greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine much greater than 5-hydroxytryptamine) be classified as ML-1 (melatonin 1). The 2-(125I)iodomelatonin binding site of hamster brain membranes possesses different binding and pharmacological characteristics from the retinal melatonin receptor site and should be classified as ML-2. 64 references.

  17. Posttranscriptional regulation of pineal melatonin synthesis in Octodon degus.

    PubMed

    Lee, Soo Jung; Liu, Tiecheng; Chattoraj, Asamanja; Zhang, Samantha L; Wang, Lijun; Lee, Theresa M; Wang, Michael M; Borjigin, Jimo

    2009-08-01

    Small laboratory animals have provided significant information about melatonin regulation, yet most of these organisms are nocturnal and regulate melatonin synthesis by mechanisms that diverge from those of humans. For example, in all rodents examined, melatonin secretion occurs with a time lag of several hours after the onset of darkness; in addition, arylalkylamine N-acetyltransferase (AANAT), the key enzyme in melatonin synthesis, displays dynamic transcriptional activation specifically at night in all rodents studied to date. In ungulates and primates including humans, on the other hand, melatonin secretion occurs immediately during the early night and is controlled by circadian posttranscriptional regulation of AANAT. We hypothesize that the diurnal Octodon degus (an Hystricognath rodent) could serve as an improved experimental model for studies of human melatonin regulation. To test this, we monitored melatonin production in degus using pineal microdialysis and characterized the regulation of melatonin synthesis by analyzing degu Aanat. Degu pineal melatonin rises with little latency at night, as in ungulates and primates. In addition, degu Aanat mRNA expression displays no detectable diurnal variation, suggesting that, like ungulates and primates, melatonin in this species is regulated by a posttranscriptional mechanism. Compared with AANAT from all rodents examined to date, the predicted amino acid sequence of degu AANAT is phylogenetically more closely related to ungulate and primate AANAT. These data suggest that Octodon degus may provide an ideal model system for laboratory investigation of mechanisms of melatonin synthesis and secretion in diurnal mammals.

  18. Genetic deletion of MT1 melatonin receptors alters spontaneous behavioral rhythms in male and female C57BL/6 mice.

    PubMed

    Adamah-Biassi, E B; Hudson, R L; Dubocovich, M L

    2014-09-01

    Behaviors vary over the 24h light/dark cycle and these temporal patterns reflect in part modulation by circadian neural circuits and hormones, such as melatonin. The goal of this study was to investigate the involvement of MT1 melatonin receptors in behavioral regulation by comparing male and female C57 wild type (WT) mice with C57 mice with genetic deletion of the MT1 receptor (MT1KO). A comprehensive array of fifteen distinct spontaneous behaviors was recorded continuously in the homecage over multiple days using the HomeCageScan system. Behaviors assessed were activity-like (i.e. come down, hang, jump, walk), exploration-like (i.e. dig, groom, rear up, sniff, stretch), resting-like (i.e. awake, remain low, rest, twitch) and ingestion-like (i.e. drink, eat). Phenotypic array and temporal distribution analysis revealed distinct behavioral rhythms that differed between WT and MT1KO mice. The rhythms were consistent from day to day in males and varied with the estrous cycle in females. We also studied the role of MT1 receptors on depressive and anxiety-like behaviors. Genetic deletion of MT1 receptors increased immobility time in the forced swim test and decreased the number of marbles buried in the marble burying test in both male and female C57 mice. We conclude that MT1 melatonin receptors are involved in neural pathways modulating diurnal rhythms of spontaneous behavior in the homecage as well as pathways regulating depressive and anxiolytic-like behaviors.

  19. Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon.

    PubMed

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2013-03-27

    The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes.

  20. Thirst Perception and Osmoregulation of Vasopressin Secretion Are Altered During Recovery From Septic Shock

    PubMed Central

    Siami, Shidasp; Polito, Andrea; Porcher, Raphael; Hissem, Tarik; Blanchard, Anne; Boucly, Catherine; Carlier, Robert; Annane, Djillali; Haymann, Jean-Philippe; Sharshar, Tarek

    2013-01-01

    Objective Vasopressin (AVP) secretion during an osmotic challenge is frequently altered in the immediate post-acute phase of septic shock. We sought to determine if this response is still altered in patients recovering from septic shock. Design Prospective interventional study Setting Intensive care unit (ICU) at Raymond Poincaré and Etampes Hospitals. Patients Normonatremic patients at least 5 days post discontinuation of catecholamines given for a septic shock. Intervention Osmotic challenge involved infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 minutes. Measurements and main results Plasma AVP levels were measured 15 minutes before the infusion and then every 30 minutes for two hours. Non-responders were defined as those with a slope of the relation between AVP and plasma sodium levels less than < 0.5 ng/mEq. Among the 30 included patients, 18 (60%) were non-responders. Blood pressure and plasma sodium and brain natriuretic peptide levels were similar in both responders and non-responders during the course of the test. Critical illness severity, hemodynamic alteration, electrolyte disturbances, treatment and outcome did not differ between the two groups. Responders had more severe gas exchange abnormality. Thirst perception was significantly diminished in non-responders. The osmotic challenge was repeated in 4 non-responders several months after discharge and the abnormal response persisted. Conclusion More than half of patients recovering from septic shock have an alteration of osmoregulation characterised by a dramatic decrease in vasopressin secretion and thirst perception during osmotic challenge. The mechanisms of this alteration but also of the relationship between haematosis and normal response remain to be elucidated. PMID:24223220

  1. Decidual-Secreted Factors Alter Invasive Trophoblast Membrane and Secreted Proteins Implying a Role for Decidual Cell Regulation of Placentation

    PubMed Central

    Menkhorst, Ellen Melaleuca; Lane, Natalie; Winship, Amy Louise; Li, Priscilla; Yap, Joanne; Meehan, Katie; Rainczuk, Adam; Stephens, Andrew; Dimitriadis, Evdokia

    2012-01-01

    Inadequate or inappropriate implantation and placentation during the establishment of human pregnancy is thought to lead to first trimester miscarriage, placental insufficiency and other obstetric complications. To create the placental blood supply, specialized cells, the ‘extravillous trophoblast’ (EVT) invade through the differentiated uterine endometrium (the decidua) to engraft and remodel uterine spiral arteries. We hypothesized that decidual factors would regulate EVT function by altering the production of EVT membrane and secreted factors. We used a proteomics approach to identify EVT membrane and secreted proteins regulated by decidual cell factors. Human endometrial stromal cells were decidualized in vitro by treatment with estradiol (10−8 M), medroxyprogesterone acetate (10−7 M) and cAMP (0.5 mM) for 14 days. Conditioned media (CM) was collected on day 2 (non-decidualized CM) and 14 (decidualized CM) of treatment. Isolated primary EVT cultured on Matrigel™ were treated with media control, non-decidualized or decidualized CM for 16 h. EVT CM was fractionated for proteins <30 kDa using size-exclusion affinity nanoparticles (SEAN) before trypsin digestion and HPLC-MS/MS. 43 proteins produced by EVT were identified; 14 not previously known to be expressed in the placenta and 12 which had previously been associated with diseases of pregnancy including preeclampsia. Profilin 1, lysosome associated membrane glycoprotein 1 (LAMP1), dipeptidyl peptidase 1 (DPP1/cathepsin C) and annexin A2 expression by interstitial EVT in vivo was validated by immunhistochemistry. Decidual CM regulation in vitro was validated by western blotting: decidualized CM upregulated profilin 1 in EVT CM and non-decidualized CM upregulated annexin A2 in EVT CM and pro-DPP1 in EVT cell lysate. Here, non-decidualized factors induced protease expression by EVT suggesting that non-decidualized factors may induce a pro-inflammatory cascade. Preeclampsia is a pro-inflammatory condition

  2. Melatonin: media hype or therapeutic breakthrough?

    PubMed

    Kendler, B S

    1997-02-01

    Currently available as a dietary supplement, the pineal hormone melatonin is portrayed by the media as a formidable weapon against disease and aging. Accordingly, primary health care providers should be cognizant of which of its proposed uses are supported by biomedical research and which are, as yet, unproven. Melatonin entrains circadian rhythms and, thus, can treat jet lag, delayed sleep phase syndrome, and sleep disorders in the blind and in some neurologically impaired children. By virtue of its hypnotic effect, melatonin can mitigate insomnia in the elderly. Reductions in melatonin secretion have been associated with many disorders, including cardiovascular disease, Alzheimer's, diabetes, SIDS, and aging; however, melatonin's role in their etiology and/or pathophysiology is unproven. Preliminary studies suggest a possible adjuvant therapeutic role for melatonin in cancer therapy. Melatonin secretion is reduced by alcohol, caffeine, and some commonly prescribed drugs. Since tolerance, fatigue, and other side effects have been reported, melatonin use on consecutive nights should be avoided and only the lowest effective hypnotic dose should be taken.

  3. Melatonin: interesting, but not miraculous.

    PubMed

    1998-12-01

    (1) In the United States melatonin is just a dietary supplement, but in Europe its status varies from country to country and also over time. It is illegal in some European member states but tolerated or authorised as a drug or dietary product elsewhere. Melatonin, a hormone secreted by the pineal gland, has been on the front cover of magazines throughout the world for its claimed effects on ageing, cancer and many other health problems, opening up a vast potential market. (2) Only its use in jet lag, sleep disorders and advanced cancer has been tested clinically (albeit scantily). (3) Melatonin seems to alleviate jet lag symptoms, but that could be linked to its moderate hypnotic effect. (4) The use of melatonin to treat major insomnia cannot be envisaged until its long-term safety has been proven. With this proviso, and if efficacy is confirmed in sufficiently large comparative trials, melatonin could prove useful for treating major sleep disorders in some patients, especially blind people and those with severe neurological disabilities. (5) According to open trials conducted by a single team, melatonin, alone or combined with interleukin-2, could slightly lengthen the survival of patients with some advanced cancers, but even partial tumour remissions are rare. (6) All other "indications" are based on simplistic hypotheses or purely commercial considerations.

  4. Long noncoding RNA H19 mediates melatonin inhibition of premature senescence of c-kit(+) cardiac progenitor cells by promoting miR-675.

    PubMed

    Cai, Benzhi; Ma, Wenya; Bi, Chongwei; Yang, Fan; Zhang, Lai; Han, Zhenbo; Huang, Qi; Ding, Fengzhi; Li, Yuan; Yan, Gege; Pan, Zhenwei; Yang, Baofeng; Lu, Yanjie

    2016-08-01

    Melatonin, a hormone secreted by the pineal gland, possesses multiple biological activities such as antitumor, antioxidant, and anti-ischemia. C-kit(+) cardiac progenitor cells (CPCs) have emerged as a promising tool for the treatment of heart diseases. However, the senescence of CPCs due to pathological stimuli leads to the decline of CPCs' functions and regenerative potential. This study was conducted to demonstrate whether melatonin antagonizes the senescence of CPCs in response to oxidative stress. Here, we found that the melatonin treatment markedly inhibited the senescent characteristics of CPCs after exposed to sublethal concentration of H2 O2 , including the increase in senescence-associated β-galactosidase (SA-β-gal)-positive CPCs, senescence-associated heterochromatin loci (SAHF), secretory IL-6 level, and the upregulation of p53 and p21 proteins. Senescence-associated proliferation reduction was also attenuated by melatonin in CPCs. Luzindole, the melatonin membrane receptor blocker, may block the melatonin-mediated suppression of premature senescence in CPCs. Interestingly, we found that long noncoding RNA H19 and its derived miR-675 were downregulated by H2 O2 in CPCs, but melatonin treatment could counter this alteration. Furthermore, knockdown of H19 or miR-675 blocked antisenescence actions of melatonin on H2 O2 -treated CPCs. It was further verified that H19-derived miR-675 targeted at the 3'UTR of USP10, which resulted in the downregulation of p53 and p21 proteins. In summary, melatonin antagonized premature senescence of CPCs via H19/miR-675/USP10 pathway, which provides new insights into pharmacological actions and potential applications of melatonin on the senescence of CPCs.

  5. The use of melatonin in Alzheimer's disease.

    PubMed

    Cardinali, Daniel P; Brusco, Luis I; Liberczuk, Cynthia; Furio, Analía M

    2002-04-01

    About 45% of Alzheimer's disease (AD) patients have disruptions in their sleep and sundowning agitation. Since melatonin secretion is greatly inhibited in AD patients we have used melatonin to treat sleep disorders in AD patients since 1995. In a first study [21] we reported, in 7 out of 10 dementia patients treated with melatonin (3 mg p.o. at bed time), a decreased sundowning. In a second study [22] we examined 14 AD patients who received 9 mg melatonin daily for 22 to 35 months, observing a significant improvement of sleep quality with stabilization of behavioral and cognitive parameters. In a third study [23] we reported two monozygotic twins with AD and similar cognitive impairment, one of them receiving 6 mg melatonin at bedtime daily for 3 years. Melatonin treatment improved sleep quality and suppressed sundowning. We now report the effect of melatonin (4-month-long treatment with 6 mg/day) in 45 AD patients with sleep disturbances. Melatonin improved sleep and suppressed sundowning, an effect seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of AD. Melatonin treatment seems to constitute a selection therapy to ameliorate sundowning and to slow evolution of cognitive impairment in AD patients.

  6. Dietary factors and fluctuating levels of melatonin

    PubMed Central

    Peuhkuri, Katri; Sihvola, Nora; Korpela, Riitta

    2012-01-01

    Melatonin is secreted principally by the pineal gland and mainly at nighttime. The primary physiological function is to convey information of the daily cycle of light and darkness to the body. In addition, it may have other health-related functions. Melatonin is synthesized from tryptophan, an essential dietary amino acid. It has been demonstrated that some nutritional factors, such as intake of vegetables, caffeine, and some vitamins and minerals, could modify melatonin production but with less intensity than light, the most dominant synchronizer of melatonin production. This review will focus on the nutritional factors apart from the intake of tryptophan that affect melatonin levels in humans. Overall, foods containing melatonin or promoting the synthesis of it by impacting the availability of tryptophan, as well those containing vitamins and minerals which are needed as co-factors and activators in the synthesis of melatonin, may modulate the levels of melatonin. Even so, the influence of daytime diet on the synthesis of nocturnal melatonin is limited, however, the influence of the diet seems to be more obvious on the daytime levels. PMID:22826693

  7. Dietary factors and fluctuating levels of melatonin.

    PubMed

    Peuhkuri, Katri; Sihvola, Nora; Korpela, Riitta

    2012-01-01

    Melatonin is secreted principally by the pineal gland and mainly at nighttime. The primary physiological function is to convey information of the daily cycle of light and darkness to the body. In addition, it may have other health-related functions. Melatonin is synthesized from tryptophan, an essential dietary amino acid. It has been demonstrated that some nutritional factors, such as intake of vegetables, caffeine, and some vitamins and minerals, could modify melatonin production but with less intensity than light, the most dominant synchronizer of melatonin production. This review will focus on the nutritional factors apart from the intake of tryptophan that affect melatonin levels in humans. Overall, foods containing melatonin or promoting the synthesis of it by impacting the availability of tryptophan, as well those containing vitamins and minerals which are needed as co-factors and activators in the synthesis of melatonin, may modulate the levels of melatonin. Even so, the influence of daytime diet on the synthesis of nocturnal melatonin is limited, however, the influence of the diet seems to be more obvious on the daytime levels.

  8. Rhythmic melatonin secretion does not correlate with the expression of arylalkylamine N-acetyltransferase, inducible cyclic amp early repressor, period1 or cryptochrome1 mRNA in the sheep pineal.

    PubMed

    Johnston, J D; Bashforth, R; Diack, A; Andersson, H; Lincoln, G A; Hazlerigg, D G

    2004-01-01

    The pineal gland, through nocturnal melatonin, acts as a neuroendocrine transducer of daily and seasonal time. Melatonin synthesis is driven by rhythmic activation of the rate-limiting enzyme, arylalkylamine N-acetyltransferase (AA-NAT). In ungulates, AA-NAT mRNA is constitutively high throughout the 24-h cycle, and melatonin production is primarily controlled through effects on AA-NAT enzyme activity; this is in contrast to dominant transcriptional control in rodents. To determine whether there has been a selective loss of circadian control of AA-NAT mRNA expression in the sheep pineal, we measured the expression of other genes known to be rhythmic in rodents (inducible cAMP early repressor ICER, the circadian clock genes Period1 and Cryptochrome1, as well as AA-NAT). We first assayed gene expression in pineal glands collected from Soay sheep adapted to short days (Light: dark, 8-h: 16-h), and killed at 4-h intervals through 24-h. We found no evidence for rhythmic expression of ICER, AA-NAT or Cryptochrome1 under these conditions, whilst Period1 showed a low amplitude rhythm of expression, with higher values during the dark period. In a second group of animals, lights out was delayed by 8-h during the final 24-h sampling period, a manipulation that causes an immediate shortening of the period of melatonin secretion. This did not significantly affect the expression of ICER, AA-NAT or Cryptochrome1 in the pineal, whilst a slight suppressive effect on overall Per1 levels was observed. The attenuated response to photoperiod change appears to be specific to the ovine pineal, as the first long day induced rapid changes of Period1 and ICER expression in the hypothalamic suprachiasmatic nuclei and pituitary pars tuberalis, respectively. Overall, our data suggest a general reduction of circadian control of transcript abundance in the ovine pineal gland, consistent with a marked evolutionary divergence in the mechanism regulating melatonin production between terrestrial

  9. A Review of Melatonin, Its Receptors and Drugs

    PubMed Central

    Emet, Mucahit; Ozcan, Halil; Ozel, Lutfu; Yayla, Muhammed; Halici, Zekai; Hacimuftuoglu, Ahmet

    2016-01-01

    After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future. PMID:27551178

  10. A Review of Melatonin, Its Receptors and Drugs.

    PubMed

    Emet, Mucahit; Ozcan, Halil; Ozel, Lutfu; Yayla, Muhammed; Halici, Zekai; Hacimuftuoglu, Ahmet

    2016-06-01

    After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activity-regulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future.

  11. Antepartum depression severity is increased during seasonally longer nights: Relationship to melatonin and cortisol timing and quantity

    PubMed Central

    Meliska, Charles J.; Martínez, Luis F.; López, Ana M.; Sorenson, Diane L.; Nowakowski, Sara; Kripke, Daniel F.; Elliott, Jeffrey; Parry, Barbara L.

    2014-01-01

    Current research suggests that mood varies from season to season in some individuals, in conjunction with light-modulated alterations in chronobiologic indices like melatonin and cortisol. The primary aim of this study was to evaluate the effects of seasonal variations in darkness on mood in depressed antepartum women, and to determine the relationship of seasonal mood variations to contemporaneous blood melatonin and cortisol measures; a secondary aim was to evaluate the influence of seasonal factors on measures of melancholic versus atypical depressive symptoms. We obtained measures of mood and overnight concentrations of plasma melatonin and serum cortisol in 19 depressed patients (DP) and 12 healthy control (HC) antepartum women, during on-going seasonal variations in daylight/darkness, in a cross-sectional design. Analyses of variance showed that in DP, but not HC, Hamilton Depression Rating Scale (HRSD) scores were significantly higher in women tested during seasonally longer vs. shorter nights. This exacerbation of depressive symptoms occurred when the dim light melatonin onset, the melatonin synthesis offset and the time of maximum cortisol secretion (acrophase) were phase-advanced (temporally shifted earlier), and melatonin quantity was reduced, in DP but not HC. Serum cortisol increased across gestational weeks in both the HC and DP groups, which did not differ significantly in cortisol concentration. Nevertheless, serum cortisol concentration correlated positively with HRSD score in DP but not HC; notably, HC showed neither significant mood changes nor altered melatonin and cortisol timing or quantity in association with seasonal variations. These findings suggest that depression severity during pregnancy may become elevated in association with seasonally-related phase-advances in melatonin and cortisol timing and reduced melatonin quantity that occur in DP, but not HC. Thus, women who experience antepartum depression may be more susceptible than their

  12. Rotating wall vessel exposure alters protein secretion and global gene expression in Staphylococcus aureus

    NASA Astrophysics Data System (ADS)

    Rosado, Helena; O'Neill, Alex J.; Blake, Katy L.; Walther, Meik; Long, Paul F.; Hinds, Jason; Taylor, Peter W.

    2012-04-01

    Staphylococcus aureus is routinely recovered from air and surface samples taken aboard the International Space Station (ISS) and poses a health threat to crew. As bacteria respond to the low shear forces engendered by continuous rotation conditions in a Rotating Wall Vessel (RWV) and the reduced gravitational field of near-Earth flight by altering gene expression, we examined the effect of low-shear RWV growth on protein secretion and gene expression by three S. aureus isolates. When cultured under 1 g, the total amount of protein secreted by these strains varied up to fourfold; under continuous rotation conditions, protein secretion by all three strains was significantly reduced. Concentrations of individual proteins were differentially reduced and no evidence was found for increased lysis. These data suggest that growth under continuous rotation conditions reduces synthesis or secretion of proteins. A limited number of changes in gene expression under continuous rotation conditions were noted: in all isolates vraX, a gene encoding a polypeptide associated with cell wall stress, was down-regulated. A vraX deletion mutant of S. aureus SH1000 was constructed: no differences were found between SH1000 and ΔvraX with respect to colony phenotype, viability, protein export, antibiotic susceptibility, vancomycin kill kinetics, susceptibility to cold or heat and gene modulation. An ab initio protein-ligand docking simulation suggests a major binding site for β-lactam drugs such as imipenem. If such changes to the bacterial phenotype occur during spaceflight, they will compromise the capacity of staphylococci to cause systemic infection and to circumvent antibacterial chemotherapy.

  13. Seasonal variation in live weight, testes size, testosterone, LH secretion, melatonin and thyroxine in Merino and Corriedale rams in a subtropical climate.

    PubMed

    Pérez Clariget, R; Forsberg, M; Rodriguez-Martinez, H

    1998-01-01

    In the present investigation we studied the seasonal changes in live weight and testes and pituitary activity in Merino and Corriedale rams in a subtropical climate. Testes activity was measured as scrotal circumference (SC), plasma concentration of testosterone (T) and release of testosterone after exogenous GnRH injection. LH pulsatility and pituitary LH responsiveness to exogenous GnRH was measured as an index of pituitary activity. In addition, we wanted to characterize the seasonal pattern of thyroxine (T4) secretion and the 24 h secretory pattern of melatonin (M) at the winter and summer solstices in the 2 breeds. Nine Corriedale and 7 Merino adult (4-6 years) rams were kept on native pasture and managed in one group. Twice a month live weight (LW) and scrotal circumference (SC) were measured. To monitor plasma concentration of testosterone (T), and thyroxine (T4), 5 animals of each breed were bled every month except during autumn (March-May), when blood samples were collected with 15 day intervals and in spring (October) with 10 day intervals. To monitor pulsatile LH secretion, 3 rams of each breed were bled at 15 min intervals for 6 h at the winter and summer solstices and spring and autumn equinoxes. Pituitary LH and testicular testosterone response to GnRH injection was performed bimonthly from 2 animals of each breed. No effect of breed was found on any of the variables investigated. An interaction between breed and sampling date was found in LW (p < 0.001) and total T response after GnRH challenge (p < 0.001). Sampling date had a significant effect (p < 0.001) on all the variables studied. In both breeds SC decreased during autumn and increased during spring with minimum T concentrations in late autumn and maximum in mid-summer/early autumn. The lowest (p < 0.05) number of LH pulses were observed in winter (June) and the highest (p < 0.05) in early autumn (March). The highest LH and testosterone response to GnRH challenge was observed in autumn (April

  14. Do androgens influence hair growth by altering the paracrine factors secreted by dermal papilla cells?

    PubMed

    Randall, V A; Hibberts, N A; Thornton, M J; Merrick, A E; Hamada, K; Kato, S; Jenner, T J; de Oliveira, I; Messenger, A G

    2001-01-01

    Androgens regulate many aspects of human hair growth in both sexes. After puberty they transform tiny vellus follicles in many areas, e.g. the face, to terminal ones producing long, thick, pigmented hairs. In genetically predisposed individuals, androgens also cause the reverse transformation of terminal scalp follicles into vellus ones, causing balding. In the current hypothesis for androgen action, androgens control most follicular cells indirectly acting via the mesenchyme-derived dermal papilla which regulates many aspects of follicular activity. In this model androgens binding to androgen receptors in dermal papilla cells alter their production of regulatory molecules which influence other follicular components; these molecules may be soluble paracrine factors and/or extracellular matrix proteins. This hypothesis is supported by immunohistochemical localisation of androgen receptors in dermal papilla cell nuclei and the demonstrations that androgen receptor content and testosterone metabolism patterns of cultured dermal papilla cells from various body sites reflect hair growth in androgen-insensitivity syndromes. The next question is whether androgens alter the paracrine factors secreted by dermal papilla cells. Cultured dermal papilla cells do release soluble, proteinaceous factors into their media which stimulate the growth of keratinocytes and other dermal papilla cells. This mitogenic potential can cross species from humans to rodents. Importantly, testosterone in vitro stimulates the mitogenic potential of beard cells, but in contrast inhibits production by balding scalp cells reflecting their in vivo androgenic responses. Since androgens in vitro do alter the secretion of paracrine factors the current focus lies in identifying specific factors produced, e.g. IGF-I and stem cell factor (SCF), using ELISA and RT-PCR, and comparing their expression in cells from follicles with varying responses to androgens in vivo or under androgen stimulation in vitro

  15. Effect of cortisol on melatonin production by the pineal organ of tilapia, Oreochromis mossambicus.

    PubMed

    Nikaido, Yoshiaki; Aluru, Neelakanteswar; McGuire, Alison; Park, Yong-Ju; Vijayan, Mathilakath M; Takemura, Akihiro

    2010-01-01

    The aim of the present study was to examine the involvement of cortisol on melatonin synthesis in the pineal organ of the Mozambique tilapia, Oreochromis mossambicus. The circulating levels of melatonin in this species exhibited daily variations with a decrease during the photophase (0600, 1200, and 1800 h) and an increase during the scotophase (0000 h), while cortisol levels peaked during the early photophase (0600 h). The pineal organ was cultured in vitro in the dark in the presence of cortisol mimicking either stressed (100 ng/mL) or resting (10 ng/mL) concentration in tilapia. High cortisol concentration significantly reduced the levels of melatonin secreted into the medium. In the fish reared under stressful conditions, the nocturnal circulating levels of cortisol increased significantly, while melatonin did not change significantly. We detected glucocorticoid receptor (GR) transcripts in the pineal organ and a quantitative real-time PCR revealed that this receptor mRNA abundance fluctuated diurnally, increasing at 0600, 1800, and 0000 h and decreasing at 1200 h. The GR mRNA abundance in the pineal organ was not altered either in vitro when the organ was cultured in the presence of 100 ng/mL cortisol or in vivo when the fish were reared under stressful conditions. On the basis of these findings, it is proposed that cortisol lowers melatonin synthesis in the pineal organ, while the role of GR signaling in this process remains to be established.

  16. [Melatonin as a regulator of metabolism].

    PubMed

    Dzherieva, I S; Volkova, N I; Rapoport, S I

    2012-01-01

    High prevalence of metabolic syndrome (MS) necessitates elucidation of its causes. Disturbed melatonin synthesis is supposed to be one of them. This work was aimed at studying melatonin (M) secretion in MS and its influence on the main symptoms of MS. It was shown that melatonin production decreases at 4 a.m. and increases in the afternoon when it is correlated with waist circumference, insulin and LDLP levels (+0.28, -0.30, -0.44). M secretion in the morning correlates with blood glucose level and mean daily AP (-0.37, -0.22). Correlation of M secretion at 4 a.m., in the afternoon and at night with MS parameters was described by coefficients R equaling 0.79, 0.75 and 0.74 respectively. It is concluded that the intragroup risk of MS development is 2.9 and increases when M secretion is disturbed.

  17. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism

    PubMed Central

    Jansen, S. W.; Akintola, A. A.; Roelfsema, F.; van der Spoel, E.; Cobbaert, C. M.; Ballieux, B. E.; Egri, P.; Kvarta-Papp, Z.; Gereben, B.; Fekete, C.; Slagboom, P. E.; van der Grond, J.; Demeneix, B. A.; Pijl, H.; Westendorp, R. G. J.; van Heemst, D.

    2015-01-01

    Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism. PMID:26089239

  18. Melatonin influences proliferation and differentiation of rat dental papilla cells in vitro and dentine formation in vivo by altering mitochondrial activity

    PubMed Central

    Liu, Jie; Zhou, Hongyu; Fan, Wenguo; Dong, Weiguo; Fu, Shenli; He, Hongwen; Huang, Fang

    2013-01-01

    Melatonin mediates a variety of biological processes ranging from the control of circadian rhythms to immune regulation. Melatonin also influences bone formation and osteointegration of dental implants. However, the effects of melatonin on dentine formation have not been examined. This study investigated the effects of melatonin on the proliferation and differentiation of rat dental papilla cells (rDPCs) in vitro and dentine formation in vivo. We found that melatonin (0, 10−12, 10−10,10−8 m) induced a dose-dependent reduction in rDPCs proliferation, increased alkaline phosphatase (ALP) activity, the expression of dentine sialoprotein (DSP), and mineralized matrix formation in vitro. In vivo melatonin (50 mg/kg, BW, i.p.) inhibited dentine formation. Melatonin (10−8 m) suppressed the activity of complex I and IV in the basal medium (OS−) and enhanced the activity of complex I and complex IV in osteogenic medium (OS+). These results demonstrate that melatonin suppresses the proliferation and promotes differentiation of rDPCs, the mechanisms of which may be related to activity of mitochondrial complex I and complex IV. PMID:22946647

  19. Do plasma melatonin concentrations decline with age?

    NASA Technical Reports Server (NTRS)

    Zeitzer, J. M.; Daniels, J. E.; Duffy, J. F.; Klerman, E. B.; Shanahan, T. L.; Dijk, D. J.; Czeisler, C. A.

    1999-01-01

    PURPOSE: Numerous reports that secretion of the putative sleep-promoting hormone melatonin declines with age have led to suggestions that melatonin replacement therapy be used to treat sleep problems in older patients. We sought to reassess whether the endogenous circadian rhythm of plasma melatonin concentration changes with age in healthy drug-free adults. METHODS: We analyzed the amplitude of plasma melatonin profiles during a constant routine in 34 healthy drug-free older subjects (20 women and 14 men, aged 65 to 81 years) and compared them with 98 healthy drug-free young men (aged 18 to 30 years). RESULTS: We could detect no significant difference between a healthy and drug-free group of older men and women as compared to one of young men in the endogenous circadian amplitude of the plasma melatonin rhythm, as described by mean 24-hour average melatonin concentration (70 pmol/liter vs 73 pmol/liter, P = 0.97), or the duration (9.3 hours vs 9.1 hours, P = 0.43), mean (162 pmol/liter vs 161 pmol/liter, P = 0.63), or integrated area (85,800 pmol x min/liter vs 86,700 pmol x min/liter, P = 0.66) of the nocturnal peak of plasma melatonin. CONCLUSION: These results do not support the hypothesis that reduction of plasma melatonin concentration is a general characteristic of healthy aging. Should melatonin replacement therapy or melatonin supplementation prove to be clinically useful, we recommend that an assessment of endogenous melatonin be carried out before such treatment is used in older patients.

  20. Do plasma melatonin concentrations decline with age?

    NASA Technical Reports Server (NTRS)

    Zeitzer, J. M.; Daniels, J. E.; Duffy, J. F.; Klerman, E. B.; Shanahan, T. L.; Dijk, D. J.; Czeisler, C. A.

    1999-01-01

    PURPOSE: Numerous reports that secretion of the putative sleep-promoting hormone melatonin declines with age have led to suggestions that melatonin replacement therapy be used to treat sleep problems in older patients. We sought to reassess whether the endogenous circadian rhythm of plasma melatonin concentration changes with age in healthy drug-free adults. METHODS: We analyzed the amplitude of plasma melatonin profiles during a constant routine in 34 healthy drug-free older subjects (20 women and 14 men, aged 65 to 81 years) and compared them with 98 healthy drug-free young men (aged 18 to 30 years). RESULTS: We could detect no significant difference between a healthy and drug-free group of older men and women as compared to one of young men in the endogenous circadian amplitude of the plasma melatonin rhythm, as described by mean 24-hour average melatonin concentration (70 pmol/liter vs 73 pmol/liter, P = 0.97), or the duration (9.3 hours vs 9.1 hours, P = 0.43), mean (162 pmol/liter vs 161 pmol/liter, P = 0.63), or integrated area (85,800 pmol x min/liter vs 86,700 pmol x min/liter, P = 0.66) of the nocturnal peak of plasma melatonin. CONCLUSION: These results do not support the hypothesis that reduction of plasma melatonin concentration is a general characteristic of healthy aging. Should melatonin replacement therapy or melatonin supplementation prove to be clinically useful, we recommend that an assessment of endogenous melatonin be carried out before such treatment is used in older patients.

  1. Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

    PubMed Central

    Quera Salva, M.A.; Hartley, S.

    2012-01-01

    Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse. PMID:23650464

  2. Melatonin regulates lipid metabolism in porcine oocytes.

    PubMed

    Jin, Jun-Xue; Lee, Sanghoon; Taweechaipaisankul, Anukul; Kim, Geon A; Lee, Byeong Chun

    2017-03-01

    It is being increasingly recognized that the processes of lipogenesis and lipolysis are important for providing an essential energy source during oocyte maturation and embryo development. Recent studies demonstrated that melatonin has a role in lipid metabolism regulation, including lipogenesis, lipolysis, and mitochondrial biogenesis. In this study, we attempted to investigate the effects of melatonin on lipid metabolism during porcine oocyte in vitro maturation. Melatonin treatment significantly enhanced the number of lipid droplets (LDs) and upregulated gene expression related to lipogenesis (ACACA, FASN, PPARγ, and SREBF1). Oocytes treated with melatonin formed smaller LDs and abundantly expressed several genes associated with lipolysis, including ATGL, CGI-58, HSL, and PLIN2. Moreover, melatonin significantly increased the content of fatty acids, mitochondria, and ATP, as indicated by fluorescent staining. Concomitantly, melatonin treatment upregulated gene expression related to fatty acid β-oxidation (CPT1a, CPT1b, CPT2, and ACADS) and mitochondrial biogenesis (PGC-1α, TFAM, and PRDX2). Overall, melatonin treatment not only altered both the morphology and amount of LDs, but also increased the content of fatty acids, mitochondria, and ATP. In addition, melatonin upregulated mRNA expression levels of lipogenesis, lipolysis, β-oxidation, and mitochondrial biogenesis-related genes in porcine oocytes. These results indicated that melatonin promoted lipid metabolism and thereby provided an essential energy source for oocyte maturation and subsequent embryonic development. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Role of melatonin in embryo fetal development.

    PubMed

    Voiculescu, S E; Zygouropoulos, N; Zahiu, C D; Zagrean, A M

    2014-01-01

    Melatonin is an indoleamine produced by the pineal gland and secreted in a circadian manner. In the past few decades, research over this topic has been enhanced. Melatonin has many important roles in the human physiology: regulator of the circadian rhythms, sleep inducer, antioxidant, anticarcinogenic. This paper reviews the involvement of melatonin in embryo fetal development. The pineal gland develops completely postpartum, so both the embryo and the fetus are dependent on the maternal melatonin provided transplacentally. Melatonin appears to be involved in the normal outcome of pregnancy beginning with the oocyte quality and finishing with the parturition. Its pregnancy night-time concentrations increase after 24 weeks of gestation, with significantly high levels after 32 weeks. Melatonin receptors are widespread in the embryo and fetus since early stages. There is solid evidence that melatonin is neuroprotective and has a positive effect on the outcome of the compromised pregnancies. In addition, chronodisruption leads to a reproductive dysfunction. Thus, the influence of melatonin on the developing human fetus may not be limited to the entertaining of circadian rhythmicity, but further studies are needed.

  4. Melatonin and Pancreatic Islets: Interrelationships between Melatonin, Insulin and Glucagon

    PubMed Central

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2013-01-01

    The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes. PMID:23535335

  5. Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice.

    PubMed

    Favero, Gaia; Stacchiotti, Alessandra; Castrezzati, Stefania; Bonomini, Francesca; Albanese, Massimo; Rezzani, Rita; Rodella, Luigi Fabrizio

    2015-10-01

    The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy-storing cells, but they play crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The dysregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice (ob/ob) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a dysregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor α, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process.

  6. Melatonin and human skin aging

    PubMed Central

    Kleszczynski, Konrad; Fischer, Tobias W.

    2012-01-01

    Like the whole organism, skin follows the process of aging during life-time. Additional to internal factors, several environmental factors, such as solar radiation, considerably contribute to this process. While fundamental mechanisms regarding skin aging are known, new aspects of anti-aging agents such as melatonin are introduced. Melatonin is a hormone produced in the glandula pinealis that follows a circadian light-dependent rhythm of secretion. It has been experimentally implicated in skin functions such as hair cycling and fur pigmentation, and melatonin receptors are expressed in many skin cell types including normal and malignant keratinocytes, melanocytes and fibroblasts. It possesses a wide range of endocrine properties as well as strong antioxidative activity. Regarding UV-induced solar damage, melatonin distinctly counteracts massive generation of reactive oxygen species, mitochondrial and DNA damage. Thus, there is considerable evidence for melatonin to be an effective anti-skin aging compound, and its various properties in this context are described in this review. PMID:23467217

  7. Effects of ethylene glycol tetraacetic acid, A23187 and calmodulin, calcium activated neutral proteinase antagonists on melatonin secretion in perifused chick pineal gland.

    PubMed

    Agapito, M T; Pablos, M; Reiter, R J; Recio, J M; Gutierrez-Baraja, R

    1998-04-10

    We have recently described, using perifused pineal glands, that calcium influx participates in the activation of chick pineal gland. This study shows that the loss of perifused chick pineal gland activity is a complex process which seems to involve the release of calcium from intracellular stores, calmodulin and calcium-activated neutral protease (CANP). Pineal glands were perifused with Krebs medium (controls) or with Krebs medium plus the drugs ethylene glycol tetraacetic acid (EGTA; calcium chelator), A23187 (calcium ionophore), EGTA plus A23187 (extra-intra cellular calcium chelation), trifluoperazine and CGS9343B (calmodulin inhibitors), and E-64 (CANP inhibitor) at the time of the natural peak of melatonin release. When EGTA or A23187 were added to the perifusion medium, no effects were observed. On the other hand, when the calcium chelator EGTA plus A23187 (free extra and intracellular calcium levels were dramatically decreased), trifluoperazine, CGS 9343B or E-64 were added to the perifusion medium melatonin synthesis increased significantly and was sustained for 8 h. We propose a prominent role for calcium output from intracellular stores in regulating melatonin production primarily by acting on Ca-calmodulin and calcium-activated neutral protease.

  8. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    PubMed

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways.

  9. Plasma Melatonin Levels in Relation to the Light-Dark Cycle and Parental Background in Domestic Pigs

    PubMed Central

    Andersson, H

    2001-01-01

    To study porcine melatonin secretion in a stable environment 3 daytime (10.00 – 15.00) and 3 nighttime (22.00 – 03.00) plasma samples were collected by jugular venipuncture from 15 gilts, 16 sows, 3 boars and 48 piglets (24 females and 24 males from 8 litters) and analysed for melatonin content. Nighttime melatonin concentrations were higher than daytime melatonin concentrations (p < 0.001), whereas no effect of sampling order could be discerned. The 3 adult Hampshire boars had higher melatonin concentrations during the day and the night, than the 31 adult Yorkshire females (p < 0.05). There was no clear difference between gilts and sows in plasma melatonin. The gilts from one of the litters had higher plasma melatonin concentrations than the gilts in 3 other litters (p < 0.05). Among the 48 piglets, the increase of nocturnal melatonin secretion differed between litters (p < 0.01), whereas the influence of father was not quite significant (p = 0.12). No difference in daytime melatonin concentrations between litters could be found, and there was no difference in melatonin levels between the male and female piglets. In conclusion, this study demonstrates that domestic pigs express a nocturnal increase of melatonin secretion in a standard stable environment. For some animals the amplitude of nighttime melatonin secretion was very low, although always higher than the daytime base levels. Furthermore, the levels of nighttime melatonin secretion differed between litters, which suggests a genetic background. PMID:11503374

  10. Altered melatonin production in TGR(mREN2)27 rats: on the regulation by adrenergic agonists, antagonists and angiotensin II in cultured pinealocytes.

    PubMed

    Enzminger, H; Witte, K; Lemmer, B

    2001-10-01

    Transgenic TGR(mREN2)27 rats (TGR), carrying an additional mouse renin gene, are characterized by severe hypertension, an inverse circadian blood pressure profile, a blunted response to photic entrainment signals, and an increased nocturnal production of the pineal hormone melatonin. In order to evaluate the contribution of the over-expressed renin-angiotensin system to the function of the pineal gland in TGR, we studied the adrenergic and angiotensin II (Ang II)-mediated regulation of melatonin synthesis using dispersed pinealocytes from TGR and from Sprague-Dawley control rats (SDR). Isoproterenol was more effective in stimulating melatonin release in pinealocytes from TGR than from SDR, whereas the maximum effect of norepinephrine (NE) stimulation did not differ between the strains. Prazosin reduced the NE-mediated melatonin release only in SDR but not in TGR pinealocytes. Competition experiments with (+/-)-, (+)-, (-)-propranolol and (+/-)-atenolol revealed one homogeneous population of beta1-adrenoceptors. Ang II had no significant effect on basal or isoproterenol-induced melatonin release in either strain. In conclusion, TGR pinealocytes were more sensitive to beta-adrenergic stimulation than SDR pinealocytes, but lacked the alpha1-adrenergic potentiation of beta-adrenergic induced melatonin release. The renin-angiotensin system was not directly involved in the regulation of melatonin synthesis by rat pinealocytes in vitro.

  11. Agomelatine, melatonin and depressive disorder.

    PubMed

    Norman, Trevor R

    2013-04-01

    Alteration of nocturnal melatonin production, along with circadian rhythm disturbance, has been demonstrated in several psychiatric disorders. It has been postulated that such disturbances might be causal reflecting a more fundamental abnormality of the function of the suprachiasmatic nucleus (SCN). The SCN contains the body's master 'clock' while the pineal-SCN nexus is intricate to the nighttime production of melatonin. The more compelling case for causality is made for major depressive disorder (MDD). Lending weight to this proposition is the introduction of agomelatine as an antidepressant agent. Through its actions on melatonin receptors agomelatine can resynchronise circadian rhythms. The circadian hypothesis would posit that normalisation of disturbance would be sufficient of itself to alleviate the symptoms of MDD. Thus, strategies designed to bring about resynchronisation of circadian rhythms should be therapeutically effective in depression. Critical examination of the efficacy of such interventions in MDD suggests that the circadian alteration may be necessary but is not sufficient for an antidepressant effect. Exogenous melatonin administration and bright light therapy have mixed results in limited controlled clinical evaluations. Furthermore, agomelatine has other actions which pre-clinical studies suggest are as important to its therapeutic effects as are its actions on melatonin receptors ipso facto its resynchronising properties. Whether circadian effects are antidepressant remains a moot point and awaits the clinical evaluation of highly selective resynchronising agents.

  12. Maraviroc reduces cytokine expression and secretion in human adipose cells without altering adipogenic differentiation.

    PubMed

    Díaz-Delfín, Julieta; Domingo, Pere; Giralt, Marta; Villarroya, Francesc

    2013-03-01

    Maraviroc (MVC) is a drug approved for use as part of HAART in treatment-experienced HIV-1 patients with CCR5-tropic virus. Despite the current concerns on the alterations in adipose tissue that frequently appear in HIV-infected patients under HAART, there is no information available on the effects of MVC on adipose tissue. Here we studied the effects of MVC during and after the differentiation of human adipocytes in culture, and compared the results with the effects of efavirenz (EFV). We measured the acquisition of adipocyte morphology; the gene expression levels of markers for mitochondrial toxicity, adipogenesis and inflammation; and the release of adipokines and cytokines to the medium. Additionally, we determined the effects of MVC on lipopolysaccharide (LPS)-induced pro-inflammatory cytokine expression in adipocytes. Unlike EFV-treated pre-adipocytes, MVC-treated pre-adipocytes showed no alterations in the capacity to differentiate into adipocytes and accumulated lipids normally. Consistent with this, there were no changes in the mRNA levels of PPARγ or SREBP-1c, two master regulators of adipogenesis. In addition, MVC caused a significant decrease in the gene expression and release of pro-inflammatory cytokines, whereas EFV had the opposite effect. Moreover, MVC lowered inflammation-related gene expression and inhibited the LPS-induced expression of pro-inflammatory genes in differentiated adipocytes. We conclude that MVC does not alter adipocyte differentiation but rather shows anti-inflammatory properties by inhibiting the expression and secretion of pro-inflammatory cytokines. Collectively, our results suggest that MVC may minimize adverse effects on adipose tissue development, metabolism, and inflammation, and thus could be a potentially beneficial component of antiretroviral therapy.

  13. The amplitude of nocturnal melatonin concentrations is not decreased by oestradiol and does not alter reproductive function in adolescent or adult female rhesus monkeys.

    PubMed

    Wilson, M E; Lackey, S; Chikazawa, K; Gordon, T P

    1993-05-01

    Nocturnal concentrations of melatonin in serum decline significantly with advancing pubertal development in both children and non-human primates and elevated levels may be associated with anovulation in adults. Three studies, using female rhesus monkeys, were performed to determine whether (1) the decline in nocturnal melatonin concentrations in adolescents was due to maturational increases in serum oestradiol, (2) the experimental elevation in nocturnal melatonin would delay the normal progression of puberty in post-menarchial monkeys, and (3) the experimental elevation in nocturnal melatonin would disrupt normal ovulatory function in adults. In experiment 1, juvenile female rhesus monkeys, housed indoors in a fixed photoperiod (12 h light:12 h darkness), were assigned randomly to one of two treatment groups: ovariectomized with no replacement therapy (control; n = 4) or ovariectomized with oestradiol replacement therapy maintaining oestradiol at approximately 90 pmol/l (treated; n = 8). Twenty-four hour as well as daytime serum samples were collected from 19 to 35 months of age. Nocturnal melatonin concentrations declined significantly in all females with advancing chronological age and this change was unaffected by oestradiol treatment. The decline in nocturnal melatonin concentrations occurred, on average, 2.0 +/- 0.2 months after the initial rise in serum LH in control females and 6.0 +/- 0.8 months in treated females. Furthermore, this decline in night-time melatonin was not related to significant developmental changes in body weight. In experiment 2, control (n = 6) and melatonin-treated (treated; n = 6) adolescent female monkeys were studied from -30 to +105 days from menarche. Beginning at 45 days following menarche, treated females received 30 days of nocturnal melatonin infusion to elevate levels to prepubertal values. Developmental changes in perineal swelling and coloration as well as serum oestradiol and insulin-like growth factor-I (IGF-I) were

  14. Altered secretion of LH does not explain seasonal effects on early pregnancy in gilts.

    PubMed

    Peltoniemi, O A; Love, R J; Klupiec, C; Revell, D K; Evans, G

    1997-12-05

    to be mediated by mechanisms other than an alteration in LH secretion.

  15. Human melatonin during continuous magnetic field exposure

    SciTech Connect

    Graham, C.; Cook, M.R.; Riffle, D.W.

    1997-05-01

    This report describes the third in a series of double-blind, laboratory-based studies that were aimed at determining the effects of nocturnal exposure to power frequency magnetic fields on blood levels of melatonin in human volunteers. The two earlier studies evaluated effects on melatonin of intermittent exposure to 60 Hz circularly polarized magnetic fields at 10 and 200 mG. No overall effects on melatonin levels were found. In the present study, men were exposed continuously rather than intermittently through the night to the same 200 mG magnetic field condition that was used previously; again, no overall effects on melatonin levels were found. The authors conclude that the intermittent and continuous exposure conditions used in the laboratory to date are not effective in altering nocturnal blood levels of melatonin in human volunteers.

  16. Altered ghrelin secretion in mice in response to diet-induced obesity and Roux-en-Y gastric bypass

    PubMed Central

    Uchida, Aki; Zechner, Juliet F.; Mani, Bharath K.; Park, Won-mee; Aguirre, Vincent; Zigman, Jeffrey M.

    2014-01-01

    The current study examined potential mechanisms for altered circulating ghrelin levels observed in diet-induced obesity (DIO) and following weight loss resulting from Roux-en-Y gastric bypass (RYGB). We hypothesized that circulating ghrelin levels were altered in obesity and after weight loss through changes in ghrelin cell responsiveness to physiological cues. We confirmed lower ghrelin levels in DIO mice and demonstrated elevated ghrelin levels in mice 6 weeks post-RYGB. In both DIO and RYGB settings, these changes in ghrelin levels were associated with altered ghrelin cell responsiveness to two key physiological modulators of ghrelin secretion – glucose and norepinephrine. In DIO mice, increases in ghrelin cell density within both the stomach and duodenum and in somatostatin-immunoreactive D cell density in the duodenum were observed. Our findings provide new insights into the regulation of ghrelin secretion and its relation to circulating ghrelin within the contexts of obesity and weight loss. PMID:25353000

  17. Altered ghrelin secretion in mice in response to diet-induced obesity and Roux-en-Y gastric bypass.

    PubMed

    Uchida, Aki; Zechner, Juliet F; Mani, Bharath K; Park, Won-Mee; Aguirre, Vincent; Zigman, Jeffrey M

    2014-10-01

    The current study examined potential mechanisms for altered circulating ghrelin levels observed in diet-induced obesity (DIO) and following weight loss resulting from Roux-en-Y gastric bypass (RYGB). We hypothesized that circulating ghrelin levels were altered in obesity and after weight loss through changes in ghrelin cell responsiveness to physiological cues. We confirmed lower ghrelin levels in DIO mice and demonstrated elevated ghrelin levels in mice 6 weeks post-RYGB. In both DIO and RYGB settings, these changes in ghrelin levels were associated with altered ghrelin cell responsiveness to two key physiological modulators of ghrelin secretion - glucose and norepinephrine. In DIO mice, increases in ghrelin cell density within both the stomach and duodenum and in somatostatin-immunoreactive D cell density in the duodenum were observed. Our findings provide new insights into the regulation of ghrelin secretion and its relation to circulating ghrelin within the contexts of obesity and weight loss.

  18. Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours

    PubMed Central

    Söderquist, Fanny; Janson, Eva Tiensuu; Rasmusson, Annica J.; Ali, Abir; Stridsberg, Mats; Cunningham, Janet L.

    2016-01-01

    Background/Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin’s endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function. PMID:27736994

  19. Cancer metastasis: Mechanisms of inhibition by melatonin.

    PubMed

    Su, Shih-Chi; Hsieh, Ming-Ju; Yang, Wei-En; Chung, Wen-Hung; Reiter, Russel J; Yang, Shun-Fa

    2017-01-01

    Melatonin is a naturally occurring molecule secreted by the pineal gland and known as a gatekeeper of circadian clocks. Mounting evidence indicates that melatonin, employing multiple and interrelated mechanisms, exhibits a variety of oncostatic properties in a myriad of tumors during different stages of their progression. Tumor metastasis, which commonly occurs at the late stage, is responsible for the majority of cancer deaths; metastases lead to the development of secondary tumors distant from a primary site. In reference to melatonin, the vast majority of investigations have focused on tumor development and progression at the primary site. Recently, however, interest has shifted toward the role of melatonin on tumor metastases. In this review, we highlight current advances in understanding the molecular mechanisms by which melatonin counteracts tumor metastases, including experimental and clinical observations; emphasis is placed on the impact of both cancer and non-neoplastic cells within the tumor microenvironment. Due to the broad range of melatonin's actions, the mechanisms underlying its ability to interfere with metastases are numerous. These include modulation of cell-cell and cell-matrix interaction, extracellular matrix remodeling by matrix metalloproteinases, cytoskeleton reorganization, epithelial-mesenchymal transition, and angiogenesis. The evidence discussed herein will serve as a solid foundation for urging basic and clinical studies on the use of melatonin to understand and control metastatic diseases. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Clinical aspects of melatonin.

    PubMed

    Reiter, Russel J; Korkmaz, Ahmet

    2008-11-01

    Melatonin is produced in the human pineal gland, particularly at night, with the circadian rhythm of blood melatonin levels closely paralleling its production within the pineal gland. Light exposure at night, or rapid transmeridian travel severely compromises the circadian production of melatonin. The disturbed melatonin rhythm contributes to jet lag and sleep inefficiency, both of which are improved by melatonin administration. Melatonin is also a highly effective direct free radical scavenger and antioxidant. In this capacity, melatonin reduces experimental cataractogenesis, traumatic injury to the spinal cord and brain, and protects against oxidative damage to neurons and glia in models of stroke, Parkinsonism, and Alzheimer's disease. Additionally, melatonin and its metabolites are highly effective in protecting against ionizing radiation. Finally, melatonin may be a treatment for hypertension. Melatonin's high efficacy, its high safety profile, and its virtual lack of toxicity make it of interest in clinical medicine.

  1. Melatonin and the circadian system: contributions to successful female reproduction.

    PubMed

    Reiter, Russel J; Tamura, Hiroshi; Tan, Dun Xian; Xu, Xiao-Ying

    2014-08-01

    To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level. Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peer-reviewed journals are cited. Not applicable. Not applicable. Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night. Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs. The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ. Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset

  2. Potency of Melatonin in Living Beings

    PubMed Central

    Choi, Donchan

    2013-01-01

    Living beings are surrounded by various changes exhibiting periodical rhythms in environment. The environmental changes are imprinted in organisms in various pattern. The phenomena are believed to match the external signal with organisms in order to increase their survival rate. The signals are categorized into circadian, seasonal, and annual cycles. Among the cycles, the circadian rhythm is regarded as the most important factor because its periodicity is in harmony with the levels of melatonin secreted from pineal gland. Melatonin is produced by the absence of light and its presence displays darkness. Melatonin plays various roles in creatures. Therefore, this review is to introduce the diverse potential ability of melatonin in manifold aspects in living organism. PMID:25949131

  3. Melatonin: a "Higgs boson" in human reproduction.

    PubMed

    Dragojevic Dikic, Svetlana; Jovanovic, Ana Mitrovic; Dikic, Srdjan; Jovanovic, Tomislav; Jurisic, Aleksandar; Dobrosavljevic, Aleksandar

    2015-02-01

    As the Higgs boson could be a key to unlocking mysteries regarding our Universe, melatonin, a somewhat mysterious substance secreted by the pineal gland primarily at night, might be a crucial factor in regulating numerous processes in human reproduction. Melatonin is a powerful antioxidant which has an essential role in controlling several physiological reactions, as well as biological rhythms throughout human reproductive life. Melatonin, which is referred to as a hormone, but also as an autocoid, a chronobiotic, a hypnotic, an immunomodulator and a biological modifier, plays a crucial part in establishing homeostatic, neurohumoral balance and circadian rhythm in the body through synergic actions with other hormones and neuropeptides. This paper aims to analyze the effects of melatonin on the reproductive function, as well as to shed light on immunological and oncostatic properties of one of the most powerful hormones.

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

    PubMed

    Pontes, Gerlândia N; Cardoso, Elaine C; Carneiro-Sampaio, Magda M S; Markus, Regina P

    2006-09-01

    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.

  5. Neurobiology, Pathophysiology, and Treatment of Melatonin Deficiency and Dysfunction

    PubMed Central

    Hardeland, Rüdiger

    2012-01-01

    Melatonin is a highly pleiotropic signaling molecule, which is released as a hormone of the pineal gland predominantly during night. Melatonin secretion decreases during aging. Reduced melatonin levels are also observed in various diseases, such as types of dementia, some mood disorders, severe pain, cancer, and diabetes type 2. Melatonin dysfunction is frequently related to deviations in amplitudes, phasing, and coupling of circadian rhythms. Gene polymorphisms of melatonin receptors and circadian oscillator proteins bear risks for several of the diseases mentioned. A common symptom of insufficient melatonin signaling is sleep disturbances. It is necessary to distinguish between symptoms that are curable by short melatonergic actions and others that require extended actions during night. Melatonin immediate release is already effective, at moderate doses, for reducing difficulties of falling asleep or improving symptoms associated with poorly coupled circadian rhythms, including seasonal affective and bipolar disorders. For purposes of a replacement therapy based on longer-lasting melatonergic actions, melatonin prolonged release and synthetic agonists have been developed. Therapies with melatonin or synthetic melatonergic drugs have to consider that these agents do not only act on the SCN, but also on numerous organs and cells in which melatonin receptors are also expressed. PMID:22629173

  6. Sleep quality, morningness-eveningness preference, mood profile, and levels of serum melatonin in migraine patients: a case-control study.

    PubMed

    Kozak, Hasan Hüseyin; Boysan, Murat; Uca, Ali Ulvi; Aydın, Adem; Kılınç, İbrahim; Genç, Emine; Altaş, Mustafa; Güngör, Dilara Cari; Turgut, Keziban; Özer, Nejla

    2017-03-01

    The melatonin as the pineal gland's secretory product is implicated in the pathophysiology of migraine. Melatonin has critical functions in human physiology, and research underscores the importance of melatonin in circadian rhythm, sleep, and mood regulation. Clinical observations have indicated that migraine attacks have a seasonal, menstrual, and circadian timing, suggesting that chronobiological mechanisms and their alterations may causally involve in the etiology of the disease. However, the topic has received relatively little attention in the migraine literature. Associations between melatonin, circadian preference, sleep, and mood states were investigated in the current study. Fifty-five patients (47 females and 8 males) were compared to 57 gender and age-matched control subjects (40 females and 17 males). A socio-demographical questionnaire, the Beck Depression Inventory, Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index (PSQI), Profile of Mood States (POMS), and Morningness-Eveningness Questionnaire were administered to volunteers. Blood samples were taken from all participants at about 1:00 AM in an unlit room not to hamper melatonin secretion, and blood melatonin levels were measured using quantitative ELISA test. In comparison with controls, melatonin levels were significantly lower among migraine patients. Migraineurs reported significantly greater scores on the BAI, confusion-bewilderment subscale of the POMS, and total and sleep latency subscale of the PSQI. Migraine patients who had nausea during the migraine attacks and who reported bouts relevant to certain food consumption, such as cheese or chocolate, had significantly lower levels of melatonin. Contrarily, groups did not reveal statistically substantial difference in circadian preferences.

  7. The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model.

    PubMed

    el-Aziz, Mohamad A Abd; Hassan, Hosny A; Mohamed, Mahmoud H; Meki, Abdel-Raheim M A; Abdel-Ghaffar, Sary K H; Hussein, Mahmoud R

    2005-12-01

    Worldwide, breast cancer is the second leading cause of cancer death among women and the third most common cancer. Although our understanding of the molecular basis of this fatal disease has improved, this malignancy remains elusive. Melatonin (Mel), retinoic acid (RA) and Nigella sativa (NS) are substances with anticancer effects. To date, our understanding of the mechanisms of therapeutic effects of these products in mammary cancer is still marginal. To look at the preventive and therapeutic values of these products, we carried out this investigation. An animal model formed of 80 rats was established. The animals were divided into eight groups of 10 animals each: (a) control group injected with the same vehicle used for treatments in the relevant dosages and routes; (b) carcinogen group injected with the known carcinogenic substance 7,12-di-methylbenz(a)anthracene (DMBA) that induces mammary carcinoma; (c) three prophylactic (Pro) groups (Mel-Pro, RA-Pro and NS-Pro) injected with test substances (Mel, RA and NS, respectively) 14 days before the intake of the carcinogenic substance DMBA and then continued until the end of the experiments; and (d) three treated (Tr) groups (Mel-Tr, RA-Tr and NS-Tr) injected with the vehicles after the intake of DMBA. In both the Pro and Tr groups, the drugs were daily administered for 3 months. The animals were killed, and their serum and tissues were evaluated for (a) markers of tumorigenicity [serum levels of total sialic acid (TSA) and lipid-bound sialic acid (LSA)], (b) markers of endocrine derangement (serum prolactin, estradiol and progesterone levels), (c) apoptotic changes [serum tumour necrosis factor (TNF)-alpha, tissue caspase-3 activity, percentage of DNA fragmentation and ultrastructural features of apoptosis] and (d) markers of oxidative stress (tissue levels of lipid peroxides and nitric oxide). Carcinoma was absent both in the control and in the NS-Pro groups. Mammary carcinoma occurred in DMBA and other Pro and Tr

  8. Melatonin and aging: prospects for human treatment.

    PubMed

    Bubenik, G A; Konturek, S J

    2011-02-01

    Human life span, with or without modern medicine is around 85-95 years. All living creatures have their inner clock that measures their daily (circadian) and their seasonal (circannual) time. These time changes are mediated by the alteration of levels of melatonin, an evolutionary ancient hormone, which is produced in many body tissues, including the pineal gland, retina and the gastrointestinal tract (GIT). Light is blocking the production of melatonin in the pineal gland, darkness is stimulating it. So, the diurnal changes of light intensity of melatonin, provide a "daily clock" and the seasonal changes provide a "seasonal clock". Finally, the reduction of melatonin observed with aging, may indicate the presence of an "age clock". Melatonin is a strong antioxidant (often it is called scavenger of free radicals), which protects the body from the effects of noxious compounds. Therefore it was hypothesized that the reduction of melatonin levels with age contributes to the aging process. So far, the only remedy to extend the life span was a 40% reduction in caloric intake, which prolonged the life in mice, rats, dogs and monkeys by 30-50%. A large group of people imitate these experiments performed on animals, but the results of these experiments will not be known for several decades. How is being hungry prolonging the life span? There is a connection between caloric reduction and melatonin levels in GIT. Several experiments indicate that fasting in animals substantially increased their production of GIT melatonin. Therefore, instead of being permanently hungry, a prolongation of human life could be achieved by a replacement melatonin therapy. A daily intake of melatonin before bed time might achieve the same effect as fasting e.g. an increase of body melatonin levels, which will protect the individual from the ravages of old age. That includes Parkinson's disease and Alzheimer's disease. There is a large group of people taking melatonin daily who believe that

  9. Melatonin: aeromedical, toxicopharmacological, and analytical aspects.

    PubMed

    Sanders, D C; Chaturvedi, A K; Hordinsky, J R

    1999-01-01

    of accidental death may allow forensic scientists and accident investigators to use the relationship between its concentration and the time of day when death occurred. The most accurate estimations of the time of death result from analysis of melatonin content of the whole pineal body, whereas less accurate estimates are obtained from serum and urine analyses. Pineal levels of melatonin are unlikely to be altered by exogenous melatonin, but its blood and urine levels would change. High blood levels in a daytime crash victim would suggest exogenous supplementation. The possible interfering effects of postmortem biochemical processes on melatonin concentrations in whole blood and in other tissues are not well understood, and there is a need for the continuing research into melatonin's chronobiological properties to define its proper applications and limitations. The indiscriminate use of melatonin by aviation professionals may pose unacceptable safety risks for air travel.

  10. Melatonin, energy metabolism, and obesity: a review.

    PubMed

    Cipolla-Neto, J; Amaral, F G; Afeche, S C; Tan, D X; Reiter, R J

    2014-05-01

    Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin functions as a hormone and a chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti-obesogen and the weight-reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion, and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G-protein-coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin-signaling pathway. Melatonin is a powerful chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated with high insulin sensitivity, and the rest/fasting is synchronized to the insulin-resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift-work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.

  11. [Alteration of thyroid hormone secretion after long-term exposure to low doses of endocrine disruptor DDT].

    PubMed

    Iaglova, N V; Iaglov, V V

    2014-01-01

    Endocrine disruptors are exogenous substances that exhibit hormone-like action and consequently disrupt homeostatic action of endogenous hormones. DDT is the most common disruptor. The objective was to evaluate changes in thyroid hormone secretion after long-term exposure to low doses of DDT. The experiment was performed on male Wistar rats. The rats were given DDT at doses of 1.89±0.86 мg/kg/day and 7.77±0.17 мg/kg/day for 6 and 10 weeks. Dose dependent increase of serum total thyroxine, total triiodthyronine, and thyroid peroxidase was revealed after 6 weeks exposure. After 10 weeks free thyroxine secretion was reduced. Such alterations of the thyroid status are typical for iodine deficient goiter. The data obtained indicate that the main mechanism of DDT action includes disruption of thyroxine secretion by thyrocytes, but not inhibition of deiodinase activity and decrease of blood thyroid binding proteins.

  12. Daytime light intensity affects seasonal timing via changes in the nocturnal melatonin levels

    NASA Astrophysics Data System (ADS)

    Kumar, Vinod; Rani, Sangeeta; Malik, Shalie; Trivedi, Amit K.; Schwabl, Ingrid; Helm, Barbara; Gwinner, Eberhard

    2007-08-01

    Daytime light intensity can affect the photoperiodic regulation of the reproductive cycle in birds. The actual way by which light intensity information is transduced is, however, unknown. We postulate that transduction of the light intensity information is mediated by changes in the pattern of melatonin secretion. This study, therefore, investigated the effects of high and low daytime light intensities on the daily melatonin rhythm of Afro-tropical stonechats ( Saxicola torquata axillaris) in which seasonal changes in daytime light intensity act as a zeitgeber of the circannual rhythms controlling annual reproduction and molt. Stonechats were subjected to light conditions simulated as closely as possible to native conditions near the equator. Photoperiod was held constant at 12.25 h of light and 11.75 h of darkness per day. At intervals of 2.5 to 3.5 weeks, daytime light intensity was changed from bright (12,000 lux at one and 2,000 lux at the other perch) to dim (1,600 lux at one and 250 lux at the other perch) and back to the original bright light. Daily plasma melatonin profiles showed that they were linked with changes in daytime light intensity: Nighttime peak and total nocturnal levels were altered when transitions between light conditions were made, and these changes were significant when light intensity was changed from dim to bright. We suggest that daytime light intensity could affect seasonal timing via changes in melatonin profiles.

  13. Influence of sleep deprivation coupled with administration of melatonin on the ultrastructure of rat pineal gland.

    PubMed

    Lan, C T; Hsu, J C; Ling, E A

    2001-08-10

    The effects of sleep deprivation with or without melatonin treatment on the pineal morphology in rats were studied. Five days after sleep deprivation and using electron microscopy, many of the pinealocytes exhibited structural alterations including dilation of the cisternae of the rough/smooth endoplasmic reticulum, Golgi saccules and mitochondria, and an increase in the numbers of lipid droplets, vacuoles and dense-core vesicles. These features were considered as morphological evidence of increased synthesis or secretion by the pineal gland. In addition, numerous membranous profiles, considered to be degraded cellular organelles, were observed in some pinealocytes and sympathetic nerve terminals. It is suggested that the occurrence of degenerating organelles had resulted from the deleterious effect of sleep deprivation. This may be attributed to an overload of secretory activity of the pineal gland during stress elicited by the long-term sleep deprivation, leading to functional exhaustion and irreversible damage of the oxidation-related organelles. In sleep-deprived rats receiving a single injection of melatonin (10 mg/kg) for 5 consecutive days, the above features indicative of pinealocytic activation were attenuated. In fact, all signs of degeneration of cellular organelles were rarely found. These results suggest that the pineal gland is itself a target for exogenously administered melatonin. Thus, melatonin when administered systemically may be used as a potential neuroprotective drug against neuronal damage induced by sleep deprivation.

  14. Alteration of the MT1 melatonin receptor gene and its expression in primary human breast tumors and breast cancer cell lines.

    PubMed

    Lai, Ling; Yuan, Lin; Cheng, Qi; Dong, Chunmin; Mao, Lulu; Hill, Steven Marc

    2009-11-01

    The MT1 melatonin receptor is bound and activated by the pineal hormone melatonin. This G protein-coupled melatonin receptor is expressed in human breast tumor cell lines, and when activated, mediates the growth-suppressive and steroid hormone/nuclear receptor modulatory actions of melatonin on breast tumor cells. In the current studies, we have examined the expression of the MT1 receptor in breast cancer cell lines and primary human breast tumors and correlated MT1 receptor expression with the deletion, rearrangement and amplification of the MT1 gene and established markers of breast cancer such as tumor size, stage, estrogen receptor alpha (ERalpha) and progesterone receptor (PR) expression. Theses studies suggest amplification of the MT1 gene in some breast tumors and an inverse correlation with ERalpha, PR and MT1 protein expression. Furthermore, these approaches employing immunohistochemical and immunofluorescent/confocal microscopic studies demonstrate that the MT1 receptor is localized to the caveoli and that MT1 expression in MCF-7 breast cancer cells can be repressed by estradiol and melatonin.

  15. Effect of zinc binding residues in growth hormone (GH) and altered intracellular zinc content on regulated GH secretion.

    PubMed

    Petkovic, Vibor; Miletta, Maria Consolata; Eblé, Andrée; Iliev, Daniel I; Binder, Gerhard; Flück, Christa E; Mullis, Primus E

    2013-11-01

    Endocrine cells store hormones in concentrated forms (aggregates) in dense-core secretory granules that are released upon appropriate stimulation. Zn(2+) binding to GH through amino acid residues His18, His21, and Glu174 are essential for GH dimerization and might mediate its aggregation and storage in secretory granules. To investigate whether GH-1 gene mutations at these positions interfere with this process, GH secretion and intracellular production were analyzed in GC cells (rat pituitary cell line) transiently expressing wt-GH and/or GH Zn mutant (GH-H18A-H21A-E174A) in forskolin-stimulated vs nonstimulated conditions. Reduced secretion of the mutant variant (alone or coexpressed with wt-GH) compared with wt-GH after forskolin stimulation was observed, whereas an increased intracellular accumulation of GH Zn mutant vs wt-GH correlates with its altered extracellular secretion. Depleting Zn(2+) from culture medium using N,N,N',N'-tetrakis(2-pyridylemethyl)ethylenediamine, a high-affinity Zn(2+) chelator, led to a significant reduction of the stimulated wt-GH secretion. Furthermore, externally added Zn(2+) to culture medium increased intracellular free Zn(2+) levels and recovered wt-GH secretion, suggesting its direct dependence on free Zn(2+) levels after forskolin stimulation. Confocal microscopy analysis of the intracellular secretory pathway of wt-GH and GH Zn mutant indicated that both variants pass through the regulated secretory pathway in a similar manner. Taken together, our data support the hypothesis that loss of affinity of GH to Zn(2+) as well as altering intracellular free Zn(2+) content may interfere with normal GH dimerization (aggregation) and storage of the mutant variant (alone or with wt-GH), which could possibly explain impaired GH secretion.

  16. Which is the best choice for gastroesophageal disorders: Melatonin or proton pump inhibitors?

    PubMed Central

    de Oliveira Torres, Joanna Dulce Favacho; de Souza Pereira, Ricardo

    2010-01-01

    Melatonin is used in many countries to improve sleep disorders. Melatonin is a hormone produced by the pineal gland and enterochromaffin cells which control sleep and gastrointestinal motility. Low levels of melatonin lead to gastroesophageal reflux disease (GERD). Most of patients with GERD have a sleep disorder. So, low melatonin levels is the main cause of insomnia. Beyond this, it has an inhibitory action on gastric acid secretion and seems to control the lower esophageal sphincter. Proton pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. Omeprazole (one of the PPIs) and melatonin have similarities in their chemical structures. Therefore, we could consider omeprazole as a rough copy of melatonin. In this paper, we compare the advantages and disadvantages of the clinical use of melatonin and PPIs. PMID:21577303

  17. [Effects of disturbances of natural magnetic field of the Earth on melatonin production in patients with coronary heart disease].

    PubMed

    Rapoport, S I; Malinovskaia, N K; Oraevskií, V N; Komarov, F I; Nosovskií, A M; Vetterberg, L

    1997-01-01

    The obtained results clearly evidence for the influence of magnetic disturbances and storms on melatonin production in patients with ischemic heart disease. Improvement of 24-hour rhythm of melatonin secretion during the period of magnetic disturbances says in favour of this influence while an overall fall of melatonin production during magnetic disturbances and storms is an apparent negative factor.

  18. Regulation of rat biliary cholesterol secretion by agents that alter intrahepatic cholesterol metabolism. Evidence for a distinct biliary precursor pool.

    PubMed Central

    Stone, B G; Erickson, S K; Craig, W Y; Cooper, A D

    1985-01-01

    Propensity for cholesterol gallstone formation is determined in part by biliary cholesterol content relative to bile salts and phospholipid. We examined the hypothesis that the rate of biliary cholesterol secretion can be controlled by availability of an hepatic metabolically active free cholesterol pool whose size is determined in part by rates of sterol synthesis, as reflected by activity of the primary rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and of sterol esterification, as reflected by the activity of the enzyme acyl coenzyme A/cholesterol acyltransferase (ACAT). Rats were prepared with biliary, venous, and duodenal catheters. The enterohepatic circulation of biliary lipids was maintained constant by infusion of a bile salt, lecithin, cholesterol replacement solution. Administration of 25-hydroxycholesterol decreased HMG CoA reductase activity, increased ACAT activity, and decreased biliary cholesterol output 26% by 1 h. By 2 h, ACAT activity and biliary cholesterol secretion were at control levels. Administration of mevinolin, a competitive inhibitor of HMG CoA reductase, had no effect on ACAT activity and decreased biliary cholesterol secretion 16%. Administration of progesterone, an inhibitor of ACAT, had no effect on HMG CoA reductase and increased biliary cholesterol output 32% at 1 h. By 2 h, all parameters were near control levels. None of these agents had any significant effect on biliary bile salt or phospholipid secretion. Thus, acutely altering rates of esterification and/or synthesis can have profound effects on biliary cholesterol secretion independent of the other biliary lipids. These experiments suggest the existence of a metabolically active pool of free cholesterol that serves as a precursor pool for biliary cholesterol secretion. Furthermore, the size of this precursor pool is determined in part both by rates of cholesterol synthesis and esterification and is a key determinant of biliary cholesterol

  19. Examination of the melatonin hypothesis in women exposed at night to EMF or bright light.

    PubMed

    Graham, C; Cook, M R; Gerkovich, M M; Sastre, A

    2001-05-01

    It has been hypothesized that the increased incidence of breast cancer in industrial societies is related to greater exposure to power-frequency electric and magnetic fields (EMF) and/or the presence of high levels of light at night (LAN). EMF and LAN are said to reduce circulating levels of the hormone melatonin which, in turn, allows estrogen levels to rise and stimulate the turnover of breast epithelial stem cells and increase the risk for malignant transformation. Three laboratory-based studies, in which a total of 53 healthy young women were exposed at night to EMF or to LAN under controlled exposure conditions, were performed to determine whether such exposures reduce melatonin and are associated with further alterations in estrogen. All-night exposure to industrial-strength magnetic fields (60 Hz, 28.3 microT) had no effect on the blood levels of melatonin or estradiol. In contrast, nocturnal melatonin levels were profoundly suppressed, and the time of peak concentration was significantly delayed in women exposed to LAN, regardless of whether they were in the follicular or luteal phase of the menstrual cycle. These changes, however, were not associated with alterations in point-for-point matching measures of estradiol. Women who chronically secrete high or low amounts of melatonin each night (area-under-curve range: 86-1,296 pg/mL) also did not differ in their blood levels of estradiol. Taken together, these results are consistent with a growing body of evidence which generally suggests that environmental EMF exposure has little or no effect on the parameters measured in this report.

  20. Seasonal changes in serum melatonin in women with previous breast cancer.

    PubMed Central

    Holdaway, I. M.; Mason, B. H.; Gibbs, E. E.; Rajasoorya, C.; Hopkins, K. D.

    1991-01-01

    A seasonal variation in the month of initial detection of breast cancer has been previously observed in pre-menopausal women, and it has been proposed that this may be due to cyclic changes in tumour growth mediated by the effects of melatonin on ovarian function. To investigate this possibility serum melatonin concentrations have been measured every 2 h for 24 h at the summer and winter solstice in 20 pre-menopausal women with previous breast cancer and nine controls. Twelve women had detected their tumour in winter and eight in summer. Overall melatonin secretion assessed by either amplitude of the nocturnal melatonin pulse or the area under the 24 h melatonin curve (AUC) was not different between breast cancer women or controls. However, the amplitude and AUC fell in winter in breast cancer patients (summer to winter 93.6 to 77.5 pg ml-1, P less than 0.002 and 743 to 634 AUC units, P less than 0.005 for amplitude and AUC respectively), whereas the winter minus summer values were significantly positive in controls compared with cancer patients. The abnormal fall in winter values in the women with previous breast cancer was confined to the group of women who had been winter detectors (mean summer to winter levels 94.9 to 72.6 pg ml-1, P less than 0.01 and 775 to 637 AUC units, P less than 0.05 for amplitude and AUC respectively) whereas there was no significant seasonal alteration in these measurements in summer detectors. The acrophase of the nocturnal pulse of serum melatonin was significantly advanced in both groups of women with previous breast cancer (change in acrophase winter to summer from 0210 h to 0140 h in summer detectors, P less than 0.01, 0330 h to 0210 h in winter detectors, P less than 0.05) with a similar although nonsignificant trend in control women. The abnormal reduction of serum melatonin seen in wintertime in winter detectors of breast cancer could promote tumour growth at this season and so contribute to the decreased survival previously

  1. Altered regulation of luteinizing hormone secretion in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male rats

    SciTech Connect

    Bookstaff, R.C.

    1989-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) severely decreases plasma androgen concentrations, yet plasma luteinizing hormone (LH) concentrations remain unchanged. The mechanism by which TCDD prevents the expected compensatory increase in plasma LH was investigated. No effect on the plasma disappearance rate of LH or on pituitary capacity to synthesize or secrete LH was detected. Rather, TCDD altered the regulation of LH secretion by substantially increasing the potency of both androgens and estrogens as feedback inhibitors of LH secretion. The mechanism by which TCDD alters androgen-regulated LH secretion was further investigated. Seven days after dosing, TCDD decreased plasma testosterone concentrations but prevented the expected compensatory increases in pituitary gonadotropin-releasing hormone (GnRH) receptor number, pituitary responsiveness to GnRH, and plasma LH concentrations as seen in similarly hypoandrogenic vehicle dosed rats. Furthermore, the TCDD dose-response relationships for preventing the compensatory increases in pituitary GnRH receptor number and plasma LH concentration were similar. However, in the absence of gonadal steroids (7 days after castration) TCDD did not affect the compensatory increases in pituitary GnRH receptor number, pituitary responsiveness to GnRH, or plasma LH concentration. All of these parameters increased substantially relative to intact TCDD treated rats, and to levels virtually identical to those seen in castrated control rats. Treatment of castrated rats with testosterone restored the ability of TCDD to prevent these compensatory increases. Taken together, these results demonstrate that the presence of androgens is required for TCDD to alter the regulation of pituitary GnRH receptors.

  2. Proteins altered by elevated levels of palmitate or glucose implicated in impaired glucose-stimulated insulin secretion

    PubMed Central

    Sol, E-ri M; Hovsepyan, Meri; Bergsten, Peter

    2009-01-01

    Background Development of type 2 diabetes mellitus (T2DM) is characterized by aberrant insulin secretory patterns, where elevated insulin levels at non-stimulatory basal conditions and reduced hormonal levels at stimulatory conditions are major components. To delineate mechanisms responsible for these alterations we cultured INS-1E cells for 48 hours at 20 mM glucose in absence or presence of 0.5 mM palmitate, when stimulatory secretion of insulin was reduced or basal secretion was elevated, respectively. Results After culture, cells were protein profiled by SELDI-TOF-MS and 2D-PAGE. Differentially expressed proteins were discovered and identified by peptide mass fingerprinting. Complimentary protein profiles were obtained by the two approaches with SELDI-TOF-MS being more efficient in separating proteins in the low molecular range and 2D-PAGE in the high molecular range. Identified proteins included alpha glucosidase, calmodulin, gars, glucose-6-phosphate dehydrogenase, heterogenous nuclear ribonucleoprotein A3, lon peptidase, nicotineamide adenine dinucleotide hydrogen (NADH) dehydrogenase, phosphoglycerate kinase, proteasome p45, rab2, pyruvate kinase and t-complex protein. The observed glucose-induced differential protein expression pattern indicates enhanced glucose metabolism, defense against reactive oxygen species, enhanced protein translation, folding and degradation and decreased insulin granular formation and trafficking. Palmitate-induced changes could be related to altered exocytosis. Conclusion The identified altered proteins indicate mechanism important for altered β-cell function in T2DM. PMID:19607692

  3. Role of melatonin in Alzheimer-like neurodegeneration.

    PubMed

    Wang, Jian-zhi; Wang, Ze-fen

    2006-01-01

    Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients. Melatonin efficiently protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Abeta generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Abeta. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Abeta pathology further enhances its potential in the prevention or treatment of AD.

  4. Prevention of melatonin suppression by nocturnal lighting: relevance to cancer.

    PubMed

    Kayumov, Leonid; Lowe, Alan; Rahman, Shadab A; Casper, Robert F; Shapiro, Colin M

    2007-08-01

    The decreased melatonin production in humans and animals caused by environmental lighting, especially short wavelength lighting (between 470 and 525 nm) has been shown to be associated with an increased risk of cancer. The purpose of this study was to investigate whether blocking light in this wavelength range under bright light may prevent the suppression of melatonin, which could help to prevent cancer. Optical filter lenses were designed, allowing selective exclusion of all wavelengths below 530 nm. Salivary melatonin levels were measured under dim light (<5 lux), bright light (800 lux) and filtered light (800 lux) at hourly intervals between 2000 and 0800 h in 11 healthy young male participants (mean age 23.5+/-1.5 years). The measurements were taken during three nonconsecutive nights over a 2-week period. The Dim Light Melatonin Onset test was used as a marker of circadian phase. Nine of the 11 participants demonstrated preserved melatonin levels in filtered light similar to their dim light secretion profile. With filtered light, the participants had a mean relative amount of melatonin of 91.2 (P>0.05 between dim light and experimental condition). Unfiltered bright light drastically suppressed melatonin production with a mean relative amount of melatonin of 25.4 (P<0.05 between dim light and experimental condition). Preventing melatonin deficiencies using lenses that block light of low wavelength from reaching the retina presents a cost-effective, practical solution to the problem of increased malignancy rates in shift workers.

  5. Absence of an increase in the duration of the circadian melatonin secretory episode in totally blind human subjects

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Zeitzer, J. M.; Duffy, J. F.; Khalsa, S. B.; Czeisler, C. A.

    2001-01-01

    The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.

  6. Absence of an increase in the duration of the circadian melatonin secretory episode in totally blind human subjects

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Zeitzer, J. M.; Duffy, J. F.; Khalsa, S. B.; Czeisler, C. A.

    2001-01-01

    The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.

  7. Roles of Melatonin in Fetal Programming in Compromised Pregnancies

    PubMed Central

    Chen, Yu-Chieh; Sheen, Jiunn-Ming; Tiao, Miao-Meng; Tain, You-Lin; Huang, Li-Tung

    2013-01-01

    Compromised pregnancies such as those associated with gestational diabetes mellitus, intrauterine growth retardation, preeclampsia, maternal undernutrition, and maternal stress may negatively affect fetal development. Such pregnancies may induce oxidative stress to the fetus and alter fetal development through the epigenetic process that may affect development at a later stage. Melatonin is an oxidant scavenger that reverses oxidative stress during the prenatal period. Moreover, the role of melatonin in epigenetic modifications in the field of developmental programming has been studied extensively. Here, we describe the physiological function of melatonin in pregnancy and discuss the roles of melatonin in fetal programming in compromised pregnancies, focusing on its involvement in redox and epigenetic mechanisms. PMID:23466884

  8. High membrane permeability for melatonin

    PubMed Central

    Yu, Haijie; Dickson, Eamonn J.; Jung, Seung-Ryoung; Koh, Duk-Su

    2016-01-01

    The pineal gland, an endocrine organ in the brain, synthesizes and secretes the circulating night hormone melatonin throughout the night. The literature states that this hormone is secreted by simple diffusion across the pinealocyte plasma membrane, but a direct quantitative measurement of membrane permeability has not been made. Experiments were designed to compare the cell membrane permeability to three indoleamines: melatonin and its precursors N-acetylserotonin (NAS) and serotonin (5-HT). The three experimental approaches were (1) to measure the concentration of effluxing indoleamines amperometrically in the bath while cells were being dialyzed internally by a patch pipette, (2) to measure the rise of intracellular indoleamine fluorescence as the compound was perfused in the bath, and (3) to measure the rate of quenching of intracellular fura-2 dye fluorescence as indoleamines were perfused in the bath. These measures showed that permeabilities of melatonin and NAS are high (both are uncharged molecules), whereas that for 5-HT (mostly charged) is much lower. Comparisons were made with predictions of solubility-diffusion theory and compounds of known permeability, and a diffusion model was made to simulate all of the measurements. In short, extracellular melatonin equilibrates with the cytoplasm in 3.5 s, has a membrane permeability of ∼1.7 µm/s, and could not be retained in secretory vesicles. Thus, it and NAS will be “secreted” from pineal cells by membrane diffusion. Circumstances are suggested when 5-HT and possibly catecholamines may also appear in the extracellular space passively by membrane diffusion. PMID:26712850

  9. Seasonal profiles of melatonin in adult rams.

    PubMed

    Sheikheldin, M A; Howland, B E; Palmer, W M

    1992-03-01

    The objective of this study was to investigate the seasonal changes in melatonin profiles based on frequently collected samples in adult rams maintained under simulated natural photoperiod. In a group of six rams, the seasonal changes of melatonin were characterized in samples collected at 10-min intervals for an equal period before and after the median of the scotophase during the spring (March) and the autumn (September) equinoxes, and also during the summer (June) and the winter (December) solstices. In an additional two rams, the rapid changes in melatonin concentrations were investigated in samples drawn at 2-min intervals for a 2-hr period before and after the median of the scotophase, but only during the summer and the winter solstices. The results show that in adult rams there is a distinct seasonal variation in the nightly rise of melatonin (P less than 0.01). Mean concentrations in June and September were higher than in March or December (P less than 0.05). There was no difference between the means in June or September. However, the means in March were lower than in December (P less than 0.05). Rapid changes in melatonin concentrations occurred in samples collected either at 10-min or 2-min intervals. In rams sampled at 2-min intervals, mean melatonin values in June were also higher than in December (P less than 0.01). The results suggest that there are distinct seasonal changes in melatonin concentrations in the ram and that rapid changes in melatonin concentrations reflect pulsatile secretion.

  10. Astrocyte-Secreted Factors Selectively Alter Neural Stem and Progenitor Cell Proliferation in the Fragile X Mouse.

    PubMed

    Sourial, Mary; Doering, Laurie C

    2016-01-01

    An increasing body of evidence indicates that astrocytes contribute to the governance and fine tuning of stem and progenitor cell production during brain development. The effect of astrocyte function in cell production in neurodevelopmental disorders is unknown. We used the Neural Colony Forming Cell assay to determine the effect of astrocyte conditioned media (ACM) on the generation of neurospheres originating from either progenitor cells or functional stem cells in the knock out (KO) Fragile X mouse model. ACM from both normal and Fmr1-KO mice generated higher percentages of smaller neurospheres indicative of restricted proliferation of the progenitor cell population in Fmr1-KO brains. Wild type (WT) neurospheres, but not KO neurospheres, showed enhanced responses to ACM from the Fmr1-KO mice. In particular, Fmr1-KO ACM increased the percentage of large neurospheres generated, representative of spheres produced from neural stem cells. We also used 2D DIGE to initiate identification of the astrocyte-secreted proteins with differential expression between Fmr1-KO and WT cortices and hippocampi. The results further support the critical role of astrocytes in governing neural cell production in brain development and point to significant alterations in neural cell proliferation due to astrocyte secreted factors from the Fragile X brain. • We studied the proliferation of neural stem and progenitor cells in Fragile X.• We examined the role of astrocyte-secreted factors in neural precursor cell biology.• Astrocyte-secreted factors with differential expression in Fragile X identified.

  11. Astrocyte-Secreted Factors Selectively Alter Neural Stem and Progenitor Cell Proliferation in the Fragile X Mouse

    PubMed Central

    Sourial, Mary; Doering, Laurie C.

    2016-01-01

    An increasing body of evidence indicates that astrocytes contribute to the governance and fine tuning of stem and progenitor cell production during brain development. The effect of astrocyte function in cell production in neurodevelopmental disorders is unknown. We used the Neural Colony Forming Cell assay to determine the effect of astrocyte conditioned media (ACM) on the generation of neurospheres originating from either progenitor cells or functional stem cells in the knock out (KO) Fragile X mouse model. ACM from both normal and Fmr1-KO mice generated higher percentages of smaller neurospheres indicative of restricted proliferation of the progenitor cell population in Fmr1-KO brains. Wild type (WT) neurospheres, but not KO neurospheres, showed enhanced responses to ACM from the Fmr1-KO mice. In particular, Fmr1-KO ACM increased the percentage of large neurospheres generated, representative of spheres produced from neural stem cells. We also used 2D DIGE to initiate identification of the astrocyte-secreted proteins with differential expression between Fmr1-KO and WT cortices and hippocampi. The results further support the critical role of astrocytes in governing neural cell production in brain development and point to significant alterations in neural cell proliferation due to astrocyte secreted factors from the Fragile X brain. Highlights: • We studied the proliferation of neural stem and progenitor cells in Fragile X. • We examined the role of astrocyte-secreted factors in neural precursor cell biology. • Astrocyte-secreted factors with differential expression in Fragile X identified. PMID:27242437

  12. Current role of melatonin in pediatric neurology: clinical recommendations.

    PubMed

    Bruni, Oliviero; Alonso-Alconada, Daniel; Besag, Frank; Biran, Valerie; Braam, Wiebe; Cortese, Samuele; Moavero, Romina; Parisi, Pasquale; Smits, Marcel; Van der Heijden, Kristiaan; Curatolo, Paolo

    2015-03-01

    Melatonin, an indoleamine secreted by the pineal gland, plays a key role in regulating circadian rhythm. It has chronobiotic, antioxidant, anti-inflammatory and free radical scavenging properties. A conference in Rome in 2014 aimed to establish consensus on the roles of melatonin in children and on treatment guidelines. The best evidence for efficacy is in sleep onset insomnia and delayed sleep phase syndrome. It is most effective when administered 3-5 h before physiological dim light melatonin onset. There is no evidence that extended-release melatonin confers advantage over immediate release. Many children with developmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and intellectual disability have sleep disturbance and can benefit from melatonin treatment. Melatonin decreases sleep onset latency and increases total sleep time but does not decrease night awakenings. Decreased CYP 1A2 activity, genetically determined or from concomitant medication, can slow metabolism, with loss of variation in melatonin level and loss of effect. Decreasing the dose can remedy this. Animal work and limited human data suggest that melatonin does not exacerbate seizures and might decrease them. Melatonin has been used successfully in treating headache. Animal work has confirmed a neuroprotective effect of melatonin, suggesting a role in minimising neuronal damage from birth asphyxia; results from human studies are awaited. Melatonin can also be of value in the performance of sleep EEGs and as sedation for brainstem auditory evoked potential assessments. No serious adverse effects of melatonin in humans have been identified. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  13. Melatonin, consciousness, and traumatic stress.

    PubMed

    Bob, Petr; Fedor-Freybergh, Peter

    2008-05-01

    Descartes intuitively anticipated the so-called 'binding problem' of consciousness and thought that the pineal gland enables spatio-temporal integration in cognitive processing. Recent findings indicate that a major role in the process of temporal integration and binding involve neurons in suprachiasmatic nuclei, specifically targeting the pineal gland and other structures, and control the neuroendocrine rhythms. Melatonin is an endocrine output signal of the clock and provides circadian information as an endogenous synchronizer which stabilizes and reinforces circadian rhythms. This integrative process occurs at the different levels of the circadian network via gene expression in some brain regions and peripheral structures that enables integration of circadian, hormonal, and metabolic information and creating temporal order of bodily and mental experience. This specific temporal order is reflected in associative sequentiality that is necessary for cognition, behavior and all processes of memory consolidation that must preserve all information in the temporal causal order and synchrony. In this context, recent findings suggest that melatonin could be a potential regulator in the processes that contribute to memory formation, long-term potentiation, and synaptic plasticity in the hippocampus and other brain regions. There is evidence that stress disrupts normal activity and memory consolidation in the hippocampus and prefrontal cortex, and this process leads to memories that are stored without a contextual or spatiotemporal frame. These findings emphasize a specific role of melatonin in mechanisms of consciousness, memory and stress and are also consistent with reported studies that indicate melatonin alterations under stressful conditions and in mental disorders.

  14. The Angiotensin-melatonin axis.

    PubMed

    Campos, Luciana A; Cipolla-Neto, Jose; Amaral, Fernanda G; Michelini, Lisete C; Bader, Michael; Baltatu, Ovidiu C

    2013-01-01

    Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies.

  15. Influence of altered CSF solute composition on parotid salivary secretion in goats.

    PubMed

    Olsson, K

    1976-06-01

    Infusions of hypertonic NaCl solution into the CSF of the lateral cerebral ventricle of the goat caused a marked reduction in parotid salivary flow concomitant with a rise in salivary [Na+]. Corresponding infusions of iso- or hypertonic glucose and glycerol solutions affected salivary secretion in the opposite direction. The possibility is discussed that a periventricular sodium-sensitive mechanism, which is of importance in the central control of fluid balance, also may participate in the regulation of parotid secretion in the goat. This interpretation of the results is to some extent obscured by the observation of a high incidence of intermittent rumination during the intraventricular infusions of glucose and glycerol solution.

  16. Melatonin attenuates methamphetamine-induced inhibition of neurogenesis in the adult mouse hippocampus: An in vivo study.

    PubMed

    Singhakumar, Rachen; Boontem, Parichart; Ekthuwapranee, Kasima; Sotthibundhu, Areechun; Mukda, Sujira; Chetsawang, Banthit; Govitrapong, Piyarat

    2015-10-08

    Methamphetamine (METH), a highly addictive psychostimulant drug, is known to exert neurotoxic effects to the dopaminergic neural system. Long-term METH administration impairs brain functions such as cognition, learning and memory. Newly born neurons in the dentate gyrus of the hippocampus play an important role in spatial learning and memory. Previous in vitro studies have shown that METH inhibits cell proliferation and neurogenesis in the hippocampus. On the other hand, melatonin, a major indole secreted by the pineal gland, enhances neurogenesis in both the subventricular zone and dentate gyrus. In this study, adult C57BL/6 mice were used to study the beneficial effects of melatonin on METH-induced alterations in neurogenesis and post-synaptic proteins related to learning and memory functions in the hippocampus. The results showed that METH caused a decrease in neuronal phenotypes as determined by the expressions of nestin, doublecortin (DCX) and beta-III tubulin while causing an increase in glial fibrillary acidic protein (GFAP) expression. Moreover, METH inhibited mitogen-activated protein kinase (MAPK) signaling activity and altered expression of the N-methyl-d-aspartate (NMDA) receptor subunits NR2A and NR2B as well as calcium/calmodulin-dependent protein kinase II (CaMKII). These effects could be attenuated by melatonin pretreatment. In conclusion, melatonin prevented the METH-induced reduction in neurogenesis, increase in astrogliogenesis and alteration of NMDA receptor subunit expression. These findings may indicate the beneficial effects of melatonin on the impairment of learning and memory caused by METH. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice.

    PubMed

    Windeløv, Johanne A; Pedersen, Jens; Holst, Jens J

    2016-06-01

    Evaluation of the impact of anesthesia on oral glucose tolerance in mice. Anesthesia is often used when performing OGTT in mice to avoid the stress of gavage and blood sampling, although anesthesia may influence gastrointestinal motility, blood glucose, and plasma insulin dynamics. C57Bl/6 mice were anesthetized using the following commonly used regimens: (1) hypnorm/midazolam repetitive or single injection; (2) ketamine/xylazine; (3) isoflurane; (4) pentobarbital; and (5) A saline injected, nonanesthetized group. Oral glucose was administered at time 0 min and blood glucose measured in the time frame -15 to +150 min. Plasma insulin concentration was measured at time 0 and 20 min. All four anesthetic regimens resulted in impaired glucose tolerance compared to saline/no anesthesia. (1) hypnorm/midazolam increased insulin concentrations and caused an altered glucose tolerance; (2) ketamine/xylazine lowered insulin responses and resulted in severe hyperglycemia throughout the experiment; (3) isoflurane did not only alter the insulin secretion but also resulted in severe hyperglycemia; (4) pentobarbital resulted in both increased insulin secretion and impaired glucose tolerance. All four anesthetic regimens altered the oral glucose tolerance, and we conclude that anesthesia should not be used when performing metabolic studies in mice.

  18. Interplay of transporters and enzymes in the Caco-2 cell monolayer: I. effect of altered apical secretion.

    PubMed

    Fan, Jianghong; Maeng, Han-Joo; Pang, K Sandy

    2010-05-01

    Interactions are expected between transporters and enzymes that compete for the substrate within the cell, and controversy exists for data interpretation on the interplay between transporters and enzymes. In the Caco-2 cell monolayer, the increase in mean residence time (MRT) of drug accompanying increased secretion has been construed as the reason for increased metabolism, whereas others hold an opposite view that increased secretion would evoke decreased metabolism in this closed system. A catenary Caco-2 cell model was used to simulate the effects of altered secretion on metabolism, estimated as the fraction of dose metabolized (f(met)) or the extraction ratio (ER). The simulations showed that both f(met) and ER varied inversely with the transporter-mediated intrinsic clearance for apical secretion (CL(int,sec)) under linear conditions. Under non-linear conditions of saturable metabolism, apical absorption, basolateral influx or efflux, the simulated f(met) consistently bore a reciprocal relationship with CL(int,sec). For saturable apical absorption or basolateral efflux, a reciprocal relationship between the ER and CL(int,sec) was also found. However, under conditions of saturable metabolism or basolateral influx, the pattern of change in the ER became dependent on the administration sites, showing increasing patterns for apical dosing but decreasing patterns for basolateral dosing with increasing values of CL(int,sec). In general, f(met) consistently demonstrated an inverse relationship with CL(int,sec), whereas ER, failing to include the drug in the donor side, would not show the same pattern of change in metabolism especially for apical dosing, since a substantial amount of drug was back-secreted into the apical compartment. Copyright (c) 2010 John Wiley & Sons, Ltd.

  19. [Melatonin as a regulator of human sleep and circadian systems].

    PubMed

    Mishima, Kazuo

    2012-07-01

    Melatonin(N-acetyl-5-methoxytryptamine) is synthesized from tryptophan and is intensively secreted into the blood only in darkness (nighttime) by the pineal gland. Melatonin is not only the most reliable marker of internal circadian phase but also a potent sleep-promoting and circadian phase regulatory agent in humans. There is evidence that daytime administered melatonin is able to exhibit short-acting hypnagogic effect and phase-shifting of the circadian rhythms such that sleep timing and associated various physiological functions realign at a new desired phase. Under favor of these properties, melatonin and melatonin receptor agonists have been shown to be potent therapeutic agents for the treatment of circadian rhythm sleep disorders and some type of insomnia.

  20. Melatonin and human reproduction: shedding light on the darkness hormone.

    PubMed

    Srinivasan, Venkatramanujam; Spence, Warren D; Pandi-Perumal, Seithikurippu R; Zakharia, Rahima; Bhatnagar, Kunwar P; Brzezinski, Amnon

    2009-12-01

    Melatonin, N-acetyl-5-methoxytryptamine, is a molecule with diverse physiological functions. This neuro-hormone affects reproductive performance in a wide variety of species. In most animals, but not exclusively all, melatonin has an antigonadotrophic effect. The seasonal changes in the number of hours per day that melatonin is secreted mediate the temporal coupling of reproductive activity to seasonal changes in day-length. These observations stimulated a search for a role for the pineal gland and melatonin in human reproduction. Clinical experience related to this issue has yielded inconclusive and sometimes conflicting results. This article reviews the current available evidence concerning the effects of melatonin on human reproductive processes (e.g., puberty, ovulation, pregnancy, and fertility). Possible reasons for the vagueness and elusiveness of the clinical effects are discussed.

  1. [Melatonin effects on the female genital system: a brief review].

    PubMed

    Maganhin, Carla C; Carbonel, Adriana Aparecida Ferraz; Hatty, Juliana Halley; Fuchs, Luiz Fernando Portugal; Oliveira-Júnior, Itamar Souza de; Simões, Manuel de Jesus; Simões, Ricardo S; Baracat, Edmund C; Soares-Jr, José Maria

    2008-01-01

    Melatonin is secreted by the pineal gland and this is linked to the day/night cycle. It is an antioxidant and plays a fundamental role in the regulation of the jet-lag stage, in several physiological reactions and in control of the biologic rhythm. Human melatonin has an important influence on the female genital system. In fact, melatonin may influence production and action of steroids, modifying cellular signalization on the target tissue. There are many evidences that the melatonin therapy may be interfering with neoplasia development, mainly of the estrogen-dependent tumor. This paper aims to analyze the actions of melatonin on the neuroendocrine, immunological and cardiovascular systems, as well as on the reproductive function.

  2. A melatonin-independent seasonal timer induces neuroendocrine refractoriness to short day lengths.

    PubMed

    Butler, Matthew P; Turner, Kevin W; Zucker, Irving

    2008-06-01

    The duration of nocturnal pineal melatonin secretion transduces effects of day length (DL) on the neuroendocrine axis of photoperiodic rodents. Long DLs support reproduction, and short DLs induce testicular regression, followed several months later by spontaneous recrudescence; gonadal regrowth is thought to reflect development of tissue refractoriness to melatonin. In most photoperiodic species, pinealectomy does not diminish reproductive competence in long DLs. Turkish hamsters (Mesocricetus brandti) deviate from this norm: elimination of melatonin secretion in long-day males by pinealectomy or constant light treatment induces testicular regression and subsequently recrudescence; the time course of these gonadal transitions is similar to that observed in males transferred from long to short DLs. In the present study, long-day Turkish hamsters that underwent testicular regression and recrudescence in constant light subsequently were completely unresponsive to the antigonadal effects of short DLs. Other hamsters that manifested testicular regression and recrudescence in short DLs were unresponsive to the antigonadal effects of pinealectomy or constant light. Long-term suppression of melatonin secretion induces a physiological state in Turkish hamsters similar or identical to the neuroendocrine refractoriness produced by short-day melatonin signals (i.e., neural refractoriness to melatonin develops in the absence of circulating melatonin secretion). A melatonin-independent interval timer, which would remain operative in the absence of melatonin during hibernation, may determine the onset of testicular recrudescence in the spring. In this respect, Turkish hamsters differ from most other photoperiodic rodents.

  3. A Melatonin-Independent Seasonal Timer Induces Neuroendocrine Refractoriness to Short Day Lengths

    PubMed Central

    Butler, Matthew P.; Turner, Kevin W.; Zucker, Irving

    2012-01-01

    The duration of nocturnal pineal melatonin secretion transduces effects of day length (DL) on the neuroendocrine axis of photoperiodic rodents. Long DLs support reproduction, and short DLs induce testicular regression, followed several months later by spontaneous recrudescence; gonadal regrowth is thought to reflect development of tissue refractoriness to melatonin. In most photoperiodic species, pinealectomy does not diminish reproductive competence in long DLs. Turkish hamsters (Mesocricetus brandti) deviate from this norm: elimination of melatonin secretion in long-day males by pinealectomy or constant light treatment induces testicular regression and subsequently recrudescence; the time course of these gonadal transitions is similar to that observed in males transferred from long to short DLs. In the present study, long-day Turkish hamsters that underwent testicular regression and recrudescence in constant light subsequently were completely unresponsive to the antigonadal effects of short DLs. Other hamsters that manifested testicular regression and recrudescence in short DLs were unresponsive to the antigonadal effects of pinealectomy or constant light. Long-term suppression of melatonin secretion induces a physiological state in Turkish hamsters similar or identical to the neuroendocrine refractoriness produced by short-day melatonin signals (i.e., neural refractoriness to melatonin develops in the absence of circulating melatonin secretion). A melatonin-independent interval timer, which would remain operative in the absence of melatonin during hibernation, may determine the onset of testicular recrudescence in the spring. In this respect, Turkish hamsters differ from most other photoperiodic rodents. PMID:18487416

  4. Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Delta-5 desaturase activity.

    PubMed

    Nishida, Shigeru; Segawa, Toshiko; Murai, Ichiro; Nakagawa, Shigeki

    2002-01-01

    The objective of this study was to investigate the effect of long-term melatonin administration on plasma levels of triglycerides, insulin and leptin, and on the fatty-acid metabolism of plasma and hepatic lipids in type 2 diabetic rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes mellitus, were divided into two groups: one untreated (n=6), and one implanted with time-releasing melatonin pellets (1.1 mg/day for 30 wk) under the abdominal skin (n=6). Age-matched Long-Evans Tokushima Otsuka (LETO) rats (n=6) were used as healthy controls. The untreated diabetic rats had the increased plasma levels of triglycerides, cholesterol, insulin and leptin at 35 wk, as compared with the healthy control rats (n=6). The diabetic rats also had augmented ratios of 20:3n-6/20:4n-6 fatty acids, owing to diminished activity of Delta-5 desaturase, an insulin-permissive enzyme, in the liver. Melatonin administration to OLETF rats reduced the hypertriglyceridemia (-39%, P < 0.05), hyperinsulinemia (-33%, P < 0.01) and hyperleptinemia (-43%, P < 0.01), and restored hepatic Delta-5 desaturase activity (148%, P < 0.005). This resulted in a return to normal ratios of 20:3n-6/20:4n-6 fatty acids in plasma and hepatic lipids. There was a significant correlation (r=0.64, P < 0.005) between plasma levels of insulin and the ratios of 20:3n-6/20:4n-6 in plasma phospholipids of all rats in the three groups. Thus, subcutaneous implantation of a melatonin-releasing pellet thus resulted in improved lipid metabolism in diabetic rats, probably through restored insulin resistance.

  5. Vasopressin release from the rat hypothalamo-neurohypophysial system: effects of gonadotrophin-releasing hormone (GnRH), its analogues and melatonin.

    PubMed

    Boczek-Leszczyk, E; Stempniak, B; Juszczak, M

    2010-08-01

    The influence of gonadotrophin-releasing hormone (GnRH) and its analogues (i.e., agonist and antagonist) on vasopressin (VP) release from the rat hypothalamo-neurohypophysial (H-N) system was studied both in vitro and in vivo. Additionally, it was determined whether the possible response of vasopressinergic neurones to these peptides could be modified by melatonin through a cAMP-dependent mechanism. In this study we demonstrate, for the first time, that the highly selective GnRH agonist (i.e., [Des-Gly(10),D-His(Bzl)(6),Pro-NHEt(9)]-LHRH; histrelin) stimulates the release of VP from the rat H-N system, while native GnRH and its antagonist remain inactive in modifying this process in vitro. Melatonin significantly inhibited basal and histrelin-induced release of VP in vitro, but displayed no significant influence on VP secretion when GnRH or its antagonist were present in a medium. Melatonin fully suppressed forskolin-stimulated VP release from the rat H-N system. On the other hand, addition of forskolin to a medium containing both histrelin and melatonin did not further alter the inhibitory influence of melatonin on the histrelin-dependent release of VP in vitro. After intracerebroventricular (i.c.v.) infusion of native GnRH or its agonist, blood plasma VP concentration was significantly higher than in control animals, which was accompanied by decreased content of the hormone in the neurohypophysis. Intravenous (i.v.) injection of melatonin did not change, in any subgroup, blood plasma VP concentration, when compared to the vehicle-injected rats. However, the neurohypophysial levels of the hormone were significantly higher after melatonin injection in control, GnRH- and histrelin-infused animals. Our present results suggest that activation of the GnRH receptor in the hypothalamus is involved in stimulation of VP secretion from the rat H-N system. We have also shown that melatonin, at a concentration close to its physiological level in the blood, significantly

  6. Storage Conditions and Passages Alter IL-6 secretion in C26 adenocarcinoma cell lines.

    PubMed

    Norden, Diana M; Devine, Raymond; McCarthy, Donna O; Wold, Loren E

    The C26 adenocarcinoma tumor line is frequently used to establish peripheral tumors in mice for the study of cancer cachexia and cancer-related fatigue. Recently, we have noticed a progressive decline in the effects of tumor growth on our biological and behavioral measures in the tumor-bearing mice. Therefore, we compared effects of three aliquots of the C26 tumor cell line that differed in storage condition and number of passages on cytokine secretion, tumor growth, weight loss and fatigue behavior. Three aliquots of the C26 tumor line were selected as alpha (α), beta (β), and gamma (γ). Aliquot α was an original C26 stock line that had been stored at -80°C. Aliquot β was stored in liquid nitrogen. Aliquot γ was taken from aliquot β and passaged three times. The three aliquots of the C26 tumor line showed differences in IL-6 mRNA and protein secretion in vitro, with aliquot β showing the greatest IL-6 secretion. These differences were mirrored in vivo. Plasma IL-6 levels were elevated in all tumor bearing mice but was greatest in group β mice. Carcass weight was decreased in all three tumor groups. Brain expression of IL-1β mRNA was greatest in group β and group β demonstrated the greatest decline in running activity at day 19. Storage conditions and number of passages influence C26 tumor cell secretion of cytokines.Variations in C26 aliquots may explain differences observed between laboratories using the same cell line.We recommend always storing cell lines in liquid nitrogen and limiting the number of passages before use in experiments.

  7. Amelioration of age-dependent increase in protein carbonyls of cerebral hemispheres of mice by melatonin and ascorbic acid.

    PubMed

    Dkhar, Preeticia; Sharma, Ramesh

    2011-12-01

    Melatonin secreted by the pineal gland acts as a free radical scavenger besides its role as a hormonal signaling agent. It detoxifies a variety of free radicals and reactive oxygen intermediates including hydroxyl radical, peroxynitrite anion and singlet oxygen. Ascorbic acid (Vitamin C), a water soluble vitamin, is a naturally occurring antioxidant and cofactor in various enzymes. Protein carbonyls are formed as a consequence of the oxidative modification of proteins by reactive oxygen species. Oxidative modification alters the function of protein and is thought to play an important role in the decline of cellular functions during aging. In the present study, the effect of melatonin and ascorbic acid on age-related carbonyl content of cerebral hemispheres in mice was investigated. Protein carbonyls of cerebral hemispheres have been found to be significantly higher in 18-month-old mice as compared to 1-month old mice. Administration of a single dose of melatonin (10 mg/kg body weight) and ascorbic acid (10 mg/kg body weight) intraperitoneally for three consecutive days decreases the carbonyl content in 1- and 18-month-old mice significantly. The present study thus suggests that the formation of protein carbonyls in the cerebral hemispheres of the aging mice can be prevented by the antioxidative effects of melatonin and ascorbic acid that could in turn be beneficial in having health benefits from age-related neurodegenerative diseases.

  8. Detection of melatonin production from the intestinal epithelium using electrochemical methods.

    PubMed

    Bertrand, Paul P; Polglaze, Kate E; Bertrand, Rebecca L; Sandow, Shaun L; Pozo, Maria J

    2014-01-01

    The role of melatonin in the gastrointestinal (GI) tract had previously been limited to its well-described anti-oxidant properties. Recent studies have, however, expanded the role of melatonin in the intestine, showing that it acts as a hormone with local paracrine actions to modulate GI function and the release of other hormones. The GI epithelium produces melatonin from the active precursor serotonin, which is thought to come from the serotonin synthesising enterochromaffin cells (EC). The receptors for melatonin, the membrane bound melatonin receptors 1 and 2, are present on some smooth muscles, neurons, and epithelium. Endogenous release of melatonin has been linked with secretory reflexes and the ileal brake reflex, while exogenous application of melatonin in pharmacological doses has been associated with reduced inflammation in a variety of animal models. Recent studies have begun to look at melatonin release from the GI epithelium using real-time electrochemical detection methods. Using these techniques, the time course of melatonin production shows similarities to that of 5-HT release while the ratio of 5-HT to melatonin is altered during aging. In addition, the effects of melatonin supplementation on the production of endogenous melatonin and its precursor serotonin are suppressed. In summary, the role of melatonin in the GI tract is coming of age. There are many studies showing a clear role for endogenously produced melatonin and clear effects of melatonin supplementation. Newly developed electrochemical techniques for exploring melatonin availability in real-time promise to accelerate our understanding of GI melatonin in the years to come.

  9. Melatonin production and light exposure of rotating night workers.

    PubMed

    Dumont, Marie; Lanctôt, Valérie; Cadieux-Viau, Raphaëlle; Paquet, Jean

    2012-03-01

    Decreased melatonin production, due to acute suppression of pineal melatonin secretion by light exposure during night work, has been suggested to underlie higher cancer risks associated with prolonged experience of night work. However, the association between light exposure and melatonin production has never been measured in the field. In this study, 24-h melatonin production and ambulatory light exposure were assessed during both night-shift and day/evening-shift periods in 13 full-time rotating shiftworkers. Melatonin production was estimated with the excretion of urinary 6-sulfatoxymelatonin (aMT6s), and light exposure was measured with an ambulatory photometer. There was no difference in total 24-h aMT6s excretion between the two work periods. The night-shift period was characterized by a desynchrony between melatonin and sleep-wake rhythms, as shown by higher melatonin production during work and lower melatonin production during sleep when working night shifts than when working day/evening shifts. Light exposure during night work showed no correlation with aMT6s excreted during the night of work (p > .5), or with the difference in 24-h aMT6s excretion between the two work periods (p > .1). However, light exposure during night work was negatively correlated with total 24-h aMT6s excretion over the entire night-shift period (p < .01). In conclusion, there was no evidence of direct melatonin suppression during night work in this population. However, higher levels of light exposure during night work may have decreased total melatonin production, possibly by initiating re-entrainment and causing internal desynchrony. This interpretation is consistent with the proposition that circadian disruption, of which decreased melatonin production is only one of the adverse consequences, could be the mediator between night shiftwork and cancer risks.

  10. Melatonin and melatonergic drugs on sleep: possible mechanisms of action.

    PubMed

    Srinivasan, Venkataramanujan; Pandi-Perumal, Seithikurippu R; Trahkt, Ilya; Spence, D Warren; Poeggeler, Burkhard; Hardeland, Ruediger; Cardinali, Daniel P

    2009-01-01

    Pineal melatonin is synthesized and secreted in close association with the light/dark cycle. The temporal relationship between the nocturnal rise in melatonin secretion and the "opening of the sleep gate" (i.e., the increase in sleep propensity at the beginning of the night), coupled with the sleep-promoting effects of exogenous melatonin, suggest that melatonin is involved in the regulation of sleep. The sleep-promoting and sleep/wake rhythm regulating effects of melatonin are attributed to its action on MT(1) and MT(2) melatonin receptors present in the suprachiasmatic nucleus (SCN) of the hypothalamus. Animal experiments carried out in rats, cats, and monkeys have revealed that melatonin has the ability to reduce sleep onset time and increase sleep duration. However, clinical studies reveal inconsistent findings, with some of them reporting beneficial effects of melatonin on sleep, whereas in others only marginal effects are documented. Recently a prolonged-release 2-mg melatonin preparation (Circadin(TM)) was approved by the European Medicines Agency as a monotherapy for the short-term treatment of primary insomnia in patients who are aged 55 or above. Several melatonin derivatives have been shown to increase nonrapid eye movement (NREM) in rats and are of potential pharmacological importance. So far only one of these melatonin derivatives, ramelteon, has received approval from the U.S. Food and Drug Administration to be used as a sleep promoter. Ramelteon is a novel MT(1) and MT(2) melatonergic agonist that has specific effects on melatonin receptors in the SCN and is effective in promoting sleep in experimental animals such as cats and monkeys. In clinical trials, ramelteon reduced sleep onset latency and promoted sleep in patients with chronic insomnia, including an older adult population. Both melatonin and ramelteon promote sleep by regulating the sleep/wake rhythm through their actions on melatonin receptors in the SCN, a unique mechanism of action not

  11. Melatonin for sleep problems in children with neurodevelopmental disorders.

    PubMed

    2015-10-01

    Children with neurodevelopmental disorders are at risk of sleep problems, typically difficulty getting to sleep, sleep/wake rhythm disturbances and reduced duration of sleep (insomnia). This may be associated with abnormally timed or inadequate secretion of melatonin, a naturally-occurring hormone involved in coordinating the body's sleep-wake cycle. Previously, we reviewed the use of a melatonin product licensed for primary insomnia in adults aged over 55 years. Here we review off-label and unlicensed use of melatonin in children with attention-deficit hyperactivity disorder (ADHD) or autism spectrum disorder or related neurodevelopmental disorders.

  12. Metabolic syndrome, its pathophysiology and the role of melatonin.

    PubMed

    Srinivasan, Venkataramanujam; Ohta, Yoshiji; Espino, Javier; Pariente, Jose A; Rodriguez, Ana B; Mohamed, Mahaneem; Zakaria, Rahimah

    2013-01-01

    Metabolic syndrome (MetS) is characterised by symptoms of obesity, insulin resistance, hypertension, dyslipidemia and diabetes mellitus. The pathophysiological mechanisms involved in MetS are complex and involved dysregulation of many biochemical and physiological regulatory mechanisms of the body. Elevated levels of low density lipoproteins like VLDL, and LDL with reduction of HDL seen in patients with MetS contribute to atherogenic dyslipedemia. Melatonin has been suggested to be effective in improving MetS through its anti-hyperlipidemic action. Melatonin reduced both adiposity, and body weight in experimental animal studies and also attenuated weight gain and obesityinduced metabolic alterations and this effect of melatonin is attributed to its anti-oxidative effects. Melatonin administration has been shown to inhibit insulin release by acting through both MT1 and MT2 melatonin receptors present in pancreatic β-cells. Melatonin also increased insulin sensitivity and glucose tolerance in animals fed with either high fat or high sucrose diet. Melatonin exerts most of its beneficial actions by acting through MT1 and MT2 melatonin receptors present in various tissues of the body and some of the metabolic actions of melatonin have been blocked by melatonin antagonist like luzindole. Ramelteon, the newly available melatonin agonist will also have more promising role in the control of MetS. The numbers of patents are available with regard to treatment of MetS. Drug related to antidepressant fluoxetine is used for treatment of MetS (US Patent No. 2008001400450). Anti-oxidants like S-adenosyl-methionine, Vitamin E, and Vitamin C have been found beneficial in treating MetS (US Patent No. 8063024). Melatonin being a powerful Antioxidant will have a promising role in treating patients with metabolic syndrome.

  13. Antiinflammatory Activity of Melatonin in Central Nervous System

    PubMed Central

    Esposito, Emanuela; Cuzzocrea, Salvatore

    2010-01-01

    Melatonin is mainly produced in the mammalian pineal gland during the dark phase. Its secretion from the pineal gland has been classically associated with circadian and circanual rhythm regulation. However, melatonin production is not confined exclusively to the pineal gland, but other tissues including retina, Harderian glands, gut, ovary, testes, bone marrow and lens also produce it. Several studies have shown that melatonin reduces chronic and acute inflammation. The immunomodulatory properties of melatonin are well known; it acts on the immune system by regulating cytokine production of immunocompetent cells. Experimental and clinical data showing that melatonin reduces adhesion molecules and pro-inflammatory cytokines and modifies serum inflammatory parameters. As a consequence, melatonin improves the clinical course of illnesses which have an inflammatory etiology. Moreover, experimental evidence supports its actions as a direct and indirect antioxidant, scavenging free radicals, stimulating antioxidant enzymes, enhancing the activities of other antioxidants or protecting other antioxidant enzymes from oxidative damage. Several encouraging clinical studies suggest that melatonin is a neuroprotective molecule in neurodegenerative disorders where brain oxidative damage has been implicated as a common link. In this review, the authors examine the effect of melatonin on several neurological diseases with inflammatory components, including dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, stroke, and brain ischemia/reperfusion but also in traumatic CNS injuries (traumatic brain and spinal cord injury) PMID:21358973

  14. The profile of melatonin production in tumour-bearing rats.

    PubMed

    Ferreira, Ana Carolina Franco; Martins, Eivor; Afeche, Solange Castro; Cipolla-Neto, José; Costa Rosa, Luís Fernando Bicudo Pereira

    2004-09-24

    The pineal gland is involved in the regulation of tumour growth through the anticancer activity of melatonin, which presents immunomodulatory, anti-proliferative and anti-oxidant effects. In this study we measured melatonin content directly in the pineal gland, in an attempt to clarify the modulation of pineal melatonin secretory activity during tumour growth. Different groups of Walker 256 carcinosarcoma bearing rats were sacrificed at 12 different time points during 24h (12h:12h light/dark cycle) on different days during the tumour development (on the first, seventh and fourteenth day after tumour inoculation). Melatonin content in the pineal gland was determined by high-performance liquid chromatography with electrochemical detection. During tumour development the amount of melatonin secreted increased from 310.9 ng/mg of protein per day from control animals, to 918.1 ng/mg of protein per day 14 days after tumour implantation, and there were changes in the pineal production profile of melatonin. Cultured pineal glands obtained from tumour-bearing rats turned out to be less responsive to noradrenaline, suggesting the existence, in vivo, of putative factor(s) modulating pineal melatonin production. The results demonstrated that during tumour development there is a modification of pineal melatonin production daily profile, possibly contributing to cachexia, associated to changes in pineal gland response to noradrenaline stimulation.

  15. Inflammaging, Metabolic Syndrome and Melatonin: A Call for Treatment Studies.

    PubMed

    Cardinali, Daniel P; Hardeland, Rüdiger

    2016-05-11

    The metabolic syndrome (MS) is a collection of risk factors for cardiovascular disease, including obesity, hypertension, hyperinsulinemia, glucose intolerance and dyslipidemia. MS is associated with low-grade inflammation of the white adipose tissue, which can subsequently lead to insulin resistance, impaired glucose tolerance and diabetes. Adipocytes secrete proinflammatory cytokines as well as leptin and trigger a vicious circle which leads to additional weight gain largely as fat. The imbalance between inflammatory and anti-inflammatory signals is crucial to aging. Healthy aging can benefit from melatonin, a compound known to possess direct and indirect antioxidant properties, to have a significant protective effect on mitochondrial function, to enhance circadian rhythm amplitudes, to modulate the immune system and to exhibit neuroprotective actions. Melatonin levels decrease in the course of senescence and are more strongly reduced in diseases related to insulin resistance. This short review article analyzes the multiple protective actions of melatonin that are relevant to the attenuation of inflammatory responses and progression of inflammaging and how melatonin is effective to curtail MS in animal models of hyperadiposity. The clinical data supporting the possible therapeutical use of melatonin in human MS are also reviewed. Since attention has been focused on the development of potent melatonin analogs with prolonged effects (ramelteon, agomelatine, tasimelteon, piromelatine) and in clinical trials these analogs were administered in doses considerably higher than those usually employed for melatonin, clinical trials on melatonin in the range of 50-100 mg/day are needed to further assess its therapeutic value in MS.

  16. [Melatonin production in hypertensive patients].

    PubMed

    Rapoport, S I; Shatalova, A M; Malinovskaia, N K; Vettenberg, L

    2000-01-01

    Hypertensive subjects were examined for production of melatonin. In severe hypertension night levels of melatonin diminished, the day production is as in the controls. The role of melatonin in pathogenesis of essential hypertension is discussed.

  17. A critical assessment of the melatonin effect on sleep in humans.

    PubMed

    Monti, J M; Cardinali, D P

    2000-01-01

    Melatonin is synthesized and secreted during the dark period of the light-dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock, located in mammals within the suprachiasmatic nucleus (SCN), and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system that can 'read' the message. In addition, direct effects of the hormone on the SCN could explain some of the melatonin effects on the circadian system. Duration of the melatonin nocturnal secretion is directly proportional to the length of the night and it has experimentally been demonstrated to be the critical parameter for photoperiod integration. The sites and mechanisms of action of melatonin for circadian and photoperiodic responses are far from being elucidated, but action through specific membrane receptor sites starts to emerge. A possible bicompartmental model of distribution for melatonin, the first compartment in plasma acting on peripheral organs and the second in the cerebrospinal fluid affecting neurally mediated functions at a much higher concentration, has recently been proposed. From earlier studies it was concluded that melatonin administration to humans reduces sleep latency and induces sleepiness and fatigue. More recently, the effect of lower pharmacologic or physiologic doses of melatonin was examined in different laboratories. These studies included young normal volunteers and patients with chronic insomnia, as well as dementia patients exhibiting sundowning syndrome. Irrespective of the method of assessment, melatonin showed effects in insomniac patients in most studies. With some exceptions, melatonin administration reduced sleep latency and/or increased total sleep time and sleep efficiency. Furthermore, melatonin was more effective when given to elderly insomniacs, or Alzheimer disease patients, although sleep improvement was not strictly correlated with prior

  18. Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors

    PubMed Central

    Renzi, Anastasia; Glaser, Shannon; DeMorrow, Sharon; Mancinelli, Romina; Meng, Fanyin; Franchitto, Antonio; Venter, Julie; White, Mellanie; Francis, Heather; Han, Yuyan; Alvaro, Domenico; Gaudio, Eugenio; Carpino, Guido; Ueno, Yoshiyuki; Onori, Paolo

    2011-01-01

    In bile duct-ligated (BDL) rats, large cholangiocytes proliferate by activation of cAMP-dependent signaling. Melatonin, which is secreted from pineal gland as well as extrapineal tissues, regulates cell mitosis by interacting with melatonin receptors (MT1 and MT2) modulating cAMP and clock genes. In the liver, melatonin suppresses oxidative damage and ameliorates fibrosis. No information exists regarding the role of melatonin in the regulation of biliary hyperplasia. We evaluated the mechanisms of action by which melatonin regulates the growth of cholangiocytes. In normal and BDL rats, we determined the hepatic distribution of MT1, MT2, and the clock genes, CLOCK, BMAL1, CRY1, and PER1. Normal and BDL (immediately after BDL) rats were treated in vivo with melatonin before evaluating 1) serum levels of melatonin, bilirubin, and transaminases; 2) intrahepatic bile duct mass (IBDM) in liver sections; and 3) the expression of MT1 and MT2, clock genes, and PKA phosphorylation. In vitro, large cholangiocytes were stimulated with melatonin in the absence/presence of luzindole (MT1/MT2 antagonist) and 4-phenyl-2-propionamidotetralin (MT2 antagonist) before evaluating cell proliferation, cAMP levels, and PKA phosphorylation. Cholangiocytes express MT1 and MT2, CLOCK, BMAL1, CRY1, and PER1 that were all upregulated following BDL. Administration of melatonin to BDL rats decreased IBDM, serum bilirubin and transaminases levels, the expression of all clock genes, cAMP levels, and PKA phosphorylation in cholangiocytes. In vitro, melatonin decreased the proliferation, cAMP levels, and PKA phosphorylation, decreases that were blocked by luzindole. Melatonin may be important in the management of biliary hyperplasia in human cholangiopathies. PMID:21757639

  19. TNF-α alters the inflammatory secretion profile of human first trimester placenta.

    PubMed

    Siwetz, Monika; Blaschitz, Astrid; El-Heliebi, Amin; Hiden, Ursula; Desoye, Gernot; Huppertz, Berthold; Gauster, Martin

    2016-04-01

    Implantation and subsequent placental development depend on a well-orchestrated interaction between fetal and maternal tissues, involving a fine balanced synergistic cross-talk of inflammatory and immune-modulating factors. Tumor necrosis factor (TNF)-α has been increasingly recognized as pivotal factor for successful pregnancy, although high maternal TNF-α levels are associated with a number of adverse pregnancy conditions including gestational hypertension and gestational diabetes mellitus. This study describes effects of exogenously applied TNF-α, mimicking increased maternal TNF-α levels, on the secretion profile of inflammation associated factors in human first trimester villous placenta. Conditioned culture media from first trimester villous placental explants were analyzed by inflammation antibody arrays and ELISA after 48 h culture in the presence or absence of TNF-α. Inflammation antibody arrays identified interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 2 (CCL2), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most abundantly secreted inflammation-associated factors under basal culture conditions. In the presence of TNF-α, secretion of GM-CSF, CCL5, and IL-10 increased, whereas IL-4 and macrophage CSF levels decreased compared with controls. ELISA analysis verified antibody arrays by showing significantly increased synthesis and release of GM-CSF and CCL5 by placental explants in response to TNF-α. Immunohistochemistry localized GM-CSF in the villous trophoblast compartment, whereas CCL5 was detected in maternal platelets adhering to perivillous fibrin deposits on the villous surface. mRNA-based in situ padlock probe approach localized GM-CSF and CCL5 transcripts in the villous trophoblast layer and the villous stroma. Results from this study suggest that the inflammatory secretion profile of human first trimester placenta shifts towards increased levels of GM-CSF, CCL5, and IL10 in response to elevated maternal

  20. Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

    PubMed Central

    Anderson, R J; Cronin, R E; McDonald, K M; Schrier, R W

    1976-01-01

    Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal

  1. Beneficial effect of melatonin treatment on age-related insulin resistance and on the development of type 2 diabetes.

    PubMed

    Tresguerres, Jesus A F; Cuesta, Sara; Kireev, Roman A; Garcia, Cruz; Acuña-Castroviejo, Dario; Vara, Elena

    2013-12-01

    Abstract This paper will review the effect of aging on glucose metabolism and insulin resistance in pancreas and in peripheral tissues and how melatonin administration could affect these parameters. In SAMP8 mice insulin levels in plasma were found to be increased together with enhanced HOMA-IR values, whereas insulin content in pancreas showed a decrease with aging. Aging in SAMP8 mice was also associated with a significant increase in the relative expression of both protein and mRNA of different pro-inflammatory mediators. Furthermore, aging was associated with a decrease in the expression of Pdx-1, FoxO 1 and FoxO 3A and Sirt 1 in pancreas SAMP8 samples. Melatonin administration was able to reduce these age-related alterations, decreasing plasma insulin levels and increasing its pancreatic content in SAMP8 mice. HOMA-IR was decreased with melatonin treatment in all animals. Conversely, in SAMP8 mice, melatonin treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin. Furthermore it was also able to increase the expression of Sirt 1, Pdx-1 and FoxO 3A. The present study has shown that aging is associated with significant alterations in the relative expression of pancreatic genes involved in both insulin secretion and glucose metabolism and that these are associated with an increase in inflammation and oxidative stress. Melatonin administration was able to reduce oxidative stress and inflammation and thus to improve pancreatic function in old mice. By doing so, insulin resistance is diminished and plasma insulin is reduced, enhancing insulin pancreatic content and reducing plasma glucose levels and HOMA index.

  2. Role of melatonin on diabetes-related metabolic disorders

    PubMed Central

    Espino, Javier; Pariente, José A; Rodríguez, Ana B

    2011-01-01

    Melatonin is a circulating hormone that is mainly released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms, its levels being high during the night and low during the day. Interestingly, insulin levels are also adapted to day/night changes through melatonin-dependent synchronization. This regulation may be explained by the inhibiting action of melatonin on insulin release, which is transmitted through both the pertussis-toxin-sensitive membrane receptors MT1 and MT2 and the second messengers 3’,5’-cyclic adenosine monophosphate, 3’,5’-cyclic guanosine monophosphate and inositol 1,4,5-trisphosphate. Melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion, but also by providing protection against reactive oxygen species, since pancreatic β-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. On the other hand, in several genetic association studies, single nucleotide polymorphysms of the human MT2 receptor have been described as being causally linked to an elevated risk of developing type 2 diabetes. This suggests that these individuals may be more sensitive to the actions of melatonin, thereby leading to impaired insulin secretion. Therefore, blocking the melatonin-induced inhibition of insulin secretion may be a novel therapeutic avenue for type 2 diabetes. PMID:21860691

  3. Melatonin Attenuates Colistin-Induced Nephrotoxicity in Rats▿

    PubMed Central

    Yousef, Jumana M.; Chen, Gong; Hill, Prue A.; Nation, Roger L.; Li, Jian

    2011-01-01

    Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n = 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-β-d-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P < 0.0001). Plasma creatinine increased significantly (P = 0.023) only in the colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic. PMID:21709095

  4. Ethanol consumption and pineal melatonin daily profile in rats.

    PubMed

    Peres, Rafael; do Amaral, Fernanda Gaspar; Madrigrano, Thiago Cardoso; Scialfa, Julieta Helena; Bordin, Silvana; Afeche, Solange Castro; Cipolla-Neto, José

    2011-10-01

    It is well known that melatonin participates in the regulation of many important physiological functions such as sleep-wakefulness cycle, motor coordination and neural plasticity, and cognition. However, as there are contradictory results regarding the melatonin production diurnal profile under alcohol consumption, the aim of this paper was to study the phenomenology and mechanisms of the putative modifications on the daily profile of melatonin production in rats submitted to chronic alcohol intake. The present results show that rats receiving 10% ethanol in drinking water for 35 days display an altered daily profile of melatonin production, with a phase delay and a reduction in the nocturnal peak. This can be partially explained by a loss of the daily rhythm and the 25% reduction in tryptophan hydroxylase activity and, mainly, by a phase delay in arylalkylamine N-acetyltransferase gene expression and a 70% reduction in its peak activity. Upstream in the melatonin synthesis pathway, the results showed that noradrenergic signaling is impaired as well, with a decrease in β1 and α1 adrenergic receptors' mRNA contents and in vitro sustained loss of noradrenergic-stimulated melatonin production by glands from alcohol-treated rats. Together, these results confirm the alterations in the daily melatonin profile of alcoholic rats and suggest the possible mechanisms for the observed melatonin synthesis modification. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.

  5. Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland

    PubMed Central

    Torres-Farfan, Claudia; Valenzuela, Francisco J; Mondaca, Mauricio; Valenzuela, Guillermo J; Krause, Bernardo; Herrera, Emilio A; Riquelme, Raquel; Llanos, Anibal J; Seron-Ferre, Maria

    2008-01-01

    Although the fetal pineal gland does not secrete melatonin, the fetus is exposed to melatonin of maternal origin. In the non-human primate fetus, melatonin acts as a trophic hormone for the adrenal gland, stimulating growth while restraining cortisol production. This latter physiological activity led us to hypothesize that melatonin may influence some fetal functions critical for neonatal adaptation to extrauterine life. To test this hypothesis we explored (i) the presence of G-protein-coupled melatonin binding sites and (ii) the direct modulatory effects of melatonin on noradrenaline (norepinephrine)-induced middle cerebral artery (MCA) contraction, brown adipose tissue (BAT) lypolysis and ACTH-induced adrenal cortisol production in fetal sheep. We found that melatonin directly inhibits the response to noradrenaline in the MCA and BAT, and also inhibits the response to ACTH in the adrenal gland. Melatonin inhibition was reversed by the melatonin antagonist luzindole only in the fetal adrenal. MCA, BAT and adrenal tissue displayed specific high-affinity melatonin binding sites coupled to G-protein (Kd values: MCA 64 ± 1 pm, BAT 98.44 ± 2.12 pm and adrenal 4.123 ± 3.22 pm). Melatonin binding was displaced by luzindole only in the adrenal gland, supporting the idea that action in the MCA and BAT is mediated by different melatonin receptors. These direct inhibitory responses to melatonin support a role for melatonin in fetal physiology, which we propose prevents major contraction of cerebral vessels, restrains cortisol release and restricts BAT lypolysis during fetal life. PMID:18599539

  6. Systemic alteration of cell-surface and secreted glycoprotein expression in malignant breast cancer cell lines.

    PubMed

    Timpe, Leslie C; Yen, Roger; Haste, Nicole V; Litsakos-Cheung, Christina; Yen, Ten-Yang; Macher, Bruce A

    2013-11-01

    Breast cancer cell lines express fewer transmembrane and secreted glycoproteins than nonmalignant ones. The objective of these experiments was to characterize the changes in the expression of several hundred glycoproteins quantitatively. Secreted and cell-surface glycoproteins were isolated using a glycoprotein capture protocol and then identified by tandem mass spectrometry. Glycoproteins expressed by a group of cell lines originating from malignant tumors of the breast were compared with those expressed by a nonmalignant set. The average number of spectral counts (proportional to relative protein abundance) and the total number of glycopeptides in the malignant samples were reduced to about two-thirds of the level in the nonmalignant samples. Most glycoproteins were expressed at a different level in the malignant samples, with nearly as many increasing as decreasing. The glycoproteins with reduced expression accounted for a larger change in spectral counts, and hence for the net loss of spectral counts in the malignant lines. Similar results were found when the glycoproteins were studied via identified glycosylation sites only, or through identified sites together with non-glycopeptides. The overall reduction is largely due to the loss of integrins, laminins and other proteins that form or interact with the basement membrane.

  7. Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth

    PubMed Central

    Han, Yuyan; DeMorrow, Sharon; Invernizzi, Pietro; Jing, Qing; Glaser, Shannon; Renzi, Anastasia; Meng, Fanyin; Venter, Julie; Bernuzzi, Francesca; White, Mellanie; Francis, Heather; Lleo, Ana; Marzioni, Marco; Onori, Paolo; Alvaro, Domenico; Torzilli, Guido; Gaudio, Eugenio

    2011-01-01

    Cholangiocarcinoma (CCA) is a devastating biliary cancer. Melatonin is synthesized in the pineal gland and peripheral organs from serotonin by two enzymes, serotonin N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT). Cholangiocytes secrete neuroendocrine factors, including serotonin-regulating CCA growth by autocrine mechanisms. Melatonin exerts its effects by interaction with melatonin receptor type 1A/1B (MT1/MT2) receptors. We propose that 1) in CCA, there is decreased expression of AANAT and ASMT and secretion of melatonin, changes that stimulate CCA growth; and 2) in vitro overexpression of AANAT decreases CCA growth. We evaluated the 1) expression of AANAT, ASMT, melatonin, and MT1/MT2 in human nonmalignant and CCA lines and control and CCA biopsy samples; 2) melatonin levels in nonmalignant and CCA lines, and bile and serum from controls and patients with intrahepatic CCA; 3) effect of melatonin on the growth and expression of AANAT/ASMT and MT1/MT2 in CCA lines implanted into nude mice; and 4) effect of AANAT overexpression on the proliferation, apoptosis, and expression of MT1/MT2 in Mz-ChA-1 cells. The expression of AANAT, ASMT, and melatonin decreased, whereas MT1/MT2 expression increased in CCA lines and biopsy samples. Melatonin secretion decreased in the supernatant of CCA lines and bile of CCA patients. Melatonin decreased xenograft CCA tumor growth in nude mice by increased AANAT/ASMT and melatonin, along with reduced MT1/MT2 expression. Overexpression of AANAT in Mz-ChA-1 cells inhibited proliferation and MT1/MT2 expression and increased apoptosis. There is dysregulation of the AANAT/ASMT/melatoninmelatonin receptor axis in CCA, which inhibited melatonin secretion and subsequently enhanced CCA growth. PMID:21778461

  8. Melatonin agonists and insomnia.

    PubMed

    Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew

    2010-02-01

    The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

  9. Inhibition of cyclophilins alters lipid trafficking and blocks hepatitis C virus secretion

    PubMed Central

    2011-01-01

    Host cyclophilin (cyp) inhibitors, such as NIM811, efficiently inhibit replication of hepatitis C virus (HCV) and have shown significant promise in recent clinical trials for the treatment of chronic HCV. It is therefore important to fully understand the mechanism of action of these therapeutic agents. Data obtained from comprehensive systems biology approaches have led to the hypothesis that the antiviral activity of cyclophilin inhibitors is mediated through impairing the cellular machinery on which HCV relies to traffic cofactors necessary for formation of the replication complex. Indeed, our results demonstrate when cyclophilins are inhibited by NIM811, lipid and protein trafficking within the VLDL pathway is impaired. Following treatment of replicon or HCV infected cells with NIM811, intracellular lipid droplets (LD) more than double in size and decrease in number. Changes in the LDs in response to cyclophilin inhibition are dependent upon expression of viral proteins. Additionally, in cells treated with NIM811, apoB accumulates in a crescent or ring shaped structure surrounding the enlarged LDs and is no longer secreted. Silencing of cypA or cyp40 using siRNA had a similar effect on LD size and apoB localization as compound treatment, suggesting these cyclophilins may play an important role in lipid and apoB trafficking. Interestingly, the decrease in apoB secretion correlates with a decrease in release of viral particles in HCV infected cells. Altogether, these results add a new level of complexity to the mechanism of action of cyclophilin inhibition, and suggest the role for cyclophilins in the virus life cycle extends beyond replication to virus release. PMID:21711559

  10. Inhibition of cyclophilins alters lipid trafficking and blocks hepatitis C virus secretion.

    PubMed

    Anderson, Leah J; Lin, Kai; Compton, Teresa; Wiedmann, Brigitte

    2011-06-28

    Host cyclophilin (cyp) inhibitors, such as NIM811, efficiently inhibit replication of hepatitis C virus (HCV) and have shown significant promise in recent clinical trials for the treatment of chronic HCV. It is therefore important to fully understand the mechanism of action of these therapeutic agents. Data obtained from comprehensive systems biology approaches have led to the hypothesis that the antiviral activity of cyclophilin inhibitors is mediated through impairing the cellular machinery on which HCV relies to traffic cofactors necessary for formation of the replication complex. Indeed, our results demonstrate when cyclophilins are inhibited by NIM811, lipid and protein trafficking within the VLDL pathway is impaired. Following treatment of replicon or HCV infected cells with NIM811, intracellular lipid droplets (LD) more than double in size and decrease in number. Changes in the LDs in response to cyclophilin inhibition are dependent upon expression of viral proteins. Additionally, in cells treated with NIM811, apoB accumulates in a crescent or ring shaped structure surrounding the enlarged LDs and is no longer secreted. Silencing of cypA or cyp40 using siRNA had a similar effect on LD size and apoB localization as compound treatment, suggesting these cyclophilins may play an important role in lipid and apoB trafficking. Interestingly, the decrease in apoB secretion correlates with a decrease in release of viral particles in HCV infected cells. Altogether, these results add a new level of complexity to the mechanism of action of cyclophilin inhibition, and suggest the role for cyclophilins in the virus life cycle extends beyond replication to virus release.

  11. Jet lag: therapeutic use of melatonin and possible application of melatonin analogs.

    PubMed

    Srinivasan, Venkataramanujan; Spence, D Warren; Pandi-Perumal, Seithikurippu R; Trakht, Ilya; Cardinali, Daniel P

    2008-01-01

    Each year millions of travelers undertake long distance flights over one or more continents. These multiple time zone flights produce a constellation of symptoms known as jet lag. Familiar to almost every intercontinental traveler is the experience of fatigue upon arrival in a new time zone, but almost as problematic are a number of other jet lag symptoms. These include reduced alertness, nighttime insomnia, loss of appetite, depressed mood, poor psychomotor coordination and reduced cognitive skills, all symptoms which are closely affected by both the length and direction of travel. The most important jet lag symptoms are due to disruptions to the body's sleep/wake cycle. Clinical and pathophysiological studies also indicate that jet lag can exacerbate existing affective disorders. It has been suggested that dysregulation of melatonin secretion and occurrence of circadian rhythm disturbances may be the common links which underlie jet lag and affective disorders. Largely because of its regulatory effects on the circadian system, melatonin has proven to be highly effective for treating the range of symptoms that accompany transmeridian air travel. Additionally, it has been found to be of value in treating mood disorders like seasonal affective disorder. Melatonin acts on MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body's master circadian clock. Melatonin resets disturbed circadian rhythms and promotes sleep in jet lag and other circadian rhythm sleep disorders, including delayed sleep phase syndrome and shift-work disorder. Although post-flight melatonin administration works efficiently in transmeridian flights across less than 7-8 times zones, in the case longer distances, melatonin should be given by 2-3 days in advance to the flight. To deal with the unwanted side effects which usually accompany this pre-departure treatment (acute soporific and sedative effects in times that may not be wanted), the

  12. Melatonin, But not auxin, affects postnatal reproductive development in the marsh rice rat (Oryzomys palustris).

    PubMed

    Edmonds, Kent E

    2013-06-01

    Melatonin and the plant hormone auxin (indole-3-acetic acid) have some structural similarity and, may thus exert comparable physiological effects on reproduction and growth. To test this possibility, I examined the effects of melatonin and auxin administration on reproductive and non-reproductive organ development in an animal model, the marsh rice rat Oryzomys palustris. Juvenile males housed under 14L:10D conditions were injected daily for four weeks with saline, melatonin, auxin, or melatonin and auxin, and the development of the testes and other organs was assessed. Melatonin alone significantly inhibited the development of the testes, seminal vesicles, Harderian glands, and overall somatic growth, but not the spleen. Auxin did not affect any endpoint measured. When melatonin was administered simultaneously with auxin, the melatonin effects dominated in suppressing reproduction and growth. The administration of melatonin or auxin in the drinking water produced results similar to the effects of melatonin and auxin injections reported herein. Lastly, both melatonin and auxin in the drinking water failed to alter any short photoperiod-induced reproductive inhibition. These data suggest that structural similarities between melatonin and auxin do not result in similar postnatal effects on reproductive and non-reproductive organ development on a long photoperiod and further suggest that melatonin and auxin do not operate through a common physiological mechanism.

  13. Evidence of melatonin synthesis in the ram reproductive tract.

    PubMed

    Gonzalez-Arto, M; Hamilton, T R dos S; Gallego, M; Gaspar-Torrubia, E; Aguilar, D; Serrano-Blesa, E; Abecia, J A; Pérez-Pé, R; Muiño-Blanco, T; Cebrián-Pérez, J A; Casao, A

    2016-01-01

    Melatonin is a ubiquitous molecule found in a wide range of fluids, one of them being ram seminal plasma, in which it can reach higher concentrations than those found in blood, suggesting an extrapineal secretion by the reproductive tract. In order to identify the source of the melatonin found in ram seminal plasma, we first tried to determine whether the melatonin levels were maintained during the day. For this purpose, melatonin concentrations were measured in seminal plasma obtained from first ejaculates of six rams at 6:00 a.m. in total darkness, at 10:00 a.m. and at 14:00 p.m. The melatonin concentration was higher (p < 0.05) in ejaculates collected at 6:00 a.m. than at 10:00 and 14:00. There was no statistical difference between the latter. To further corroborate an extrapineal secretion of melatonin, the presence of the two key enzymes involved in melatonin synthesis, arylalkylamine-N-acetyltransferase (AANAT) and N-acetylserotonin-O-methyltransferase (ASMT) was analyzed by RT-PCR, q-PCR and Western-blot in ram testes, epididymis, and accessory glands. The RT-PCR showed the presence of the m-RNA codifying both AANAT and ASTM in all the tissues under study, but the q-PCR and Western-blot revealed that gene expression of these enzymes was significantly higher in the testis (p < 0.05). Immunohistochemistry confirmed the presence of AANAT and ASMT in the testis and revealed that they were found in the Leydig cells, spermatocytes, and spermatids. Also, measurable levels of melatonin were found in testicular tissue and the tail of the epididymis. In conclusion, our study indicates that the testes are one of the likely sources of the high levels of melatonin found in ram seminal plasma, at least during the day.

  14. Melatonin deficiencies in women.

    PubMed

    Rohr, Uwe D; Herold, Jens

    2002-04-15

    The pineal hormone melatonin is the mediator of external light to physiologic adaptation to day and night rhythms, it regulates reproduction in animals but attempts to utilize melatonin in women for contraception have failed. Melatonin seems to be the natural hormone to facilitate sleep in insomniac patients and causes no hang over. When applied together with benzodiazepine it allows reduction of benzodiazepine without withdrawal effects. It should be applied 2 h before sleeping time in doses between 3 and 5 mg. Melatonin acts via the gamma-aminobutyric acid- and benzodiazepine receptor explaining its success in treatment of seizures in children and in adults. Constant application of benzodiazepine reduced the production of natural melatonin in rats, supporting the evidence that long-term application of benzodiazepine in humans does not restore sleeping habits but reduces natural sleeping habits even more. Low melatonin levels were seen in bulimia or neuralgia and in women with fibromyalgia; replacement reduced pain, sleeping disorders, and depression in fibromyalgia and bulimia. Melatonin profiles are a diagnostic tool to distinguish between several forms of depression, like major depression, winter depression (SAD), unipolar depression, delayed sleep phase syndrome (DSPS). In patients with a major depression success with antidepressants correlated with an increase in their melatonin profiles but only patients suffering from DSPS can be successfully treated with melatonin. In perimenopausal women melatonin administration did produce a change in LH, FSH and thyroid hormones. Some oncostatic properties are supported by cell culture work and studies in animals. In Nordic countries indigenous people suffer less from breast and prostate cancer, winter darkness seems to protect. The supposedly increased melatonin levels created the 'melatonin hypothesis'. Epidemiological studies did show that blind people indeed have half the rate of breast cancers, supporting the

  15. Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging.

    PubMed

    Reiter, Russel J; Tan, Dun Xian; Manchester, Lucien C; El-Sawi, Mamdouh R

    2002-04-01

    Melatonin has a number of properties as a consequence of which it could be beneficial to animals as they age. Of particular interest are its ubiquitous actions as a direct and indirect antioxidant and free radical scavenger. Besides directly detoxifying a variety of reactive oxygen and reactive nitrogen species, at least one product that is formed as a result of these interactions is also a potent free radical scavenger. Thus, the product that is formed when melatonin detoxifies hydrogen peroxide, that is, N1-acetyl-N2-formyl-5-methoxykynuramine is an efficient scavenger, at least equivalent to melatonin itself. This antioxidant cascade increases the ability of melatonin to resist oxidative damage. Other actions of melatonin, such as stimulation of antioxidative enzymes also improves its status as an antioxidant. Finally, recent observations documenting melatonin's ability to stimulate electron transport and ATP production in the inner-mitochondrial membrane also has relevance for melatonin as an agent that could alter processes of aging. These findings, coupled with diminished melatonin production in advanced age, has prompted scientists to consider melatonin in the context of aging. As of this writing there is no definitive evidence to prove that melatonin alters the rate of aging, although data relating to melatonin deferring some age-related degenerative conditions is accumulating rapidly.

  16. Melatonin in perimenopausal and postmenopausal women: associations with mood, sleep, climacteric symptoms, and quality of life.

    PubMed

    Toffol, Elena; Kalleinen, Nea; Haukka, Jari; Vakkuri, Olli; Partonen, Timo; Polo-Kantola, Päivi

    2014-05-01

    Melatonin synthesis and secretion are partly modulated by estrogen and progesterone. Changes in melatonin concentrations, possibly related to the menopausal transition, may be associated with climacteric mood, sleep, and vasomotor symptoms. The aims of this study were to compare the serum concentrations of melatonin in perimenopausal and postmenopausal women and to evaluate melatonin's influence on mood, sleep, vasomotor symptoms, and quality of life. We analyzed the data of 17 healthy perimenopausal women (aged 43-51 y) and 18 healthy postmenopausal women (aged 58-71 y) who participated in a prospective study. On study night (9:00 pm-9:00 am), serum melatonin was sampled at 20-minute (9:00 pm-12:00 midnight; 6:00-9:00 am) and 1-hour (12:00 midnight-6:00 am) intervals. Questionnaires were used to assess depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), insomnia and sleepiness (Basic Nordic Sleep Questionnaire [BNSQ]), subjective sleep quality, vasomotor symptoms, and quality of life (EuroQoL). Postmenopausal women had lower nighttime serum melatonin concentrations than perimenopausal women. The duration of melatonin secretion tended to be shorter in postmenopause, whereas melatonin peak time did not differ. Mean melatonin concentrations and exposure levels did not correlate with follicle-stimulating hormone level, estradiol level, body mass index, Beck Depression Inventory score, State-Trait Anxiety Inventory score, BNSQ insomnia score, BNSQ sleepiness score, subjective sleep score, climacteric vasomotor score, or quality of life. In perimenopause, the later is the melatonin peak, the higher is the level of anxiety (P = 0.022), and the longer is the melatonin secretion, the better is the quality of life (P < 0.001). Longitudinal research is needed to better understand the possible contributory role of menopause in lower melatonin levels.

  17. The Type III Secretion System and Cytotoxic Enterotoxin Alter the Virulence of Aeromonas hydrophila

    PubMed Central

    Sha, Jian; Pillai, Lakshmi; Fadl, Amin A.; Galindo, Cristi L.; Erova, Tatiana E.; Chopra, Ashok K.

    2005-01-01

    Many gram-negative bacteria use a type III secretion system (TTSS) to deliver effector proteins into host cells. Here we report the characterization of a TTSS chromosomal operon from the diarrheal isolate SSU of Aeromonas hydrophila. We deleted the gene encoding Aeromonas outer membrane protein B (AopB), which is predicted to be involved in the formation of the TTSS translocon, from wild-type (WT) A. hydrophila as well as from a previously characterized cytotoxic enterotoxin gene (act)-minus strain of A. hydrophila, thus generating aopB and act/aopB isogenic mutants. The act gene encodes a type II-secreted cytotoxic enterotoxin (Act) that has hemolytic, cytotoxic, and enterotoxic activities and induces lethality in a mouse model. These isogenic mutants (aopB, act, and act/aopB) were highly attenuated in their ability to induce cytotoxicity in RAW 264.7 murine macrophages and HT-29 human colonic epithelial cells. The act/aopB mutant demonstrated the greatest reduction in cytotoxicity to cultured cells after 4 h of infection, as measured by the release of lactate dehydrogenase enzyme, and was avirulent in mice, with a 90% survival rate compared to that of animals infected with Act and AopB mutants, which caused 50 to 60% of the animals to die at a dose of three 50% lethal doses. In contrast, WT A. hydrophila killed 100% of the mice within 48 h. The effects of these mutations on cytotoxicity could be complemented with the native genes. Our studies further revealed that the production of lactones, which are involved in quorum sensing (QS), was decreased in the act (32%) and aopB (64%) mutants and was minimal (only 8%) in the act/aopB mutant, compared to that of WT A. hydrophila SSU. The effects of act and aopB gene deletions on lactone production could also be complemented with the native genes, indicating specific effects of Act and the TTSS on lactone production. Although recent studies with other bacteria have indicated TTSS regulation by QS, this is the first

  18. Melatonin differentially affects vascular blood flow in humans.

    PubMed

    Cook, Jonathan S; Sauder, Charity L; Ray, Chester A

    2011-02-01

    Melatonin is synthesized and released into the circulation by the pineal gland in a circadian rhythm. Melatonin has been demonstrated to differentially alter blood flow to assorted vascular beds by the activation of different melatonin receptors in animal models. The purpose of the present study was to determine the effect of melatonin on blood flow to various vascular beds in humans. Renal (Doppler ultrasound), forearm (venous occlusion plethysmography), and cerebral blood flow (transcranial Doppler), arterial blood pressure, and heart rate were measured in 10 healthy subjects (29±1 yr; 5 men and 5 women) in the supine position for 3 min. The protocol began 45 min after the ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the other substance. Melatonin did not alter heart rate and mean arterial pressure. Renal blood flow velocity (RBFV) and renal vascular conductance (RVC) were lower during the melatonin trial compared with placebo (RBFV, 40.5±2.9 vs. 45.4±1.5 cm/s; and RVC, 0.47±0.02 vs. 0.54±0.01 cm·s(-1)·mmHg(-1), respectively). In contrast, forearm blood flow (FBF) and forearm vascular conductance (FVC) were greater with melatonin compared with placebo (FBF, 2.4±0.2 vs. 1.9±0.1 ml·100 ml(-1)·min(-1); and FVC, 0.029±0.003 vs. 0.023±0.002 arbitrary units, respectively). Melatonin did not alter cerebral blood flow measurements compared with placebo. Additionally, phentolamine (5-mg bolus) after melatonin reversed the decrease in RVC, suggesting that melatonin increases sympathetic outflow to the kidney to mediate renal vasoconstriction. In summary, exogenous melatonin differentially alters vascular blood flow in humans. These data suggest the complex nature of melatonin on the vasculature in humans.

  19. Alterations of pancreatic amylase secretion in the reserpinized rat model of cystic fibrosis. Effects of cerulein and EGF.

    PubMed

    Morisset, J; Bérubé, F L; Vanier, M; Benrezzak, O

    1994-08-01

    Reserpine treatment resulted in altered enzyme secretion from rat pancreatic acini in response to carbamylcholine and secretin (1,2). This study was undertaken: (1) To evaluate if the alterations caused by reserpine can be prevented by EGF and/or cerulein treatments; (2) To determine the time-course of secretion recovery after reserpine treatment; and (3) To establish if EGF and/or cerulein treatments can accelerate such a recovery after the reserpine treatment. Male Sprague-Dawley rats (250-265 g) were used in these experiments. In experiment I, rats divided into three groups received either reserpine (R) or the reserpine vehicle for the controls (C) and the pair-fed controls (PF) for 7 d. During treatment, PF and R rats were given SC, twice a day, saline, EGF (10 micrograms/kg), cerulein (1 microgram/kg), or both at the same dose. C rats received saline in gelatin. In experiment II, rats were treated for 7 d with reserpine or the vehicle as described in experiment I, were allowed a 30-d recovery period and then were killed. In experiment III, C, PF, and R rats were treated for 7 d as described in experiment I; on the 8th d and for the next 6 d, reserpine rats received saline (reserpine-saline), cerulein, EGF, or both cerulein +EGF at the same dose as indicated in experiment I. C and PF rats received saline in gelatin. After sacrifice, acini were prepared, and amylase dose-response curves to carbamylcholine (Cch) and secretin were established. EGF, cerulein, or their combination given to R rats did not improve the desensitized secretory response to Cch.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Altered adherence in strains of Candida albicans harbouring null mutations in secreted aspartic proteinase genes.

    PubMed

    Watts, H J; Cheah, F S; Hube, B; Sanglard, D; Gow, N A

    1998-02-01

    The aspartate proteinase inhibitor pepstatin A has been shown previously to reduce the adherence of Candida albicans yeast cells to human surfaces. This suggests that in addition to their presumed function facilitating tissue penetration, the secreted aspartate proteinases (Saps) of this fungal pathogen may have auxiliary roles as cellular adhesins. We therefore examined the relative adherence of yeast cells of a parental wild-type strain of C. albicans in relation to yeast cells of strains harbouring specific disruptions in various members of the SAP gene family in an otherwise isogenic background. The adhesiveness of delta sap1, delta sap2, delta sap3 null mutants and a triple delta sap 4-6 disruptant was examined on three surfaces--glass coated with poly-L-lysine or a commercial cell-free basement membrane preparation (Matrigel) and on human buccal epithelial cells. Pepstatin A reduced adherence to all surfaces. Adherence of the each of the single SAP null mutants to these three substrates was either reduced or not affected significantly compared to that of the parental strain. The adherence of the delta sap4-6 mutant was reduced on poly-L-lysine and Matrigel, but increased on buccal cells. The results suggest that in addition to a primary enzymatic role, various SAPs may also act singly or synergistically to enhance the adhesiveness to C. albicans cells to certain human tissues.

  1. Alterations in gastric mucus secretion in rhesus monkeys after exposure to ionizing radiation

    SciTech Connect

    Shea-Donohue, T.; Danquechin-Dorval, E.; Montcalm, E.; El-Bayar, H.; Durakovic, A.; Conklin, J.J.; Dubois, A.

    1985-03-01

    The aim of the present study was to evaluate the effect of gamma-irradiation on soluble gastric mucus. Six conscious chair-adapted rhesus monkeys were studied once before and twice after exposure to ionizing irradiation (800 rads). Using a marker (/sup 99m/Tc-DTPA) dilution technique, acidic glycoprotein (AG), neutral glycoprotein (NG), ion, and fluid output were determined during a basal period and after the administration of an 80-ml water load. Irradiation significantly increased the outputs of both AG and NG during the basal period. After the water load, NG output remained elevated but irradiation abolished postload AG output thus inhibiting the normal rise in AG output stimulated by the load. Two days after irradiation NG output had returned to control levels whereas AG output was still suppressed. Sodium and potassium ion outputs were unaltered by irradiation. Chloride and fluid outputs were significantly inhibited on the day of irradiation but had returned to control levels within 3 days. These results indicate that irradiation produces significant changes in both the quantity and nature of the soluble mucus glycoproteins secreted into the gastric juice. It is suggested that these changes may compromise the protective ability of gastric mucus.

  2. Carbamate Insecticides Target Human Melatonin Receptors.

    PubMed

    Popovska-Gorevski, Marina; Dubocovich, Margarita L; Rajnarayanan, Rajendram V

    2017-02-20

    Carbaryl (1-naphthyl methylcarbamate) and carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate) are among the most toxic insecticides, implicated in a variety of diseases including diabetes and cancer among others. Using an integrated pharmacoinformatics based screening approach, we have identified these insecticides to be structural mimics of the neurohormone melatonin and were able to bind to the putative melatonin binding sites in MT1 and MT2 melatonin receptors in silico. Carbaryl and carbofuran then were tested for competition with 2-[(125)I]-iodomelatonin (300 pM) binding to hMT1 or hMT2 receptors stably expressed in CHO cells. Carbaryl and carbofuran showed higher affinity for competition with 2-[(125)I]-iodomelatonin binding to the hMT2 compared to the hMT1 melatonin receptor (33 and 35-fold difference, respectively) as predicted by the molecular modeling. In the presence of GTP (100 μM), which decouples the G-protein linked receptors to modulate signaling, the apparent efficacy of carbaryl and carbofuran for 2-[(125)I]-iodomelatonin binding for the hMT1 melatonin receptor was not affected but significantly decreased for the hMT2 melatonin receptor compatible with receptor antagonist/inverse agonist and agonist efficacy, respectively. Altogether, our data points to a potentially new mechanism through which carbamate insecticides carbaryl and carbofuran could impact human health by altering the homeostatic balance of key regulatory processes by directly binding to melatonin receptors.

  3. The role of the thalamus in sleep, pineal melatonin production, and circadian rhythm sleep disorders.

    PubMed

    Jan, James E; Reiter, Russel J; Wasdell, Michael B; Bax, Martin

    2009-01-01

    The thalamus has a strong nonphotic influence on sleep, circadian rhythmicity, pineal melatonin production, and secretion. The opening of the sleep gate for nonrapid eye movement sleep is a thalamic function but it is assisted by melatonin which acts by promoting spindle formation. Thus, melatonin has a modulatory influence on sleep onset and maintenance. A remarkable similarity exists between spindle behavior, circadian rhythmicity, and pineal melatonin production throughout life. Together, the thalamic and chronobiological control of sleep leads to a new and improved understanding of the pathophysiology of circadian rhythm sleep disorders and also of the principles of sleep hygiene interventions.

  4. Melatonin modulates the fetal cardiovascular defense response to acute hypoxia

    PubMed Central

    Thakor, Avnesh S; Allison, Beth J; Niu, Youguo; Botting, Kimberley J; Serón-Ferré, Maria; Herrera, Emilio A; Giussani, Dino A

    2015-01-01

    Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability. PMID:25908097

  5. Melatonin prevents obesity through modulation of gut microbiota in mice.

    PubMed

    Xu, Pengfei; Wang, Jialin; Hong, Fan; Wang, Sheng; Jin, Xi; Xue, Tingting; Jia, Li; Zhai, Yonggong

    2017-05-01

    Excess weight and obesity are severe public health threats worldwide. Recent evidence demonstrates that gut microbiota dysbiosis contributes to obesity and its comorbidities. The body weight-reducing and energy balancing effects of melatonin have been reported in several studies, but to date, no investigations toward examining whether the beneficial effects of melatonin are associated with gut microbiota have been carried out. In this study, we show that melatonin reduces body weight, liver steatosis, and low-grade inflammation as well as improving insulin resistance in high fat diet (HFD)-fed mice. High-throughput pyrosequencing of the 16S rRNA demonstrated that melatonin treatment significantly changed the composition of the gut microbiota in mice fed an HFD. The richness and diversity of gut microbiota were notably decreased by melatonin. HFD feeding altered 69 operational taxonomic units (OTUs) compare with a normal chow diet (NCD) group, and melatonin supplementation reversed 14 OTUs to the same configuration than those present in the NCD group, thereby impacting various functions, in particular through its ability to decrease the Firmicutes-to-Bacteroidetes ratio and increase the abundance of mucin-degrading bacteria Akkermansia, which is associated with healthy mucosa. Taken together, our results suggest that melatonin may be used as a probiotic agent to reverse HFD-induced gut microbiota dysbiosis and help us to gain a better understanding of the mechanisms governing the various melatonin beneficial effects. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Melatonin Modulates Prohibitin and Cytoskeleton in the Retinal Pigment Epithelium.

    PubMed

    Sripathi, Srinivas R; Prigge, Cameron L; Elledge, Beth; He, Weilue; Offor, Johnpaul; Gutsaeva, Diana R; Jahng, Wan Jin

    2017-07-01

    The retinal pigment epithelium (RPE) plays imperative roles in normal retinal function by photoreceptor protection from light and phagocytosis of rod and cone outer segments during disc shedding. Melatonin is the free radical scavenger and circadian determinant to protect the RPE and retina from oxidative stress and regulate the circadian clock. The current study tested the hypothesis whether melatonin could affect cytoskeletal structure within RPE. Our Western blot analysis demonstrated that melatonin treatment up-regulated prohibitin 3-fold compared to control. β-tubulin levels were also up-regulated by melatonin but to a lesser extent. Initial cell shape of ARPE-19 is epitheloid, however, after 30-minute treatment with melatonin, RPE cells undergo a morphological change to a fusiform shape with spindle outgrowth. Cells return to epitheloid shape after 12 hours in untreated medium. Melatonin treated cells showed increased and dissimilar distribution of prohibitin and β-tubulin compared to non-treated cells, thus altered cytoskeletal and mitochondrial structure in the RPE. Our data implies that melatonin may play a protective role under oxidative stress, which is shown by the marker prohibitin in terms of increased expression and nuclear distribution. During the protective process, cells change their morphology. Our results suggest that melatonin treatment could be beneficial to protect mitochondria under oxidative stress and treat certain ocular diseases, including age-related macular degeneration.

  7. Hypernatremia-induced vasopressin secretion is not altered in TRPV1-/- rats.

    PubMed

    Tucker, Andrew Blake; Stocker, Sean D

    2016-09-01

    Changes in osmolality or extracellular NaCl concentrations are detected by specialized neurons in the hypothalamus to increase vasopressin (VP) and stimulate thirst. Recent in vitro evidence suggests this process is mediated by an NH2-terminal variant of the transient receptor potential vanilloid type 1 (TRPV1) channel expressed by osmosensitive neurons of the lamina terminalis and vasopressinergic neurons of the supraoptic nucleus. The present study tested this hypothesis in vivo by analysis of plasma VP levels during acute hypernatremia in awake control and TRPV1(-/-) rats. TRPV1(-/-) rats were produced by a Zinc-finger-nuclease 2-bp deletion in exon 13. Intravenous injection of the TRPV1 agonist capsaicin produced hypotension and bradycardia in control rats, but this response was absent in TRPV1(-/-) rats. Infusion of 2 M NaCl (1 ml/h iv) increased plasma osmolality, electrolytes, and VP levels in both control and TRPV1(-/-) rats. However, plasma VP levels did not differ between strains at any time. Furthermore, a linear regression between plasma VP versus osmolality revealed a significant correlation in both control and TRPV1(-/-) rats, but the slope of the regression lines was not attenuated in TRPV1(-/-) versus control rats. Hypotension produced by intravenous injection of minoxidil decreased blood pressure and increased plasma VP levels similarly in both groups. Finally, both treatments stimulated thirst; however, cumulative water intakes in response to hypernatremia or hypotension were not different between control and TRPV1(-/-) rats. These findings suggest that TRPV1 channels are not necessary for VP secretion and thirst stimulated by hypernatremia.

  8. Liver triglyceride secretion and lipid oxidative metabolism are rapidly altered by leptin in vivo.

    PubMed

    Huang, Wan; Dedousis, Nikolas; Bandi, Archana; Lopaschuk, Gary D; O'Doherty, Robert M

    2006-03-01

    Leptin has potent lipid-lowering effects in peripheral tissues and plasma that are proposed to be important for the prevention of cellular lipotoxicity and insulin resistance. The current study addressed in vivo the effects of acute leptin delivery on liver triglyceride (TG) metabolism, the consequence of hepatic leptin action on whole-body TG homeostasis, and the mechanisms of leptin action. A 120-min iv leptin infusion (plasma leptin, approximately 14 ng/ml) decreased liver TG levels (53 +/- 3%; P = 0.001), but not skeletal muscle TG levels, and increased liver phosphatidylinositol 3-kinase activity (341 +/- 95%; P = 0.01) in lean rats. Leptin had no effect on liver TG levels or phosphatidylinositol 3-kinase activity in diet-induced obese rats. In lean animals, leptin decreased the plasma TG concentration (20 +/- 7%; P = 0.017), the rate of TG accumulation in plasma after tyloxapol administration (26 +/- 6%; P = 0.003), and TG secretion from isolated liver (51 +/- 8%; P = 0.004). To determine possible metabolic fates of depleted hepatic TG, we assessed leptin effects on liver oxidative metabolism. Leptin increased hepatic acetyl-coenzyme A carboxylase phosphorylation (85 +/- 13%; P = 0.006), fatty acid oxidation (49 +/- 7%; P = 0.001) and ketogenesis (69 +/- 15%; P = 0.004). Finally, intracerebroventricular delivery of leptin for 120 min had no effect on liver TG levels, but did increase signal transducer and activator of transcription 3 phosphorylation (162 +/- 40%; P = 0.02). These data present in vivo evidence for a role for leptin in the acute regulation of hepatic TG metabolism, and whole body TG homeostasis. A likely contributing mechanism for these effects is leptin-induced partitioning of TG into oxidative pathways.

  9. Melatonin modulates the functions of porcine granulosa cells via its membrane receptor MT2 in vitro.

    PubMed

    He, Ya-Mei; Deng, Hong-Hui; Shi, Mei-Hong; Bodinga, Bello Musa; Chen, Hua-Li; Han, Zeng-Sheng; Jiang, Zhong-Liang; Li, Qing-Wang

    2016-09-01

    Melatonin (N-acetyl-5-methoxytryptamine) is documented as a hormone involved in the circadian regulation of physiological and neuroendocrine function in mammals. Herein, the effects of melatonin on the functions of porcine granulosa cells in vitro were investigated. Porcine granulosa cells were cultivated with variable concentrations of melatonin (0, 0.001, 0.01, 0.1, 1.0, and 10ng/mL) for 48h. Melatonin receptor agonist (IIK7) and antagonist (Luzindole, 4P-PDOT) were used to further examine the action of melatonin. The results showed optimum cell viability and colony-forming efficiency of porcine granulosa cells at 0.01ng/mL melatonin for 48-h incubation period. The percentage of apoptotic granulosa cells was significantly reduced by 0.01 and 0.1ng/mL melatonin within the 48-h incubation period as compared with the rest of the treatments. Estradiol biosynthesis was significantly stimulated by melatonin supplementation and suppressed for the progesterone secretion; the minimum ratio of progesterone to estradiol was 1.82 in 0.01ng/mL melatonin treatment after 48h of cultivation. Moreover, the expression of BCL-2, CYP17A1, CYP19A1, SOD1, and GPX4 were up-regulated by 0.01ng/mL melatonin or combined with IIK7, but decreased for the mRNA levels of BAX, P53, and CASPASE-3, as compared with control or groups treated with Luzindole or 4P-PDOT in the presence of melatonin. In conclusion, the study demonstrated that melatonin mediated proliferation, apoptosis, and steroidogenesis in porcine granulosa cells predominantly through the activation of melatonin receptor MT2 in vitro, which provided evidence of the beneficial role of melatonin as well as its functional mechanism in porcine granulosa cells in vitro. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Pineal volume and evening melatonin in young people with affective disorders.

    PubMed

    Carpenter, Joanne S; Abelmann, Amy C; Hatton, Sean N; Robillard, Rébecca; Hermens, Daniel F; Bennett, Maxwell R; Lagopoulos, Jim; Hickie, Ian B

    2016-11-03

    Affective disorders in young people have been associated with disruptions in circadian rhythms, including abnormalities in secretion of the pineal hormone melatonin. Previous research reports relationships between pineal gland volumes, melatonin secretion, and sleep-wake cycles, but the relationship between these factors has not been explored in affective disorders. This study aimed to characterize these factors and explore associations with mood symptoms and functioning in a sample of young people with affective disorders. Pineal volume from magnetic resonance imaging and melatonin assay from evening dim-light saliva collection were evaluated in 50 individuals (15-30 years old; 72 % female) with bipolar, depressive, or anxiety disorders. Actigraphy monitoring was also conducted for approximately two weeks to derive sleep-wake measures. Pineal volume was associated with melatonin secretion across the evening, replicating previous findings in psychiatrically healthy individuals. Pineal volume was smaller in participants in which melatonin onset was not detected. Timing of melatonin secretion was related to sleep timing, but amount of melatonin and pineal volume were not related to any sleep-wake measures. A shorter phase angle between onset of melatonin secretion and sleep onset was associated with longer total sleep time. Lower melatonin levels were associated with poorer social and occupational functioning. Although pineal volume is not directly related to sleep disturbances or symptoms, melatonin may influence both sleep-wake cycles and functioning in the early stages of affective disorder. Causal links remain to be established, however, treatments that target circadian rhythms may be useful in improving functioning in young people with affective disorders.

  11. Clinical aspects of melatonin intervention in Alzheimer's disease progression.

    PubMed

    Cardinali, Daniel P; Furio, Analía M; Brusco, Luis I

    2010-09-01

    Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called "sundowning"). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were "Alzheimer" and "melatonin". Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated.

  12. Biological rhythms and melatonin in mood disorders and their treatments.

    PubMed

    Lanfumey, Laurence; Mongeau, Raymond; Hamon, Michel

    2013-05-01

    Affective disorders such as major depression, bipolar disorders and seasonal affective disorders have been described as alterations of various neuronal systems. In addition to the classical monoaminergic hypotheses that have been long proposed to explain the pathophysiology of these disorders, a strong association between circadian rhythms and mood regulation has been suggested in the light of several clinical and preclinical findings. In this review, we summarize the different hypotheses on pathophysiology mechanisms underlying depressive disorders and put a special emphasis on the alterations of melatonin secretion and associated changes in biological rhythms that characterize mood disorders. Causal relationships between alterations in circadian rhythms and mood disorders are strongly supported by the antidepressant efficacy of innovative pharmacological treatments aimed at resynchronizing endogenous rhythms in depressed patients. Genetic, epigenetic and environmental factors generating desynchronization between endogenous biological rhythms and exogenous rhythms driven by environmental and societal constraints are very probably involved in the vulnerability to mood disorders. Further investigations of the molecular/cellular bases of the relationships between stress axis dysfunctions, endogenous biological rhythm dysregulations and associated functional and anatomical brain alterations should allow important progress in the knowledge of pathophysiological mechanisms of affective disorders and the downstream development of innovative, more effective and better tolerated, therapies.

  13. Melatonin, Circadian Rhythms, and Sleep.

    PubMed

    Zhdanova, Irina V.; Tucci, Valter

    2003-05-01

    Experimental data show a close relationship among melatonin, circadian rhythms, and sleep. Low-dose melatonin treatment, increasing circulating melatonin levels to those normally observed at night, promotes sleep onset and sleep maintenance without changing sleep architecture. Melatonin treatment can also advance or delay the phase of the circadian clock if administered in the evening or in the morning, respectively. If used in physiologic doses and at appropriate times, melatonin can be helpful for those suffering from insomnia or circadian rhythm disorders. This may be especially beneficial for individuals with low melatonin production, which is established by measuring individual blood or saliva melatonin levels. However, high melatonin doses (over 0.3 mg) may cause side effects and disrupt the delicate mechanism of the circadian system, dissociating mutually dependent circadian body rhythms. A misleading labeling of the hormone melatonin as a "food supplement" and lack of quality control over melatonin preparations on the market continue to be of serious concern.

  14. Melatonin mitigates mitochondrial malfunction.

    PubMed

    León, Josefa; Acuña-Castroviejo, Darío; Escames, Germane; Tan, Dun-Xian; Reiter, Russel J

    2005-01-01

    Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson's, Alzheimer's, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known. Recently, mitochondria, which are implicated in the intrinsic pathway of apoptosis, have been identified as a target for melatonin actions. It is known that melatonin scavenges oxygen and nitrogen-based reactants generated in mitochondria. This limits the loss of the intramitochondrial glutathione and lowers mitochondrial protein damage, improving electron transport chain (ETC) activity and reducing mtDNA damage. Melatonin also increases the activity of the complex I and complex IV of the ETC, thereby improving mitochondrial respiration and increasing ATP synthesis under normal and stressful conditions. These effects reflect the ability of melatonin to reduce the harmful reduction in the mitochondrial membrane potential that may trigger mitochondrial transition pore (MTP) opening and the apoptotic cascade. In addition, a reported direct action of melatonin in the control of currents through the MTP opens a new perspective in the understanding of the regulation of apoptotic cell death by the indoleamine.

  15. Melatonin: an overlooked factor in schizophrenia and in the inhibition of anti-psychotic side effects.

    PubMed

    Anderson, George; Maes, Michael

    2012-06-01

    This paper reviews melatonin as an overlooked factor in the developmental etiology and maintenance of schizophrenia; the neuroimmune and oxidative pathophysiology of schizophrenia; specific symptoms in schizophrenia, including sleep disturbance; circadian rhythms; and side effects of antipsychotics, including tardive dyskinesia and metabolic syndrome. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this review using keywords: schizophrenia, psychosis, tardive dyskinesia, antipsychotics, metabolic syndrome, drug side effects and melatonin. Articles were selected on the basis of relevance to the etiology, course and treatment of schizophrenia. Melatonin levels and melatonin circadian rhythm are significantly decreased in schizophrenic patients. The adjunctive use of melatonin in schizophrenia may augment the efficacy of antipsychotics through its anti-inflammatory and antioxidative effects. Further, melatonin would be expected to improve sleep disorders in schizophrenia and side effects of anti-psychotics, such as tardive dyskinesia, metaboilic syndrome and hypertension. It is proposed that melatonin also impacts on the tryptophan catabolic pathway via its effect on stress response and cortisol secretion, thereby impacting on cortex associated cognition, amygdala associated affect and striatal motivational processing. The secretion of melatonin is decreased in schizophrenia, contributing to its etiology, pathophysiology and management. Melatonin is likely to have impacts on the metabolic side effects of anti-psychotics that contribute to subsequent decreases in life-expectancy.

  16. Regulation of melatonin production and intracellular calcium concentrations in the trout pineal organ.

    PubMed

    Meissl, H; Kroeber, S; Yáñez, J; Korf, H W

    1996-12-01

    The present in vitro study correlates measurements of the melatonin production from trout pineal organs with those of the intracellular calcium concentration in pinealocytes. Melatonin production increases with decreasing irradiance and shows maximal values in darkness. Some pinealocytes exhibit spontaneous calcium oscillations, although most of them have a stable basal calcium concentration. Diminishing extracellular calcium and enhancing magnesium reduces melatonin release in the light-and dark-adapted state. The application of Co2+ decreases melatonin secretion in the mesopic and scotopic range, reversibly blocks spontaneous calcium oscillations, reduces the basal intracellular calcium concentration in non-oscillating pinealocytes, and inhibits the KCl-induced rise in intracellular calcium. Application of glutamate, norepinephrine, isoproterenol, or dopamine has no significant effect on melatonin secretion. Norepinephrine does not influence the calcium concentration in any of the trout pinealocytes. Treatment with the GABAA-receptor agonist muscimol causes a slight reduction of melatonin release in the mesopic and scotopic range of illumination, without affecting intracellular calcium concentrations. Thus, Co2+ and low calcium/high magnesium buffer reduce melatonin release through an action on the calcium concentration in trout pinealocytes and not through a blockade of synaptic transmission. All the data show that the trout pineal organ synthesizes and releases melatonin in relation to the irradiance of the incident light and that neuronal inputs have a minor, if any, influence on melatonin synthesis.

  17. Alterations in immune cell subsets and their cytokine secretion profile in childhood idiopathic thrombocytopenic purpura (ITP).

    PubMed

    Talaat, R M; Elmaghraby, A M; Barakat, S S; El-Shahat, M

    2014-05-01

    Immune thrombocytopenic purpura (ITP) is acquired autoimmune disease in children characterized by the breakdown of immune tolerance. This work is designed to explore the contribution of different lymphocyte subsets in acute and chronic ITP children. Imbalance in the T helper type 1 (Th1)/Th2 cytokine secretion profile was investigated. The frequency of T (CD3(+), CD4(+), CD8(+)) and B (CD19(+)) lymphocytes, natural killer (NK) (CD16(+) 56(+)) and regulatory T (T(reg)) [CD4(+) CD25(+high) forkhead box protein 3 (FoxP3)(+) ] cells was investigated by flow cytometry in 35 ITP children (15 acute and 20 chronic) and 10 healthy controls. Plasma levels of Th1 cytokines [interferon (IFN-γ) and tumour necrosis factor (TNF-α)] and Th2 [interleukin (IL)-4, IL-6 and IL-10)] cytokines were measured using enzyme-linked immunosorbent assay (ELISA). The percentage of Treg (P < 0·001) and natural killer (NK) (P < 0·001) cells were significantly decreased in ITP patients compared to healthy controls. A negative correlation was reported between the percentage of T(reg) cells and development of acute (r = -0·737; P < 0·01) and chronic (r = -0·515; P < 0·01) disease. All evaluated cytokines (IFN-γ, TNF-α, IL-4, IL-6 and IL-10) were elevated significantly in ITP patients (P < 0·001, P < 0·05, P < 0·05, P < 0·05 and P < 0·001, respectively) compared to controls. In conclusion, our data shed some light on the fundamental role of immune cells and their related cytokines in ITP patients. The loss of tolerance in ITP may contribute to the dysfunction of T(regs). Understanding the role of T cell subsets will permit a better control of autoimmunity through manipulation of their cytokine network. © 2014 British Society for Immunology.

  18. Melatonin regulates proteomic changes during leaf senescence in Malus hupehensis.

    PubMed

    Wang, Ping; Sun, Xun; Xie, Yinpeng; Li, Mingjun; Chen, Wei; Zhang, Sheng; Liang, Dong; Ma, Fengwang

    2014-10-01

    Despite the relationship between melatonin and aging, the overall changes and regulation of proteome profiling by long-term melatonin exposure during leaf senescence is not well understood. In this study, leaf senescence in Malus hupehensis plants was delayed when exogenous melatonin was regularly applied to the roots for 2 months compared with natural leaf senescence. Proteins of samples 0 and 50 day for both treatments were extracted and labeled with TMT regents before being examined via NanoLC-MS/MS. The proteomics data showed that 622 and 309 proteins were altered by senescence and melatonin, respectively. Our GO analysis by Blast2GO revealed that most of the altered proteins that are involved in major metabolic processes exhibited hydrolase activity and were mainly located in the plastids. These proteins were classified into several senescence-related functional categories, including degradation of macromolecules, redox and stress responses, transport, photosynthesis, development, and other regulatory proteins. We found that melatonin treatment led to the downregulation of proteins that are normally upregulated during senescence. The melatonin-related delay in senescence might have occurred due to the altering of proteins involved in processes associated with senescence. And as well, there are many unknown regulatory proteins possibly being involved in the melatonin's function. This study is the first to demonstrate changes at the proteome level in response to exogenous melatonin in plants. Our findings provide a set of informative and fundamental data about the role of melatonin in apple leaf senescence. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Alzheimer's disease: roles for mitochondrial damage, the hydroxyl radical, and cerebrospinal fluid deficiency of melatonin.

    PubMed

    Maurizi, C P

    2001-08-01

    A deficiency of cerebrospinal fluid melatonin is postulated to be critical for the development of Alzheimer's disease. Some melatonin is normally secreted directly into the fluid inducing higher levels than in simultaneously sampled blood. Melatonin is carried into the ventricular system via choroid plexus portals. The neurohormone is a potent antioxidant that passes through cell membranes with ease and is concentrated in mitochondria. Neural tissue in contact with the ventricular system will have high levels of cellular melatonin. In Alzheimer's disease, inadequate melatonin allows hydroxyl radicals produced by mitochondrial complex IV to damage mitochondria and initiate a cascade of oxygen radicals that causes the neuropathological changes in Alzheimer's disease. Results from initial therapeutic trials of melatonin in Alzheimer's disease patients have demonstrated improved function, decreased 'sundowning', improved sleep, and a significant slowing of the progression of the disease. Copyright 2001 Harcourt Publishers Ltd.

  20. A physiologically based pharmacokinetics model for melatonin--effects of light and routes of administration.

    PubMed

    Peng, Henry T; Bouak, Fethi; Vartanian, Oshin; Cheung, Bob

    2013-12-15

    Physiologically based pharmacokinetic (PBPK) models were developed using MATLAB Simulink(®) to predict diurnal variations of endogenous melatonin with light as well as pharmacokinetics of exogenous melatonin via different routes of administration. The model was structured using whole body, including pineal and saliva compartments, and parameterized based on the literature values for endogenous melatonin. It was then optimized by including various intensities of light and various dosage and formulation of melatonin. The model predictions generally have a good fit with available experimental data as evaluated by mean squared errors and ratios between model-predicted and observed values considering large variations in melatonin secretion and pharmacokinetics as reported in the literature. It also demonstrates the capability and usefulness in simulating plasma and salivary concentrations of melatonin under different light conditions and the interaction of endogenous melatonin with the pharmacokinetics of exogenous melatonin. Given the mechanistic approach and programming flexibility of MATLAB Simulink(®), the PBPK model could provide predictions of endogenous melatonin rhythms and pharmacokinetic changes in response to environmental (light) and experimental (dosage and route of administration) conditions. Furthermore, the model may be used to optimize the combined treatment using light exposure and exogenous melatonin for maximal phase advances or delays. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  1. Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years.

    PubMed

    Lyseng-Williamson, Katherine A

    2012-11-01

    Melatonin prolonged release (PR) 2 mg is approved for the treatment of primary insomnia characterized by poor sleep quality in patients aged ≥55 years in the EU and elsewhere. Patients may receive treatment with melatonin PR for up to 13 weeks. Production of endogenous nocturnal melatonin, which helps regulate circadian rhythm, may be decreased in older adults. Administration of melatonin PR 2 mg 1-2 h before bedtime mimics the natural secretion pattern of melatonin, thereby leading to improvements in the circadian regulation of the sleep-wake cycle. In older adults, melatonin PR 2 mg had no effect on psychomotor functions, memory recall or driving skills during the night or the next morning relative to placebo, and was associated with significantly less impairment on many of these tasks relative to zolpidem 10 mg alone or in combination with melatonin PR 2 mg. In 3-week and 6-month, randomized, double-blind clinical trials in patients with primary insomnia aged ≥55 years, melatonin PR 2 mg 1-2 h before bedtime was associated with significant improvements relative to placebo in many sleep and daytime parameters, including sleep quality and latency, morning alertness and health-related quality of life. Melatonin PR 2 mg was very well tolerated in clinical trials in older patients, with a tolerability profile that was similar to that of placebo. Short- or longer-term treatment with melatonin PR 2 mg was not associated with dependence, tolerance, rebound insomnia or withdrawal symptoms.

  2. L-aspartate-evoked inhibition of melatonin production in rat pineal glands.

    PubMed

    Yamada, H; Yamaguchi, A; Moriyama, Y

    1997-06-06

    Our previous studies in rat indicated that pinealocytes secrete L-glutamate through microvesicle-mediated exocytosis to regulate negatively melatonin production. Recently, we further found that pinealocytes secrete L-aspartate through microvesicle-mediated exocytosis. In the present study, we investigated the role of L-aspartate in the melatonin production in isolated rat pineal glands. It was found that L-aspartate inhibits norepinephrine-stimulated melatonin production as well as serotonin N-acetyltransferase activity reversibly and dose-dependently, the concentrations required for 50% inhibition being 150 and 175 microM, respectively. L-Asparagine and oxaloacetate, metabolites of L-aspartate, had no effect on the melatonin production. These results suggest that pinealocytes use L-aspartate, as well as L-glutamate, as a negative regulator for melatonin production.

  3. Mucin secreting cells in the stomach and colon are altered by combination antiretroviral treatment in an obese rat model.

    PubMed

    Truter, Danélle; Strijdom, Hans; Everson, Frans; Kotzé, Sanet H

    2017-03-01

    Mucins, secreted by intestinal goblet cells, form an integral part of the intestinal biofilm, which is important for the functioning of a healthy gastrointestinal tract (GIT). This mucous layer is sensitive to factors such as diet, drugs and inflammation. Histochemically, mucins can be classified as neutral or acidic, where acidic mucins can contain sulphate groups (sulphomucins) or sialic acid (sialomucins). The aim of the present study was to determine the composition of various mucin secreting cells using histochemical stains in rats fed on a high calorie diet (HCD) treated with antiretroviral therapy (ART). Wistar rats (N=24) were divided into a lean control group (C/ART-), high calorie diet group (C/HCD+), ART group (C/ART+) and HCD and ART group (HCD+/ART+). The body of the stomach as well as the colon were stained with Alcian Blue Periodic Schiff (ABPAS) to distinguish between neutral and acidic mucins and Alcian Blue Aldehyde Fuschin (ABAF) to distinguish between sialo-and sulphomucins. An increase of the total gastric mucous cells was observed in the HCD+/ART+ group compared to the C/ART- group using both ABPAS and ABAF. A decrease of neutral cells in the distal part of the colonic crypts in the C/HCD+ and C/ART+ groups compared to the C/ART- group were observed. Mixed goblet cells in the colonic crypts of the C/ART- and HCD+/ART+ groups were decreased in comparison to the C/ART+ group. The study showed that the total mean percentage of mucous cells in the stomach as well as the total amount of neutral goblet cells in the colon were most affected by ART and a HCD. These changes in a rat model suggest that the quality of the biofilm may be altered and should be considered when ART is prescribed to obese patients.

  4. Melatonin-insulin interactions in patients with metabolic syndrome.

    PubMed

    Robeva, R; Kirilov, G; Tomova, A; Kumanov, Ph

    2008-01-01

    Metabolic syndrome (MS) as a group of risk factors is strongly associated with diabetes type 2 and cardiovascular disease. Insulin resistance plays a key role in the pathogenesis of MS. Recent studies have shown that melatonin may influence insulin secretion and glucose homeostasis. Therefore, the present study analyzed the relationships between the melatonin and the insulin in patients with MS and controls. The melatonin rhythm, insulin and lipid levels were studied in 40 subjects (21 patients and 19 controls) in reproductive age. The night melatonin-insulin ratio was correlated negatively with low-density lipoprotein cholesterol (r = -0.370, p = 0.024) and total cholesterol (r = -0.348, p = 0.030), and positively with high-density lipoprotein cholesterol levels (r = +0.414, p = 0.010). Night-time melatonin levels were related to night-time insulin concentrations (r = +0.313, p = 0.049). The correlation was pronounced in patients with MS (r = +0.640, p = 0.002), but did not reach statistical significance in controls (P > 0.05). In the patients with MS unlike the controls the night-day melatonin difference (%) correlated negatively with the fasting glucose (r = -0.494, p = 0.023) and positively to daily insulin (r = +0.536, p = 0.012). Our results show that melatonin-insulin interactions may exist in patients with MS, as well as relationships between melatonin-insulin ratio and the lipid profile. Pineal disturbances could influence the pathogenesis and the phenotype variations of the MS. Larger studies are needed to confirm or reject this hypothesis and to clarify the role of the melatonin in the metabolic disturbances.

  5. THE ESTROGENIC AND ANTIANDROGENIC PESTICIDE METHOXYCHLOR ALTERS THE REPRODUCTIVE TRACT AND BEHAVIOR WITHOUT AFFECTING PITUITARY SIZE OR LH AND PROLACTIN SECRETION IN MALE RATS

    EPA Science Inventory

    The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats.

    Gray LE Jr, Ostby J, Cooper RL, Kelce WR.

    Endocrinology Branch, United States Environment...

  6. THE ESTROGENIC AND ANTIANDROGENIC PESTICIDE METHOXYCHLOR ALTERS THE REPRODUCTIVE TRACT AND BEHAVIOR WITHOUT AFFECTING PITUITARY SIZE OR LH AND PROLACTIN SECRETION IN MALE RATS

    EPA Science Inventory

    The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats.

    Gray LE Jr, Ostby J, Cooper RL, Kelce WR.

    Endocrinology Branch, United States Environment...

  7. Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment.

    PubMed

    Masters, Alina; Pandi-Perumal, Seithikurippu R; Seixas, Azizi; Girardin, Jean-Louis; McFarlane, Samy I

    Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic.

  8. Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment

    PubMed Central

    Masters, Alina; Pandi-Perumal, Seithikurippu R; Seixas, Azizi; Girardin, Jean-Louis; McFarlane, Samy I.

    2015-01-01

    Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic. PMID:25705578

  9. Alterations in expression of endometrial genes coding for proteins secreted into the uterine lumen during conceptus elongation in cattle

    PubMed Central

    2013-01-01

    Background We hypothesized that genes that are up-regulated in the uterine endometrium at the initiation of conceptus elongation in cattle, and that encode for secreted proteins, contribute to the composition of the uterine luminal fluid (ULF) and ultimately, drive conceptus elongation. The aims of this study were to: 1) screen endometrial transcriptomic data for genes that encode secreted proteins on Day 13; 2) determine temporal changes in the expression of these genes during the estrous cycle/early pregnancy; 3) determine if expression of these genes is affected by altered concentrations of progesterone (P4) in vivo and 4) determine if the protein products of these genes are detectable in ULF. Results Of the fourteen candidate genes examined, quantitative real-time PCR analysis revealed the expression of APOA1, ARSA, DCN, LCAT, MUC13, NCDN, NMN, NPNT, NXPH3, PENK, PLIN2 and TINAGL1 was modulated in the endometrium (P<0.05) as the estrous cycle/early pregnancy progressed. APOA1, DCN and NPNT expression was higher in cyclic compared to pregnant heifers, and pregnancy increased (P<0.05) the expression of LCAT, NCDN, NMN, PLIN2 and TINAGL1. The magnitude of the increase in expression of APOA1, PENK and TINAGL1 on Day 13 was reduced (P<0.05) in heifers with low P4. Furthermore, low P4 decreased (P<0.05) the expression of LCAT and NPNT on Day 7, while an early increase (P<0.05) in the expression of NXPH3 and PLIN2 was observed in heifers with high P4. The protein products of 5 of the candidate genes (APOA1, ARSA, LCAT, NCDN and PLIN) were detected in the ULF on either Days 13, 16 or 19 of pregnancy. Conclusion Using a candidate gene approach, we determined that both P4 concentration and the presence of the conceptus alter endometrial expression of PLIN2, TINAGL1, NPNT, LCAT, NMN and APOA1. Comparison of the expression profiles of these genes to proteins detected in ULF during conceptus elongation (i.e., Days 13 through 19) revealed the presence of APOA1, ARSA, LCAT

  10. Hyperprolactinemia after neonatal prolactin (PRL) deficiency in rats: evidence for altered anterior pituitary regulation of PRL secretion.

    PubMed

    Shah, G V; Shyr, S W; Grosvenor, C E; Crowley, W R

    1988-05-01

    Previous findings from this laboratory suggest a role for milk-borne PRL in the development of the inhibitory neuroendocrine controls over PRL secretion. Thus, rats that consumed milk deficient in PRL on days 2-5 postpartum show reduced concentrations and turnover of DA in the median eminence and elevated serum levels of PRL at 30-35 days of age. The present experiments were undertaken to investigate whether these consequences of neonatal PRL deficiency persist beyond puberty, and whether alterations in pituitary responsiveness to hypothalamic hormones may be involved. Lactating rats received sc injections of either saline or the dopamine (DA) agonist bromocriptine (125 micrograms/rat.day) on each of days 2-5 postpartum, a treatment that reduces the amount of PRL in milk without abolishing lactation. Blood samples were obtained from male and female offspring at various postnatal ages, and PRL concentrations were determined by RIA. Serum PRL concentrations in offspring from both groups were low until after weaning, but the female offspring of bromocriptine-treated mothers showed significantly elevated serum PRL between days 30 and 90 postpartum. Male offspring of bromocriptine-treated mothers also had transiently increased serum PRL levels, which returned to control levels by day 40. The turnover rate of DA in the median eminence, calculated from the rate of decline after synthesis inhibition, was reduced on day 35 in neonatally PRL-deficient offspring, as shown previously. However, no differences in DA turnover between the two groups were apparent on day 60, indicating a recovery of normal dopaminergic activity. Anterior pituitary cells of 100-day-old control and neonatally PRL-deficient animals were dispersed, cultured for 3 days, and then exposed to either TRH, to stimulate PRL release, or to the DA agonist bromocriptine, which inhibits PRL release. Pituitary cells of neonatally PRL-deficient offspring were almost completely unresponsive to bromocriptine with

  11. Melatonin in Alzheimer's disease.

    PubMed

    Lin, Li; Huang, Qiong-Xia; Yang, Shu-Sheng; Chu, Jiang; Wang, Jian-Zhi; Tian, Qing

    2013-07-12

    Alzheimer's disease (AD), an age-related neurodegenerative disorder with progressive cognition deficit, is characterized by extracellular senile plaques (SP) of aggregated β-amyloid (Aβ) and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Multiple factors contribute to the etiology of AD in terms of initiation and progression. Melatonin is an endogenously produced hormone in the brain and decreases during aging and in patients with AD. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning and slows down the progression of cognitive impairment in AD patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting the cholinergic system and in anti-inflammation. The aim of this review is to stimulate interest in melatonin as a potentially useful agent in the prevention and treatment of AD.

  12. Melatonin and Oral Cavity

    PubMed Central

    Cengiz, Murat İnanç; Cengiz, Seda; Wang, Hom-Lay

    2012-01-01

    While initially the oral cavity was considered to be mainly a source of various bacteria, their toxins and antigens, recent studies showed that it may also be a location of oxidative stress and periodontal inflammation. Accordingly, this paper focuses on the involvement of melatonin in oxidative stress diseases of oral cavity as well as on potential therapeutic implications of melatonin in dental disorders. Melatonin has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue, and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a coadjuvant in the treatment of certain conditions of the oral cavity. However, the most important effect of melatonin seems to result from its potent antioxidant, immunomodulatory, protective, and anticancer properties. Thus, melatonin could be used therapeutically for instance, locally, in the oral cavity damage of mechanical, bacterial, fungal, or viral origin, in postsurgical wounds caused by tooth extractions and other oral surgeries. Additionally, it can help bone formation in various autoimmunological disorders such as Sjorgen syndrome, in periodontal diseases, in toxic effects of dental materials, in dental implants, and in oral cancers. PMID:22792106

  13. Comparison of melatonin with growth factors in promoting precursor cells proliferation in adult mouse subventricular zone

    PubMed Central

    Sotthibundhu, Areechun; Ekthuwapranee, Kasima; Govitrapong, Piyarat

    2016-01-01

    Melatonin, secreted mainly by the pineal gland, plays roles in various physiological functions including protecting cell death. We showed in previous study that the proliferation and differentiation of precursor cells from the adult mouse subventricular zone (SVZ) can be modulated by melatonin via the MT1 melatonin receptor. Since melatonin and epidermal growth factor receptor (EGFR) share some signaling pathway components, we investigated whether melatonin can promote the proliferation of precursor cells from the adult mouse SVZ via the extracellular signal-regulated protein kinase /mitogen-activated protein kinase (ERK/MAPK) pathways in comparison with epidermal growth factor (EGF). Melatonin-induced ERK/MAPK pathways compared with EGF were measured by using in vitro and vivo models. We used neurosphere proliferation assay, immunocytochemistry, and immuno-blotting to analyze significant differences between melatonin and growth factor treatment. We also used specific antagonist and inhibitors to confirm the exactly signaling pathway including luzindole and U0126. We found that significant increase in proliferation was observed when two growth factors (EGF+bFGF) and melatonin were used simultaneously compared with EGF + bFGF or compared with melatonin alone. In addition, the present result suggested the synergistic effect occurred of melatonin and growth factors on the activating the ERK/MAPK pathway. This study exhibited that melatonin could act as a trophic factor, increasing proliferation in precursor cells mediated through the melatonin receptor coupled to ERK/MAPK signaling pathways. Understanding the mechanism by which melatonin regulates precursor cells may conduct to the development of novel strategies for neurodegenerative disease therapy. PMID:28275319

  14. Effect of L-NAME-induced hypertension on melatonin receptors and melatonin levels in the pineal gland and the peripheral organs of rats.

    PubMed

    Benova, Miroslava; Herichova, Iveta; Stebelova, Katarina; Paulis, Ludovit; Krajcirovicova, Kristina; Simko, Fedor; Zeman, Michal

    2009-04-01

    Melatonin plays a role in blood pressure (BP) control. The aim of this study was to determine whether melatonin concentrations and melatonin receptor levels are altered in L-NAME-treated, NO-deficient hypertensive rats. Two groups of male adult Wistar rats were investigated: rats (n=36) treated with NO-synthase inhibitor L-NAME (40 mg kg(-1)) and age-matched controls (n=36). BP was measured weekly by tail-cuff plethysmography. After 4 weeks, L-NAME administration increased BP (178+/-1 vs. control 118+/-1 mm Hg). At the end of treatment, rats were killed in regular 4 h intervals over a 24-h period. Melatonin concentrations in the plasma, pineal gland, heart and kidney and melatonin receptor (MT(1)) density in the aorta were determined. A significant daily rhythm of melatonin concentrations was found in the blood, pineal gland, kidney and heart of both control and hypertensive rats. Peak nighttime pineal melatonin concentrations were higher in L-NAME-treated rats than in controls (3.38+/-0.48 vs. 1.75+/-0.33 ng per pineal gland). No differences between both groups were found in melatonin concentrations in blood, kidney and heart or in the MT(1) receptor density in the aorta. Our results suggest that L-NAME treatment enhances melatonin production in the pineal gland, potentially by decreasing an inhibitory effect of NO on melatonin production in the pineal gland. However, the enhanced pineal melatonin formation was insufficient to increase melatonin concentrations in circulation, heart and kidney of L-NAME-treated rats, indicating an increased use of melatonin in hypertensive animals.

  15. Melatonin for primary insomnia?

    PubMed

    2009-07-01

    Melatonin, a hormone produced by the pineal gland, has a key role in regulating circadian rhythms, most importantly, the sleep-wake cycle. Melatonin's action has led to its being tried as a treatment for a wide range of sleep disorders, such as jet lag, primary insomnia, sleep-wake cycle disruption and sleep problems in children with neuro-developmental disorders. Until recently, it had not been licensed in the UK for any indication. Prolonged-release melatonin (Circadin - Lundbeck) has now been licensed as a treatment for primary insomnia. Here we consider whether this product has a place in the management of people with this condition.

  16. Seasonal variation in the daily pattern of plasma melatonin in a wild mammal: the mountain hare (Lepus timidus).

    PubMed

    Iason, G R; Ebling, F J

    1989-01-01

    Seasonal differences in daily patterns of plasma melatonin concentration were investigated in both free-living and captive mountain hares, in relation to reproductive activity. There was a marked increase in plasma melatonin concentrations at night at all times of the year. The period of elevation of plasma melatonin above the daytime values was longer in winter than in summer, correlating with the longer duration of darkness. The magnitude of the nighttime rise in melatonin concentrations did not differ significantly between seasons. There was no change in the plasma melatonin profile under similar photoperiods before the summer solstice when hares are sexually active or after the summer solstice when gonadal regression occurs, indicating that melatonin is not directly pro- or antigonadal. These field and laboratory observations support the view that the daily rhythm of melatonin secretion plays a role in the transduction of photoperiodic information in the mountain hare. Furthermore, they favor the hypotheses that the circadian melatonin rhythm transduces photoperiod information by means of the duration of nocturnal melatonin secretion or by the coincidence of elevated melatonin with a particular sensitive period, rather than by the amplitude of the nocturnal rise.

  17. Tributyltin and dibutyltin alter secretion of tumor necrosis factor alpha from human natural killer cells and a mixture of T cells and natural killer cells.

    PubMed

    Hurt, Kelsi; Hurd-Brown, Tasia; Whalen, Margaret

    2013-06-01

    Butyltins (BTs) have been in widespread use. Tributyltin (TBT) has been used as a biocide in a variety of applications and is found in human blood samples. Dibutyltin (DBT) has been used as a stabilizer in polyvinyl chloride plastics and as a de-worming agent in poultry. DBT, like TBT, is found in human blood. Human natural killer (NK) cells are the earliest defense against tumors and viral infections and secrete the cytokine tumor necrosis factor-alpha (TNF-α). TNF-α is an important regulator of adaptive and innate immune responses. TNF-α promotes inflammation and an association between malignant transformation and inflammation has been established. Previously, we have shown that TBT and DBT were able to interfere with the ability of NK cells to lyse tumor target cells. Here we show that BTs alter cytokine secretion by NK cells as well as a mixture of T and NK lymphocytes (T/NK cells). We examined 24-, 48-h and 6-day exposures to TBT (200-2.5 nM) and DBT (5-0.05 μM) on TNF-α secretion by highly enriched human NK cells and T/NK cells. The results indicate that TBT (200-2.5 nM) decreased TNF-α secretion from NK cells. In the T/NK cells, 200 nM TBT decreased secretion whereas 100-5 nM TBT increased secretion of TNF-α. NK cells or T/NK cells exposed to higher concentrations of DBT showed decreased TNF-α secretion whereas lower concentrations showed increased secretion. The effects of BTs on TNF-α secretion are seen at concentrations present in human blood.

  18. Neuropeptide Y (NPY): genetic variation in the human promoter alters glucocorticoid signaling, yielding increased NPY secretion and stress responses.

    PubMed

    Zhang, Kuixing; Rao, Fangwen; Miramontes-Gonzalez, Jose Pablo; Hightower, C Makena; Vaught, Brian; Chen, Yuhong; Greenwood, Tiffany A; Schork, Andrew J; Wang, Lei; Mahata, Manjula; Stridsberg, Mats; Khandrika, Srikrishna; Biswas, Nilima; Fung, Maple M; Waalen, Jill; Middelberg, Rita P; Heath, Andrew C; Montgomery, Grant W; Martin, Nicholas G; Whitfield, John B; Baker, Dewleen G; Schork, Nicholas J; Nievergelt, Caroline M; O'Connor, Daniel T

    2012-10-23

    confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same -880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes. We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇-880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  19. Loss of C. elegans GON-1, an ADAMTS9 Homolog, Decreases Secretion Resulting in Altered Lifespan and Dauer Formation.

    PubMed

    Yoshina, Sawako; Mitani, Shohei

    2015-01-01

    ADAMTS9 is a metalloprotease that cleaves components of the extracellular matrix and is also implicated in transport from the endoplasmic reticulum (ER) to the Golgi. It has been reported that an ADAMTS9 gene variant is associated with type 2 diabetes. The underlying pathology of type 2 diabetes is insulin resistance and beta-cell dysfunction. However, the molecular mechanisms underlying ADAMTS9 function in beta cells and peripheral tissues are unknown. We show that loss of C. elegans GON-1, an ADAMTS9 homolog, alters lifespan and dauer formation. GON-1 loss impairs secretion of proteins such as insulin orthologs and TGF-beta, and additionally impacts insulin/IGF-1 signaling in peripheral tissues. The function of the GON domain, but not the protease domain, is essential for normal lifespan and dauer formation in these scenarios. We conclude that the GON domain is critical for ADAMTS9/GON-1 function across species, which should help the understanding of type 2 diabetes in humans.

  20. Loss of C. elegans GON-1, an ADAMTS9 Homolog, Decreases Secretion Resulting in Altered Lifespan and Dauer Formation

    PubMed Central

    Yoshina, Sawako; Mitani, Shohei

    2015-01-01

    ADAMTS9 is a metalloprotease that cleaves components of the extracellular matrix and is also implicated in transport from the endoplasmic reticulum (ER) to the Golgi. It has been reported that an ADAMTS9 gene variant is associated with type 2 diabetes. The underlying pathology of type 2 diabetes is insulin resistance and beta-cell dysfunction. However, the molecular mechanisms underlying ADAMTS9 function in beta cells and peripheral tissues are unknown. We show that loss of C. elegans GON-1, an ADAMTS9 homolog, alters lifespan and dauer formation. GON-1 loss impairs secretion of proteins such as insulin orthologs and TGF-beta, and additionally impacts insulin/IGF-1 signaling in peripheral tissues. The function of the GON domain, but not the protease domain, is essential for normal lifespan and dauer formation in these scenarios. We conclude that the GON domain is critical for ADAMTS9/GON-1 function across species, which should help the understanding of type 2 diabetes in humans. PMID:26218657

  1. Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats.

    PubMed

    Sheen, Jiunn-Ming; Chen, Yu-Chieh; Hsu, Mei-Hsin; Tain, You-Lin; Huang, Ying-Hsien; Tiao, Mao-Meng; Li, Shih-Wen; Huang, Li-Tung

    2016-08-20

    Bile duct ligation (BDL)-treated rats display cholestasis and liver damages. The potential protective activity of melatonin in young BDL rats in terms of apoptosis, mitochondrial function, and endoplasmic reticulum (ER) homeostasis has not yet been evaluated. Three groups of young male Sprague-Dawley rats were used: one group received laparotomy (Sham), a second group received BDL for two weeks (BDL), and a third group received BDL and intraperitoneal melatonin (100 mg/day) for two weeks (BDL + M). BDL group rats showed liver apoptosis, increased pro-inflamamtory mediators, caspases alterations, anti-apoptotic factors changes, and dysfunction of ER homeostasis. Melatonin effectively reversed apoptosis, mainly through intrinsic pathway and reversed ER stress. In addition, in vitro study showed melatonin exerted its effect mainly through the melatonin 2 receptor (MT2) in HepG2 cells. In conclusion, BDL in young rats caused liver apoptosis. Melatonin rescued the apoptotic changes via the intrinsic pathway, and possibly through the MT2 receptor. Melatonin also reversed ER stress induced by BDL.

  2. Metabolic effects of melatonin on oxidative stress and diabetes mellitus.

    PubMed

    Nishida, Shigeru

    2005-07-01

    Melatonin, which is synthesized in the pineal gland and other tissues, has a variety of physiological, immunological, and biochemical functions. It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. Melatonin also reduces serum lipid levels in mammalian species, and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. This review will focus on the physiological and metabolic effects of melatonin and highlight its potential use for the treatment of cholesterol/lipid and carbohydrate disorders.

  3. Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats

    PubMed Central

    Sheen, Jiunn-Ming; Chen, Yu-Chieh; Hsu, Mei-Hsin; Tain, You-Lin; Huang, Ying-Hsien; Tiao, Mao-Meng; Li, Shih-Wen; Huang, Li-Tung

    2016-01-01

    Bile duct ligation (BDL)-treated rats display cholestasis and liver damages. The potential protective activity of melatonin in young BDL rats in terms of apoptosis, mitochondrial function, and endoplasmic reticulum (ER) homeostasis has not yet been evaluated. Three groups of young male Sprague-Dawley rats were used: one group received laparotomy (Sham), a second group received BDL for two weeks (BDL), and a third group received BDL and intraperitoneal melatonin (100 mg/day) for two weeks (BDL + M). BDL group rats showed liver apoptosis, increased pro-inflamamtory mediators, caspases alterations, anti-apoptotic factors changes, and dysfunction of ER homeostasis. Melatonin effectively reversed apoptosis, mainly through intrinsic pathway and reversed ER stress. In addition, in vitro study showed melatonin exerted its effect mainly through the melatonin 2 receptor (MT2) in HepG2 cells. In conclusion, BDL in young rats caused liver apoptosis. Melatonin rescued the apoptotic changes via the intrinsic pathway, and possibly through the MT2 receptor. Melatonin also reversed ER stress induced by BDL. PMID:27556445

  4. Klebsiella pneumoniae O antigen loss alters the outer membrane protein composition and the selective packaging of proteins into secreted outer membrane vesicles.

    PubMed

    Cahill, Bethaney K; Seeley, Kent W; Gutel, Dedra; Ellis, Terri N

    2015-11-01

    Klebsiella pneumoniae is a nosocomial pathogen which naturally secretes lipopolysaccharide (LPS) and cell envelope associated proteins into the environment through the production of outer membrane vesicles (OMVs). The loss of the LPS O antigen has been demonstrated in other bacterial species to significantly alter the composition of OMVs. Therefore, this study aimed to comprehensively analyze the impact of O antigen loss on the sub-proteomes of both the outer membrane and secreted OMVs from K. pneumoniae. As determined by LC-MS/MS, OMVs were highly enriched with outer membrane proteins involved in cell wall, membrane, and envelope biogenesis as compared to the source cellular outer membrane. Deletion of wbbO, the enzyme responsible for O antigen attachment to LPS, decreased but did not eliminate this enrichment effect. Additionally, loss of O antigen resulted in OMVs with increased numbers of proteins involved in post-translational modification, protein turnover, and chaperones as compared to secreted vesicles from the wild type. This alteration of OMV composition may be a compensatory mechanism to deal with envelope stress. This comprehensive analysis confirms the highly distinct protein composition of OMVs as compared to their source membrane, and provides evidence for a selective sorting mechanism that involves LPS polysaccharides. These data support the hypothesis that modifications to LPS alters both the mechanics of protein sorting and the contents of secreted OMVs and significantly impacts the protein composition of the outer membrane.

  5. [Relationship between insulin, leptin, and melatonin contents in patients with metabolic syndrome].

    PubMed

    2011-01-01

    Melatonin, leptin, and insulin secretion was studied in 25 men with metabolic syndrome (MS) verified against IDF criteria (2005) (mean age 44 +/- 2 yr). The control group was constituted by 23 healthy men (mean age 45.1 yr). Melatonin secretion was estimated from 6-oxymelatonin sulfate (6-OMS) level in urine samples collected at 4 a.m. (in the darkness). It was shown to increase at this time in both groups but was lower in MS patients than in controls (t = 2, p < 0.05). The Pearson correlation analysis revealed moderate negative correlation between 6-SOMT level in urine and insulin and glucose levels in plasma (r = 0.95). Peak 6-SOMT level showed strong negative correlation with the leptin level. Multiple regression analysis demonstrated strong linear relationship of 6-OMS and insulin levels (r = 0.93) and 6SOMT and leptin levels (r = 0.95). The calculated odds ratio suggests that the risk of insulin resistance in patients displaying a peakless melatonin secretion profile is 3 times that in control subjects (OR = 3.0; 95% CI = 1.3-7). It is concluded that patients with MS present with disturbances of melatonin secretion manifest as the absence of its physiological elevation at night hours; they are characterized by negative correlation between melatonin, leptin and insulin levels and changes in melatonin secretion in relation to abnormal production of insulin and leptin.

  6. Arabidopsis Transcriptome Analysis Reveals Key Roles of Melatonin in Plant Defense Systems

    PubMed Central

    Weeda, Sarah; Zhang, Na; Zhao, Xiaolei; Ndip, Grace; Guo, Yangdong; Buck, Gregory A.; Fu, Conggui; Ren, Shuxin

    2014-01-01

    Melatonin is a ubiquitous molecule and exists across kingdoms including plant species. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. Much less attention has been drawn to its affect on genome-wide gene expression. To comprehensively investigate the role(s) of melatonin at the genomics level, we utilized mRNA-seq technology to analyze Arabidopsis plants subjected to a 16-hour 100 pM (low) and 1 mM (high) melatonin treatment. The expression profiles were analyzed to identify differentially expressed genes. 100 pM melatonin treatment significantly affected the expression of only 81 genes with 51 down-regulated and 30 up-regulated. However, 1 mM melatonin significantly altered 1308 genes with 566 up-regulated and 742 down-regulated. Not all genes altered by low melatonin were affected by high melatonin, indicating different roles of melatonin in regulation of plant growth and development under low and high concentrations. Furthermore, a large number of genes altered by melatonin were involved in plant stress defense. Transcript levels for many stress receptors, kinases, and stress-associated calcium signals were up-regulated. The majority of transcription factors identified were also involved in plant stress defense. Additionally, most identified genes in ABA, ET, SA and JA pathways were up-regulated, while genes pertaining to auxin responses and signaling, peroxidases, and those associated with cell wall synthesis and modifications were mostly down-regulated. Our results indicate critical roles of melatonin in plant defense against various environmental stresses, and provide a framework for functional analysis of genes in melatonin-mediated signaling pathways. PMID:24682084

  7. Melatonin promotes adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes.

    PubMed

    Kato, Hisashi; Tanaka, Goki; Masuda, Shinya; Ogasawara, Junetsu; Sakurai, Takuya; Kizaki, Takako; Ohno, Hideki; Izawa, Tetsuya

    2015-09-01

    Melatonin is synthesized in the pineal gland, but elicits a wide range of physiological responses in peripheral target tissues. Recent advances suggest that melatonin controls adiposity, resulting in changes in body weight. The aim of this study was to investigate the effect of melatonin on adipogenesis and mitochondrial biogenesis in 3T3-L1 mouse embryo fibroblasts. Melatonin significantly increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipogenesis, and promoted differentiation into adipocytes. Melatonin-treated cells also formed smaller lipid droplets and abundantly expressed several molecules associated with lipolysis, including adipose triglyceride lipase, perilipin, and comparative gene identification-58. Moreover, the hormone promoted biogenesis of mitochondria, as indicated by fluorescent staining, elevated the citrate synthase activity, and upregulated the expression of PPAR-γ coactivator 1 α, nuclear respiratory factor-1, and transcription factor A. The expression of uncoupling protein 1 was also observable both at mRNA and at protein level in melatonin-treated cells. Finally, adiponectin secretion and the expression of adiponectin receptors were enhanced. These results suggest that melatonin promotes adipogenesis, lipolysis, mitochondrial biogenesis, and adiponectin secretion. Thus, melatonin has potential as an anti-obesity agent that may reverse obesity-related disorders. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Effect of melatonin on kidney cold ischemic preservation injury

    PubMed Central

    Aslaner, Arif; Gunal, Omer; Turgut, Hamdi Taner; Celik, Erdal; Yildirim, Umran; Demirci, Rojbin Karakoyun; Gunduz, Umut Riza; Calis, Hasan; Dogan, Sami

    2013-01-01

    Melatonin is a potent free radical scavenger of reactive oxygen species, nitric oxide synthase inhibitor and a well-known antioxidant secreted from pineal gland. This hormone has been reported to protect tissue from oxidative damage. In this study, we aim to investigate the effect of melatonin on kidney cold ischemia time when added to preservation solution. Thirty male Wistar albino rats were divided equally into three groups; Ringer Lactate (RL) solution, University of Wisconsin (UW) solution with and without melatonin. The serum Lactate Dehydrogenase (LDH) activities of the preservation solutions at 2nd, 24th, 36th, and 48th hours were determined. Tissue malondialdehyde (MDA) levels were also measured and a histological examination was performed at 48th hour. Melatonin that added to preservation solution prevented enzyme elevation and decreased lipid peroxidation in preservation solution when compared to the control group (p<0.05). The histological examination revealed that UW solution containing melatonin significantly prevented the kidney from pathological injury (p<0.05). Melatonin added to preservation solutions such as UW solution seemed to protect the tissue preserved effectively from cold ischemic injury for up to 48 hour. PMID:24179573

  9. Nocturnal Melatonin Profiles in Patients with Delayed Sleep-Wake Phase Disorder and Control Sleepers.

    PubMed

    Micic, Gorica; Lovato, Nicole; Gradisar, Michael; Burgess, Helen J; Ferguson, Sally A; Kennaway, David J; Lack, Leon

    2015-10-01

    A significant delay in the timing of endogenous circadian rhythms has been associated with delayed sleep phase disorder (DSPD). More recently, other mechanisms have also been proposed to account for this disorder. To further explore the etiology of DSPD, the present study compared nocturnal melatonin profiles of 26 DSPD patients (18 males, 8 females; age, 21.73 ± 4.98 years) and 17 normally timed good sleepers (10 males, 7 females; age, 23.82 ± 5.23 years) in a time-free, dim-light (<10 lux) laboratory environment. A 30-h modified constant routine with alternating 20-min sleep opportunities and 40 min of enforced wakefulness was used to measure the endogenous melatonin circadian rhythm. Salivary melatonin was sampled half-hourly from 1820 h to 0020 h and then hourly from 0120 h to 1620 h. DSPD patients had significantly later timed melatonin profiles that were delayed by approximately 3 h compared to normal sleepers, and there were no notable differences in the relative duration of secretion between groups. However, melatonin secretion between dim-light melatonin onset (DLMO) and acrophase was less prominent in DSPD patients compared to good sleepers, who showed a more acute initial surge of melatonin following the DLMO. Although the regulatory role of melatonin is unknown, abnormal melatonin profiles have been linked to psychiatric and neurological disorders (e.g., major depression, obsessive compulsive disorder, Parkinson disease). These results therefore suggest that in addition to a delayed endogenous circadian rhythm, a diminished initial surge of melatonin secretion following DLMO may contribute to the etiology of DSPD.

  10. Expression of tranferrin receptors in the pineal gland of postnatal and adult rats and its alteration in hypoxia and melatonin treatment.

    PubMed

    Kaur, C; Sivakumar, V; Ling, E A

    2007-02-01

    Transferrin receptors (Tfrc) are membrane bound glycoproteins which function to mediate cellular uptake of iron from transferrin. We examined expression of Tfrc in the pineal gland of rats of different ages from 1 day to 12 weeks. The mRNA and protein expression of Tfrc increased up to 6 weeks of age and decreased in 12 week rats. Tfrc immunoreactivity was observed on pinealocytes and macrophages/microglia. By immunoelectron microscopy, the immunoreaction in pinealocytes was observed in the cytosol, on mitochondria and plasma membrane whereas in macrophages/microglia it was localized on the plasma membrane in 1-day to 2-week old rats. In older rats, the immunoreaction product in pinealocytes was associated with the plasma membrane and mitochondria only. Iron localization was observed in pinealocytes as well as macrophages/microglia. It is suggested that Tfrc are required for uptake of iron for cell proliferation and maturation in the pineal gland upto 6 weeks of age. The significance of Tfrc expression on mitochondria is speculative. They may be involved in iron transport to the mitochondria or for regulation of the secretory activity of pinealocytes. The TfrcmRNA and protein expression increased significantly in response to hypoxia in 12-week rats and this coincided with intense iron staining of the pinealocytes and macrophages/microglia. It is concluded that increased expression of Tfrc in response to hypoxia leads to excess cellular uptake of iron which may be damaging to the cells. Melatonin administration in hypoxic rats may prove to be beneficial as it reduced the Tfrc expression.

  11. The Role of Melatonin in the Treatment of Primary Headache Disorders

    PubMed Central

    Gelfand, Amy A.; Goadsby, Peter J.

    2016-01-01

    Objective To provide a summary of knowledge about the use of melatonin in the treatment of primary headache disorders. Background Melatonin is secreted by the pineal gland; its production is regulated by the hypothalamus and increases during periods of darkness. Methods We undertook a narrative review of the literature on the role of melatonin in the treatment of primary headache disorders. Results There are randomized placebo-controlled trials examining melatonin for preventive treatment of migraine and cluster headache. For cluster headache, melatonin 10 mg was superior to placebo. For migraine, a randomized placebo-controlled trial of melatonin 3 mg (immediate release) was positive, though an underpowered trial of melatonin 2 mg (sustained release) was negative. Uncontrolled studies, case series, and case reports cover melatonin’s role in treating tension-type headache, hypnic headache, hemicrania continua, SUNCT/SUNA and primary stabbing headache. Conclusions Melatonin may be effective in treating several primary headache disorders, particularly cluster headache and migraine. Future research should focus on elucidating the underlying mechanisms of benefit of melatonin in different headache disorders, as well as clarifying optimal dosing and formulation. PMID:27316772

  12. Tryptophan affects both gastrointestinal melatonin production and interrenal activity in stressed and nonstressed rainbow trout.

    PubMed

    Lepage, Olivier; Larson, Earl T; Mayer, Ian; Winberg, Svante

    2005-05-01

    The present experiments were designed to test the hypothesis that elevated dietary levels of l-tryptophan (Trp) result in elevated plasma levels of melatonin and that this increase in plasma melatonin concentration is caused by elevated melatonin production and secretion by the gastro-intestinal-tract (GIT). Feeding juvenile rainbow trout (Oncorhynchus mykiss) Trp-supplemented feed for 7 days resulted in elevated daytime plasma levels of melatonin and reduced poststress plasma cortisol concentrations. Nighttime plasma melatonin concentrations were, however, not affected by elevated dietary Trp. Moreover, stress caused a reduction in daytime plasma levels of melatonin in fish fed Trp-supplemented feed, an effect that was counteracted by treatment with an alpha-receptor antagonist. These results clearly suggest that elevated dietary intake of Trp results in an increase in the GIT production of melatonin in rainbow trout. A suggestion that was further supported by the results from an in vitro experiment demonstrating that addition of Trp to the incubation medium stimulates melatonin production and release by incubated rainbow trout GIT. The results from this study led us to suggest a possible mechanism for melatonin in mediating the effects of elevated dietary Trp on poststress plasma cortisol concentrations and aggressive behavior in rainbow trout.

  13. Elevated production of melatonin in transgenic rice seeds expressing rice tryptophan decarboxylase.

    PubMed

    Byeon, Yeong; Park, Sangkyu; Lee, Hyoung Yool; Kim, Young-Soon; Back, Kyoungwhan

    2014-04-01

    A major goal of plant biotechnology is to improve the nutritional qualities of crop plants through metabolic engineering. Melatonin is a well-known bioactive molecule with an array of health-promoting properties, including potent antioxidant capability. To generate melatonin-rich rice plants, we first independently overexpressed three tryptophan decarboxylase isogenes in the rice genome. Melatonin levels were altered in the transgenic lines through overexpression of TDC1, TDC2, and TDC3; TDC3 transgenic seed (TDC3-1) had melatonin concentrations 31-fold higher than those of wild-type seeds. In TDC3 transgenic seedlings, however, only a doubling of melatonin content occurred over wild-type levels. Thus, a seed-specific accumulation of melatonin appears to occur in TDC3 transgenic lines. In addition to increased melatonin content, TDC3 transgenic lines also had enhanced levels of melatonin intermediates including 5-hydroxytryptophan, tryptamine, serotonin, and N-acetylserotonin. In contrast, expression levels of melatonin biosynthetic mRNA did not increase in TDC3 transgenic lines, indicating that increases in melatonin and its intermediates in these lines are attributable exclusively to overexpression of the TDC3 gene.

  14. Advances in the Research of Melatonin in Autism Spectrum Disorders: Literature Review and New Perspectives

    PubMed Central

    Tordjman, Sylvie; Najjar, Imen; Bellissant, Eric; Anderson, George M.; Barburoth, Marianne; Cohen, David; Jaafari, Nemat; Schischmanoff, Olivier; Fagard, Rémi; Lagdas, Enas; Kermarrec, Solenn; Ribardiere, Sophie; Botbol, Michel; Fougerou, Claire; Bronsard, Guillaume; Vernay-Leconte, Julie

    2013-01-01

    Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests. PMID:24129182

  15. Melatonin receptors in diabetes: a potential new therapeutical target?

    PubMed

    She, Meihua; Laudon, Moshe; Yin, Weidong

    2014-12-05

    Melatonin is synthesized and secreted mainly by the pineal gland in a circadian fashion, and it thus mediates endogenous circadian rhythms and influences other physiological functions. Both the G-protein coupled receptors MT1 (encoded by MTNR1A) and MT2 (encoded by MTNR1B) in mammals mediate the actions of melatonin. Evidence from in vivo and in vitro studies proved a key role of melatonin in the regulation of glucose metabolism and the pathogenesis of diabetes, as further confirmed by the recent studies of human genetic variants of MTNR1B. Remarkably, it was also suggested that genetic variations within MTNR1B disordered β-cells function directly, i.e. insulin secretion. This indicated the functional link between MT2 and T2D risk at the protein level, and it may represent the prevailing pathomechanism for how impaired melatonin signaling causes metabolic disorders and increases the T2D risk. It is speculated that melatonin and its receptors may be a new therapeutic avenue in diabetes.

  16. Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene.

    PubMed

    Mulder, H; Nagorny, C L F; Lyssenko, V; Groop, L

    2009-07-01

    Melatonin is a circulating hormone that is primarily released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms; its levels are high during the night and low during the day. Interestingly, insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release. Indeed, both melatonin receptor 1A (MTNR1A) and MTNR1B are expressed in pancreatic islets. The role of melatonin in the regulation of glucose homeostasis has been highlighted by three independent publications based on genome-wide association studies of traits connected with type 2 diabetes, such as elevated fasting glucose, and, subsequently, of the disease itself. The studies demonstrate a link between variations in the MTNR1B gene, hyperglycaemia, impaired early phase insulin secretion and beta cell function. The risk genotype predicts the future development of type 2 diabetes. Carriers of the risk genotype exhibit increased expression of MTNR1B in islets. This suggests that these individuals may be more sensitive to the actions of melatonin, leading to impaired insulin secretion. Blocking the inhibition of insulin secretion by melatonin may be a novel therapeutic avenue for type 2 diabetes.

  17. Analysis Method and Experimental Conditions Affect Computed Circadian Phase from Melatonin Data

    PubMed Central

    Klerman, Hadassa; St. Hilaire, Melissa A.; Kronauer, Richard E.; Gooley, Joshua J.; Gronfier, Claude; Hull, Joseph T.; Lockley, Steven W.; Santhi, Nayantara; Wang, Wei; Klerman, Elizabeth B.

    2012-01-01

    Accurate determination of circadian phase is necessary for research and clinical purposes because of the influence of the master circadian pacemaker on multiple physiologic functions. Melatonin is presently the most accurate marker of the activity of the human circadian pacemaker. Current methods of analyzing the plasma melatonin rhythm can be grouped into three categories: curve-fitting, threshold-based and physiologically-based linear differential equations. To determine which method provides the most accurate assessment of circadian phase, we compared the ability to fit the data and the variability of phase estimates for seventeen different markers of melatonin phase derived from these methodological categories. We used data from three experimental conditions under which circadian rhythms - and therefore calculated melatonin phase - were expected to remain constant or progress uniformly. Melatonin profiles from older subjects and subjects with lower melatonin amplitude were less likely to be fit by all analysis methods. When circadian drift over multiple study days was algebraically removed, there were no significant differences between analysis methods of melatonin onsets (P = 0.57), but there were significant differences between those of melatonin offsets (P<0.0001). For a subset of phase assessment methods, we also examined the effects of data loss on variability of phase estimates by systematically removing data in 2-hour segments. Data loss near onset of melatonin secretion differentially affected phase estimates from the methods, with some methods incorrectly assigning phases too early while other methods assigning phases too late; missing data at other times did not affect analyses of the melatonin profile. We conclude that melatonin data set characteristics, including amplitude and completeness of data collection, differentially affect the results depending on the melatonin analysis method used. PMID:22511928

  18. Altered secretion of selected arachidonic acid metabolites during subclinical endometritis relative to estrous cycle stage and grade of fibrosis in mares.

    PubMed

    Gajos, Katarzyna; Kozdrowski, Roland; Nowak, Marcin; Siemieniuch, Marta J

    2015-08-01

    Mares that fail to become pregnant after repeated breeding, without showing typical signs of clinical endometritis, should be suspected of subclinical endometritis (SE). Contact with infectious agents results in altered synthesis and secretion of inflammatory mediators, including cytokines and arachidonic acid metabolites, and disturbs endometrial functional balance. To address the hypothesis that SE affects the immune endocrine status of the equine endometrium, spontaneous secretion of prostaglandin E(2) (PGE(2)), prostaglandin F(2α) (PGF(2α)), 6-keto-PGF(1α )(a metabolite of prostacyclin I(2)), leukotriene B(4) (LTB(4)), and leukotriene C(4) (LTC(4)) was examined. In addition, secretion of these factors was examined relative to the grade of inflammation, fibrosis, and estrous cycle stage. Eighty-two warmblood mares, of known breeding history, were enrolled in this study. On the basis of histopathologic assessment, mares were classified as suffering from first-grade SE, second-grade SE, or being healthy. The grade of fibrosis and the infiltration of endometrial tissue with polymorphonuclear leukocytes were examined by routine hematoxylin-eosin staining. In mares suffering from SE, the secretion profiles of PGE(2), 6-keto-PGF(1α), LTB(4), and LTC(4) were changed compared to mares that did not suffer from endometritis. The secretion of PGE(2) and 6-keto-PGF1α was increased, whereas that of LTB(4) and LTC(4) was decreased. Secretion of 6-keto-PGF(1α) was increased in first- and second-grade SE (P < 0.01). The concentration of PGI(2) metabolite was increased only in inflamed endometrium, independently of the inflammation grade, but was not affected by fibrosis. Prostaglandin E(2) secretion was increased in second-grade SE (P < 0.05). The secretion of LTB(4) decreased in both first- and second-grade SE (P < 0.05), whereas secretion of LTC(4) was decreased only in second-grade SE (P < 0.05). Fibrosis did not change the secretion profile of PGE(2), PGF(2α), and 6

  19. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease.

    PubMed

    Videnovic, Aleksandar; Noble, Charleston; Reid, Kathryn J; Peng, Jie; Turek, Fred W; Marconi, Angelica; Rademaker, Alfred W; Simuni, Tanya; Zadikoff, Cindy; Zee, Phyllis C

    2014-04-01

    Diurnal fluctuations of motor and nonmotor symptoms and a high prevalence of sleep-wake disturbances in Parkinson disease (PD) suggest a role of the circadian system in the modulation of these symptoms. However, surprisingly little is known regarding circadian function in PD and whether circadian dysfunction is involved in the development of sleep-wake disturbances in PD. To determine the relationship between the timing and amplitude of the 24-hour melatonin rhythm, a marker of endogenous circadian rhythmicity, with self-reported sleep quality, the severity of daytime sleepiness, and disease metrics. A cross-sectional study from January 1, 2009, through December 31, 2012, of 20 patients with PD receiving stable dopaminergic therapy and 15 age-matched control participants. Both groups underwent blood sampling for the measurement of serum melatonin levels at 30-minute intervals for 24 hours under modified constant routine conditions at the Parkinson's Disease and Movement Disorders Center of Northwestern University. Twenty-four hour monitoring of serum melatonin secretion. Clinical and demographic data, self-reported measures of sleep quality (Pittsburgh Sleep Quality Index) and daytime sleepiness (Epworth Sleepiness Scale), and circadian markers of the melatonin rhythm, including the amplitude, area under the curve (AUC), and phase of the 24-hour rhythm. Patients with PD had blunted circadian rhythms of melatonin secretion compared with controls; the amplitude of the melatonin rhythm and the 24-hour AUC for circulating melatonin levels were significantly lower in PD patients (P < .001). Markers of the circadian phase were not significantly different between the 2 groups. Compared with PD patients without excessive daytime sleepiness, patients with excessive daytime sleepiness (Epworth Sleepiness Scale score ≥10) had a significantly lower amplitude of the melatonin rhythm and 24-hour melatonin AUC (P = .001). Disease duration, Unified Parkinson's Disease

  20. Twice daily melatonin peaks in Siberian but not Syrian hamsters under 24 h light:dark:light:dark cycles.

    PubMed

    Raiewski, Evan E; Elliott, Jeffrey A; Evans, Jennifer A; Glickman, Gena L; Gorman, Michael R

    2012-11-01

    The daily pattern of blood-borne melatonin varies seasonally under the control of a multi-oscillator circadian pacemaker. Here we examine patterns of melatonin secretion and locomotor activity in Siberian and Syrian hamsters entrained to bimodal LDLD8:4:8:4 and LD20:4 lighting schedules that facilitate novel temporal arrangements of component circadian oscillators. Under LDLD, both species robustly bifurcated wheel-running activity in distinct day scotophase (DS) and night scotophase (NS) bouts. Siberian hamsters displayed significant melatonin increases during each scotophase in LDLD, and in the single daily scotophase of LD20:4. The bimodal melatonin secretion pattern persisted in acutely extended 16 h scotophases. Syrian hamsters, in contrast, showed no significant increases in plasma melatonin during either scotophase of LDLD8:4:8:4 or in LD20:4. In this species, detectable levels were observed only when the DS of LDLD was acutely extended to yield 16 h of darkness. Established species differences in the phase lag of nocturnal melatonin secretion relative to activity onset may underlie the above contrast: In non-bifurcated entrainment to 24 h LD cycles, Siberian hamsters show increased melatonin secretion within ≈ 2 h after activity onset, whereas in Syrian hamsters, detectable melatonin secretion phase lags activity onset and the L/D transition by at least 4 h. The present results provide new evidence indicating multi-oscillator regulation of the waveform of melatonin secretion, specifically, the circadian control of the onset, offset and duration of nocturnal secretion.

  1. In vitro seasonal variations of LH, FSH and prolactin secretion of the male rat are dependent on the maternal pineal gland.

    PubMed

    Díaz, E; Vázquez, N; Fernández, C; Jiménez, V; Esquifino, A; Díaz, B

    2012-01-17

    The maternal pineal gland is involved in the seasonal rhythms entrainment. We evaluate the effect of maternal pinealectomy (PIN-X), also melatonin replacement (PIN-X+MEL) during pregnancy on "in vitro" gonadotropins and prolactin seasonal variations. Male offspring from control, PIN-X and PIN-X+MEL mother Wistar rats were studied at 31 and 60 days of age. In vitro LH release from controls was season-dependent during prepubertal and pubertal periods showing reduced values in winter. The mother pineal gland seems to be important in the entrainment of seasonal variations of in vitro pituitary LH release, since altered secretion showing very high values was observed in summer. Melatonin treatment to PIN-X mothers partially restored the LH response. The effect of pinealectomy upon LH secretion disappears at the pubertal phase. A different pattern was observed for FSH release, without seasonal variations at 31 or at 60 days of age in control offspring, but pinealectomy to mothers or melatonin treatment resulted in seasonal variations. Seasonal influence was also observed in the prolactin pituitary release of controls. PIN-X mother offspring showed delayed seasonal variations at 31 and 60 days of age. The effect of maternal melatonin treatment during pregnancy was observed up to 60 days of age.

  2. Pilot Investigation of the Circadian Plasma Melatonin Rhythm across the Menstrual Cycle in a Small Group of Women with Premenstrual Dysphoric Disorder

    PubMed Central

    Shechter, Ari; Lespérance, Paul; Ng Ying Kin, N. M. K.; Boivin, Diane B.

    2012-01-01

    Women with premenstrual dysphoric disorder (PMDD) experience mood deterioration and altered circadian rhythms during the luteal phase (LP) of their menstrual cycles. Disturbed circadian rhythms may be involved in the development of clinical mood states, though this relationship is not fully characterized in PMDD. We therefore conducted an extensive chronobiological characterization of the melatonin rhythm in a small group of PMDD women and female controls. In this pilot study, participants included five women with PMDD and five age-matched controls with no evidence of menstrual-related mood disorders. Participants underwent two 24-hour laboratory visits, during the follicular phase (FP) and LP of the menstrual cycle, consisting of intensive physiological monitoring under “unmasked”, time-isolation conditions. Measures included visual analogue scale for mood, ovarian hormones, and 24-hour plasma melatonin. Mood significantly (P≤.03) worsened during LP in PMDD compared to FP and controls. Progesterone was significantly (P = .025) increased during LP compared to FP, with no between-group differences. Compared to controls, PMDD women had significantly (P<.05) decreased melatonin at circadian phases spanning the biological night during both menstrual phases and reduced amplitude of its circadian rhythm during LP. PMDD women also had reduced area under the curve of melatonin during LP compared to FP. PMDD women showed affected circadian melatonin rhythms, with reduced nocturnal secretion and amplitude during the symptomatic phase compared to controls. Despite our small sample size, these pilot findings support a role for disturbed circadian rhythms in affective disorders. Possible associations with disrupted serotonergic transmission are proposed. PMID:23284821

  3. Effect of melatonin on hemolymph glucose and lactate levels in the fiddler crab Uca pugilator.

    PubMed

    Tilden, A; McGann, L; Schwartz, J; Bowe, A; Salazar, C

    2001-09-01

    Melatonin was injected into intact and eyestalk-ablated fiddler crabs (Uca pugilator), and its effects on hemolymph glucose and lactate levels were studied. In intact crabs, glucose and lactate levels cycled simultaneously, with peaks occurring during early and late photophase. Melatonin caused a shift in the glucose and lactate cycles, with only one peak occurring closer to mid-photophase. In eyestalk-ablated animals, the glucose rhythmicity was lost; lactate cycled, but levels were significantly lower than in intact animals. Melatonin caused a delayed hyperglycemia in eyestalk-ablated animals, with concurrent but much lower increases in lactate. Overall, melatonin demonstrated delayed hyperglycemic effects that do not appear to be mediated solely via eyestalk factors such as crustacean hyperglycemic hormone (CHH), though involvement of the eyestalks cannot be ruled out. An influence on extra-eyestalk CHH secretion is a potential mechanism of melatonin activity.

  4. Cultured fibroblast monolayers secrete a protein that alters the cellular binding of somatomedin-C/insulinlike growth factor I

    SciTech Connect

    Clemmons, D.R.; Elgin, R.G.; Han, V.K.; Casella, S.J.; D'Ercole, A.J.; Van Wyk, J.J.

    1986-05-01

    We studied somatomedin-C/insulinlike growth factor (Sm-C/IGF-I) binding to human fibroblasts in both adherent monolayers and in suspension cultures. The addition of Sm-C/IGF-I in concentrations between 0.5 and 10 ng/ml to monolayers cultures resulted in a paradoxical increase in /sup 125/I-Sm-C/IGF-I binding and concentrations between 25 and 300 ng/ml were required to displace the labeled peptide. The addition of unlabeled insulin resulted in no displacement of labeled Sm-C/IGF-I from the adherent cells. When fibroblast suspensions were used Sm-C/IGF-I concentrations between 1 and 10 ng/ml caused displacement, the paradoxical increase in /sup 125/I-Sm-C/IGF-I binding was not detected, and insulin displaced 60% of the labeled peptide. Affinity cross-linking to fibroblast monolayers revealed a 43,000-mol wt /sup 125/I-Sm-C-binding-protein complex that was not detected after cross-linking to suspended cells. The 43,000-mol wt complex was not detected after cross-linking to smooth muscle cell monolayers, and binding studies showed that /sup 125/I-Sm-C/IGF-I was displaced greater than 90% by Sm-C/IGF-I using concentrations between 0.5 and 10 ng/ml. Because fibroblast-conditioned medium contains the 43,000-mol wt complex, smooth muscle cells were incubated with conditioned medium for 24 h prior to initiation of the binding studies. /sup 125/I-Sm-C/IGF-I-binding increased 1.6-fold compared to control cultures and after cross-linking the 43,000-mol wt complex could be detected on the smooth muscle cell surface. Human fibroblast monolayers secrete a protein that binds /sup 125/I-Sm-C/IGF-I which can be transferred to the smooth muscle cell surface and alters 125I-Sm-C/IGF-I binding.

  5. Experimental and clinical aspects of melatonin and clock genes in diabetes.

    PubMed

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2015-08-01

    The pineal hormone melatonin influences insulin secretion, as well as glucagon and somatostatin secretion, both in vivo and in vitro. These effects are mediated by two specific, high-affinity, seven transmembrane, pertussis toxin-sensitive, Gi-protein-coupled melatonin receptors, MT1 and MT2. Both isoforms are expressed in the β-cells, α-cells as well as δ-cells of the pancreatic islets of Langerhans and are involved in the modulation of insulin secretion, leading to inhibition of the adenylate cyclase-dependent cyclic adenosine monophosphate as well as cyclic guanosine monophosphate formation in pancreatic β-cells by inhibiting the soluble guanylate cyclase, probably via MT2 receptors. In this way, melatonin also likely inhibits insulin secretion, whereas using the inositol triphosphate pathway after previous blocking of Gi-proteins by pertussis toxin, melatonin increases insulin secretion. Desynchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genomewide association studies pinpointing variances of the MT2 receptor as a risk factor for this rapidly spreading metabolic disturbance. As melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. Observations of the circadian expression of clock genes (Clock, Bmal1, Per1,2,3, and Cry1,2) in pancreatic islets, as well as in INS1 rat insulinoma cells, may indicate that circadian rhythms are generated in the β-cells themselves. The circadian secretion of insulin from pancreatic islets is clock-driven. Disruption of circadian rhythms and clock function leads to metabolic disturbances, for example, type 2 diabetes. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship between these two hormones. Both type 2 diabetic rats and patients exhibit decreased melatonin levels and slightly increased

  6. Exacerbation of methamphetamine-induced neurochemical deficits by melatonin.

    PubMed

    Gibb, J W; Bush, L; Hanson, G R

    1997-11-01

    Methamphetamine (METH), administered in large, repeated doses, compromises the dopaminergic and serotonergic systems as indicated by prolonged suppression of tyrosine hydroxylase and tryptophan hydroxylase activity and concurrent decreases in the content of dopamine and 5-hydroxytryptamine. Because dopamine is necessary for these dopaminergic and serotonergic deficits we postulated that dopamine and/or its reactive metabolites are responsible for these degenerative alterations. Because we previously demonstrated that in vitro reducing conditions reverse the decrease in tryptophan hydroxylase activity, we reasoned that melatonin, a purported endogenous antioxidant, may alter this response. Rats were treated with METH and/or melatonin and trytophan hydroxylase activity and 5-hydroxytryptamine content were assessed; tyrosine hydroxylase activity and dopamine content were also measured. Not only did melatonin not prevent METH-induced deficits in serotonergic and dopaminergic parameters, but coadministration of melatonin with METH actually enhanced most of the monoaminergic effects of METH. This enhancing effect could not be attributed to alteration of body temperature. Because METH abuse causes insomnia and melatonin is promoted in some countries for insomnia, the implications of the interaction between these two drugs could be clinically important.

  7. Melatonin and brain inflammaging.

    PubMed

    Hardeland, Rüdiger; Cardinali, Daniel P; Brown, Gregory M; Pandi-Perumal, Seithikurippu R

    2015-04-01

    Melatonin is known to possess several properties of value for healthy aging, as a direct and indirect antioxidant, protectant and modulator of mitochondrial function, antiexcitotoxic agent, enhancer of circadian amplitudes, immune modulator and neuroprotectant. It is levels tend to decrease in the course of senescence and are more strongly reduced in several neurodegenerative disorders, especially Alzheimer's disease, and in diseases related to insulin resistance such as diabetes type 2. Although the role of melatonin in aging and age-related diseases has been repeatedly discussed, the newly emerged concept of inflammaging, that is, the contribution of low-grade inflammation to senescence progression has not yet been the focus of melatonin research. This review addresses the multiple protective actions of melatonin and its kynuramine metabolites that are relevant to the attenuation of inflammatory responses and progression of inflammaging in the brain, i.e. avoidance of excitotoxicity, reduction of free radical formation by support of mitochondrial electron flux, prevention of NADPH oxidase activation and suppression of inducible nitric oxide synthase, as well as downregulation of proinflammatory cytokines. The experimental evidence is primarily discussed on the basis of aging and senescence-accelerated animals, actions in the immune system, and the relationship between melatonin and sirtuins, having properties of aging suppressors. Sirtuins act either as accessory components or downstream factors of circadian oscillators, which are also under control by melatonin. Inflammaging is assumed to strongly contribute to neurodegeneration of the circadian master clock observed in advanced senescence and, even more, in Alzheimer's disease, a change that affects countless physiological functions.

  8. A direct influence of moonlight intensity on changes in melatonin production by cultured pineal glands of the golden rabbitfish, Siganus guttatus.

    PubMed

    Takemura, Akihiro; Ueda, Satomi; Hiyakawa, Nanae; Nikaido, Yoshiaki

    2006-04-01

    Rabbitfish are a restricted lunar-synchronized spawner that spawns around a species-specific lunar phase. It is not known how the fish perceive changes in cues from the moon. One possible explanation is that rabbitfish utilize changes in moonlight intensity to establish synchrony. The purpose of the present study was to examine whether or not the pineal gland of the golden rabbitfish can directly perceive changes in moonlight intensity. Isolated pineal glands were statically cultured under natural or artificial light conditions and melatonin secreted into the culture medium was measured using a time-resolved fluoroimmunoassay. Under an artificial light/dark cycle, melatonin secretion significantly increased during the dark phase. Under continuous light conditions, melatonin secretion was suppressed, while culture under continuous dark conditions seemed to duplicate melatonin secretion corresponding to the light/dark cycle in which the fish were acclimated. When cultured pineal glands were kept under natural light conditions on the dates of the full and the new moon, small amounts of melatonin were secreted at night. Moreover, exposure of cultured pineal glands to artificial and natural light conditions resulted in a significant decrease of melatonin secretion within 2 hr. These results suggest that the isolated pineal gland of golden rabbitfish responds to environmental light cycles and that 'brightness' of the night moon has an influence on melatonin secretion from the isolated pineal gland.

  9. Vascular endothelial cells and dysfunctions: role of melatonin.

    PubMed

    Rodella, Luigi Fabrizio; Favero, Gaia; Foglio, Eleonora; Rossini, Claudia; Castrezzati, Stefania; Lonati, Claudio; Rezzani, Rita

    2013-01-01

    Several pathological conditions, including hypertension, atherosclerosis, diabetes, ischemia/reperfusion injury and nicotine-induced vasculopathy, are associated with vascular endothelial dysfunction characterized by altered secretory output of endothelial cells. Therefore there is a search for molecules and interventions that could restore endothelial function, in particular augmenting NO production, reducing the generation of free radicals and vasoconstrictors and preventing undesired inflammation. The pineal hormone melatonin exhibits several endothelium protective properties: it scavenges free radicals, activates antioxidant defence enzymes, normalizes lipid and blood pressure profile and increases NO bioavailability. Melatonin improved vascular function in experimental hypertension, reducing intimal infiltration and restoring NO production. Melatonin improved the NO pathway also in animal models for the study of diabetes and prevented NO down-regulation and adhesive molecules up-regulation in nicotine-induced vasculopathy. The protection against endothelial damage, vasoconstriction, platelet aggregation and leukocyte infiltration might contribute to the beneficial effects against ischemia-reperfusion injury by melatonin. Therefore, melatonin administration has endothelium-protective potential in several pathological conditions. Nevertheless, it still needs to be established, whether melatonin is able to revert already established endothelial dysfunction in these conditions.

  10. The role of melatonin in anaesthesia and critical care

    PubMed Central

    Kurdi, Madhuri S; Patel, Tushar

    2013-01-01

    Melatonin is a neurohormone secreted by the pineal gland. It is widely present in both plant and animal sources. In several countries, it is sold over the counter as tablets and as food supplement or additive. Currently, it is most often used to prevent jet lag and to induce sleep. It has been and is being used in several clinical trials with different therapeutic approaches. It has sedative, analgesic, anti-inflammatory, anti-oxidative and chronobiotic effects. In the present review, the potential therapeutic benefits of melatonin in anaesthesia and critical care are presented. This article aims to review the physiological properties of melatonin and how these could prove useful for several clinical applications in perioperative management, critical care and pain medicine. The topic was handsearched from textbooks and journals and electronically from PubMed, and Google scholar using text words. PMID:23825812

  11. Melatonin regulates catecholamine biosynthesis by modulating bone morphogenetic protein and glucocorticoid actions.

    PubMed

    Komatsubara, Motoshi; Hara, Takayuki; Hosoya, Takeshi; Toma, Kishio; Tsukamoto-Yamauchi, Naoko; Iwata, Nahoko; Inagaki, Kenichi; Wada, Jun; Otsuka, Fumio

    2017-01-01

    Melatonin is functionally involved in the control of circadian rhythm and hormonal secretion. In the present study, we investigated the roles of melatonin in the interaction of catecholamine synthesis with adrenocortical steroids by focusing on bone morphogenetic protein (BMP)-4 expressed in the adrenal medulla using rat pheochromocytoma PC12 cells. Melatonin treatment significantly reduced the mRNA expression of catecholamine synthases, including the rate-limiting enzyme tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanine decarboxylase and dopamine-β-hydroxylase expressed in PC12 cells. In accordance with changes in the expression levels of enzymes, dopamine production and cAMP synthesis determined in the culture medium and cell lysate were also suppressed by melatonin. The MT1 receptor, but not the MT2 receptor, was expressed in PC12 cells, and luzindole treatment reversed the inhibitory effect of melatonin on Th expression, suggesting that MT1 is a functional receptor for the control of catecholamine synthesis. Interestingly, melatonin enhanced the inhibitory effect of BMP-4 on Th mRNA expression in PC12 cells. Melatonin treatment accelerated BMP-4-induced phosphorylation of SMAD1/5/8 and transcription of the BMP target gene Id1. Of note, melatonin significantly upregulated Alk2 and Bmpr2 mRNA levels but suppressed inhibitory Smad6/7 expression, leading to the enhancement of SMAD1/5/8 signaling in PC12 cells, while BMP-4 did not affect Mt1 expression. Regarding the interaction with adrenocortical steroids, melatonin preferentially enhanced glucocorticoid-induced Th mRNA through upregulation of the glucocorticoid receptor and downregulation of Bmp4 expression, whereas melatonin repressed Th mRNA expression induced by aldosterone or androgen without affecting expression levels of the receptors for mineralocorticoid and androgen. Collectively, the results indicate that melatonin plays a modulatory role in catecholamine synthesis by cooperating with BMP-4 and

  12. Comparative photosynthetic and metabolic analyses reveal mechanism of improved cold stress tolerance in bermudagrass by exogenous melatonin.

    PubMed

    Hu, Zhengrong; Fan, Jibiao; Xie, Yan; Amombo, Erick; Liu, Ao; Gitau, Margaret Mukami; Khaldun, A B M; Chen, Liang; Fu, Jinmin

    2016-03-01

    Melatonin (N-acetyl-5-methoxytryptamine) has been reported to participate in plant development and abiotic stress responses. The main objective of this study was to investigate the role of melatonin in the cold-sensitive (S) and the cold-tolerant (T) bermudagrass genotypes' response to cold stress. The genotypes were treated with 100 μM melatonin and exposed to 4 °C temperature for 3 days. In both genotypes, cold stress increased the endogenous melatonin levels, and more prominently in T than S. Physiological responses indicated that exogenous melatonin triggered antioxidant activities in both genotypes, while it alleviated cell damage in the T genotype response to cold stress. Melatonin treatment under cold stress increased fluorescence curve levels for both genotypes, and higher in T than S genotypes. In both genotypes, the alterations in photosynthetic fluorescence parameters after melatonin treatment highlighted the participation of melatonin in improving photosystem response to cold stress, particularly for the cold-tolerant genotype. The metabolic analyses revealed the alterations of 44 cold-responsive metabolites in the two genotypes, mainly including carbohydrates, organic acids and amino acids. After exogenous melatonin treatment under cold condition, there was high accumulation of metabolites in the cold-tolerant regimes than their cold-sensitive counterparts. Collectively, the present study revealed differential modulations of melatonin between the cold-sensitive and the cold-tolerant genotypes in response to cold stress. This was mainly by impacting antioxidant system, photosystem II, as well as metabolic homeostasis.

  13. Photic and circadian regulation of melatonin production in the Mozambique tilapia Oreochromis mossambicus.

    PubMed

    Nikaido, Yoshiaki; Ueda, Satomi; Takemura, Akihiro

    2009-01-01

    Diverse circadian systems related to phylogeny and ecological adaptive strategies are proposed in teleosts. Recently, retinal photoreception was reported to be important for the circadian pacemaking activities of the Nile tilapia Oreochromis niloticus. We aimed to confirm the photic and circadian responsiveness of its close relative-the Mozambique tilapia O. mossambicus. Melatonin production in cannulated or ophthalmectomized fish and its secretion from cultured pineal glands were examined under several light regimes. Melatonin production in the cannulated tilapias was measured at 3-h intervals; it fluctuated daily, with a nocturnal increase and a diurnal decrease. Exposing the cannulated fish to several light intensities (1500-0.1 lx) and to natural light (0.1 and 0.3 lx) suppressed melatonin levels within 30 min. Static pineal gland culture under light-dark and reverse light-dark cycles revealed that melatonin synthesis increased during the dark periods. Rhythmic melatonin synthesis disappeared on pineal gland culture under constant dark and light conditions. After ophthalmectomy, plasma melatonin levels did not vary with light-dark cycles. These results suggest that (1) Mozambique tilapias possess strong photic responsiveness, (2) their pineal glands are sensitive to light but lack circadian pacemaker activity, and (3) they require lateral eyes for rhythmic melatonin secretion from the pineal gland.

  14. Lack of effect of ghrelin treatment on melatonin production in rat pineal and Harderian glands.

    PubMed

    Djeridane, Yasmina; Touitou, Yvan

    2005-04-01

    The effects of ghrelin, a peptide hormone secreted from the stomach, on melatonin remain unknown. The aim of the study was to investigate possible ghrelin-melatonin interactions by studying the effect of ghrelin treatment on melatonin production in rat pineal and Harderian glands. Young (9 weeks) and old (20 months) male Wistar rats, maintained under a light:dark cycle regimen of 12:12, were assigned randomly to either a single subcutaneous (s.c.) injection of saline or ghrelin (1 microg/rat or 15 microg/rat) 1 h before sacrifice in the middle of the dark phase, or repeated s.c. saline or ghrelin injections (15 microg/rat), 3, 2 and 1 h before sacrificed in the middle of the dark phase. Neither ghrelin doses (1 microg/rat or 15 microg/rat) nor type of treatment (acute or repeated) influenced melatonin levels or the melatonin synthesizing enzymes N-acetyltransferase and hydroxyindole-O-methyltransferase activities, either in pineal gland or in Harderian glands. At the concentrations used, ghrelin does not influence melatonin production in rat pineal and Harderian glands, and therefore is not involved in the regulation of melatonin secretion, at least under our experimental conditions.

  15. Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults

    PubMed Central

    Gooneratne, Nalaka S.; Edwards, Alena Y. Z.; Zhou, Chen; Cuellar, Norma; Grandner, Michael A.; Barrett, Jeffrey S.

    2013-01-01

    Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low dose (<0.5 mg) and high dose (>2 mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low (0.4 mg) and high (4.0 mg) dose melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine if melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3 hrs vs 1.5 hrs), elimination half-life (1.8 hrs vs 2.1 hrs), and apparent total clearance (379 l/hr vs 478 l/hr) did not differ significantly between the low and high dose arms, respectively. The maximum concentration was 405±93 pg/ml for the low dose arm and 3999±700 pg/ml for the high dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high dose arm maintained melatonin levels >50 pg/ml for an average of 10 hours, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6 weeks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes. PMID:22348451

  16. Circadian regulation of bird song, call, and locomotor behavior by pineal melatonin in the zebra finch.

    PubMed

    Wang, Gang; Harpole, Clifford E; Trivedi, Amit K; Cassone, Vincent M

    2012-04-01

    As both a photoreceptor and pacemaker in the avian circadian clock system, the pineal gland is crucial for maintaining and synchronizing overt circadian rhythms in processes such as locomotor activity and body temperature through its circadian secretion of the pineal hormone melatonin. In addition to receptor presence in circadian and visual system structures, high-affinity melatonin binding and receptor mRNA are present in the song control system of male oscine passeriform birds. The present study explores the role of pineal melatonin in circadian organization of singing and calling behavior in comparison to locomotor activity under different lighting conditions. Similar to locomotor activity, both singing and calling behavior were regulated on a circadian basis by the central clock system through pineal melatonin, since these behaviors free-ran with a circadian period and since pinealectomy abolished them in constant environmental conditions. Further, rhythmic melatonin administration restored their rhythmicity. However, the rates by which these behaviors became arrhythmic and the rates of their entrainment to rhythmic melatonin administration differed among locomotor activity, singing and calling under constant dim light and constant bright light. Overall, the study demonstrates a role for pineal melatonin in regulating circadian oscillations of avian vocalizations in addition to locomotor activity. It is suggested that these behaviors might be controlled by separable circadian clockworks and that pineal melatonin entrains them all through a circadian clock.

  17. Effects of moonlight exposure on plasma melatonin rhythms in the seagrass rabbitfish, Siganus canaliculatus.

    PubMed

    Rahman, Md Saydur; Kim, Byung-Ho; Takemura, Akihiro; Park, Chang-Bum; Lee, Young-Don

    2004-08-01

    Influences of light-dark (LD) cycle and moonlight exposure on plasma melatonin rhythms in the seagrass rabbitfish, Siganus canaliculatus, a lunar synchronized spawner, were determined by time-resolved fluoroimmunoassay (TR-FIA). When the fish were exposed to a natural LD (12:12) cycle, plasma melatonin levels exhibited a clear daily rhythm, with higher levels at midnight and lower levels during the day. These rhythms were not evident under either constant light (LL) or constant dark (DD) conditions. Plasma melatonin levels under LL condition were low and high under DD condition. These results indicate that plasma melatonin rhythms are driven by LD cycle in this species. When the fish were exposed to the 4 lunar phases, plasma melatonin levels around the new moon were significantly higher than during the first quarter moon and the full moon. Exposure to experimental new moon and full moon conditions caused significant increases and decreases of plasma melatonin levels, respectively. The synchronous rhythmicity of melatonin levels in the plasma support the hypothesis that the seagrass rabbitfish perceives moonlight intensity and responds with secretion of melatonin into the bloodstream.

  18. Melatonin dietary supplement as an anti-aging therapy for age-related bone loss.

    PubMed

    Tresguerres, Isabel F; Tamimi, Faleh; Eimar, Hazem; Barralet, Jake E; Prieto, Santiago; Torres, Jesús; Calvo-Guirado, José Luis; Tresguerres, Jesús A F

    2014-08-01

    Previous studies have shown that melatonin, an anti-oxidant molecule secreted from the pineal gland, is a positive regulator of bone mass. However, the potential effects of melatonin on bone mass have never been investigated in an old population. The aim of this study was to assess the effects of dietary melatonin supplementation on mass accrual and biomechanical properties of old rat femora. Twenty 22-month-old male Wistar rats were divided into two randomly assigned groups. The first group was treated for 10 weeks with melatonin, whereas the second group was untreated (control). Rat femurs were collected, and their phenotypes and biomechanical properties were investigated by micro-computed tomography, histomorphometry, and a three-point-bending test. Statistical analyses were performed by the Student two-tailed unpaired t-test. In all experiments, a value of p<0.05 was considered significant. Rats treated with melatonin had higher bone volume, bone trabecular number, trabecular thickness, and cortical thickness in comparison to the control group. Histomorphometric analyses confirmed the increase of bone volume in melatonin-treated rats. In agreement with these findings, melatonin-treated rats showed higher bone stiffness, flexural modulus, and ultimate load compared to controls. These compelling results are the first evidence indicating that dietary melatonin supplementation is able to exert beneficial effects against age-related bone loss in old rats, improving the microstructure and biomechanical properties of aged bones.

  19. The association between melatonin production and electrophysiology of the guinea pig pineal gland.

    PubMed

    McCance, I; Parkington, H C; Coleman, H A

    1996-09-01

    Melatonin production by isolated pineal glands from guinea pigs was examined under conditions that affect membrane potential or the firing of action potential-like spikes. In glands from superior cervical ganglionectomized animals, depolarization resulting from increasing extracellular potassium concentration to 100 mM did not initiate melatonin production, and it delayed the response to the beta-adrenoceptor agonist orciprenaline. In glands from intact animals melatonin production was initiated by exposure to 100 mM potassium with a time-course similar to the response to orciprenaline. A proportion of this response was propanol resistant, suggesting that the normal control of melatonin production may involve a neurotransmitter in addition to norepinephrine. Exposure to verapamil or nifedipine, or removal of extracellular calcium, previously shown to eliminate action potential-like spikes, did not substantially affect the increase in melatonin production induced by orciprenaline. Phenylephrine, which stimulates spiking, produced only a slight increase in melatonin production. It is concluded that the depolarization and the spiking are not closely related to the stimulation of melatonin production, but may relate principally to the secretion of a substance other than melatonin.

  20. Melatonin rhythms in the Australian freshwater crocodile (Crocodylus johnstoni): a reptile lacking a pineal complex?

    PubMed

    Firth, Bruce T; Christian, Keith A; Belan, Ingrid; Kennaway, David J

    2010-01-01

    The vertebrate pineal gland is the primary source of melatonin, the rhythmic secretion of which is influenced by environmental light and temperature, thereby providing animals with information about seasonally changing photoperiod and thermoperiod. Although pineal glands are present in the majority of vertebrate species, a discrete organ is reported to be absent in the Crocodilia. However, if the melatonin rhythm is crucial to the survival of the organism, it would be expected that the rhythm would be present in crocodiles. In the present study, we measured blood plasma melatonin over a 30-h period in aestivating Australian freshwater crocodiles (Crocodylus johnstoni) in their natural habitat at the end of the dry season (November) and found no discernible melatonin rhythm. However, another group of captive-reared C. johnstoni, maintained under natural light and temperature cycles and sampled in the early dry season (June) showed a clear melatonin rhythm. These results suggest that there is either an extrapineal source of melatonin in this crocodile species or that there is melatonin producing tissue elsewhere which heretofore has not been discovered. Further studies are needed to determine why the melatonin rhythm is intermittently expressed and whether this may be related to seasonal changes in the expression of the rhythm linked to tropical environments.

  1. Rapid effects of melatonin on hormonal and behavioral stressful responses in ewes.

    PubMed

    Guesdon, Vanessa; Malpaux, Benoît; Delagrange, Philippe; Spedding, Michael; Cornilleau, Fabien; Chesneau, Didier; Haller, József; Chaillou, Elodie

    2013-08-01

    Sheep are gregarious mammals with complex social interactions. As such, they are very sensitive to social isolation and constitute a relevant animal model to study specifically the biological consequences of social stress. We examined previously the behavioral and endocrine responses in ewes isolated socially in the familiar conspecific withdrawal model (FCW) and showed that stressful responses increased and maintenance behaviors decreased, confirming that social isolation is a strong stressor in sheep. Melatonin synchronizes seasonal and circadian rhythms; and several studies reported its implication in cognitive processes as emotion. Here we investigated its role in the modulation of social stressful responses. Firstly, we studied ewes in the FCW model during the day (characterized by low melatonin levels) and the night (characterized by high melatonin levels). We found lower stressful responses (significant lower levels of cortisol plasma, number of foot pawings, of circling attempts) during the night as compared to the day. To investigate whether these effects were due to melatonin or to darkness, we submitted ewes to FCW during the night with lights on, a condition that suppresses melatonin secretion. Ewes infused with melatonin under these conditions showed decreased stressful responses (significant lower levels cortisol plasma, number of vocalizations, time spent with the head out of the cage) as compared to ewes infused with saline. These findings demonstrate that melatonin diminishes the endocrine and behavioral impact of social isolation in ewes and support the idea that melatonin has a calming effect in socially stressful situations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Maternal diabetes alters birth weight in glucokinase-deficient (MODY2) kindred but has no influence on adult weight, height, insulin secretion or insulin sensitivity.

    PubMed

    Velho, G; Hattersley, A T; Froguel, P

    2000-08-01

    Altered fetal insulin secretion caused by fetal or maternal glucokinase mutations influence birth weight. Here, we attempt to answer two additional questions: firstly, whether this variation in birth weight (from low birth weight to macrosomia) has an effect on adult height or weight. Secondly, whether maternal hyperglycaemia during fetal life has an effect on metabolic phenotypes of the adult offspring. We studied 447 family members from 37 MODY2 kindred, divided into four groups according to the presence or absence of a glucokinase mutation in the subject (S+ or S-, respectively) and his/her mother (M+ or M-). Birth weight data were obtained from a questionnaire sent to the mothers. Birth weight was reduced in the presence of a fetal mutation (M-S+) and increased in the presence of a maternal mutation (M+ S-). These effects are additive as similar birth weights were observed in M+ S+ and M-S- offspring. Adult height, weight or body mass index (weight/height2) were, however, similar in the four groups of subjects. Non-diabetic adult offspring, regardless of the glycaemic status of the mothers (M+ S- or M-S-), had similar insulin secretion, insulin sensitivity, blood pressures and lipid profiles. These variables as well as the severity of hyperglycaemia were similar in adult M+ S+ and M-S+ MODY2 subjects. Maternal environment and fetal genotypes could alter growth in utero by changing fetal insulin secretion but these effects do not result in a persistent programming in latter life.

  3. Melatonin and the pathologies of weakened or dysregulated circadian oscillators.

    PubMed

    Hardeland, Rüdiger

    2017-01-01

    Dynamic aspects of melatonin's actions merit increasing future attention. This concerns particularly entirely different effects in senescent, weakened oscillators and in dysregulated oscillators of cancer cells that may be epigenetically blocked. This is especially obvious in the case of sirtuin 1, which is upregulated by melatonin in aged tissues, but strongly downregulated in several cancer cells. These findings are not at all controversial, but are explained on the basis of divergent changes in weakened and dysregulated oscillators. Similar findings can be expected to occur in other accessory oscillator components that are modulated by melatonin, among them several transcription factors and metabolic sensors. Another cause of opposite effects concerns differences between nocturnally active laboratory rodents and the diurnally active human. This should be more thoroughly considered in the field of metabolic syndrome and related pathologies, especially with regard to type 2 diabetes and other aspects of insulin resistance. Melatonin was reported to impair glucose tolerance in humans, especially in carriers of the risk allele of the MT2 receptor gene, MTNR1B, that contains the SNP rs10830963. These findings contrast with numerous reports on improvements of glucose tolerance in preclinical studies. However, the relationship between melatonin and insulin may be more complex, as indicated by loss-of-function mutants of the MT2 receptor that are also prodiabetic, by the age-dependent time course of risk allele overexpression, by progressive reduction in circadian amplitudes and melatonin secretion, which are aggravated in diabetes. By supporting high-amplitude rhythms, melatonin may be beneficial in preventing or delaying diabetes.

  4. Melatonin in Glycyrrhiza uralensis: response of plant roots to spectral quality of light and UV-B radiation.

    PubMed

    Afreen, F; Zobayed, S M A; Kozai, T

    2006-09-01

    Melatonin (N-acetyl-5-methoxytryptamine) is known to be synthesized and secreted by the pineal gland in vertebrates. Evidence for the occurrence of melatonin in the roots of Glycyrrhiza uralensis plants and the response of this plant to the spectral quality of light including red, blue and white light (control) and UV-B radiation (280-315 nm) for the synthesis of melatonin were investigated. Melatonin was extracted and quantified in seed, root, leaf and stem tissues and results revealed that the root tissues contained the highest concentration of melatonin; melatonin concentrations also increased with plant development. After 3 months of growth under red, blue and white fluorescent lamps, the melatonin concentrations were highest in red light exposed plants and varied depending on the wavelength of light spectrum in the following order red > blue > or = white light. Interestingly, in a more mature plant (6 months) melatonin concentration was increased considerably; the increments in concentration were X4, X5 and X3 in 6-month-old red, blue and white light exposed (control) plants, respectively. The difference in melatonin concentrations between blue and white light exposed (control) plants was not significant. The concentration of melatonin quantified in the root tissues was highest in the plants exposed to high intensity UV-B radiation for 3 days followed by low intensity UV-B radiation for 15 days. The reduction of melatonin under longer periods of UV-B exposure indicates that melatonin synthesis may be related to the integrated (intensity and duration) value of UV-B irradiation. Melatonin in G. uralensis plant is presumably for protection against oxidative damage caused as a response to UV irradiation.

  5. Alleviation of cold damage to photosystem II and metabolisms by melatonin in Bermudagrass

    PubMed Central

    Fan, Jibiao; Hu, Zhengrong; Xie, Yan; Chan, Zhulong; Chen, Ke; Amombo, Erick; Chen, Liang; Fu, Jinmin

    2015-01-01

    As a typical warm-season grass, Bermudagrass [Cynodon dactylon (L).Pers.] is widely applied in turf systems and animal husbandry. However, cold temperature is a key factor limiting resource utilization for Bermudagrass. Therefore, it is relevant to study the mechanisms by which Burmudagrass responds to cold. Melatonin is a crucial animal and plant hormone that is responsible for plant abiotic stress responses. The objective of this study was to investigate the role of melatonin in cold stress response of Bermudagrass. Wild Bermudagrass pre-treated with 100 μM melatonin was subjected to different cold stress treatments (−5°C for 8 h with or without cold acclimation). The results showed lower malondialdehyde (MDA) and electrolyte leakage (EL) values, higher levels of chlorophyll, and greater superoxide dismutase and peroxidase activities after melatonin treatment than those in non-melatonin treatment under cold stress. Analysis of chlorophyll a revealed that the chlorophyll fluorescence transient (OJIP) curves were higher after treatment with melatonin than that of non-melatonin treated plants under cold stress. The values of photosynthetic fluorescence parameters increased after treatment with melatonin under cold stress. The analysis of metabolism showed alterations in 46 metabolites in cold-stressed plants after melatonin treatment. Among the measured metabolites, five sugars (arabinose, mannose, glucopyranose, maltose, and turanose) and one organic acid (propanoic acid) were significantly increased. However, valine and threonic acid contents were reduced in melatonin-treated plants. In summary, melatonin maintained cell membrane stability, increased antioxidant enzymes activities, improved the process of photosystem II, and induced alterations in Bermudagrass metabolism under cold stress. PMID:26579171

  6. The oncostatic action of melatonin in an ovarian carcinoma cell line.

    PubMed

    Petranka, J; Baldwin, W; Biermann, J; Jayadev, S; Barrett, J C; Murphy, E

    1999-04-01

    Melatonin is reported to reduce proliferation in many cell types, but the effect is small and the results are inconsistent. Information on the mechanism by which melatonin exerts its antiproliferative effects might provide insight into the variability of the response. In an ovarian adenocarcinoma cell line (BG-1), we find that melatonin at concentrations of 10(-9)-10(-7) M caused a 20-25% reduction in cell number. Melatonin also resulted in a similar reduction in [3H]-thymidine incorporation with no significant increase in cell death as measured by trypan blue incorporation. The Kd for melatonin reduction in cell number was approximately 5 x 10(-10) M. Melatonin ML2 receptors have a Kd for melatonin binding in the low nM range and are linked to the production of the calcium mobilizing agent inositol-1,4,5-trisphosphate (IP3). To investigate whether melatonin signaling involves an increase in cytosolic-free calcium. BG-1 cells were loaded with the calcium sensitive indicator, fura-2. Acute addition of melatonin (10(-5)-10(-9) M) did not alter cytosolic calcium. Addition of the putative nuclear receptor agonist CGP52608 caused a dose-dependent inhibition of cell number with a Kd of approximately 2 x 10(-9) M. Addition of CGP52608 caused a similar reduction in [3H]-thymidine incorporation. Neither melatonin (10(-8) M-10(-5) M) nor CGP52608 at concentrations below 10(-7) M induced cell death associated with the inhibition of cell proliferation; however, addition of CGP52608 at a high dose (10(-7) M) caused an increase in cell death, consistent with apoptosis. Growth inhibition by melatonin or CGP52608 did not alter the percentage of cells in G1 versus S/G2/M.

  7. Alleviation of cold damage to photosystem II and metabolisms by melatonin in Bermudagrass.

    PubMed

    Fan, Jibiao; Hu, Zhengrong; Xie, Yan; Chan, Zhulong; Chen, Ke; Amombo, Erick; Chen, Liang; Fu, Jinmin

    2015-01-01

    As a typical warm-season grass, Bermudagrass [Cynodon dactylon (L).Pers.] is widely applied in turf systems and animal husbandry. However, cold temperature is a key factor limiting resource utilization for Bermudagrass. Therefore, it is relevant to study the mechanisms by which Burmudagrass responds to cold. Melatonin is a crucial animal and plant hormone that is responsible for plant abiotic stress responses. The objective of this study was to investigate the role of melatonin in cold stress response of Bermudagrass. Wild Bermudagrass pre-treated with 100 μM melatonin was subjected to different cold stress treatments (-5°C for 8 h with or without cold acclimation). The results showed lower malondialdehyde (MDA) and electrolyte leakage (EL) values, higher levels of chlorophyll, and greater superoxide dismutase and peroxidase activities after melatonin treatment than those in non-melatonin treatment under cold stress. Analysis of chlorophyll a revealed that the chlorophyll fluorescence transient (OJIP) curves were higher after treatment with melatonin than that of non-melatonin treated plants under cold stress. The values of photosynthetic fluorescence parameters increased after treatment with melatonin under cold stress. The analysis of metabolism showed alterations in 46 metabolites in cold-stressed plants after melatonin treatment. Among the measured metabolites, five sugars (arabinose, mannose, glucopyranose, maltose, and turanose) and one organic acid (propanoic acid) were significantly increased. However, valine and threonic acid contents were reduced in melatonin-treated plants. In summary, melatonin maintained cell membrane stability, increased antioxidant enzymes activities, improved the process of photosystem II, and induced alterations in Bermudagrass metabolism under cold stress.

  8. Investigational melatonin receptor agonists.

    PubMed

    Hardeland, Rüdiger

    2010-06-01

    Melatonin is a major chronobiological regulator involved in circadian phasing, sleep, and numerous other functions including cyto-/neuroprotection, immune modulation, and energy metabolism. The suitability of melatonin as a drug is limited because of its short half-life. Therefore, various indolic and non-indolic melatonergic agonists have been developed. Frequent health problems such as sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance are targeted by melatonergic agonists. Various synthetic melatonergic drugs are compared with regard to receptor affinities, selectivity, effects on sleep, endogenous melatonin, circadian phase and insulin-related metabolism. The chemical design of melatonin receptor agonists is discussed in relation to consequences for receptor affinity, selectivity, metabolism, and spectrum of effects. Melatonergic agonists are suitable for phase-shifting circadian rhythms, and may be used for treating disorders related to circadian dysfunction including sleep difficulties. Facilitation of sleep onset is a general property, whereas promotion of sleep maintenance is demonstrable but not always fully sufficient. Details are especially available for tasimelteon. Support of insulin sensitivity may become a new area of application for compounds such as NEU-P11. Some drugs acting additionally as serotonergic antagonists display antidepressant properties.

  9. Acute melatonin and para-chloroamphetamine interactions on pineal, brain and serum serotonin levels as well as stress hormone levels.

    PubMed

    Manzana, E J; Chen, W J; Champney, T H

    2001-08-03

    para-Chloroamphetamine, an amphetamine analog, alters serotonergic neurochemistry. In previous reports, melatonin (MEL), when administered with other amphetamine analogs, altered the decline in serotonin content produced by these analogs. The present studies assessed the effects of various doses of melatonin and p-chloroamphetamine on serotonin levels in numerous brain regions in male rats. Melatonin (10, 25 or 50 mg/kg, s.c.) and p-chloroamphetamine (3 or 5 mg/kg, s.c.) were administered and, 3 h later, brain samples and serum were collected. Serotonin levels in the serum and various regions of the brain were assayed using high-performance liquid chromatography. Melatonin in combination with a high dose of p-chloroamphetamine (5 mg/kg) produced cumulative deficits in serotonin levels in the serum. However, serotonin levels in the pineal, cortex or brain stem in all combined melatonin and p-chloroamphetamine groups were not significantly different from groups that received p-chloroamphetamine alone. Serum adrenocorticotropin (ACTH) and corticosterone levels were significantly elevated in the melatonin and p-chloroamphetamine combined groups, suggesting that animals receiving both treatments were more stressed than control animals or animals receiving melatonin or p-chloroamphetamine alone. These results indicate that melatonin does not alter p-chloroamphetamine-induced deficits in central serotonin levels. The increased serum adrenocorticotropic hormone, corticosterone and serotonin levels observed following melatonin and p-chloroamphetamine treatment suggest that this combination may have adverse peripheral effects.

  10. Melatonin and melatonin agonist for delirium in the elderly patients.

    PubMed

    Chakraborti, Dwaipayan; Tampi, Deena J; Tampi, Rajesh R

    2015-03-01

    The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study.

  11. Melatonin: Buffering the Immune System

    PubMed Central

    Carrillo-Vico, Antonio; Lardone, Patricia J.; Álvarez-Sánchez, Nuria; Rodríguez-Rodríguez, Ana; Guerrero, Juan M.

    2013-01-01

    Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed. PMID:23609496

  12. Cysteamine blocks somatostatin secretion without altering the course of insulin or glucagon release. A new model for the study of islet function

    SciTech Connect

    Sorenson, R.L.; Grouse, L.H.; Elde, R.P.

    1983-04-01

    Cysteamine (300 mg/kg) administered subcutaneously depletes pancreatic somatostatin to 36% of control levels, but does not alter pancreatic insulin or glucagon content. Although perfusion of pancreata from normal animals with glucose (300 mg/dl) markedly stimulated somatostatin release, pancreata from cysteamine-treated animals failed to secrete somatostatin in response to glucose. Cysteamine treatment was without effect on insulin and glucagon release under the conditions tested. The isolated perfused pancreas from the cysteamine-treated rat provides a model for further investigations into regulation of islet hormone release in the absence of stimulated somatostatin release.

  13. Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes.

    PubMed

    Peschke, Elmar; Wolgast, Sabine; Bazwinsky, Ivonne; Pönicke, Klaus; Muhlbauer, Eckhard

    2008-11-01

    It is well-documented that melatonin influences insulin secretion. The effects are mediated by specific, high-affinity, pertussis-toxin-sensitive, G protein-coupled membrane receptors (MT(1) as well MT(2)), which are present in both the pancreatic tissue and islets of rats and humans, as well as in rat insulinoma cells (INS1). Via the Gi-protein-adenylatecyclase-3',5'-cyclic adenosine monophosphate (cAMP) and, possibly, the guanylatecyclase-cGMP pathways, melatonin decreases insulin secretion, whereas, by activating the Gq-protein-phospholipase C-IP(3) pathway, it has the opposite effect. For further analysis of the interactions between melatonin and insulin, diabetic rats were investigated with respect to melatonin synthesis in the pineal gland and plasma insulin levels. In this context, recent investigations have proven that type 2 diabetic rats and humans display decreased melatonin levels, whereas type 1 diabetic IDDM rats or those with diabetes induced by streptozotocin (STZ) of the present study show increased plasma melatonin levels and elevated AA-NAT-mRNA. Furthermore, the mRNA of pineal insulin receptors and beta1-adrenoceptors, including the clock genes Per1 and Bmal1 and the clock-controlled output gene Dbp, increases in both young and middle-aged STZ rats. The results therefore indicate that the decreased insulin levels in STZ-induced type 1 diabetes are associated with higher melatonin plasma levels. In good agreement with earlier investigations, it was shown that the elevated insulin levels observed in type 2 diabetes, are associated with decreased melatonin levels. The results thus prove that a melatonin-insulin antagonism exists. Astonishingly, notwithstanding the drastic metabolic disturbances in STZ-diabetic rats, the diurnal rhythms of the parameters investigated are maintained.

  14. Effects of bilateral and unilateral ophthalmectomy on plasma melatonin in Rana tadpoles and froglets under various experimental conditions.

    PubMed

    Wright, Mary L; Francisco, Lucy L; Scott, Jessica L; Richardson, Shaun E; Carr, James A; King, Amy B; Noyes, Arielle G; Visconti, Rachael F

    2006-06-01

    The effect of ophthalmectomy (enucleation) on plasma melatonin in Rana tadpoles and froglets was studied under various experimental conditions to determine if ocular melatonin is released into the circulation from the eyes and to study the factors which might affect this process. Where operations occurred in early or mid-photophase on a 12 light:12 dark (12L:12D) cycle (light onset at 08:00 h), sampling in mid-light and mid-dark revealed that scotophase plasma melatonin was reduced at all developmental stages, with the more significant effects occurring before metamorphic climax. Experiments sampling prometamorphic tadpoles six times in a 24h period on 18L:6D, 12L:12D, or 6L:18D five days after enucleation also showed a significant lowering of plasma melatonin in the dark, so that the scotophase peak was virtually eliminated on all the LD cycles. These findings indicated that the reduction in plasma melatonin after bilateral eye removal was independent of the LD cycle and the metamorphic stage, and that it abolished the diel melatonin rhythm at the expense of the scotophase peak. Experiments carried out for 5 weeks suggested that compensatory secretion of melatonin by other organs after eye removal might partially restore the plasma melatonin level over time. Unilateral ophthalmectomy tended to reduce, but not eliminate, the night peak of plasma melatonin, and did not result in a compensatory increase in ocular melatonin in the remaining eye. Ophthalmectomized tadpoles exhibited darkening of the skin after the operation, which was not associated with a significant change in pituitary alpha-melanotropin. The findings overall indicate that the eyes in Rana tadpoles and froglets contribute up to somewhat over one-half of the circulating melatonin, particularly during the scotophase, and provide experimental evidence for ocular secretion into the blood for the first time in the Amphibia.

  15. Plasma melatonin in the horse: measurements in natural photoperiod and in acutely extended darkness throughout the year.

    PubMed

    Guerin, M V; Deed, J R; Kennaway, D J; Matthews, C D

    1995-08-01

    Plasma melatonin was measured at the winter and summer solstices and the autumn and spring equinoxes in four mares held under natural conditions at 35 degrees S. At all seasons the onset of the nightly elevated melatonin was coincident with or after the time of sunset and the melatonin offset after the time of sunrise. The duration of elevated melatonin was not different from the duration of natural scotophase for each season, with the duration of elevated melatonin longer in winter than the other seasons. Immediately following each 24 hr sampling two mares were resampled in acutely extended darkness to determine the melatonin profile of the endogenous rhythm of the circadian pacemaker, originating from the suprachiasmatic nuclei (SCN). At each season melatonin secretion commenced earlier and decreased later than that measured under the natural photoperiodic condition, suggesting that the expression of the melatonin rhythm is normally gated by natural environmental light both at dusk and dawn. The interval from the onset of melatonin measured under acutely extended darkness to the time of sunset was greater in the spring/summer than the autumn/winter suggesting a possible alternating signal throughout the year. Thus the mare appears to exhibit a similar interaction between endogenous circadian rhythmic activity and the natural photoperiod as the ewe which may underlie the mechanism for timing reproductive activity through the year.

  16. Decreased concentration of serum melatonin in nighttime compared with daytime female medical technologists in South Korea.

    PubMed

    Song, GiSeon; Yoon, Kyong-Ah; Chi, HyunYoung; Roh, Jaehoon; Kim, Jin-Hee

    2016-01-01

    Working during the night can disrupt the normal circadian rhythm by altering the melatonin level. A low level of melatonin is associated with an increased risk of cancer, possibly by decreasing the expression of tumor-suppressor genes, such as p53. To determine whether nighttime work is associated with melatonin level in serum as well as the expression of related genetic markers, we enrolled 100 female nighttime medical technologists employed at a hospital in South Korea. Melatonin concentration and melatonin receptor 1 (MT1) expression were significantly lower in nighttime than in daytime workers (1.84 pg/mL versus 4.04 pg/mL; 1.16 versus 1.61, respectively). However, p53 expression showed no difference between the groups. In summary, nighttime work could be an important risk factor for circadian disruption, but not a direct risk factor for cancer in medical technologists in South Korea.

  17. Sex differential nectar secretion in protandrous Alstroemeria aurea (Alstroemeriaceae): is production altered by pollen removal and receipt?

    PubMed

    Aizen, M; Basilio, A

    1998-02-01

    We examined diurnal and nocturnal nectar secretion across sexual stages in protandrous Alstroemeria aurea, a bumble bee-pollinated herb with long-lived flowers native to the southern Andes. We found the following patterns: (1) most nectar was produced diurnally and (2) three times more sugar was secreted during the male than female phase, not only because the male phase lasted longer but also because the rate of nectar production was higher. This 3:1 ratio in nectar production matched the ratio of the minimum number of bumble bee visits required on average to saturate male (pollen removal) vs. female (seed set) functions. Standing crop of nectar, on the other hand, did not differ greatly between male- and female- stage flowers left open to visitors, because the high-production male-phase flowers were visited more frequently than female- phase flowers. In an experiment concurrent with the repeated nectar sampling of individual flowers over their life-span, we removed pollen from anthers or deposited pollen on stigmas by hand. Neither treatment, designed to mimic effects of visits by Alstroemeria's native bumble bee pollinator, affected nectar production. The absence of plasticity in nectar secretion in relation to pollination events may reflect a low cost of nectar production, or may result from developmental constraints related to the evolution of the synchronous protandry that characterizes A. aurea.

  18. The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes.

    PubMed

    Leonardo-Mendonça, Roberto C; Martinez-Nicolas, Antonio; de Teresa Galván, Carlos; Ocaña-Wilhelmi, Javier; Rusanova, Iryna; Guerra-Hernández, Eduardo; Escames, Germaine; Acuña-Castroviejo, Darío

    2015-01-01

    Exercise can induce circadian phase shifts depending on the duration, intensity and frequency. These modifications are of special meaning in athletes during training and competition. Melatonin, which is produced by the pineal gland in a circadian manner, behaves as an endogenous rhythms synchronizer, and it is used as a supplement to promote resynchronization of altered circadian rhythms. In this study, we tested the effect of melatonin administration on the circadian system in athletes. Two groups of athletes were treated with 100 mg day(-1) of melatonin or placebo 30 min before bed for four weeks. Daily rhythm of salivary melatonin was measured before and after melatonin administration. Moreover, circadian variables, including wrist temperature (WT), motor activity and body position rhythmicity, were recorded during seven days before and seven days after melatonin or placebo treatment with the aid of specific sensors placed in the wrist and arm of each athlete. Before treatment, the athletes showed a phase-shift delay of the melatonin circadian rhythm, with an acrophase at 05:00 h. Exercise induced a phase advance of the melatonin rhythm, restoring its acrophase accordingly to the chronotype of the athletes. Melatonin, but not placebo treatment, changed daily waveforms of WT, activity and position. These changes included a one-hour phase advance in the WT rhythm before bedtime, with a longer nocturnal steady state and a smaller reduction when arising at morning than the placebo group. Melatonin, but not placebo, also reduced the nocturnal activity and the activity and position during lunch/nap time. Together, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep-wake cycle, improving sleep efficiency.

  19. Neurotoxins: Free Radical Mechanisms and Melatonin Protection

    PubMed Central

    Reiter, Russel J.; Manchester, Lucien C.; Tan, Dun-Xian

    2010-01-01

    Toxins that pass through the blood-brain barrier put neurons and glia in peril. The damage inflicted is usually a consequence of the ability of these toxic agents to induce free radical generation within cells but especially at the level of the mitochondria. The elevated production of oxygen and nitrogen-based radicals and related non-radical products leads to the oxidation of essential macromolecules including lipids, proteins and DNA. The resultant damage is referred to as oxidative and nitrosative stress and, when the molecular destruction is sufficiently severe, it causes apoptosis or necrosis of neurons and glia. Loss of brain cells compromises the functions of the central nervous system expressed as motor, sensory and cognitive deficits and psychological alterations. In this survey we summarize the publications related to the following neurotoxins and the protective actions of melatonin: aminolevulinic acid, cyanide, domoic acid, kainic acid, metals, methamphetamine, polychlorinated biphenyls, rotenone, toluene and 6-hydroxydopamine. Given the potent direct free radical scavenging activities of melatonin and its metabolites, their ability to indirectly stimulate antioxidative enzymes and their efficacy in reducing electron leakage from mitochondria, it would be expected that these molecules would protect the brain from oxidative and nitrosative molecular mutilation. The studies summarized in this review indicate that this is indeed the case, an action that is obviously assisted by the fact that melatonin readily crosses the blood brain barrier. PMID:21358970

  20. Melatonin promotes ripening and improves quality of tomato fruit during postharvest life.

    PubMed

    Sun, Qianqian; Zhang, Na; Wang, Jinfang; Zhang, Haijun; Li, Dianbo; Shi, Jin; Li, Ren; Weeda, Sarah; Zhao, Bing; Ren, Shuxin; Guo, Yang-Dong

    2015-02-01

    In this study, the effect of melatonin on the postharvest ripening and quality improvement of tomato fruit was carried out. The tomatoes were immersed in exogenous melatonin for 2h, and then the related physiological indicators and the expression of genes during post-harvest life were evaluated. Compared with control check (CK), the 50 µM melatonin treatment significantly increased lycopene levels by 5.8-fold. Meanwhile, the key genes involved in fruit colour development, including phytoene synthase1 (PSY1) and carotenoid isomerase (CRTISO), showed a 2-fold increase in expression levels. The rate of water loss from tomato fruit also increased 8.3%, and the expression of aquaporin genes, such as SlPIP12Q, SlPIPQ, SlPIP21Q, and SlPIP22, was up-regulated 2- to 3-fold under 50 µM melatonin treatment. In addition, 50 µM melatonin treatment enhanced fruit softening, increased water-soluble pectin by 22.5%, and decreased protopectin by 19.5%. The expression of the cell wall modifying proteins polygalacturonase (PG), pectin esterase1 (PE1), β-galactosidase (TBG4), and expansin1 (Exp1) was up-regulated under 50 µM melatonin treatment. Melatonin increased ethylene production by 27.1%, accelerated the climacteric phase, and influenced the ethylene signalling pathway. Alteration of ethylene production correlated with altered 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS4) expression. The expression of ethylene signal transduction-related genes such as NR, SlETR4, SlEIL1, SlEIL3, and SlERF2, was enhanced by 50 µM melatonin. The effect of melatonin on ethylene biosynthesis, ethylene perception, and ethylene signalling may contribute to fruit ripening and quality improvement in tomato. This research may promote the application of melatonin on postharvest ripening and quality improvement of tomato fruit as well as other horticultural productions in the future.

  1. Light intensity exposure, sleep duration, physical activity, and biomarkers of melatonin among rotating shift nurses.

    PubMed

    Grundy, Anne; Sanchez, Maria; Richardson, Harriet; Tranmer, Joan; Borugian, Marilyn; Graham, Charles H; Aronson, Kristan J

    2009-10-01

    Long-term, night shiftwork has been identified as a potential carcinogenic risk factor. It is hypothesized that increased light at night exposure during shiftwork reduces melatonin production, which is associated with increased cancer risk. Sleep duration has been hypothesized to influence both melatonin levels and cancer risk, and it has been suggested that sleep duration could be used as a proxy for melatonin production. Finally, physical activity has been shown to reduce cancer risk, and laboratory studies indicate it may influence melatonin levels. A cross-sectional study of light exposure, sleep duration, physical activity, and melatonin levels was conducted among 61 female rotating shift nurses (work schedule: two 12 h days, two 12 h nights, five days off). Light intensity was measured using a light-intensity data logger, and sleep duration and physical activity were self-reported in a study diary and questionnaire. Melatonin concentrations were measured from urine and saliva samples. The characteristics of nurses working day and night shifts were similar. Light intensity was significantly higher during sleep for those working at night (p< 0.0001), while urinary melatonin levels following sleep were significantly higher among those working days (p = 0.0003). Mean sleep duration for nurses working during the day (8.27 h) was significantly longer than for those working at night (4.78 h, p< 0.0001). An inverse association (p = 0.002) between light exposure and urinary melatonin levels was observed; however, this was not significant when stratified by shift group. There was no significant correlation between sleep duration and melatonin, and no consistent relationship between physical activity and melatonin. Analysis of salivary melatonin levels indicated that the circadian rhythms of night workers were not altered, meaning peak melatonin production occurred at night. This study indicates that two nights of rotating shift work may not change the timing of

  2. Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.

    PubMed

    Williams, Wilbur P Trey; McLin, Dewey E; Dressman, Marlene A; Neubauer, David N

    2016-09-01

    Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.

  3. Melatonin and Aircrew: Is an Operational Use Recommended?

    DTIC Science & Technology

    2001-06-01

    natural hormone, derived from modification of dietary intake being the most often serotonin, which is secreted by the pineal gland cited. Physical...journey. 25 hour periodicity characteristic of the suprachi- asmatic nucleus to one of 24 hours. Thus, the PHARMACOLOGIC MANAGEMENT OF JET pineal gland ...REFERENCES during rapid deployment missions. NATO - RTA - AMP Meeting, 29 Sep-3 Oct 1997, Rotterdam. 1. Arendt J. Melatonin and the mammalian pineal gland

  4. Melatonin transport into mitochondria.

    PubMed

    Mayo, Juan C; Sainz, Rosa M; González-Menéndez, Pedro; Hevia, David; Cernuda-Cernuda, Rafael

    2017-08-21

    Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole's protective actions. Melatonin's mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.

  5. ER stress in adipocytes inhibits insulin signaling, represses lipolysis, and alters the secretion of adipokines without inhibiting glucose transport.

    PubMed

    Xu, L; Spinas, G A; Niessen, M

    2010-08-01

    The endoplasmic reticulum (ER) is the intra-cellular site, where secreted and membrane proteins are synthesized. ER stress and activation of the unfolded protein response (UPR) contribute to insulin resistance and the development of diabetes in obesity. It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK), which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. Here we describe how ER stress affects insulin signaling and the biological function of adipocytes. In addition to inhibition of IRS we found that ER stress downregulates the expression of the insulin receptor. Concomitantly, insulin-induced activation of Akt/PKB and of ERK1/2 was strongly inhibited. Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signaling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. ER stress inhibited expression and insulin-induced phosphorylation of AS160, reduced lipolysis but did not inhibit glucose transport. Finally, supernatants collected from 3T3-L1 adipocytes undergoing ER stress improved or impaired proliferation when used to condition the culture medium of INS-1E beta-cells dependent on the degree of ER stress. It appears that ER stress in adipocytes might initially lead to changes resembling early prediabetic stages, which at least in part support the regulation of systemic energy homeostasis. Copyright Georg Thieme Verlag KG Stuttgart New York.

  6. Melatonin production in infants.

    PubMed

    Tauman, Riva; Zisapel, Nava; Laudon, Moshe; Nehama, Haim; Sivan, Yakov

    2002-05-01

    This study investigated the relationships of the excretion of the melatonin metabolite, 6-sulfatoxymelatonin, to prenatal, natal, and postnatal variables and its possible relation to psychomotor development. nocturnal urinary excretion of 6-sulfatoxymelatonin was studied over a 13-hour period in 355 term infants at 8 weeks of age (n = 320) and 16 weeks of age (n = 96). data on a variety of perinatal factors including pregnancy course, delivery, early postnatal course, birth weight, medical problems, growth (length, weight, and head circumference), and psychomotor development were collected at 1, 3, 6, 9, 12, and 18 months. the relationship between nocturnal 6-sulfatoxymelatonin excretion at 8 and 16 weeks of age and these factors was investigated and analyzed. 6-sulfatoxymelatonin levels at 16 weeks of age were significantly lower in infants with abnormal vs normal development at 3 months of age (7.27 + 1.44 vs 7.97 + 1.06, p = 0.05) as well as at 6 months of age (7.15 + 1.29 vs 7.95 + 1.10, p = 0.04). no other significant relation was evident among growth, perinatal complications, medical problems, and 6-sulfatoxymelatonin excretion at 8 weeks of age and at 16 weeks of age. low melatonin excretion in the first weeks of life correlates with delayed psychomotor achievements at 3 and 6 months of age. this association suggests a causal or predictive link between melatonin and neurodevelopment in infants.

  7. Insulin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland.

    PubMed

    Garcia, Rodrigo Antonio Peliciari; Afeche, Solange Castro; Scialfa, Julieta Helena; do Amaral, Fernanda Gaspar; dos Santos, Sabrina Heloísa José; Lima, Fabio Bessa; Young, Martin Elliot; Cipolla-Neto, José

    2008-01-02

    The mammalian pineal gland synthesizes melatonin in a circadian manner, peaking during the dark phase. This synthesis is primarily regulated by sympathetic innervations via noradrenergic fibers, but is also modulated by many peptidergic and hormonal systems. A growing number of studies reveal a complex role for melatonin in influencing various physiological processes, including modulation of insulin secretion and action. In contrast, a role for insulin as a modulator of melatonin synthesis has not been investigated previously. The aim of the current study was to determine whether insulin modulates norepinephrine (NE)-mediated melatonin synthesis. The results demonstrate that insulin (10(- 8)M) potentiated norepinephrine-mediated melatonin synthesis and tryptophan hydroxylase (TPOH) activity in ex vivo incubated pineal glands. When ex vivo incubated pineal glands were synchronized (12h NE-stimulation, followed by 12h incubation in the absence of NE), insulin potentiated NE-mediated melatonin synthesis and arylalkylamine-N-acetyltransferase (AANAT) activity. Insulin did not affect the activity of hydroxyindole-O-methyltranferase (HIOMT), nor the gene expression of tpoh, aanat, or hiomt, under any of the conditions investigated. We conclude that insulin potentiates NE-mediated melatonin synthesis in cultured rat pineal gland, potentially through post-transcriptional events.

  8. Melatonin prevents neural tube defects in the offspring of diabetic pregnancy.

    PubMed

    Liu, Shangming; Guo, Yuji; Yuan, Qiuhuan; Pan, Yan; Wang, Liyan; Liu, Qian; Wang, Fuwu; Wang, Jingjing; Hao, Aijun

    2015-11-01

    Melatonin, an endogenous neurohormone secreted by the pineal gland, has a variety of physiological functions and neuroprotective effects. However, its protective role on the neural tube defects (NTDs) was not very clear. The aim of this study was to investigate the effects of melatonin on the incidence of NTDs (including anencephaly, encephalocele, and spina bifida) of offspring from diabetic pregnant mice as well as its underlying mechanisms. Pregnant mice were given 10 mg/kg melatonin by daily i.p. injection from embryonic day (E) 0.5 until being killed on E11.5. Here, we showed that melatonin decreased the NTDs (especially exencephaly) rate of embryos exposed to maternal diabetes. Melatonin stimulated proliferation of neural stem cells (NSCs) under hyperglycemic condition through the extracellular regulated protein kinases (ERK) pathway. Furthermore, as a direct free radical scavenger, melatonin decreased apoptosis of NSCs exposed to hyperglycemia. In the light of these findings, it suggests that melatonin supplementation may play an important role in the prevention of neural malformations in diabetic pregnancy.

  9. Time keeping by the quail's eye: circadian regulation of melatonin production.

    PubMed

    Steele, Christopher T; Tosini, Gianluca; Siopes, Thomas; Underwood, Herbert

    2006-02-01

    Previous studies have shown that eye removal disrupts the circadian body temperature and activity rhythms of Japanese quail supporting the hypothesis that the eyes act as pacemakers within the quail circadian system. Furthermore, the putative ocular pacemakers are coupled to the rest of the circadian system via neural and hormonal outputs. Although the neural pathway has yet to be identified, experiments suggest that the daily rhythm of ocular melatonin synthesis and release is the hormonal output. We sought to strengthen the hypothesis that the eyes are the loci of circadian pacemakers, and that melatonin output is involved, by examining melatonin secretion in cultured quail retinas. Using an in vitro flow-through system we demonstrated that (1) isolated retinal tissue could exhibit a rhythm of melatonin release, (2) the rhythm of melatonin synthesis is directly entrainable by 24-h light-dark cycles, and (3) supplementation of the culture medium with serotonin is necessary for robust, rhythmic production of melatonin in constant darkness. These results show definitively that the eyes are the loci of a biological clock and, in light of previous studies showing the disruptive effects of blinding on the circadian system, strengthen the hypothesis that the ocular clock is a circadian pacemaker that can affect the rest of the circadian system via the cyclic synthesis and release of melatonin. The quail retina is proving to be a valuable in vitro model for investigating properties of circadian pacemakers.

  10. Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF.

    PubMed

    González, Alicia; González-González, Alicia; Alonso-González, Carolina; Menéndez-Menéndez, Javier; Martínez-Campa, Carlos; Cos, Samuel

    2017-04-01

    Vascular endothelial growth factor (VEGF) produced from tumor cells plays a crucial role in the pathogenesis and neovascularization of neuroblastoma. Inhibition of VEGF secretion by tumor cells, as well as VEGF-regulated signaling in endothelial cells, are important to reduce the angiogenesis and growth of neuroblastoma. Since melatonin has anti-angiogenic effects in tumor cell lines, the aim of the present study was to study melatonin modulation of the pro-angiogenic effects of VEGF in neuroblastoma cells (SH-SY5Y). We used co-cultures of SH-SY5Y and endothelial cells. VEGF expression and protein levels were analyzed by quantitative RT-PCR and ELISA, respectively. Endothelial cell migration was assessed by wound-healing assay and endothelial angiogenesis by a tube formation assay. Melatonin inhibited the pro-angiogenic effects of SH-SY5Y cells. The conditioned medium collected from the neuroblastoma cells was angiogenically active and stimulated proliferation, migration and tube formation in endothelial cells. This effect was significantly counteracted by the addition of either anti-VEGF or melatonin. Melatonin inhibited VEGF expression and secretion in SH-SY5Y cells, decreasing the levels of VEGF available for endothelial cells. Melatonin has anti-angiogenic effects at different steps of the angiogenic process in SH-SY5Y neuroblastoma cells, through the downregulation of VEGF.

  11. Calcium and melatonin production in dissociated trout pineal photoreceptor cells in culture.

    PubMed

    Bégay, V; Bois, P; Collin, J P; Lenfant, J; Falcón, J

    1994-07-01

    Trout pineal cells maintained in primary culture produce melatonin in high amounts during night time and low amounts during daytime. The dark-induced increase in melatonin production was enhanced, in a dose-dependent manner, by elevating extracellular calcium concentration. Low external calcium concentration reduced nocturnal and diurnal melatonin production. Bay K 8644 increased, in a dose-dependent manner, the dark-induced rise in melatonin output, and this effect was antagonized by nifedipine and verapamil. This suggests a role for the dihydropyridine calcium channels in the regulation of the melatonin output. To confirm this, patch-clamp recordings (whole-cell perforated) were run in a 20 mmol/l barium medium at different holding potentials from -80 mV. A voltage-dependent inward current was activated from -30 mV to +40 mV with a maximal amplitude being observed at 0 mV. This current was drastically increased in the presence of Bay K 8644. Nifedipine inhibited the current both in the absence or in the presence of Bay K 8644. Our results are consistent with the idea that extracellular calcium participates in the control of melatonin secretion by photoreceptor cells. It is suggested that activation of the voltage-dependent L-type channel may modulate this secretion.

  12. Persistent diel melatonin rhythmicity during the Arctic summer in free-living willow warblers.

    PubMed

    Silverin, Bengt; Gwinner, Eberhard; Van't Hof, Thomas J; Schwabl, Ingrid; Fusani, Leonida; Hau, Michaela; Helm, Barbara

    2009-06-01

    Arctic environments are challenging for circadian systems. Around the solstices, the most important zeitgeber, the change between night and day, is reduced to minor fluctuations in light intensities. However, many species including songbirds nonetheless show clear diel activity patterns. Here we examine the possible physiological basis underlying diel rhythmicity under continuous Arctic summer light. Rhythmic secretion of the hormone melatonin constitutes an important part of the songbird circadian system and its experimental suppression, e.g., by constant light, usually leads to behavioral arrhythmia. We therefore studied melatonin patterns in a free-living migratory songbird, the willow warbler (Phylloscopus trochilus), that maintains diel activity during the Arctic summer. We compared melatonin profiles during late spring and summer solstice in two Swedish populations from the south (58 degrees N) and near the Arctic circle (66 degrees N). We found the northern Swedish population maintained clear diel changes in melatonin secretion during the summer solstice, although peak concentrations were lower than in southern Sweden. Melatonin levels were highest before midnight and in good accordance with periods of reduced activity. The maintenance of diel melatonin rhythmicity under conditions of continuous light may be one of the physiological mechanisms that enables continued functioning of the circadian system.

  13. Melatonin: Protection against age-related cardiac pathology.

    PubMed

    Favero, Gaia; Franceschetti, Lorenzo; Buffoli, Barbara; Moghadasian, Mohammed H; Reiter, Russel J; Rodella, Luigi F; Rezzani, Rita

    2017-05-01

    Aging is a complex and progressive process that involves physiological and metabolic deterioration in every organ and system. Cardiovascular diseases are one of the most common causes of mortality and morbidity among elderly subjects worldwide. Most age-related cardiovascular disorders can be influenced by modifiable behaviours such as a healthy diet rich in fruit and vegetables, avoidance of smoking, increased physical activity and reduced stress. The role of diet in prevention of various disorders is a well-established factor, which has an even more important role in the geriatric population. Melatonin, an indoleamine with multiple actions including antioxidant properties, has been identified in a very large number of plant species, including edible plant products and medical herbs. Among products where melatonin has been identified include wine, olive oil, tomato, beer, and others. Interestingly, consumed melatonin in plant foods or melatonin supplementation may promote health benefits by virtue of its multiple properties and it may counteract pathological conditions also related to cardiovascular disorders, carcinogenesis, neurological diseases and aging. In the present review, we summarized melatonin effects against age-related cardiac alterations and abnormalities with a special focus on heart ischemia/reperfusion (IR) injury and myocardial infarction. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Monozygotic twins with Alzheimer's disease treated with melatonin: Case report.

    PubMed

    Brusco, L I; Márquez, M; Cardinali, D P

    1998-12-01

    Monozygotic twins with Alzheimer's disease of 8 years duration were studied. The onset of the disease differed by about 6 months between twins and was characterized by a primary impairment of memory function. Clinical evaluation at the time of diagnosis indicated a similar cognitive and neuroimaging alteration in both patients, as well as a similar neuropsychologic impairment. A possible genetic origin of the disease was suggested by a similar disease suffered by the mother. Patients were initially treated with vitamin E (800 I.U./day). Starting at approximately the same time (about 3 years ago), they received 50 mg/day thioridazine because of the behavioral and sleep disorder. One of the patients was treated with melatonin (6 mg orally) at bed time daily for 36 months. Evolution of the disease in the melatonin-treated patient indicated a milder impairment of memory function, with substantial improvement of sleep quality and reduction of sundowning. This led to discontinuance (after 3 months) of thioridazine treatment. Present clinical evaluation indicated a difference in functional stage of the disease between the twins (Functional Assessment Tool For Alzheimer's Disease, FAST), with a score of 5 in the twin who received melatonin and of 7b in the twin who did not receive it. Since experimental data on melatonin in animals indicated its antioxidant, antiapoptotic, and beta-amyloid-decreasing activity, the hypothesis that melatonin has a beneficial effect in Alzheimer's disease patients should be considered.

  15. Melatonin protects uterus and oviduct exposed to nicotine in mice

    PubMed Central

    Saadat, Seyedeh Nazanin Seyed; Jahromi, Sina Khajeh; Homafar, Mohammad Amin; Haghiri, Mostafa

    2014-01-01

    Smoking is associated with higher infertility risk. The aim of this study was to evaluate protective effects of melatonin on the uterus and oviduct in mice exposed to nicotine. Adult female mice (n=32) were divided into four groups. Group A: control animals received normal saline, Group B: injected with nicotine 40µg/kg, Group C: injected with melatonin 10 µg, Group D: injected with nicotine 40µg/kg and melatonin 10 µg. All animals were treated over 15 days intraperitoneally. On the 16th day, animals in the estrus phase were dissected and their uterus and oviducts were removed. Immunohistochemistry was recruited for studying apoptosis and for detection of estrogen receptor (ER) alpha in luminal epithelium of the uterus and oviduct. Enzyme-linked immunosorbent assay was used for serum estradiol level determination. Nicotine in group B decreased estradiol level and ERalpha numbers both in the uterus and oviduct (p<0.05). Co-administration of melatonin-nicotine in Group D ameliorated the histology of the uterus and oviduct, increased ERalpha numbers and reduced apoptosis in the uterus and oviduct compared with the nicotine Group B (p<0.05). This study indicates that nicotine impairs the histology of the uterus and oviduct and co-administration of melatonin-nicotine ameliorates these findings, partly through alteration in ERalpha numbers and reduction of apoptosis. PMID:26038675

  16. Melatonin, Light and Circadian Cycles

    DTIC Science & Technology

    1989-12-25

    bifida occulta, and sarcoidosis, all show loss of the melatonin circadian rhythm, with psoriasis vulgaris, spina bifida occulta, and sarcoidosis...autonomic neuro- pathy show decreased nocturnal melatonin (Checkley and Palazidou, 1988). Klinefelter’s syndrome, Turners syndrome, psoriasis vulgaris, spina

  17. Melatonin, clock genes and mitochondria in sepsis.

    PubMed

    Acuña-Castroviejo, Darío; Rahim, Ibtissem; Acuña-Fernández, Carlos; Fernández-Ortiz, Marisol; Solera-Marín, Jorge; Sayed, Ramy K A; Díaz-Casado, María E; Rusanova, Iryna; López, Luis C; Escames, Germaine

    2017-08-07

    After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1β and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.

  18. Impact of maternal melatonin suppression on forced swim and tail suspension behavioral despair tests in adult offspring

    PubMed Central

    Voiculescu, SE; Rosca, AE; Zeca, V; Zagrean, L; Zagrean, AM

    2015-01-01

    Melatonin is an essential hormone, which regulates circadian rhythms and has antioxidative and anticarcinogenic effects. As melatonin secretion is suppressed by light, this effect was examined on the offspring of the Wistar rat females exposed to continuous light (500 lux) during the second half of the pregnancy (day 12 to 21). Control rats were kept under a 12:12 light-dark cycle. The resulted male offspring have been behaviorally assessed for depression after postnatal day 60 by using Forced Swim Test (FST) and Tail Suspension Test (TST). Animals resulted from the melatonin deprived pregnancies have developed an abnormal response in the TST, but a normal FST behavior. Also, TST active movement was different in the melatonin suppression group compared to the control group. These findings suggest that intrauterine melatonin deprivation might be linked to the depressive like behavior in adult male offspring. PMID:25866579

  19. The influence od melatonin receptors antagonists, luzindole and 4-phenyl-2-propionamidotetralin (4-P-PDOT), on melatonin-dependent vasopressin and adrenocorticotropic hormone (ACTH) release from the rat hypothalamo-hypophysial system. In vitro and in vivo studies.

    PubMed

    Juszczak, M; Roszczyk, M; Kowalczyk, E; Stempniak, B

    2014-12-01

    Melatonin exerts its biological role acting via G protein-coupled membrane receptors - MT1 and MT2, as well as through cytoplasmic and/or nuclear receptors. Melatonin has previously been shown to change vasopressin (AVP) and adrenocorticotropic hormone (ACTH) secretion dependently on its concentration. To determine whether the response of vasopressinergic neurones to different concentrations of melatonin is mediated through the membrane MT1 and/or MT2 receptors, the influence of luzindole - an antagonist of both MT1 and MT2 receptors, and 4-phenyl-2-propionamidotetralin (4-P-PDOT) - a selective MT2 receptor antagonist, on melatonin-dependent AVP release from the rat hypothalamo-neurohypophysial (H-NH) system was studied in vitro (melatonin at the concentrations of 10(-9), 10(-7) and 10(-3) M) and in vivo (melatonin at the concentrations of 10(-9) and 10(-7) M). Moreover, the second goal of this study was to find out whether melatonin receptors MT1 and/or MT2 are involved in the regulation of ACTH and corticosterone secretion into the blood. We have demonstrated that melatonin, at the concentrations of 10(-9) and 10(-7) M, significantly inhibited AVP secretion from isolated rat H-NH explants when antagonists solvent (i.e. 0.1% DMSO) was present in the medium. Neither luzindole, nor 4-P-PDOT, applied without melatonin, did influence AVP release in vitro. Luzindole applied together with melatonin (10(-7) M and 10(-9) M) significantly suppressed melatonin-dependent effect, while 4-PPDOT did not eliminate the inhibitory influence of 10(-7) M and 10(-9) M melatonin on AVP secretion from isolated rat H-NH explants. Melatonin at a concentration of 10(-3) M significantly increased AVP release when the H-NH explants were incubated in the medium containing luzindole or 4-P-PDOT. Under present experimental in vivo conditions, infused intracerebroventricularly (i.c.v.) melatonin, at a concentration close to its physiological level in the blood, significantly diminished AVP

  20. Critical time delay of the pineal melatonin rhythm in humans due to weak electromagnetic exposure.

    PubMed

    Halgamuge, Malka N

    2013-08-01

    Electromagnetic fields (EMFs) can increase free radicals, activate the stress response and alter enzyme reactions. Intracellular signalling is mediated by free radicals and enzyme kinetics is affected by radical pair recombination rates. The magnetic field component of an external EMF can delay the "recombination rate" of free radical pairs. Magnetic fields thus increase radical life-times in biological systems. Although measured in nanoseconds, this extra time increases the potential to do more damage. Melatonin regulates the body's sleep-wake cycle or circadian rhythm. The World Health Organization (WHO) has confirmed that prolonged alterations in sleep patterns suppress the body's ability to make melatonin. Considerable cancer rates have been attributed to the reduction of melatonin production as a result of jet lag and night shift work. In this study, changes in circadian rhythm and melatonin concentration are observed due to the external perturbation of chemical reaction rates. We further analyze the pineal melatonin rhythm and investigate the critical time delay or maturation time of radical pair recombination rates, exploring the impact of the mRNA degradation rate on the critical time delay. The results show that significant melatonin interruption and changes to the circadian rhythm occur due to the perturbation of chemical reaction rates, as also reported in previous studies. The results also show the influence of the mRNA degradation rate on the circadian rhythm's critical time delay or maturation time. The results support the hypothesis that exposure to weak EMFs via melatonin disruption can adversely affect human health.

  1. Role of melatonin in reducing hypoxia-induced oxidative stress and morphological changes in the liver of male mice.

    PubMed

    El-Sokkary, Gamal H; Khidr, Bothaina M; Younes, Hala A

    2006-07-01

    Oxygen deficiency during critical illness may cause profound changes in cellular metabolism and subsequent tissue and organ dysfunction. Thus, the present study was designed to determine the effects of hypoxia and reoxygenation on the levels of lipid peroxidation and the morphological changes in the liver of male mice as well as the protective role of melatonin as an antioxidant. Two experiments were carried out in this study. Experiment I includes three groups of mice (control, hypoxic, and hypoxic+melatonin) while the experiment II includes two groups (reoxygenated and reoxygenated+melatonin). The levels of oxidized lipids were measured and the morphological changes were investigated using light and electron microscopy. In experiment I, hypoxia strongly stimulated lipid peroxidation levels (88%) while melatonin administration inhibited this increase (69%). Severe morphological changes (necrosis, dilated congested blood vessels, collection of inflammatory cells, condensed heterochromatic with irregular outlines nuclei, and mitochondrial degeneration) were detected in the liver of hypoxic mice. In experiment II, reoxygenation inhibited the levels of oxidized lipids (42%) versus hypoxic mice and some morphological changes were detected. When melatonin was given before reoxygenation, it inhibited the levels of lipid peroxidation by 66% versus hypoxic mice. Also, melatonin enhanced the recovery profile by 41% when compared with mice that reoxygenated with room air only. All morphological alterations that detected in both hypoxic and reoxygenated mice were repaired when melatonin administered. These results indicate that hypoxia and reoxygenation induce severe alterations in the liver and that melatonin exerts beneficial role in restoring tissue alterations after subjection to hypoxia.

  2. Npas4 Is Activated by Melatonin, and Drives the Clock Gene Cry1 in the Ovine Pars Tuberalis

    PubMed Central

    West, A.; Dupré, S.M.; Yu, L.; Paton, I.R.; Miedzinska, K.; McNeilly, A.S.; Davis, J.R.E.

    2013-01-01

    Seasonal mammals integrate changes in the duration of nocturnal melatonin secretion to drive annual physiologic cycles. Melatonin receptors within the proximal pituitary region, the pars tuberalis (PT), are essential in regulating seasonal neuroendocrine responses. In the ovine PT, melatonin is known to influence acute changes in transcriptional dynamics coupled to the onset (dusk) and offset (dawn) of melatonin secretion, leading to a potential interval-timing mechanism capable of decoding changes in day length (photoperiod). Melatonin offset at dawn is linked to cAMP accumulation, which directly induces transcription of the clock gene Per1. The rise of melatonin at dusk induces a separate and distinct cohort, including the clock-regulated genes Cry1 and Nampt, but little is known of the up-stream mechanisms involved. Here, we used next-generation sequencing of the ovine PT transcriptome at melatonin onset and identified Npas4 as a rapidly induced basic helix-loop-helix Per-Arnt-Sim domain transcription factor. In vivo we show nuclear localization of NPAS4 protein in presumptive melatonin target cells of the PT (α-glycoprotein hormone-expressing cells), whereas in situ hybridization studies identified acute and transient expression in the PT of Npas4 in response to melatonin. In vitro, NPAS4 forms functional dimers with basic helix loop helix-PAS domain cofactors aryl hydrocarbon receptor nuclear translocator (ARNT), ARNT2, and ARNTL, transactivating both Cry1 and Nampt ovine promoter reporters. Using a combination of 5′-deletions and site-directed mutagenesis, we show NPAS4-ARNT transactivation to be codependent upon two conserved central midline elements within the Cry1 promoter. Our data thus reveal NPAS4 as a candidate immediate early-response gene in the ovine PT, driving molecular responses to melatonin. PMID:23598442

  3. GnRH Episodic Secretion Is Altered by Pharmacological Blockade of Gap Junctions: Possible Involvement of Glial Cells.

    PubMed

    Pinet-Charvet, Caroline; Geller, Sarah; Desroziers, Elodie; Ottogalli, Monique; Lomet, Didier; Georgelin, Christine; Tillet, Yves; Franceschini, Isabelle; Vaudin, Pascal; Duittoz, Anne

    2016-01-01

    Episodic release of GnRH is essential for reproductive function. In vitro studies have established that this episodic release is an endogenous property of GnRH neurons and that GnRH secretory pulses are associated with synchronization of GnRH neuron activity. The cellular mechanisms by which GnRH neurons synchronize remain largely unknown. There is no clear evidence of physical coupling of GnRH neurons through gap junctions to explain episodic synchronization. However, coupling of glial cells through gap junctions has been shown to regulate neuron activity in their microenvironment. The present study investigated whether glial cell communication through gap junctions plays a role in GnRH neuron activity and secretion in the mouse. Our findings show that Glial Fibrillary Acidic Protein-expressing glial cells located in the median eminence in close vicinity to GnRH fibers expressed Gja1 encoding connexin-43. To study the impact of glial-gap junction coupling on GnRH neuron activity, an in vitro model of primary cultures from mouse embryo nasal placodes was used. In this model, GnRH neurons possess a glial microenvironment and were able to release GnRH in an episodic manner. Our findings show that in vitro glial cells forming the microenvironment of GnRH neurons expressed connexin-43 and displayed functional gap junctions. Pharmacological blockade of the gap junctions with 50 μM 18-α-glycyrrhetinic acid decreased GnRH secretion by reducing pulse frequency and amplitude, suppressed neuronal synchronization and drastically reduced spontaneous electrical activity, all these effects were reversed upon 18-α-glycyrrhetinic acid washout.

  4. Alteration of the intestinal barrier and GLP2 secretion in Berberine-treated type 2 diabetic rats.

    PubMed

    Shan, C Y; Yang, J H; Kong, Y; Wang, X Y; Zheng, M Y; Xu, Y G; Wang, Y; Ren, H Z; Chang, B C; Chen, L M

    2013-09-01

    For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.

  5. Melatonin receptors trigger cAMP production and inhibit chloride movements in nonpigmented ciliary epithelial cells.

    PubMed

    Huete-Toral, Fernando; Crooke, Almudena; Martínez-Águila, Alejandro; Pintor, Jesús

    2015-01-01

    Melatonin and its analog 5-MCA-NAT (5-methylcarboxyamino-N-acetyl tryptamine) are active compounds reducing intraocular pressure (IOP). This action is mediated through MT2 and the putative MT3 melatonin receptor, producing a transient reduction of IOP that lasts for a few hours and has not yet been characterized. The use of melatonin and its analog are causing a decrease in chloride efflux from rabbit nonpigmented epithelial cells (NPE), possibly explaining the decrease in IOP. Melatonin and 5-MCA-NAT inhibited rabbit NPE chloride release in a concentration-dependent manner, whereas the pD2 values were between 4.5 ± 1.2 and 4.4 ± 1.0, respectively. Melatonin hypotensive action was enhanced by the presence of MT2 antagonists, such as DH97 (N-pentanoyl-2-benzyltryptamine) and 4-P-P-DOT (4-phenyl-2-propionamidotetralin) and by the nonselective melatonin receptor antagonist luzindole. Prazosin (1.5 µM) partially reverses the melatonin action by acting as a selective MT3 antagonist. However, at 15 nM it acts as an α-adrenergic receptor antagonist, enhancing the melatonin effect. Regarding the intracellular pathways triggered by melatonin receptors, neither phospholipase C/protein kinase C pathway nor the canonical reduction of intracellular cAMP was responsible for melatonin or 5-MCA-NAT actions. On the contrary, the application of these substances produced a concentration-dependent increase of cAMP, with pD2 values of 4.6 ± 0.2 and 4.9 ± 0.7 for melatonin and 5-MCA-NAT, respectively. In summary, melatonin reduces the release of chloride concomitantly to cAMP generation. The reduction of Cl(-) secretion accounts for a decrease in the water outflow and therefore a decrease in aqueous humor production. This could be one of the main mechanisms responsible for the reduction of IOP after application of melatonin and 5-MCA-NAT. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Long-term oral melatonin administration reduces ethanol-induced increases in duodenal mucosal permeability and motility in rats.

    PubMed

    Sommansson, A; Yamskova, O; Schiöth, H B; Nylander, O; Sjöblom, M

    2014-10-01

    Increased intestinal epithelial permeability is associated with intestinal inflammation and dysfunction. The aim of the present study was to investigate the role of long-term oral melatonin administration on ethanol-induced increases in duodenal mucosal permeability and hypermotility. Male Sprague-Dawley rats were administered melatonin in their tap water (0.1 mg mL(-1) or 0.5 mg mL(-1) ) for 2 or 4 weeks. After the treatment period, the rats were anaesthetized with Inactin(®) , and a 30-mm duodenal segment was perfused in situ. The effects on duodenal mucosal paracellular permeability, bicarbonate secretion, fluid flux and motor activity were studied. The expression levels of the tight junction components, zona occludens (ZO)-1, ZO-2, and ZO-3, claudin-2, claudin-3, claudin-4, occludin, and myosin light chain kinase and of the melatonin receptors MT1 and MT2 were assessed using qRT-PCR. Melatonin administration for 2 weeks significantly reduced the basal paracellular permeability, an effect that was absent after 4 weeks. Perfusing the duodenal segment with 15% ethanol induced marked increases in duodenal paracellular permeability, bicarbonate secretion and motor activity. Melatonin for 2 weeks dose-dependently reduced ethanol-induced increases in permeability and motor activity. Four weeks of melatonin administration reduced the ethanol-induced increases in duodenal motility and bicarbonate secretion but had no effect on the increases in permeability. Two weeks of melatonin administration upregulated the expression of MT1 and MT2 , although both were downregulated after 4 weeks. Melatonin downregulated the expression of ZO-3 and upregulated the expression of claudin-2, even as all other mRNA-levels investigated were unaffected. Although further studies are needed, our data demonstrate that melatonin administration markedly improves duodenal barrier functions, suggesting its utility in clinical applications when intestinal barrier functions are compromised.

  7. Aromatase inhibitor-induced joint pain: melatonin's role.

    PubMed

    Burk, R

    2008-12-01

    Aromatase inhibitors (AIs) enjoy increasing use in breast cancer adjuvant therapy. But the joint pain associated with AIs significantly reduces patient adherence despite the clear survival benefits of this class of drugs. Two clues point to a novel hypothesis for this unexplained symptom. First, realizing that joint pain is associated with virtually all estrogen-depleting breast cancer treatments suggests that the cause is broader than this particular class of drugs. Second, the strongly circadian nature of these symptoms suggests circadian hormone involvement. This puts new light on some existing research findings: that estrogen depletion can increase pineal melatonin, that the ability of light to suppress pineal melatonin is more variable than once thought, and that an altered melatonin cycle is associated with rheumatoid arthritis patients, where identical circadian symptoms present. It is hypothesized that when AIs decrease estrogen levels, light-induced melatonin suppression (LIMS) loses efficacy, leading to an abnormal melatonin cycle as seen in rheumatoid arthritis patients, producing (via mechanisms not yet understood) the symptoms of morning stiffness. Not all frequencies of retinal light are equally effective at suppressing pineal melatonin; most artificial lighting has less relevant spectral density than sunlight. This hypothesis predicts that some patients can suppress the circadian joint pain associated with aromatase inhibitors merely by getting sufficient hours of daily retinal sunlight. A single patient history is discussed, in which a series of treatments had no effect on AI joint pain, while extended exposure to sunlight produced a definitive elimination of symptoms the next morning. To conclusively demonstrate the role of melatonin, light-emitting diodes of an appropriate frequency were mounted on a cap for the patient to wear. If worn first thing in the morning, the cap sharply curtailed the duration of morning stiffness. If worn for a

  8. Developmental effect of light deprivation on synaptic plasticity of rats’ hippocampus: implications for melatonin

    PubMed Central

    Talaei, Sayyed Alireza; Azami, Abolfazl; Salami, Mahmoud

    2016-01-01

    Objective(s): There are few reports have demonstrated the effect of a change-in-light experience on the structure and function of hippocampus. A change-in-light experience also affects the circadian pattern of melatonin secretion. This study aimed to investigate developmental effect of exogenous melatonin on synaptic plasticity of hippocampus of light deprived rats. Materials and Methods: The effects of intracerebroventricular (ICV) injection of 2μg/5μl melatonin was evaluated on the basic and tetanized field excitatory post-synaptic potentials (fEPSPs) recorded in the hippocampal CA3-CA1 pathway of normal light-reared (LR) and dark-reared (DR) rats at 2, 4, and 6 weeks of age. Using RT-PCR and western blotting, developmental changes in the expression of melatonin receptors, MT1 and MT2, in the hippocampus were also evaluated. Results: The amplitude of basic responses decreased across age in the LR rats. While light deprivation increased the amplitude of baseline fEPSPs, it decreased the degree of potentiation in post-tetanus responses. Melatonin injection also increased the amplitude of fEPSPs and suppressed the induction of long-term potentiation in both LR and DR rats. The expression of melatonin receptors increased in the hippocampus during brain development, and dark rearing reversed the expression patterns of both receptors. Conclusion: Although melatonin changed basic and tetanized responses of CA1 neurons across age during critical period of brain development, the pattern of its effects did not match the expression pattern of melatonin receptors in the hippocampus. Thus, the effects of melatonin on hippocampal neuronal responses may be exerted through other ways, like intercellular molecules and nuclear hormone receptors. PMID:27746873

  9. Prospective Study on Salivary Evening Melatonin and Sleep before and after Pinealectomy in Humans.

    PubMed

    Slawik, Helen; Stoffel, Michael; Riedl, Lina; Veselý, Zdenko; Behr, Michael; Lehmberg, Jens; Pohl, Corina; Meyer, Bernhard; Wiegand, Michael; Krieg, Sandro M

    2016-02-01

    Melatonin is secreted systemically from the pineal gland maximally at night but is also produced locally in many tissues. Its chronobiological function is mainly exerted by pineal melatonin. It is a feedback regulator of the main circadian pacemaker in the hypothalamic suprachiasmatic nuclei and of many peripheral oscillators. Although exogenous melatonin is approved for circadian rhythm sleep disorders and old-age insomnia, research on endogenous melatonin in humans is hindered by the great interindividual variability of its amount and circadian rhythm. Single case studies on pinealectomized patients report on disrupted but also hypersomnic sleep. This is the first systematic prospective report on sleep with respect to pinealectomy due to pinealocytoma World Health Organization grade I without chemo- or radiotherapy. Before and after pinealectomy, 8 patients completed questionnaires on sleep quality and circadian rhythm (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Morningness-Eveningness Questionnaire), 2 nights of polysomnography, salivary evening melatonin profiles, and qualitative assessment of 2 weeks of actigraphy and sleep logs. Six patients were assessed retrospectively up to 4 years after pinealectomy. Before pinealectomy, all but 1 patient showed an evening melatonin rise typical for indifferent chronotypes. After pinealectomy, evening saliva melatonin was markedly diminished, mostly below the detection limit of the assay (0.09 pg/mL). No systematic change in subjective sleep quality or standard measures of polysomnography was found. Mean pre- and postoperative sleep efficiency was 94% and 95%, and mean sleep-onset latency was 21 and 17 min, respectively. Sleep-wake rhythm during normal daily life did not change. Retrospective patients had a reduced sleep efficiency (90%) and more stage changes, although this was not significantly different from prospective patients. In conclusion, melatonin does seem to have a modulatory, not a

  10. Seasonal variations in the nycthemeral rhythm of plasma melatonin in the camel (Camelus dromedarius).

    PubMed

    El Allali, K; Achaaban, M R; Vivien-Roels, B; Bothorel, B; Tligui, N S; Pévet, P

    2005-09-01

    Seasonal changes in the pattern of plasma melatonin were investigated in two groups of camels (Camelus dromedarius): 11 adult and six young camels. Animals were subjected to the outdoor conditions of a desert environment. Blood samples were taken at regular intervals of about 3 hr (added to particular samples at 1 hr before then 30 min and 1 hr after sunset, and 1 hr before and 1 hr after sunrise) for 24 hr at both solstices and equinoxes of the year. The plasma melatonin levels steeply increased soon after sunset and remained elevated throughout all the night. Then, melatonin concentrations progressively declined shortly before sunrise and returned to daytime basal levels 1 hr later. There was no seasonal variation in the amplitude or in the offset of the melatonin peak or in the daytime basal levels. The onset of the nocturnal peak was delayed by 2 hr in June at the summer solstice (P < 0.05), which can be related to the changes in night length between the two solstices. A significant effect of age was observed in all seasons. Melatonin levels were higher in the young camel group (fall equinox: P < 0.001; spring equinox: P < 0.01; winter solstice: P < 0.01; summer solstice: P < 0.05). The pattern of melatonin secretion in the camel showed a significant seasonal variation parallel to the photoperiodic changes of the year. The observed decline of melatonin levels during an extra-light pulse in the middle of the night indicates the light control of melatonin synthesis. It is not yet known if, in this low latitude desert region, the seasonal breeding period of the camel is cued by the photoperiod. The data obtained, however, clearly demonstrate that the camel has the capacity to follow and to integrate photoperiodic changes through melatonin changes.

  11. Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals.

    PubMed

    Fischer, Stefan; Smolnik, Rüdiger; Herms, Markus; Born, Jan; Fehm, Horst L

    2003-11-01

    In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. The Zeitgeber influence of light on the timing of sleep is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Here, we investigated whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in blind individuals. In a double-blind crossover study, 12 totally blind subjects received 5 mg melatonin and placebo orally 1 h before bedtime starting at 2300 h. The dose used enhanced blood melatonin concentrations to clearly supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P < 0.05, respectively) and reduced time awake (P < 0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01) and a slight increase in rapid eye movement sleep (P < 0.06). Most important, melatonin normalized in parallel the temporal pattern of ACTH and cortisol plasma concentration. While after placebo, ACTH and cortisol levels did not differ between early and late sleep, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and a distinct rise during late sleep (P < 0.01, respectively). Cortisol nadir values were also decreased after melatonin (P < 0.05). We conclude from these data that in totally blind individuals the single administration of a clearly pharmacological dose of melatonin can improve sleep function by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes.

  12. Melatonin, a potential therapeutic agent for smooth muscle-related pathological conditions and aging.

    PubMed

    Pozo, M J; Gomez-Pinilla, P J; Camello-Almaraz, C; Martin-Cano, F E; Pascua, P; Rol, M A; Acuña-Castroviejo, D; Camello, P J

    2010-01-01

    Increases or decreases in the contractile response of smooth muscle underlie important pathological conditions such as hypertension, incontinence and altered gastrointestinal transit. These disorders are also frequently encountered in the aged population. Oxidative stress and inflammation are key features in the initiation, progression, and clinical manifestations of smooth muscle disorders. Melatonin, the major secretory product of the pineal gland, has free radical scavenging and antioxidative properties and protects against oxidative insult. Recently, widespread interest has grown regarding the apparent protective effects of melatonin on smooth muscle dysfunction. "In vitro" studies have shown that melatonin decreased vascular tone of vascular beds from control, hypertensive or aged animals, through the reduction of adrenergic contraction and the increase in acetylcholine-induced relaxation. "In vivo", melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. In the gastrointestinal tract, melatonin treatment improves age-related impairments in gallbladder contractility and prevents deleterious effects of cholecystitis on smooth muscle and the enteric nervous system through suppression of oxidative stress. In addition, melatonin improves colonic transit time in constipation-predominant IBS patients. Melatonin is also able to restore impaired contractility of the detrusor muscle from old animals through normalization of Ca(2+) dependent and independent contraction, mitochondrial polarity, neuromuscular function and oxidative stress, which would explain the ef