bluuebunny/crossref_metadata_2025 huggingface dataset:
Melatonin and farm animals: Endogenous rhythms and exogenous applications
Authors: Paterson Andrew M. , Foldes Andrew
Published: February 2007

Paterson AM, Foldes A. Melatonin and farm animals: Endogenous rhythms and exogenous applications. J. Pineal Res. 1994:16:167–177.

Studies on farm animals have contributed significantly to our increased understanding of basic melatonin‐related physiological mechanisms, as well as to the regulation of reproduction and pelage in individual domestic species. This review concentrates on recent work on the role of melatonin in the regulation of porcine reproduction, cervine endocrine, and behavioral cycles and wool and cashmere production which has added to this knowledge base. Early studies of the domestic pig indicated that melatonin secretion in this species differed markedly from that in other domestic and laboratory animals. There is now clear evidence that this is not the case and that the domestic pig uses a circadian rhythm of melatonin release for the transduction of photoperiodic information. Apparent inconsistencies among reports may be due, in part, to differences in the conditions under which the experiments were performed and to the assay systems employed to measure circulating melatonin, the concentrations of which are much lower than in other domestic species. Appropriately administered exogenous melatonin advances the onset of puberty in gilts, and may prove to be effective in overcoming seasonal infertility in female pigs. Appropriately timed melatonin and/or photoperiod treatments, administered to ruminants in utero, influence the reproductive physiology of the offspring, indicating that even in species which don't develop an endogenous melatonin rhythm till some weeks postnatally, awareness of photo environment, presumably via maternal melatonin, predates birth. Pre‐ or early postnatal melatonin‐related treatments also influence the development/cycle frequency of pelage. Areas requiring further investigation include the hormonal/growth factors involved, reasons for the transient nature of the effects in sheep and goats, and the reason for similar effects on pelage of augmenting or inactivating melatonin. Aspects of endogenous melatonin rhythms in farm species which require further study include: the significance of the abolition of the nocturnal melatonin peak in the sheep by prolonged short day exposure; the increased pineal bloodflow in sheep bred to produce high wool yields; the presence of high daytime melatonin levels immediately prior to the rut in the fallow buck; and the low amplitude of the rhythm in the domestic pig.
Effects of aging on photoperiodic responsiveness and specific 2‐[125I]‐iodomelatonin binding sites in the pars tuberalis and suprachiasmatic nuclei of Siberian hamsters
Authors: Duncan Marilyn J. , Purvis Cheryl C.
Published: February 2007

Duncan MJ, Purvis CC. Effects of aging on photoperiodic responsiveness and specific 2‐[125I]‐iodomelatonin binding sites in the pars tuberalis and suprachiasmatic nuclei of Siberian hamsters. J. Pineal Res. 1994:16:184–187.

Siberian hamsters undergo reproductive quiescence during exposure to a short day photoperiod, but this response appears to diminish with age. This study investigated whether age‐related losses in photoperiodic responsiveness may be related to decreases in specific 2‐[125I]‐iodomelatonin binding sites in the suprachiasmatic nuclei or pars tuberalis. Adult male Siberian hamsters (group 1: 3–6 months of age and group 2: 9–12 months of age) were exposed to short photoperiod (10 hr of light/day) for 10 weeks. Profound testicular regression was evident in the majority of the hamsters in group 1, but in only a few of the hamsters in group 2. There were no significant differences between the groups in the density or affinity of the specific 2‐[125I]‐iodomelatonin binding sites in either the suprachiasmatic nuclei or the pars tuberalis. These findings suggest that the failure of older hamsters to respond to short photoperiod is not caused by a loss of specific 2‐[125I]‐iodomelatonin binding sites in the suprachiasmatic nuclei or pars tuberalis.
Pharmacological effects of melatonin treatment on both locomotor activity and brain serotonin release in rats
Authors: Chuang Jih‐lng , Lin Mao‐Tsun
Published: February 2007

Chuang J‐I, Lin M‐T. Pharmacological effects of melatonin treatment on both locomotor activity and brain serotonin release in rats. J. Pineal Res. 1994: 17: 11–16.

The effects of intraperitoneal administration of pharmacological doses of melatonin (60 mg/kg) on both locomotor activity and brain monoamine release were assessed in rats. The spontaneous levels of either horizontal motion, vertical motion, or total distance traveled were decreased following melatonin injection. On the other hand, the spontaneous levels of postural freezing increased after treatment. External heat exposure (36°C) produced increases in locomotion (including horizontal motion, vertical motion, and total distance traveled) as well as decreases of postural freezing in rats. The heat‐induced increases of horizontal motion and total distance traveled as well as decreases of postural freezing were attenuated by melatonin treatment. In addition, cold exposure (4 C) produced increases of vertical motion as well as decreases of postural freezing. Again, the cold‐induced behavioral responses were attenuated by melatonin treatment. Biochemical data revealed that the serum levels of melatonin were decreased by both heat and cold exposure in rats. Furthermore, voltammetric data revealed that intraperitoneal administration of melatonin (60 mg/kg) decreased serotonin, but not the dopamine, release in the hypothalamus, the corpus striatum or nucleus accumbens of rat brain. Neither the locomotor activity responses to thermal stress nor brain monoamine release was affected by a smaller dose of melatonin (30 mg/kg, i. p.). The results suggest that systemic administration of melatonin, at pharmacological doses, inhibits brain serotonin release and results in a reduction in both the spontaneous locomotion and the thermal stress‐induced locomotor activity responses in rats.
Pharmacologic characterization of melatonin mediated phosphoinositide hydrolysis in pigeon brain
Authors: Mullins U. Lena , Eison Arlene S.
Published: February 2007

Mullins UL, Eison AS. Pharmacologic characterization of melatonin‐mediated phosphoinositide hydrolysis in pigeon brain. J. Pineal Res. 1994: 17: 33–38.

High densities of [125I]‐iodomelatonin binding sites have been demonstrated in pigeon brain. Melatonin binding sites have been shown to be linked to signal transduction mechanisms in other species. The present study investigated the melatonin‐mediated second messenger response of phosphoinositide hydrolysis in slices of telencephalon, optic tectum, cerebellum, hypothalamus, and pons medulla of pigeon brain. The highest rates of melatonin‐mediated phosphoinositide hydrolysis were observed in telencephalon and pons/medulla. Relative potencies of melatonin agonists to induce phosphoinositide hydrolysis were as follows: 2‐iodomelatonin > 6‐chloromelatonin > N‐acetylserotonin > melatonin ≫ serotonin (5‐HT). Agonist‐induced phosphoinositide hydrolysis was blocked by N‐acetyltryptamine (NAT), a melatonin antagonist, but not by ketanserin, a 5HT2A/2C receptor antagonist, demonstrating that phosphoinositide hydrolysis did not result from 5HT2A or 5HT2C receptor stimulation. In addition, the effects of melatonin agonists were sensitive to prazosin, an alpha‐adrenergic antagonist reported to exhibit nanomolar affinity for melatonin binding sites in hamster brain, but not to phentolamine, an alpha‐adrenergic antagonist that shows no affinity for melatonin binding sites. These data provide evidence that signal transduction associated with melatonin in pigeon brain involves the induction of phosphoinositide hydrolysis as a second messenger.
Melatonin is involved in cholecystokinin‐induced changes of ileal motility in rats
Authors: Benouali‐Pellissier S.
Published: February 2007

Benouali‐Pellisier S. Melatonin is involved in cholecystokinin‐induced changes of ileal motility in rats. J. Pineal Res. 1994: 17: 79–85. ©Munksgaard 1994

The aim of this study was to determine, in the rat, the interaction between melatonin and cholecystokinin in the regulation of the ileal interdigestive motility. This was analyzed by the chronic electromyography technique. Ileal motility was defined by the presence of intermittent spike bursts corresponding to the contractile activity of the organe. In control rats, these spike bursts were organized in cyclic myoelectrical complexes. Each complex is characterized by two successive spiking activity phases: the irregular phase (ISA) followed by the regular phase (RSA). Pinealectomy suppressed the RSA phase so ileal motility was constituted only by the ISA phase. When melatonin (1 mg/kg i. v.) was injected into pinealectomized rats, RSA phases were immediately and definitively restored. RSA phases were also re‐established when the “alimentary” type of cholecystokinin receptors (CCKA) were blocked by selective antagonists such as L364,718 or SR27897 (1 mg/kg i. v.). The latter had better brain accessibility than L364,718. Unlike the effects of melatonin, the effect of these antagonists was neither immediate (the latency is longer for L364,718 than for SR27897) nor definitive. In control rats, cholecystokinin (5 |μg/kg i. v.) induced a characteristic long‐lasting (29 |Mp 2 min) excitomotor effect on the ileum. This effect was suppressed in pinealectomized rats and was restored after melatonin treatment. These results suggest that, via the central nervous system, melatonin is involved in the modulation of cholecystokinin action on ileal motility.
Age‐related differences in the structure of human pineal calcium deposits: Results of transmission electron microscopy and mineralographic microanalysis
Authors: Schmid Hermann A. , Raykhtsaum Gregory
Published: February 2007

Abstract: Pineal tissue calcifications (male, ages 14, 47, 62, 82), which were metallographically embedded and polished at controlled levels and studied by transmission electron microscopy and microanalytic spectroscopy, showed age‐related differences. Results show that concentrically arranged crescent‐shaped lamellae increase in number and decrease in width with age. Calcium (Ca) and phosphorus (P) per point measurements in dark and light lamellae at various distances from the core show Ca/P molar ratios between 1.49–1.62 in the 82‐year‐old specimen as compared to 1.26 to 1.41 in the younger specimens. The 62‐year‐old specimens show a decrease in P and an increase in Ca from periphery to center. These data and other descriptive details suggest that the sum of these changes represent remodelling of the mineralogical structure within the same calcification throughout the life span.
The pineal gland of the aging rat: Calcium localization and variation in the number of pinealocytes
Authors: Humbert Willy , Pévet Paul
Published: February 2007

Abstract: In the present study, we investigated the population of pinealocytes in the pineal gland of aging rats. Dark and light pinealocytes were analyzed as to their calcium content. Calcium localization was realized in dark and light cells by means of cytochemistry and X‐ray microanalysis. Calcium was mainly localized in dark pinealocytes characterized by many ultrastructural signs of degeneration. The number of pinealocytes per square surface of aged rats (28 months) was com‐pared to young ones (3–4 months). While there is a significant increase in the number of dark pinealocytes there is a decrease in the total number of pinealo‐cytes in aged rats. This age‐related loss of pinealocytes may explain the age‐related functional decline of the pineal gland activity (e.g., the decrease of the nocturnal melatonin production).
T‐Helper‐2 lymphocytes as a peripheral target of melatonin*
Authors: Maestroni Georges J.M.
Published: February 2007

Abstract: In the past several years we demonstrated that the pineal neurohormone melatonin has immunoenhancing properties and can counteract the immunodepres‐sion that may follow acute stress, drug treatment, and viral diseases or aging. Sev‐eral laboratories have subsequently confirmed and extended our findings. It soon appeared evident that T‐derived cytokines constitute the main mediators of the im‐munological effect of melatonin. We have recently found a high affinity (Kd: 346 |Mp 24 pM) binding site for 125I‐melatonin on T‐helper‐type 2 lymphocytes in the bone marrow. Activation of this putative melatonin receptor, with both physiologi‐cal and pharmacological concentrations of melatonin, resulted in an enhanced pro‐duction of interleukin‐4 (IL4), which in turn acted on bone marrow stromal cells and induced the release of hematopoietic growth factors. This melatonin‐cytokine cascade showed the remarkable capacity of rescuing hematopoietic functions in mice treated with cancer chemotherapeutic compounds without interfering with the anticancer action of these agents. The very low concentration (0.1 nM) at which melatonin is active may well reflect a physiological function of endogenous melatonin. The pineal gland has been, in fact, reported to signal the blood forming system. The evidence of IL4 involvement is relevant to our understanding of many melatonin effects and may be part of a pineal‐immune axis involving also Th 1 cy‐tokines. The ability of rescuing hematopoiesis against the toxic action of cancer chemotherapeutic compounds and the presence of high‐affinity IL4 receptors on human tumors provide a further promising rationale for the clinical use of melatonin
Pineal gene expression: Dawn in a dark matter
Authors: Stehle Jorg H.
Published: February 2007

Abstract: The mammalian pineal gland serves as a neuroendocrine interface to convert environmental lighting conditions into a humoral message, the nocturnally elevated synthesis of melatonin. Regulation and fine tuning of the circadian melatonin production in response to external cues requires complex interactions of transsynaptic signalling. These requirements are fulfilled by a high degree of plasticity on all levels between receptor activation and cellular response. Many receptors on pinealocytic membranes and enzymes involved in melatonin synthesis are linked to the second messenger cAMP. Cross talk between second and third messengers converges in the pineal gland—as in other tissues—eventually on a modulated activity of transcription factors. Of fundamental importance for genes involved in the transsynaptic signalling to create a circadian profile in melatonin synthesis is the cAMP‐inducible promoter element, the CRE (cAMP responsive element). Indeed, the CRE is shared by many pineal genes that are of physiological importance. Recently, the deciphering of molecular determinants regulating expression of cAMP‐inducible genes in the mammalian pineal gland, like NAT, c‐jun, or the β‐adrenergic receptor, suggests a modulation in their transcription by a dual regulatory mechanism: posttransiational activation of the early third messenger CREB (cAMP responsive element binding protein) stimulates, cis‐acting cAMP‐induced transcriptional upregulation of the late third messenger 1CER (inducible cAMP early repressor) inhibits genes with a CRE.
Melatonin counteracts lipid peroxidation induced by carbon tetrachloride but does not restore glucose‐6 phosphatase activity
Authors: Daniels William M.U. , Reiter Russel J. , Melchiorri Daniela , Sewerynek Ewa , Pablos Marta I. , Ortiz Genaro G.
Published: February 2007

Abstract: Carbon tetrachloride (CC14) exerts its toxic effects by the generation of free radicals. In this study we investigated whether melatonin, a potent free radical scavenger, could prevent the deleterious effects of CC14. Liver homogenates and liver microsomes were incubated with CCI4 in the presence of melatonin and lipid peroxidation and glucose‐6 phosphatase (G6Pase) activity were determined. All doses of CC14 (1, 0.5, 0.1 raM) produced significantly high levels of lipid peroxidation, as reflected by increased levels of malonaldehyde and 4‐hydroxyalkenals, in both liver homogenates and liver microsomes. These doses of CC14 concommitantly reduced the activity of microsomal G6Pase. Co‐incubation with melatonin dose‐dependently (2, 1, 0.5 raM) inhibited the production of lipid peroxidation, but it was unable to restore the activity of G6Pase. In in vivo studies, rats were also treated with melatonin (10 mg/kg, i.p.), given 30 min before and 60 min after the administration of CC14 (5 ml/kg, i.p.). Significantly elevated levels of lipid peroxidation were measured in the liver and kidney. Melatonin prevented the CCl4‐induced lipid peroxidation in the kidney, but not in the liver. These data suggest that melatonin may provide protection against some of the damaging effects of CCI4, possibly due to its ability to scavenge toxic free radicals.
Exogenous melatonin entrains rhythm and reduces amplitude of endogenous melatonin: An in vivo microdialysis study
Authors: Drijfhout W. J. , Homan E. J. , Brons H. F. , Oakley N. R. , Skingle M. , Grol C. J. , Westerink B.H.C.
Published: February 2007

Abstract: The circadian rhythm of melatonin production was studied using on‐line, in vivo microdialysis in the rat pineal gland. With this technique it was possible to record a pronounced melatonin rhythm with very high time resolution. Three phase‐markers of the rhythm were calculated from the data, indicating increase (IT50), decrease (DT50) and amplitude of the rhythm. Comparing these phase markers led to several conclusions. Entrainment of the rhythm under constant darkness was performed with melatonin administration at different circadian stages [circadian time (CT) 8 and CT12] and for different periods of time (2 weeks and 4 weeks). Also, entrainment was established by applying 15 min light pulses at CTO. Entrainment of IT50 with melatonin partially uncoupled it from DT50. Four weeks entrainment in constant darkness (DD) caused a phase‐delay in DT50 of 2.2 hr. Entrainment of IT50 with light at CTO for 2 weeks in DD caused a phase‐advance in DT50 of 1.3 hr. The entrainment with melatonin was restricted to a narrow window for melatonin to be applied, since injections at CT8 did not result in entrainment. Exogenous melatonin reduced the amplitude of the rhythm of endogenous melatonin. This effect was not circadian time dependent, since administration at CT8 for 2 weeks and at CT12 for 4 weeks resulted in a highly significant decrease. Light did not seem to have an effect on the amplitude. The data presented here provide us with new information about the nature of entrainment by melatonin. Since the present development of melatonergic agents for clinical use focuses on the entrainment capacity, effects of these compounds on amplitude of circadian rhythms needs to be addressed. In vivo microdialysis seems to be a good technique for that.
The hypothermic effect of melatonin on core body temperature: Is more better?
Authors: Dawson Drew , Gibbon Samantha , Singh Parmjit
Published: February 2007

Abstract: Recent studies have shown that melatonin is both hypnotic and hypothermic at physiological levels. Indeed, the hypnotic effect may be mediated via the hypothermic action. If this is the case, it is important to explore the dose‐response relationships for the thermoregulatory effects of melatonin. Four groups of eight healthy adults (n = 32), aged between 18 and 38, each underwent two 12‐hr bedrest protocols in which core body temperature (CT) and plasma melatonin levels were measured concurrently between 0800 and 2000 hr. For each group, subjects ingested either sucrose placebo or a 0.1, 0.5, 1.0, or 5.0 mg melatonin capsule at 1600 hr in a double‐blind counterbalanced cross‐over design. Melatonin was absorbed rapidly, with peak levels being reached after 1 hr at all dose levels. Mean peak plasma melatonin levels increased from physiological to pharmacological levels in a dose‐dependent manner. Elimination for all dose levels was rapid, with mean plasma half‐lives between 33 and 47 min. At the lower doses the mean drop in CT was between 0.05 and 0.15°C and took between 2 and 3 hr. At the higher doses (1.0 and 5.0 mg), CT fell by 0.25–0.3°C within 30–60 min following ingestion and at the highest dose (5 mg) remained suppressed for the duration of the study. While the magnitude and duration of the drop increased in what appeared to be a dose‐dependent manner, it is unlikely that this relationship reflects a simple dose‐response curve. There was considerable variability in plasma profiles following administration, particularly at the two lowest doses (0.1 and 0.5 mg). The lower mean drop in CT probably reflects the lower proportion of subjects achieving physiological plasma levels, and therefore a hypothermic effect, at the two lowest doses. If melatonin is to be used to improve sleep onset and maintenance by lowering CT, doses between 1.0 and 5.0 mg appear to be the lowest that produce a consistent drop in CT across all subjects.
The L‐type Ca2+ channel is involved in microvesicle‐mediated glutamate exocytosis from rat pinealocytes
Authors: Yamada Hiroshi , Yamamoto Akitsugu , Takahashi Masami , Michibata Hitoshi , Kumon Hiromi , Moriyama Yoshinori
Published: February 2007

Abstract: Pinealocytes, parenchymal cells of the pineal gland, secrete glutamate through microvesicle‐mediated exocytosis upon depolarization by KC1 in the presence of Ca2+, which is involved in a novel paracrine‐like intercellular signal transduction mechanism in neuroendocrine organs. In the present study, we investigated whether or not the L‐type Ca2+ channel is involved in the microvesicle‐mediated glutamate secretion from cultured rat pinealocytes. Nifedipine, a specific antagonist of the L‐type Ca2+ channel, inhibited the Ca2+‐dependent glutamate exocytosis by 48% at 20 uM. Other L‐type Ca2+ channel antagonists, such as nitrendipine, showed similar effects. 1,4‐Dihydro‐2,6‐dimethyl‐5‐nitro‐4[2‐(trifluoromethyl)‐phenyl]‐3‐pyridinecarboxylic acid methyl ester (BAY K8644), an agonist of the L‐type Ca2+ channel, at 1 uM, on the other hand, stimulated the glutamate exocytosis about 1.6‐fold. Consistently, these Ca2+ channel antagonists inhibited about 50% of the Ca2+ uptake, whereas BAY K8644 increased the uptake 5.3‐fold. An antibody against the carboxyl‐terminal region of the rabbit L‐type Ca2+ channel recognized polypeptides of pinealocytes with apparent molecular masses of 250 and 270 kDa, respectively, and immunostained the plasma membrane region of the pinealocytes. These results strongly suggested that the entry of Ca2+ through L‐type Ca2+ channel(s), at least in part, triggers microvesicle‐mediated glutamate exocytosis in pinealocytes.
Apamin blocks the direct relaxant effect of melatonin on rat ileal smooth muscle
Authors: Reyes‐Vázquez C. , Naranjo‐Rodríguez E.B. , García‐Segoviano J.A. , Trujillo‐Santana J. , Prieto‐Gómez B.
Published: February 2007

Reyes‐Vázquez C, Naranjo‐Rodríguez EB, García‐Segoviano JA, Trujillo‐Santana J, Prieto‐Gómez B. Apamin blocks the direct relaxant effect of melatonin on rat ileal smooth muscle. J. Pineal Res. 1997; 22:1–8. © Munksgaard, Copenhagen

The present study investigated the mechanisms of melatonin‐induced inhibition of the ileal smooth muscle contraction. Rat isolated ileal smooth muscle strips were stimulated in an organ bath using carbachol (CAR) or potassium chloride (KC1) depolarization. Under these conditions, melatonin produced a concentration‐dependent inhibition of muscle contraction (mean inhibitory concentration, IC50: 17.3 times 10‐6 M), which was not blocked by either tetrodotoxin (10‐6 M), hexamethonium (10‐4M), or phentolamine (10‐6M). The inhibitory effect of melatonin during CAR stimulation was blocked in a concentration‐dependent manner by the presence of apamin (4.8 times 10‐9 M), a K+‐channel blocker. By contrast, other K+‐channel blockers such as 4‐aminopyridine (lf‐4M to 5 times 10‐3 M), tetraethylammonium (10‐4 M to 10‐1 M), and glibenclamide (10‐5 M) were ineffective. Additionally, the Ca2+‐channel antagonists nitrendipine (IC50: 2.4 times 10‐9 M) and verapamil (IC50: 1.1 times 10‐7 M) also blocked the inhibitory action of melatonin. These results suggest that melatonin may interact with an apamin‐sensitive, possibly Ca2+‐activated, K+ channel and thus cause an inhibition of ileal smooth muscle contractions.
Nocturnal urinary 6‐sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age‐matched controls and shows negative correlation with tumor‐size
Authors: Bartsch Christian , Bartsch Hella , Karenovics Angela , Franz Heiko , Peiker Gertrud , Mecke Dieter
Published: February 2007

Bartsch C, Bartsch H, Karenovics A, Franz H, Peiker G, Mecke D. Nocturnal urinary 6‐sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age‐matched controls and shows negative correlation with tumor‐size. J. Pineal Res. 1997; 23:53–58. © Munksgaard, Copenhagen

In previous studies a tumor‐size dependent decline of the circadian amplitude of serum melatonin was found in primary unoperated breast cancer patients, which was not due to changes of the hepatic metabolism of melatonin since its main peripheral metabolite, 6‐sulphatoxymelatonin (aMT6s), showed similar serum levels. The aim of the current study was to verify these previous results by measurements of the nocturnal excretion of aMT6s in urine. The determination of aMT6s was carried out by radioimmunoassay. 17 primary unoperated breast cancer (BC) patients and 34 age‐matched control patients with different types of benign gynecological diseases awaiting operation (breast diseases, n=13; ovarian diseases, n=12; and uterine diseases, n=9) were analysed. The median nocturnal urinary aMT6s excretion (22:00–6:00 hr) was significantly lower (‐48%, P =0.033) in BC patients than in controls. Controls showed a significant negative linear regression with age (r = ‐0.419, P= 0.014). According to multivariate linear regression analysis, BC revealed no age‐dependency but a significant negative effect of increasing tumor‐size on aMT6s‐excretion (P= 0.036) was detected. These results confirm previous findings of a decreased pineal melatonin secretion in BC patients as well as an inverse relationship with tumor‐size excluding a possible distortion due to age. The mechanisms involved are unknown but indicate that BC may lead to an impaired production of pineal melatonin. The clinical relevance of these findings from therapeutic and diagnostic point of view is discussed.
Melatonin entrainment of the circadian N‐acetyltransferase rhythm in the newborn rat pineal gland
Authors: Trávníčková Zdeňka , Illnerová Helena
Published: February 2007

Trávníčková Z, Illnerová H. Melatonin entrainment of the circadian N‐acetyltransferase rhythm in the newborn rat pineal gland. J. Pineal Res. 1997; 23:136–141. © Munksgaard, Copenhagen

In 15‐day‐old control and vehicle‐treated rats, the evening rise of the pineal N‐acetyltransferase occurred at the same time as in their mothers, whereas in 5‐day‐old pups, the rise occurred by 2–3 hr earlier. Four‐day administration of melatonin in the late day phase advanced the N‐acetyltransferase rise in 15‐day‐old rats as compared with the rise in the vehicle‐treated animals; a slight melatonin induced phase advance in 5‐ and 27‐day‐old rats was not significant. The data indicate that the newborn rat's circadian pacemaker controlling the rhythmic N‐acetyltransferase rise may be entrained by exogenous melatonin. It appears, however, that the maternal melatonin transferred via milk cannot entrain the pup's pacemaker by phase advancing it, since the N‐acetyltransferase rise in the pups begins earlier or at the same time as maternal melatonin production driven by the N‐acetyltransferase rhythm.
Antioxidative protection in a high‐melatonin organism: The dinoflagellate Gonyaulax polyedra is rescued from lethal oxidative stress by strongly elevated, but physiologically possible concentrations of melatonin
Authors: Antolín Isaac , Obst Barbara , Burkhardt Susanne , Hardeland Rüdiger
Published: February 2007

Antolín I, Obst B, Burkhardt S, Hardeland R. Antioxidative protection in a high‐melatonin organism: The dinoflagellate Gonyaulax polyedra is rescued from lethal oxidative stress by strongly elevated, but physiologically possible concentrations of melatonin. J. Pineal Res. 1997; 23:182–190. © Munksgaard, Copenhagen

Lethal oxidative stress was investigated in the dinoflagellate Gonyaulax polyedra by measuring the dying‐peak of bioluminescence during circadian phases of low physiological light emission, low bioluminescence capacity, and low sensitivity to stimulatory agents. Measurements were carried out in constant darkness after transfer of cells from light at CT 6 (circadian time, 0600 hr). H2O2(0.08 mM), when administered 1 hr after transfer of cells, led to a multifold, long‐lasting enhancement of light emission, which is typical for lethal cell damage. At the circadian phases of investigation, melatonin did not substantially stimulate bioluminescence up to concentrations of 0.5 mM. At this concentration, addition of melatonin prevented the dying‐peak and reduced bioluminescence to almost basal values. The high concentration of melatonin applied is not unphysiological in Gonyaulax, because the indoleamine can increase to levels of several millimolar, e.g., in response to temperature signals. These protective effects of melatonin seem to be caused mainly by the direct action of melatonin as an antioxidant, because the major enzymes of antioxidative protection were not stimulated by melatonin, although some of them responded to H2O2. The activities of neither superoxide dismutase, hemoperoxidase/catalase, glutathione peroxidase, nor haloperoxidase were enhanced under the influence of melatonin; glutathione 5‐transferase activity increased only slightly.
Melatonin increases nerve growth factor in mouse submandibular gland
Authors: Pongsa‐Asawapaiboon Anchalee , Asavaritikrai Pundit , Withyachumnarnkul Boonsirm , Sumridthong Ayuthaya
Published: February 2007

Pongsa‐Asawapaiboon A, Asavaritikrai P, Withyachumnarnkul B, Sumridthong A. Melatonin increases nerve growth factor in mouse submandibular gland. J. Pineal Res. 1998; 24:73–77. © Munksgaard, Copenhagen

The effect of melatonin administration on nerve growth factor (NGF) was studied in the submandibular glands of adult Swiss male mice. Melatonin injection, at 1 μg daily for 30 days, resulted in an increase in the NGF content as detected by immunohistochemistry. The submandibular gland weight and the area of the granular convoluted tubules, which contained NGF, were also increased significantly. These effects were not observed when the dose of melatonin was increased to 10 and 50 μg daily. None of the melatonin treatments used influenced the weights or histology of the testes or seminal vesicles of the mice. The results suggest that melatonin, at physiological concentrations, directly regulates NGF synthesis in the mouse submandibular gland.
Effects of melatonin on proliferation of cancer cell lines
Authors: Papazisis Konstantinos T. , Kouretas Demetrios , Geromichalos George D. , Sivridis Efthimios , Tsekreli Olga K. , Dimitriadis Konstantinos A. , Kortsaris Alexander H.
Published: February 2007

Papazisis KT, Kouretas D, Geromichalos GD, Sivridis E, Tsekreli OK, Dimitriadis KA, Kortsaris A.H. Effects of melatonin on proliferation of cancer cell lines. J. Pineal Res. 1998; 25:211–218. © Munksgaard, Copenhagen

The pineal hormone melatonin has been reported to have in vitro antiproliferative effects on estrogen receptor‐positive human breast cancer cell lines at concentrations near to plasma physiological concentrations (1 times 10‐11to 1 times 10‐9M). Its growth inhibitory actions have been thought to be linked to the estrogen‐receptor system. We tested the cytotoxic effects of melatonin on MCF‐7 and T47D human breast cancer cell lines by using the SRB (sulforhodamine‐B), XTT‐tetrazolium, and bromodeoxyuridine (BrdU) assays in 96‐well microtiter plates. After a 3 or 4 day exposure, melatonin did not have any significant effect on breast cancer cell proliferation and survival in doses up to 1 times 10‐4M. Doses higher than 1 mM exhibited a potent cytotoxic effect, which was not mediated by the estrogen‐receptor or by protein tyrosine kinases and was not specific for breast cancer cell lines. Intracellular glutathione levels did not seem to play any role in the sensitivity of breast cancer cells to melatonin, since the addition of L‐buthionine‐[S,R]‐sulfoximine, ethacrynic acid, or exogenous glutathione did not modify our results. We conclude that under our experimental conditions melatonin has no inhibitory effects on human breast cancer cells at low (physiological or supraphysiological) concentrations. The different experimental procedures that were utilized in the present study can partially explain the divergence between our results and the literature.
Melatonin excretion is not related to sleep in the elderly
Authors: Youngstedt Shawn D. , Kripke Daniel F. , Elliott Jeffrey A.
Published: February 2007

Abstract: We examined the association between 6‐sulphatoxymelatonin (6‐SMT) excretion and sleep in 68 volunteers 60–79 years of age who complained of insomnia or depression. An Actillume wrist monitor was worn for 5–7 consecutive days and nights in home‐living conditions. Activity was used to estimate total sleep time (TST) and wake after sleep onset (WASO). Throughout two 24 hr periods, urine was collected approximately every 2 hr during the day and after any voidings during the sleep period. During the next week, subjects spent 5 nights and 4 days in the laboratory. Sleep was measured and scored with standard polysomnographic techniques. Urine was collected, as for home recording, on days 1 and 4. Urinary concentrations of 6‐SMT were assayed. Cosine‐ fitting of urine data across both days at home and both laboratory collections established the mesors and amplitudes of 24 hr 6‐SMT excretion rhythms, but neither was significantly correlated with sleep. Mean and peak 6‐SMT excretion during the sleep period was also determined. Significant correlations were found between mean 6‐SMT during the laboratory sleep period and TST and WASO. However, these associations were not independent of circadian timing: sleep was better when sleep occurred near the circadian acrophase of 6‐SMT excretion. These data indicate that low melatonin production may not be an important factor in insomnia among the elderly.
Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenetetrazole in mice
Authors: Lapin Lzyaslav P. , Mirzaev Said M. , Ryzov Ivan V. , Oxenkrug Gregory F.
Published: February 2007

Abstract: Melatonin was tested in an ongoing attempt to find the endogenous antagonists of quinolinic acid, an endogenous convulsant. Among a great number of metabolites that have been tried before, only a few were found (cerulein and quinaldic acid in mice and kynurenic acid in rats). In SHR (bred from Swiss) male mice, intracerebroventricular (i.c.v.) pretreatment with melatonin (1.25–10.0 μg) attenuated (in the descending order of potency) the convulsant effect of i.c.v. administered kainate, quinolinate, glutamate, N‐methyl‐D‐aspartate, and pentylenetetrazole. Melatonin was ineffective against i.p. administered pentylenetetrazole. Systemically (intraperitoneal, i.p.) administered melatonin (12.5–100.0 mg/kg) attenuated the convulsant effect of quinolinate, while the action of other convulsants used remained unaltered. It is suggested that melatonin could be tried against grand ma1 seizures in epileptic patients.
Modulation of plasma melatonin concentrations by changes in posture
Authors: Nathan Pradeep J. , Jeyaseelan Angela S. , Burrows Graham O. , Norman Trevor R.
Published: February 2007

Abstract: Posture change from a lying position to a standing position results in a decrease in plasma volume, which leads to an increase in plasma constituents, especially that of proteins and blood constituents bound to them. The aim of the present study was to investigate the physiological effects of postural changes on plasma nocturnal melatonin concentrations in healthy human volunteers. The study was divided into four stages. During stage one, subjects were seated from 21.00 hr to 01.00 hr. In stage two, subjects were lying at ground level from 21.00 hr to 01.00 hr. In stage three, subjects were is a sitting position from 2100 hr to 2300 hr and then in a standing position from 23.00 hr to 24.00 hr, and back to the sitting position from 24.00 hr to 01.00 hr. In the final stage, subjects were in a lying position from 21.00 hr to 23.00 hr and then in a standing position from 23.00 rh to 24.00 hr and back to the lying position from 24.00 hr to 01.00 hr. AUC analysis showed significant differences between sitting and lying positions (t=2.84; P<0.05; df=5), with higher melatonin levels associated with the sitting position (mean difference in peak concentration of 17.1 pg/ml). Furthermore a change in posture from the lying to the standing position produced a statistically significant increase in melatonin concentrations (final stage) (t=−3.37; P<0.05; df=5) (mean difference in peak concentration of 28.5 pg/ml). No differences were found with a change in posture from a sitting to a standing position. The hemoconcentration and hemodilution associated with posture changes may play a role in altering plasma protein bound hormones such as melatonin.
Melatonin directly suppresses steroid production by preovulatory follicles in the cyclic hamster
Authors: Tamura Hiroshi , Nakamura Yasuhiko , Takiguchi Shuji , Kashida Shiro , Yamagata Yoshiaki , Sugino Norihiro , Kato Hiroshi
Published: February 2007

Abstract: The purpose of these studies was to investigate the effects of melatonin on the production of steroids (progesterone, testosterone, and estradiol) and cAMP by preovulatory follicles and to examine changes in melatonin concentrations in the ovary during the estrous cycle. Adult cyclic hamsters were used in this study. Melatonin concentrations in the ovary, pineal gland, and serum were measured at mid‐light and mid‐dark during the estrous cycle. Effects of melatonin on steroidogenesis by preovulatory follicles, thecae, and granulosa cells were examined, and its effect on cAMP production by preovulatory follicles was also investigated. Melatonin (0.1–10 ng/ml) had no effect on steroid production in the absence of hCG, but melatonin decreased progesterone and estradiol production by preovulatory follicles in a dose‐dependent and time‐dependent manner in the presence of hCG (100 mlU/ml). The target of melatonin was thecae but not granulosa cells, and melatonin significantly reduced cAMP production by preovulatory follicles. Melatonin concentrations in the ovary showed a similar phasic variation with high levels during mid‐dark and low during mid‐light, as in the pineal gland and serum. These results show that the ovarian melatonin levels also exhibit a circadian rhythm and suggest that the high melatonin milieu in the ovary may induce gonadal regression in the cyclic hamster.
Melatonin receptors in PC3 human prostate tumor cells
Authors: Gilad Eli , Laufer Menachem , Matzkin Haim , Zisapel Nava
Published: February 2007

Abstract: Melatonin, secreted nocturnally by the pineal gland, can bind to human benign prostate epithelial cells and attenuate their growth and viability. In the present study, melatonin binding and responses were explored in the human steroid‐independent PC3 prostatic tumor cells. PC3 cells bound 125I‐melatonin with low affinity (Kd ca. 0.9 nM) at high as well as low cell density. Melatonin enhanced cGMP and 3H‐thymidine incorporation at low, but attenuated them at high cell density. In addition, melatonin inhibited cAMP at low, but augmented it at high cell density. These effects were associated with an increase in cell count at low‐ but not high‐density cultures. Pertussis toxin treatment suppressed 125I‐melatonin binding and ablated all the effects of melatonin on 3H‐thymidine incorporation, cAMP, and cGMP at both cell densities. Cholera toxin treatment failed to block the effects of melatonin on 3H‐thymidine incorporation, but prevented the modulation by melatonin of cAMP at low and cGMP at high cell density. The cGMP analog 8‐Br‐cGMP, inhibited melatonin's effects on 3H‐thymidine incorporation at both cell densities. H89, a protein kinase A inhibitor, prevented melatonin's effects on 3H‐thymidine incorporation at low but not high cell density. These results provide the first demonstration of direct interaction of melatonin with hormone‐insensitive prostate tumor cells. The melatonin receptors in the PC3 cells are coupled to pertussis toxin‐sensitive G proteins to induce cell density‐dependent changes in cGMP, cAMP, and cell growth.
Melatonin content in plasma and large intestine of patients with colorectal carcinoma before and after surgery
Authors: Vician M. , Zeman M. , Herichová I. , Juráni M. , BlaŽiČek P. , Matis P.
Published: February 2007

Abstract: The distinct melatonin rhythm with higher concentrations during the darktime was found in plasma of both control patients and patients with colorectal carcinoma. Moderate surgery did not induce any changes in plasma melatonin levels, but a pronounced increase in both the day‐ and nighttime melatonin concentrations was found after surgical treatment for colon cancer. The melatonin content in the tumor tissue did not differ from that in the proximal and the distal parts of the resected gut, which were without signs of malignant changes. Neither concentrations of serotonin nor 5‐hydroxyindole acetic acid differed among analyzed parts of the gut. Daytime melatonin concentrations in gut tissue (314.7 ± 87.8 pg/g of wet tissue) were more than ten times higher than the daytime levels in circulation. It was hypothesized that increased levels of this hormone in the gastrointestinal tract may play an important protective role against the development of colorectal cancer via stimulation of the immune system, protection against free radicals, and interaction with fatty acid uptake and metabolism.
Melatonin protects against age‐related DNA damage in the brains of female senescence‐accelerated mice
Authors: Morioka Nobuyuki , Okatani Yuji , Wakatsuki Akihiko
Published: February 2007

Abstract: We investigated whether melatonin reduces the age‐related susceptibility of brain to oxidative DNA damage. Brain tissues and blood samples were obtained in the middle of dark period of the daily light:dark cycle from female senescence‐accelerated mice (SAM‐P/6) at ages 4, 8, and 12 months. Serum melatonin concentrations and the contents of deoxyguanosine (dG) and 8‐hydroxydeoxyguanosine (8‐OHdG) in DNA extracted from these brain homogenates were measured by high‐performance liquid chromatography. Contents of 8‐OHdG showed a significant age‐related increase (P < 0.001), while that of dG did not. The 8‐OHdG:dG ratio also exhibited a significant age‐related increase (P < 0.001). Serum melatonin concentration decreased markedly between 8 (159.7 ± 4.5 pg/mL) and 12 (46.8 ± 4.5 pg/mL) months of age (P < 0.0001). Oral melatonin administration (2 μg/mL in water) starting at 8 months of age, which produced a significant increase in serum melatonin concentration at 12 months (187.6 ± 18.3 pg/mL) compared with untreated animals (P < 0.0001), also resulted in significant decreases in brain 8‐OHdG contents and 8‐OHdG:dG ratios. These results indicate that administration of a physiologic dose of melatonin to SAM‐P/6 mice may prevent the age‐related oxidative DNA damage in the brain.
Role of photoperiod and the pineal gland in T cell‐dependent humoral immune reactivity in the Siberian hamster
Authors: Yellon Steven M. , Teasley Laura A. , Fagoaga Omar R. , Nguyen Hellen C. , Truong Huy N. , Nehlsen‐Cannarella Sandra L.
Published: February 2007

Abstract: The present study tested the hypothesis that antibody production in response to xenoantigen is modulated by daylength and dependent upon the pineal gland. After injection of sheep erythrocytes (SRBC), serum immunoglobulin (Ig) concentrations were 5‐fold lower in hamsters in short versus long days. Pinealectomy (Pinx) abolished the nocturnal melatonin rhythm, blocked short‐day‐mediated testis regression, and eliminated the short‐day reduction in Ig production after SRBC treatment. Antibody titers in response to SRBC were equivalently augmented in short‐day Pinx and long‐day sham hamsters. The results indicate that photoperiodic effects on T cell‐dependent humoral immunity are dependent upon the pineal gland. These findings raise the possibility that day length‐associated changes in some immune system functions are mediated by the pineal melatonin rhythm.
Hydroxyapatite–Carbon Nanotube Composites for Biomedical Applications: A Review
Authors: White Ashley A. , Best Serena M. , Kinloch Ian A.
Published: February 2007

Hydroxyapatite (HA) has been used in clinical bone graft procedures for more than 25 years. However, its poor tensile strength and fracture toughness compared with bone make it unsuitable for major load‐bearing devices. Carbon nanotubes (CNTs), with their high aspect ratio and excellent mechanical properties, have the potential to strengthen and toughen HA without offsetting its bioactivity, thus opening up a wider range of possible clinical uses for the material. This review discusses techniques for synthesizing and processing HA–CNT composites, as well as barriers that still remain to their successful development for clinical application.
Two Photon Polymerization of Polymer–Ceramic Hybrid Materials for Transdermal Drug Delivery
Authors: Ovsianikov A. , Chichkov B. , Mente P. , Monteiro‐Riviere N. A. , Doraiswamy A. , Narayan R. J.
Published: February 2007

Three‐dimensional microneedle devices were created by femtosecond laser two photon polymerization (2PP) of organically modified ceramic (Ormocer®) hybrid materials. Arrays of in‐plane and out‐of‐plane hollow microneedles (microneedle length=800 μm, microneedle base diameter=150–300 μm) with various aspect ratios were fabricated. The fracture and penetration properties of the microneedle arrays were examined using compression load testing. In these studies, the microneedle arrays penetrated cadaveric porcine adipose tissue without fracture. Human epidermal keratinocyte viability on the Ormocer® surfaces polymerized using 2PP was similar to that on control surfaces. These results suggest that 2PP is able to create microneedle structures for transdermal drug delivery with a larger range of geometries than conventional microfabrication techniques.
MOISTURE ADSORPTION INFLUENCES ON RICE
Authors: KUNZE OTTO R.
Published: February 2007

Rice is a hygroscopic grain which adsorbs or desorbs moisture depending on its ambient environment. Moisture desorption is associated with rice drying. Much research has been conducted to determine those drying procedures which produce the highest head rice yield. Moisture adsorption is associated with water reentering the rice grain. This occurs when the vapor pressure within the grain is lower than the vapor pressure in the surrounding air. Rapid moisture readsorption causes the rice grain to fissure. Fissured grains usually break during subsequent hulling and milling operations. This paper reviews the literature related to moisture adsorption and fissuring of the rice grain, and discusses those preharvest and postharvest conditions where rice grains are subjected to moisture‐adsorbing environments which have the potential to fissure the grain and subsequently reduce head rice yield.
PROTEOLYSIS BY IMMOBILIZED TRYPSIN
Authors: GRULKE ERIC A. , OKOS MARTIN R. , SYVERSON ALDRICH
Published: February 2007

Trypsin immobilized on a phenol‐formaldehyde resin was used as a model system to hydrolyze bovine serum albumin. An inhibitor was used during coupling to reduce autolysis. An automated GPC column showed that the reaction product distribution of the immobilized trypsin was different from that of the soluble enzyme. Enzyme loading affected the reaction product distribution. A 5% loss in proteolytic activity was found after 31 days of use.