bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of melatonin and L‐tryptophan in prevention of acute gastric lesions induced by stress, ethanol, ischemia, and aspirin
Authors: Brzozowski Tomasz , Konturek Peter Ch. , Konturek Stanislaw J. , Pajdo Robert , Bielanski Wladyslaw , Brzozowska Iwona , Stachura Jerzy , Hahn Eckhart G.
Published: February 2007

Brzozowski T, Konturek PCh, Konturek SJ, Pajdo R, Bielanski W, Brzozowska I, Stachura J, Hahn EG. The role of melatonin and L‐tryptophan in prevention of acute gastric lesions induced by stress, ethanol, ischemia, and aspirin. J. Pineal Res. 1997; 23:79–89. ©Munksgaard, Copenhagen

Melatonin, a pineal hormone, synthesized from L‐tryptophan, is known to exist in the gut and to scavenge oxygen free radicals but its role in gastroprotection against acute lesions induced by various strong irritants has been little studied. In this study, we determined the effects of melatonin and L‐tryptophan on gastric secretion and the formation of acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), stress, and ischemia‐reperfusion (I/R). Area of gastric lesions was determined by planimetry, gastric blood flow (GBF) was measured using a H2‐gas clearance technique, and blood was withdrawn for the measurement of free radicals, plasma gastrin, and melatonin concentration by specific radioimmunoassay. Intragastric (ig) administration of melatonin (2.5–10 mg/kg) or L‐tryptophan (25–200 mg/kg) failed to affect gastric lesions by ethanol and ASA but dose‐dependently reduced the lesions provoked by stress and I/R; this protective effect was accompanied by a significant rise in plasma melatonin level, GBF, and DNA synthesis and by a marked fall in blood free radicals. L‐tryptophan, which significantly elevated the plasma melatonin by about 3–5‐fold, also reduced the stress and I/R‐induced lesions and blood levels of free radicals, while increasing the GBF, DNA synthesis, and plasma gastrin levels. Inhibition of mucosal generation of PGE2 by indomethacin abolished the protection and the rise of GBF afforded by melatonin and L‐tryptophan, whereas pretreatment with NG‐nitro‐L‐arginine (L‐NNA), to suppress nitric oxide (NO) synthase, was without any effect. We conclude that melatonin applied exogenously in pharmacological doses and that released by the administration of its precursor, L‐tryptophan, protect gastric mucosa from the damage induced by stress and I/R possibly by a mechanism involving the scavenging of free radicals and gastric hyperemia probably mediated by endogenous prostaglandin but not NO.
The effect of atenolol, a p!‐adrenergic antagonist, on nocturnal plasma melatonin secretion: Evidence for a dose‐response relationship in humans
Authors: Nathan Pradeep J. , Maguire Kay R , Burrows Graham D. , Norman Trevor R.
Published: February 2007

Nathan PJ, Maguire KP, Burrows GD, Norman T.R. The effect of atenolol, a β1‐adrenergic antagonist, on nocturnal plasma melatonin secretion: Evidence for a dose‐response relationship in humans. J. Pineal Res. 1997; 23:131–135. © Munksgaard, Copenhagen

Pineal β1‐adrenergic receptors are involved in the regulation of melatonin secretion. The involvement of β1adrenergic receptors has been demonstrated by the ability of acute administration ofβ‐antagonists to suppress the nocturnal rise of circulating melatonin and its urinary metabolite 6‐sulphatoxymelatonin (aMT6s). The present study was undertaken to examine the relationship between increasing doses of atenolol and nocturnal plasma melatonin concentrations. Six healthy subjects participated in the study for a period of 5 weeks. Subjects were administered placebo, 12.5, 25, 37.5, and 50 mg doses of atenolol in a randomized single blind design. Each dose was separated by a 1 week washout period. Blood samples were collected at regular intervals from 19.00 hr to 06.00 hr. Repeated measures analysis of variance showed a dose‐dependent decrease in plasma melatonin concentrations (P < 0.01). A Student Newman‐Keuls post hoc test indicated significant differences between placebo and all doses of atenolol (P < 0.05). The results demonstrate a dose‐dependent relationship between β1‐receptor blockade and suppression of nocturnal plasma melatonin in humans.
Use of a newly developed technique to isolate rat pinealoeytes and study the effects of adenosine agonists on melatonin production
Authors: Nicholls Julia , Skene Debra J. , Hourani Susanna M.O.
Published: February 2007

Nicholls J, Skene DJ, Hourani SMO. Use of a newly developed technique to isolate rat pinealoeytes and study the effects of adenosine agonists on melatonin production. J. Pineal Res. 1997; 23:164–168. © Munksgaard, Copenhagen

Recent studies have suggested a role for adenosine in the regulation of rat pineal melatonin synthesis. The data, however, are conflicting and therefore the aim of this study was to characterize adenosine receptors more fully in vitro by using a range of selective adenosine agonists and the adenosine antagonist 8‐sulphophenyltheophylline (8‐SPT). A simple method for the mechanical separation of rat pinealoeytes was developed. Pinealoeytes were briefly (15 min) incubated with drugs followed by a 4 hr drug‐free incubation period after which melatonin concentrations in the incubation medium were measured by radioimmunoassay. The β‐adrenoceptor agonist isoprenaline gave a dose‐related increase in melatonin production, demonstrating that this pinealocyte preparation technique is suitable to evaluate the effect of drugs on pineal melatonin synthesis. Our results show that adenosine, N6‐(phenylisopropyl)adenosine (R‐PIA) and 2‐p‐(2‐carboxethyl) phenethylamino‐5 '‐N‐ethylcarboxamidoadenosine (CGS21680) did not affect melatonin synthesis alone or in combination with isoprenaline. However 5'‐N‐ethylcarboxamidoadenosine (NEC A) (100 uM) potentiated the stimulatory effect of isoprenaline (3 μM) on pineal melatonin production and this effect appeared to be antagonized by 8‐SPT (50 uM). These results are consistent with activation by NECA of an A2b adenosine receptor.
Alterations in F‐actin distribution in cells treated with melatonin
Authors: Matsui Denise Hitomi , Machado‐Santelli Gláucia Maria
Published: February 2007

Matsui DH, Machado‐Santelli G.M. Alterations in F‐actin distribution in cells treated with melatonin. J. Pineal Res. 1997; 23:169–175. © Munksgaard, Copenhagen

One of the possible pathways of action of melatonin is its effect on the cytoskeleton. In this work we looked for alterations in the cytoskeleton of cells treated with melatonin at physiological concentrations. T‐47D, Hs‐578T (human breast carcinoma cell lines), and MDCK (normal dog kidney) cells were maintained in MCDB 153 supplemented with 1% fetal bovine serum (FBS), or in Dulbecco's modified Eagle's medium (DMEM) supplemented with 5% FBS and treated with melatonin (10‐‐9M or 10‐‐10M) for 2 and 5 days, with or without 10‐‐8 M estradiol. F‐actin was stained with phalloidin‐fluorescein isothiocyanate (FITC). Cytokeratin 19 and β‐tubulin filaments were detected with specific monoclonal antibodies and secondary antibodies bound to FITC. Melatonin‐treated T‐47D cells observed in a transmission electronic microscope (TEM) showed an irregular nuclear shape and intermediate filaments disposed around the nucleus, which was not observed in control cells. Immunofluorescence analysis of cytokeratin filaments did not show significant differences between their distribution in control and treated cells. Melatonin did not induce significant alterations in cytokeratin filaments of T‐47D, Hs578T or MDCK cells in DMEM and MCDB 153, or T‐47D cells in DMEM. Melatonin induced the derangement of F‐actin both in T‐47D and MDCK cells kept in MCDB 153. The same was not observed when estradiol was also present. We did not observe significant alterations in the distribution of F‐actin in T‐47D or Hs‐578T cells grown in DMEM. In DMEM, melatonin‐treated MDCK cells were more elongated, with a slight concentration of F‐actin on the cell boundary. Melatonin induced very slight alterations in microtubule organization of all cell lines studied.
Effects of sympathicolytic and sympathomimetic drugs on plasma immunoreactive melatonin in the domestic pig
Authors: Lewczuk Bogdan , Przybylska‐Gornowicz Barbara
Published: February 2007

Lewczuk B, Przybylska‐Gornowicz B. Effects of sympathicolytic and sympathicomimetic drugs on plasma immunoreactive melatonin in the domestic pig. J. Pineal Res. 1997; 23:209–220. © Munksgaard, Copenhagen

Plasma immunoreactive melatonin was monitored for 110 hr in sexually immature female domestic pigs kept under 12L:12D light conditions and treated with two sympathicolytic (α‐methyl‐p‐tyrosine, propranolol) and three sympathicomimetic (clorgyline, isoproterenol, dobutamine) drugs. Mean levels of plasma melatonin in the control pigs showed significant diurnal changes with the highest values during the scotophase. In the individual gilts the diurnal changes of plasma melatonin were markedly irregular; melatonin increases were not consistently noted at night, and melatonin levels during light and darkness varied considerably between days. The lack of consistency in the diurnal patterns of plasma melatonin in individual pigs during consecutive days explains the large inter‐individual differences observed in previous short‐term studies. Administration of α‐methyl‐p‐tyrosine resulted in the decrease in both daytime and nighttime melatonin levels, compared with the control group, but it did not eliminate the increases in melatonin during the night. Treatment with other drugs did not significantly change the level of plasma melatonin compared with the control group, however they had modulatory effects on melatonin rhythm. The results suggest that the plasma melatonin in the domestic pig is controlled by the adrenergic nervous system, but the pharmacology of the secretion and/or metabolism of this pineal hormone is different than described in other species.
Comparison of the antioxidant activity of melatonin and pinoline in vitro
Authors: Pähkla Rein , Zilmer Mihkel , Kullisaar Tiiu , Rägo Lembit
Published: February 2007

Pahkla R, Zilmer M, Kullisaar T, Rago L. Comparison of the antioxidant activity of melatonin and pinoline in vitro. J. Pineal Res. 1998; 24:96–101. © Munksgaard, Copenhagen

Several recent experiments have shown that melatonin is an efficient antioxidant and free radical scavenger. In the present study the antioxidative effect of melatonin was compared with that of pinoline. Pinoline (6‐methoxy‐tetrahydro‐β‐carboline) can be formed in the mammalian body under physiological conditions from 5‐hydroxytryptamine or as a tricyclic metabolite of melatonin. Both melatonin and pinoline inhibited lipid peroxidation and showed comparable activity in a total antioxidant status test. Melatonin and pinoline concentration‐dependently scavenged hydroxyl radicals with IC5011.4±1.0 (J.M for melatonin and 62.3±3.8 uM for pinoline. These results support the importance of the indolic part of the molecule and the 5‐methoxy group common to both compounds in terms of the ability of these molecules to quench the hydroxyl radicals. As pinoline has been shown to exert an antidepressant‐like effect in behavioral experiments and has been reported to have a low toxicity, this compound should be further studied as a potential antidepressant with pronounced antioxidative effects. These results further support the importance of pineal gland in antioxidative protection. Rein Pahkla,1 Mihkel Zilmer,2 Tiiu Kullisaar,2 and Lembit Rago1 Departments of 'Pharmacology and biochemistry, University of Tartu, EE2400 Tartu, Estonia
Postnatal developmental changes in NSE and NNE mRNA expression in the rat pineal gland: In situ hybridization histochemistry
Authors: Feng Xue‐Lian , Usui Hiroshi , Fujita Toshiya , Ichikawa Tomio , Katagiri Takashi , Washiyama Kazuo , Kumanishi Toshiro
Published: February 2007

Feng X‐L, Usui H, Fujita T, Ichikawa T, Katagiri T, Washiyama K, Kumanishi T. Postnatal developmental changes in NSE and NNE mRNA expression in the rat pineal gland: In situ hybridization histochemistry. J. Pineal Res. 1998; 24:108–116. © Munksgaard, Copenhagen

By in situ hybridization, neuron‐specific enolase (NSE) and non‐neuronal enolase (NNE) mRNAs were examined in the rat pineal gland at the postnatal developmental and adult stages. The distributions of hybridized signals were analyzed in comparison with immunohistochemical staining of synaptophysin (SYN), which is a marker for pinealocytes. In SYN‐positive areas that were observed throughout postnatal developmental and adult stages, we detected both NSE and NNE signals, which increased simultaneously during early postnatal development and thereafter became stationary. Quantitative analysis revealed that NNE signals were 2‐ to 3‐fold greater in number than NSE signals at any given stage. This predominant expression pattern of NNE differed from that in neurons, which usually showed both signals at similar levels and seemed to reflect the difference in physiological function from neurons. During the early postnatal stages, a cord‐like arrangement of cells without distinct SYN staining was observed. This arrangement was the thickest at postnatal day 0 and became dispersed and thinner with development, showing a relationship with formation of vascularized connective tissue stroma. By in situ hybridization, many of the constituent cells showed weak NNE signals but no distinct NSE signals. However, some cells also showed weak NSE signals, suggesting heterogeneity of these cells. The characteristic NSE and NNE expression patterns in the pineal gland cells clarified in this study might provide a basis for further studies of the differentiation and function of the pineal gland.
Melatonin and prolactin secretion profile in naturally occurring scrapie in ewe
Authors: Picard‐Hagen N. , Gayrard V. , Andreoletti O. , Galea J. , Grandjean C. , Mandon‐Maurice F. , Cabanie P. , Schelcher F. , Toutain R.L.
Published: February 2007

Picard‐Hagen N, Gayrard V, Andreoletti O, Galea J, Grandjean C, Mandon‐Maurice F, Cabanié P, Schelcher F, Toutain P.L. Melatonin and prolactin secretion profile in naturally occurring scrapie in ewe. J. Pineal Res. 1998; 24:117–122. © Munksgaard, Copenhagen

The 24 hr pattern of melatonin secretion was determined in scrapie‐affected ewes during the clinical course of the disease. The melatonin response to a night interruption by a 1 hr period of illumination was also measured. Fourteen ewes (seven control and seven scrapie‐affected ewes) were subjected to artificial short days (9L:15D). Four 24 hr blood sampling sessions separated by about 10 days were performed. Ewes were sacrificed when clinical signs had progressed to irreversible recumbency and the scrapie diagnosis was confirmed by histopathology. Plasma melatonin was assayed in all samples and prolactin was analysed in samples obtained during the second sampling session using RIA methods. The instantaneous amplitude of elevation of plasma melatonin concentrations was calculated for each ewe and each sampling session and the within‐ewe repeatability of this parameter was evaluated. The within‐ewe repeatability of instantaneous amplitude of melatonin secretion was apparently greater in control than in scrapie‐affected ewes (72% vs. 39%). The light stimulus induced an abrupt decrease of night melatonin concentrations in all ewes. Prolactin secretion was not affected by the disease. It was concluded that the 24 hr pattern of melatonin secretion was maintained in scrapie‐affected ewes. The retino‐hypothalamic tract transducing light information remained functional in diseased ewes despite some evidence of histopathological changes of the pineal gland. The instability of melatonin secretion during the clinical course of scrapie could reflect a disturbance of pineal function. However, whether this effect exists or not, it could not be used to discriminate scrapie‐affected ewes from control ones.
Inhibition of cell proliferation: A mechanism likely to mediate the prevention of neuronal cell death by melatonin
Authors: Mayo Juan Carlos , Sainz Rosa Maria , Una Higinio , Antolin Isaac , Esteban Manuel M , Rodriguez Carmen
Published: February 2007

ABSTRACT: In a previous work we demonstrated that melatonin is able to prevent apoptosis induced by low doses of 6‐hydroxydopamine (6‐OHDA) in undifferentiated and neuronal PC 12 cells. We also reported how this neurohormone was able to prevent the decrease in the mRNA for antioxidant enzymes caused by 6‐OHDA. Although the antioxidant capability of melatonin seems to be clearly implicated in its antiapoptotic activity, literature suggests that its antiproliferative property could also be involved in its prevention of apoptosis. In the present work we demonstrated that melatonin is able to inhibit cell proliferation in undifferentiated PC 12 cells, decreasing cell number and the total amount of DNA, and the mRNA for the histone H4, which are known to increase during DNA synthesis. Melatonin does not decrease the number of cells in nonproliferating PC12 cells, indicating that it does not cause cell death. Additionally, we demonstrate that other inhibitors of cell proliferation, as well as other antioxidants, are able to mimic the antiapoptotic effect of melatonin. This is interpreted to mean that melatonin acts by both mechanisms to inhibit apoptosis caused by 6‐OHDA and the findings support the hypothesis of a relationship between oxidative stress and regulation of the cell cycle.
Effect of daytime oral melatonin administration on neurobehavioral performance in humans
Authors: Rogers Naomi L. , Phan Oanh , Kennaway David J. , Dawson Drew
Published: February 2007

ABSTRACT: The pineal hormone melatonin has been proposed as a potential treatment for insomnia and circadian rhythm disorders, as experienced by shiftworkers and transmeridian travellers. If melatonin is to be used in a clinical setting, it is important that the neurobehavioral performance effects associated with its administration be identified. As with other drugs that increase sleepiness, e.g., sedatives and antihistamines, inappropriate effects on neurobehavioral performance could result in a corresponding increase in side effects and potential risk to users. The aim of this study was to investigate the effects of 5 mg oral melatonin, administered at 12.30 hr to 16 young (22.4±1.8 years), healthy subjects (ten males and six females), on the following neurobehavioral performance tasks: two‐choice visual reaction and response time, unpredictable tracking, extended two‐choice visual reaction and response time, and simple auditory response and reaction time, in a randomised, double‐blind crossover protocol. Following melatonin administration, significant decrements in performance on the tracking task and on response and reaction time scores for the visual choice and extended two‐choice visual tasks were observed. The profile of these performance decrements across the experimental sessions were found to closely map the profile of salivary melatonin levels. The findings of the present study highlight the significant neurobehavioral performance effects associated with the daytime administration of melatonin.
The impact of photoperiods and melatonin on gonadal development in juvenile Turkish hamsters (Mesocricetus brandti)
Authors: Gündüz Bülent , Stetson Milton H.
Published: February 2007

Gündüz B, Stetson M.H. The impact of photoperiods and melatonin on gonadal development in juvenile Turkish hamsters (Mesocricetus brandti). J. Pineal Res. 1998; 25:193–200. © Munksgaard, Copenhagen

The reproductive response of both intact adult and juvenile Turkish hamsters has been thoroughly studied and shown to be similar, unlike the golden hamster where juveniles remain aphotoperiodic until approximately 8 weeks of age. Unstudied to date, however, is the role of the pineal and its hormone melatonin in generating the testicular response to photoperiod in juvenile Turkish hamsters. Therefore, in this study we examined the reproductive response of prepubertal male Turkish hamsters, subjected to four different photoperiods (8L: 16D, 16L: 8D, 20L: 4D, and 24L: 0D) with altered pineal gland function. At 15 days of age, long‐day‐born (16L: 8D) hamsters were either pinealectomized, received melatonin implants, or remained untreated. Testes sizes were measured every 2 weeks. Testicular growth occurred only in untreated and beeswax implanted groups in 16L: 8D. Exposure to other photoperiods inhibited testicular development in untreated and beeswax implanted animals. Removal of the pineal gland, masking of the daily melatonin rhythm with constant release subcutaneous melatonin implants, or eliminating the daily rhythm of melatonin by continuous light exposure resulted in inhibition of gonadal development. These results demonstrate that juvenile Turkish hamsters respond similarly to adults on all photoperiods and under all conditions of pineal function tested.
δ‐Aminolevulinic acid‐induced lipid peroxidation in rat kidney and liver is attenuated by melatonin: An in vitro and in vivo study
Authors: Carneiro Regina C.G. , Reiter Russel J.
Published: February 2007

Abstract: Acute intermittent porphyria (AIP) is a genetically inherited disease characterized by a partial block in liver heme biosynthesis and by increased urinary excretion of the δ‐aminolevulinic acid (ALA). Recently, it has been proposed that the toxic effects of ALA are related to the generation of free radicals. In the present study the in vitro and in vivo effect of melatonin, a recently described antioxidative agent, on ALA‐induced lipid peroxidation in rat liver and kidney was determined. The concentration of malonaldehyde (MDA) and 4‐hydroxyalkenals (4‐HDA) was assayed as an index of induced membrane oxidative damage. In vitro melatonin protected, in a concentration‐dependent manner, against ALA‐induced lipid peroxidation in liver and kidney homogenates. In in vivo experiments as well, it was demonstrated that ALA (40 mg/kg)‐induced lipid peroxidation in liver and kidney was reduced by acute melatonin (10 m/g) treatment. The results support the involvement of free radicals in ALA toxicity and show that in vitro and in vivo melatonin confers protection against this toxicity, likely due to the antioxidative capability of the indole.
Regulation of calcium influx and phospholipase C activity by indoleamines in dinoflagellate Crypthecodiniurn cohnii
Authors: Tsim Siu‐Tai , Wong Joseph T.Y. , Wong Yung H.
Published: February 2007

Abstract: Exogenous indoleamines such as melatonin and 5‐methoxytryptamine have been shown to induce cyst formation (encystment) in many species of dinoflagellate. Induction of inositol phosphates formation by indoleamine has previously been demonstrated in Crypthecodiniurn cohnii. In addition, depletion of extracellular Ca2+ blocks the indoleamine‐induced encystment. In the present study, 12 indoleamines (including melatonin and related compounds) were examined for their abilities to induce Ca2+ influx, inositol phosphates formation, and encystment in C. cohnii. The results showed that melatonin, 5‐methoxytryptamine, and the peptide toxin mastoparan stimulated 45Ca2+ influxes in dose‐ and time‐dependent manners. The EC50 values of 5‐methoxytrypramine and mastoparan to stimulate 45Ca2+ uptake were 2 mM and 35 μM, respectively. The 5‐methoxytryptamine‐ and mastoparan‐induced 45Ca2+ influx were partially attenuated by the calcium channel blockers, verapamil and ruthenium red. A series of indoleamines were examined for their structure‐activity relationship on the induction of encystment and formation of inositol phosphates. Melatonin‐induced inositol phosphates formation was completely blocked by U73122, indicating the possible involvement of phospholipase C. Taken together, we conclude that indoleamines may induce encystment of the dinoflagellate C. cohnii via parallel activation of phospholipase C and Ca2+ influx signaling pathways. However, activation of phospholipase C and Ca2+ influx are not always necessary or sufficient for inducing encystment. Also, these data provided the first direct evidence of a Ca2+ influx regulating mechanism in dinoflagellate C. cohnii.
N‐acetyl‐serotonin (normelatonin) and melatonin protect neurons against oxidative challenges and suppress the activity of the transcription factor NF‐κB
Authors: Lezoualc'h Frank , Sparapani Mauro , Behl Christian
Published: February 2007

Abstract: It is now well established that the formation of free radicals and oxidative stress‐induced neuronal cell death can be involved in various neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pineal hormone melatonin has been suggested to be a neuroprotective antioxidant. To better understand the molecular mechanism of this activity, we compared the ability of melatonin and its precursor, N‐acetyl‐serotonin (normelatonin), to protect human neuroblastoma SK‐N‐MC cells and primary cerebellar granular neurons against oxidative stress. We found that normelatonin and melatonin have differential neuroprotective effects depending on the neuronal cell type. Normelatonin was more protective against hydrogen peroxide (H2O2) and glutamate‐induced cell death in SK‐N‐MC cells compared to melatonin which was more effective to protect primary cerebellar granular neurons against the toxicity of H2O2, glutamate and N‐methyl‐D‐aspartate when compared to normelatonin. At the molecular level, we tested the capacity of normelatonin and melatonin to inhibit the oxidative stress‐induced NF‐κB activation in both neuronal systems. Whereas normelatonin was more potent in the suppression of the activation of NF‐κB by H2O2 in SK‐N‐MC cells compared to melatonin, no apparent differences in the extent of suppression could be detected in primary neurons. Normelatonin's and melatonin's neuroprotective activity in SK‐N‐MC neuroblastoma cells may be mediated by the suppression of NF‐κB activation.
Opioidergic innervation of the tree shrew pineal gland: An immunohistochemical study
Authors: Phansuwan‐Pujito Pansiri , Jitjaijamjang Wipaporn , Ebadi Manuchair , Govitrapong Piyarat , Meller Morten
Published: February 2007

Abstract: The tree shrew (Tupaia glis) has been described as a missing link relating primate to insectivore stock. The pineal gland of the tree shrew consists of a superficial pineal and a deep pineal, which are connected by long and slender pineal stalk. A monoclonal antibody against leu‐enkephalin was used in an immunohistochemical investigation of the tree shrew pineal gland. A moderate innervation of leu‐enkephalin immunoreactive nerve fibers has been demonstrated in both superficial and deep pineal gland of the tree shrew. The density of the nerve fibers was slightly higher in the superficial pineal than that of the deep one. The number of immunoreactive nerve fibers were observed in the capsule of the pineal gland from where they entered the pineal parenchyma. Only a few immunoreactive fibers were found in the habenular area and the area rostra1 to the pineal recess, connecting the habenula and the deep pineal. Furthermore, some positive fibers were located in the pineal stalk. There was no evidence of leu‐enkephalin immunoreactive intrapineal cells as seen in the other species of mammal. Therefore, the interspecies variation of opioidergic innervation among the mammals may exist. The lack of intrapineal perikarya is interpreted to indicate that the sources of leu‐enkephalin nerve fibers were outside the gland. The anatomical location of the leu‐enkephalin immunoreactive nerve fibers in the tree shrew pineal gland supports to both central and peripheral pinealopetal pathways in this species.
The efficacy of vitamin E and melatonin as antioxidants against lipid peroxidation in rat retinal homogenates
Authors: Siu Andrew W. , Reiter Russel J. , To Chi Ho
Published: February 2007

Abstract: Free radical‐induced oxidation can cause severe cell damage in biological systems. Melatonin, a pineal secretory product, is a recently identified antioxidant that protects cells from the damaging effects of free radicals. We compared the effect of melatonin and vitamin E, another antioxidant, against lipid peroxidation (LPO) in rat retinal homogenates. The aim was to characterize the antioxidative efficacy of melatonin in retina, a tissue highly susceptible to oxidative damage. The LPO product, malondialdehyde (MDA), was determined to provide an index of cell damage in vitro. After the incubation with iron(II) ions, the free radical scavenging effectiveness of four different concentrations (i.e., 0.5, 1.0, 2.0, and 4.0 mM) of vitamin E and melatonin were determined by comparing the final levels of MDA. Lipid peroxidation product levels were significantly reduced in a dose‐response manner by all concentrations of vitamin E. Melatonin, in concentrations of either 2.0 or 4.0 mM, also significantly reduced LPO. Statistical analysis of the data showed that vitamin E treatment always yielded a lower level of LPO products than did the same concentration of melatonin. The concentrations of each agent required to inhibit 50% of the lipid damage (IC50) were 0.69 mM and 4.98 mM for vitamin E and melatonin, respectively. Both vitamin E and melatonin protect the retina against LPO in a dose‐dependent manner. Although the IC50 value for melatonin is about 7.2 times higher than that of vitamin E, melatonin's pharmacological and physiological role in the treatment and/or prevention of certain retinal diseases in vivo should be further investigated.
The seasonal interrelationship between melatonin, vasopressin, and serum osmolality in elderly subjects
Authors: Asplund Ragnar , Aberg Hans , Wetterberg Lennart
Published: February 2007

Abstract: Plasma concentration of arginine vasopressin (AVP) and melatonin and serum osmolality were measured at noon and at midnight in individuals living in the northern hemisphere on March 22–23, June 13–14, September 26–27, and December 12–13 in 35 healthy volunteers (15 men and 20 women) aged 60–74 years. The nocturnal increase in melatonin was highest in the autumn and lowest in the winter in both sexes. The midnight serum osmolality level was lower in the autumn than in any other time of the year. In both the men and the women the AVP level was higher in winter than in any other season (P < 0.01 and P < 0.0001, respectively). In men, the AVP level was higher at noon than at midnight in 49% of the investigated 24 hr periods, at the same level in 15% and lower in 36% (NS). The corresponding figures for women were 55%, 25%, and 20%, respectively (P < 0.05). This study suggests a possible relationship between melatonin and serum osmolality.
Protective role of melatonin and retinol palmitate in oxidative stress and hyperlipidemic nephropathy induced by adriamycin in rats
Authors: Montilla Pedro Lopez , Túnez Isaac Fiñana , de Agueda Carmen Muñoz , Gascón Felix Luna , López Soria Juan Vicente
Published: February 2007

Abstract: We have studied the effects of melatonin and retinol palmitate (RP) on the nephropathy and oxidative stress induced by a single and high dose of adriamycin (AD) in Wistar male rats. A dose of melatonin (75 μg/ kg/day) and a dose of RP (0.25 g oily solution/kg/day, sc) were injected 3 and 9 days before and after the administration of AD (25 mg/kg, i.p.), respectively. After the decapitation, samples were taken from the neck vascular trunk in order to determine the triglycerides, total cholesterol, phospholipids, HDL‐cholesterol, total proteins, urea, lipoperoxides, and reduced glutathione (GSH). We estimated the lipoperoxide and glutathione (GSH) contents in renal homogenates, and the excretion of proteins in urine over a 24 hr period. The administration of AD caused significant increases in proteinuria and in the other parameters studied [lipids (triglycerides, total cholesterol, phospholipids, and HDL‐cholesterol), nonprotein nitrogen compounds, and lipoperoxides]. AD increased the lipoperoxide content, but it decreased the GSH content in the kidney. Both melatonin and RP, although melatonin more significantly, decreased the intensity of the changes produced by the administration of AD alone. In fact, melatonin was quite efficient in reducing the formation of lipoperoxides, restoring renal GSH content and decreasing remarkably the severity of proteinuria. These results support the powerful antioxidant action of melatonin at renal level and a lower antioxidant action of retinol. Likewise, these data reinforce the hypothesis which supports the pathogenetic role and the close relation between the oxidative stress and the expression of the nephropathy induced by AD. However, in spite of this obvious antioxidant effect of melatonin in the kidney, additional studies are required to establish accurately the role of this pineal indole in the regulation and dynamics of the antioxidative defense enzyme system, which neutralizes the damaging effect of free radicals, both endogenous and exogenous, in this organ.
Urinary 6‐sulfatoxymelatonin profiles in male Djungarian hamsters (Phodopus sungorus) responding and not responding to short‐day photoperiods: Possible role of elevated daytime levels
Authors: Niehaus Michael , Lerchl Alexander
Published: February 2007

Abstract: The lack of endocrine and physiological responses of some Djungarian hamsters (Phodopus sungorus) to the transition from long to short photoperiods (L:D 16:8 → L:D 8:16) has been known for a long time but is not yet understood. We investigated the role of melatonin synthesis in this context because melatonin, as part of the circadian system, may play a role in non‐responsiveness. In ten responding and ten non‐responding male hamsters, the urinary 24 hr 6‐sulfatoxymelatonin (aMT6s) profiles under L:D 8:16 and L:D 16:8 were measured. Both short day responding and non‐responding hamsters showed diurnal aMT6s excretion rhythms. Whereas responders reacted to the transition L:D 16:8 → L:D 8:16 with a marked elevation of aMT6s excretion, in non‐responders no adjustment of the melatonin rhythm to the change of the photoperiod was seen. Furthermore, under L:D 16:8 the daytime levels of aMT6s were significantly (p<0.001) lower in responders compared to non‐responders whereas under L: D 8: 16 these levels were higher (p<0.01). It is speculated that high daytime levels of aMT6s under long‐day photoperiods in non‐responders result in down‐regulation of melatonin receptors of the nucleus suprachiasmaticus, the pacemaker for the pineal gland, leading to a lack of response to the transition to short‐day photoperiods.
Circannual reproductive rhythm in the European hamster (Cricetus cricetus): Demonstration of the existence of an annual phase of sensitivity to short photoperiod
Authors: Saboureau M. , Masson‐Pévet M. , Canguilhem B. , Pévet P.
Published: February 2007

Abstract: In the European hamster (Cricetus cricetus) short photoperiod (SP) is responsible for the transition between the breeding and the resting season and data obtained previously suggest that a circannual “clock” drives the annual rhythm of reproduction. This hypothesis implies the existence of a SP‐sensitive phase of the circannual system that occurs independently of the photoperiodic regime perceived by the animals after their arousal from hibernation at the end of March. In control animals kept outside, testicular atrophy occurs in August. When the animals were transferred from outdoors to controlled SP conditions (LD 10:14 and ambient temperature Ta = 18 ± 2°C), immediately (Group II) or 2, 4, 6 wk after capture (Groups IV, V, VI, respectively), sexual arrest occurs at the same time between mid‐June and mid‐July. In the other groups, transfer from outdoors to SP either after 6, 8, 10, 12 or 14 wk (Groups VI, VII, IX, X, XI, respectively) after capture, is followed directly within 4 wk by the gonadal atrophy. When SP was applied from the beginning of August (Group XII) gonadal atrophy was observed after only 2 wk. In this last group, however, the rapid involution is the consequence of the already initiated decline in sexual activity induced by the short daylengths from July. When comparing the effect of SP in two different ambient temperatures (Ta: 18 ± 2°C vs 7 ± 2°C), immediately (Groups II vs III), 8 (Groups VII vs VIII) or 16 (Groups XII vs XIII) wk after capture, it appears that low temperature does not affect the physiological process described above. In the European hamster, after the gonadal regrowth at the end of hibernation, the animals do not need to experience increasing long days to react against SP. Gonadal inhibition is induced when, following our hypothesis, SP coincides with an endogenous period of sensitivity that extends from mid‐May to at least July‐August. The present findings complement and extend earlier evidence to support the existence of an endogenous circannual control of seasonal reproduction in the European hamster.
The relationship between electromagnetic field and light exposures to melatonin and breast cancer risk: A review of the relevant literature
Authors: Brainard George C. , Kavet Robert , Kheifets Leeka I.
Published: February 2007

Abstract: Worldwide, breast cancer is the most common malignancy accounting for 20–32% of all female cancers. This review summarizes the peer‐reviewed, published data pertinent to the hypothesis that increased breast cancer in industrialized countries is related to the increased use of electricity [Stevens. R. G., S. Davis 1996]. That hypothesis specifically proposes that increased exposure to light at night and electromagnetic fields (EMF) reduce melatonin production. Because some studies have shown that melatonin suppresses mammary tumorigenesis in rats and blocks estrogen‐induced proliferation of human breast cancer cells in vitro, it is reasoned that decreased melatonin production leads to increased risk of breast cancer. To evaluate this hypothesis, the paper reviews epidemiological data on associations between electricity and breast cancer, and assesses the data on the effects of EMF exposure on melatonin physiology in both laboratory animals and humans. In addition, the results on the effects of melatonin on in vivo carcinogenesis in animals are detailed along with the controlled in vitro studies on melatonin's effects on human breast cancer cell lines. The literature is evaluated for strength of evidence, inter‐relationships between various lines of evidence, and gaps in our knowledge. Based on the published data, it is currently unclear if EMF and electric light exposure are significant risk factors for breast cancer, but further study appears warranted. Given the ubiquitous nature of EMF and artificial light exposure along with the high incidence of breast cancer. even a small risk would have a substantial public health impact.
The effects of near‐ultraviolet light on serotoninN‐acetyltransferase activity in the chick pineal gland
Authors: Zawilska Jolanta B. , Rosiak Jolanta , Trzepizur Kazimiera , Nowak Jerzy Z.
Published: February 2007

Abstract:Effects of near‐ultraviolet light (UV‐A; 325–390 nm, peak at 365 nm) on the activity of the pineal serotoninN‐acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthesis) were examined in chicks. Acute exposure of dark‐adapted animals to UV‐A radiation produced a marked decline in NAT activity of the pineal gland. The magnitude of this suppression was dependent upon duration of the light pulse and the age of the animals. The decrease in the nighttime NAT activity evoked by a 5 min pulse of UV‐A light applied during the fourth hour of the dark phase of the 12 hr light:12 hr dark cycle (LD) gradually deepened during the first 40 min after the return of animals to constant darkness, then the enzyme activity began to rise, reaching control values by 2 hr. Exposure of chicks to a 5 min pulse of UV‐A light during the ninth hour of the dark phase produced a marked decline in pineal NAT activity, which was reversible after 15 min of darkness. Pretreatment of animals with an inhibitor of catecholamine synthesis, α‐methyl‐ρ‐tyrosine (300 mg/kg, i. p.), or with a blocker of α2‐adrenergic receptors, yohimbine (2 mg/kg, i. p.), antagonized the suppressive effect of UV‐A light on nighttime NAT activity of the chick pineal gland. It is concluded that UV‐A irradiation, similar to visible light, potently suppresses melatonin biosynthesis in the chick pineal gland, with an α2‐noradrenergic signal playing the role of an intermediate in this action.
Melatonin affects the metabolism of the β‐amyloid precursor protein in different cell types
Authors: Lahiri Debomoy K.
Published: February 2007

Abstract: Melatonin is released in mammals during the dark phase of the circadian cycle, and its production declines with age in animals and humans. Since supplemental administration of melatonin may be beneficial in delaying age‐related degenerative conditions, it is necessary to study its effect on neuronal differentiation and the processing of key neuronal proteins, such as β‐amyloid precursor protein (βAPP) and synaptophysin. One of the important pathological hallmarks of Alzheimer's disease (AD) is the cerebrovascular deposition of amyloid plaques. The amyloid in senile plaques is mainly composed of the amyloid β‐peptide (Aβ) of 39–43 amino acids derived from a larger βAPP. The proteolytic cleavage by ‘χ‐secretase’generate soluble derivatives of βAPP (sAPP), lacking the cytoplasmic tail. transmembrane domain, and a small portion of the extracellular domain. Here levels of sAPP and βAPP were analyzed in cell lines of different origins by Western immunoblot of samples from conditioned media and cell lysates, respectively. Normal levels of secretion of sAPP into conditioned media were severely inhibited by treating different cell lines with a high dose of melatonin. In PC12 cells, levels of the fully matured βAPP forms of the post‐Golgi compartment were more drastically decreased than the unglycosylated βAPP of the endoplasmic‐reticulum (ER) forms. In other cell types, the unglycosylated ER‐bound βAPP derivatives are predominant forms that were marginally affected by melatonin treatment. When the treatment of cells with melatonin was withdrawn, the normal level of secretion of sAPP was restored. Melatonin reduces the secretion of soluble Aβ. Melatonin also inhibits the secretion of synaptophysin in PC12 cells. Taken together, these data suggest that melatonin probably affects the secretion of sAPP in the conditioned medium by interfering with its full maturation, and melatonin also affects the presysnaptic terminal marker.
Sexual dimorphism in N‐acetyltransferase and melatonin levels in the giant freshwater prawn Macrobrachium rosenbergii de Man
Authors: Withyachumnarnkul Boonsirm , Ajpru Supaporn , Rachawong Supanrat , Pongsa‐Asawapaiboon Anchalee , Sumridthong Ayuthaya
Published: February 2007

Abstract: N‐acetyltransferase (NAT) and melatonin were determined in the optic lobe of the giant freshwater prawn Macrobrachium rosembergii de Man. The prawns were divided into three groups: fast‐growing “jumper” males; slow‐growing “laggard” males; and females. Both NAT and melatonin levels in the jumper and laggard males were comparable, whereas those of the female were significantly lower. The results suggested a sexual dimorphism in the NAT and melatonin in the optic lobe of this species. It was also found that when one optic lobe was isolated, the level of NAT and melatonin in the contralateral optic lobe did not show a compensatory increase in either males or females. On the contrary, melatonin was suppressed in the remaining optic lobes in both sexes.
RETRACTED: Regulation of prostaglandin production in carrageenan‐induced pleurisy melatonin
Authors: Cuzzocrea Salvatore , Costantino Giuseppina , Mazzon Emanuela , Caputi Achille P.
Published: February 2007

Abstract: The aim of the present study was to investigate the effect of melatonin on the production of the inflammatory mediator prostaglandins in a model of acute inflammation, carrageenan‐induced pleurisy, where prostaglandins are known to play a crucial role. The results show that melatonin (12.5, 25, and 50 mg/kg, intraperitoneally, 15 min before the carrageenan) inhibits the inflammatory response (pleural exudate formation, polymorphonuclear cell infiltration, and prostaglandin production) in a dose‐dependent manner. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to cyclooxygenase‐2 (COX‐2) in the lungs of carrageenan‐treated rats. Pretreatment of carrageenan‐treated rats with melatonin (50 mg/kg, intraperitoneally, 15 min before the carrageenan) prevented COX‐2 expression. The present results demonstrate that melatonin exerts potent anti‐inflammatory effects. Part of these anti‐inflammatory effects may be related to a reduction of prostaglandin production during the inflammatory process.
Melatonin and the reduction or alleviation of stress1
Authors: Kirby Albert W. , Clayton Melanie , Rivera Pik , Comperatore Carlos A.
Published: February 2007

Abstract: In a double blind and placebo controlled study designed to investigate the effect of melatonin administration at 13:00 hr on menstrual characteristics, prolactin, and premenstrual syndrome‐like symptoms during simulated eastward travel, it was noted that melatonin reduces or alleviates the stress associated with the simulated travel. Bright lights were utilized to simulate eastward movement across six time zones. Melatonin (10 mg) was given to healthy females for 5 consecutive days during the late follicular and early luteal phases of the menstrual cycle. Hourly blood samples, used for analysis of melatonin and prolactin levels, were obtained for 24 hr before entering the dose administration phase of the study and again on the last dose day. Volunteers also completed a profile of moods state questionnaire upon waking on each of 8 days which overlapped the in‐house dose administration days. The placebo group showed a prolactin peak at 13:00 hr (dose time) on the last dose day/blood draw, while the melatonin group showed a prolactin peak at 15:00 hr. The prolactin peak at 13:00 hr is likely the result of stress, since stress is known to elicit the release of prolactin. The peak at 15:00 hr in the melatonin group was likely elicited by the administration of melatonin. Stress reduction in the melatonin group was supported by results from the profile of moods state questionnaire. The melatonin group consistently demonstrated scores indicative of less stress.
Regulation of AA‐NAT and HIOMT gene expression by butyrate and cyclic AMP in Y79 human retinoblastoma cells
Authors: Wiechmann Allan F. , Burden Marisha A.
Published: February 2007

Abstract: Two key enzymes involved in the synthesis of melatonin, hydroxyindole‐O‐methyltransferase (HIOMT) and arylalkylamine N‐acetyltransferase (AA‐NAT), are present in Y79 human retinoblastoma cells. Under certain conditions these cells produce melatonin and secrete it into the culture medium. In a previous study, it was observed that melatonin levels increase dramatically over control levels after the addition of dibutyryl cyclic AMP (dbcAMP), whereas after treatment with butyrate melatonin levels decreased. The changes in melatonin levels appeared to be the result of increases in AA‐NAT activity or decreases in HIOMT activity, following dbcAMP or butyrate treatment. In this study, mechanisms by which these agents influence HIOMT and AA‐NAT gene expression were examined. Levels of AA‐NAT and HIOMT RNA expression in response to treatment of Y79 cultures with 4 mM dbcAMP or 2 mM butyrate were measured by semi‐quantitative reverse‐transcription/polymerase chain reaction. Butyrate and dbcAMP showed no effect on AA‐NAT gene expression, whereas HIOMT gene expression was reduced by treatment with these agents. Levels of β‐actin RNA were increased following dbcAMP or butyrate treatment. This analysis suggests that the reduction in HIOMT activity caused by dbcAMP or butyrate treatment is the result of a decrease in HIOMT RNA synthesis or accumulation. Conversely, since AA‐NAT RNA levels were unaffected by dbcAMP or butyrate treatment, the increase in AA‐NAT activity previously observed may be the result of changes in the activational state of the AA‐NAT protein.