melatonin


Table of Contents
image Central effect of Melatonin against stress-induced gastric ulcers in rats.
image Melatonin protects bovine cerebral endothelial cells from hyperoxia-induced DNA damage and death.
image Hyperlipidemic nephropathy induced by adriamycin: Effect of Melatonin administration.
image A relationship between heat loss and sleepiness: Effects of postural change and Melatonin administration.
image Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4(+) cells - A possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes.
image Melatonin in osteosarcoma: An effective drug?.
image Long term Melatonin treatment in blind children and young adults with circadian sleep-wake disturbances.
image Cataractogenesis and lipid peroxidation in newborn rats treated with buthionine sulfoximine: Preventive actions of melatonin.
image Melatonin and N-tert-butyl-alpha-phenylnitrone block 60-Hz magnetic field-induced DNA single and double strand breaks in rat brain cells.
image Nocturnal plasma Melatonin profile and melatonin kinetics during infusion in status migrainosus.
image Melatonin inhibits vasopastic action of hydrogen peroxide in human umbilical artery.
image Retinal neurones containing kainate receptors are influenced by exogenous kainate and ischaemia while neurones lacking these receptors are not - melatonin counteracts the effect of ischaemia and kainate.
image Suppressive effect of Melatonin administration on ethanol- induced gastroduodenal injury in rats in vivo.
image Melatonin administration protects CA1 hippocampal neurons after transient forebrain ischemia in rats.

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Central effect of Melatonin against
stress-induced gastric ulcers in rats.

Kato K Murai I Asai S Komuro S Matsuno Y Matsukawa Y Kurosaka H Iwasaki A Ishikawa K Arakawa Y
Neuroreport 1997 JUL 7;8(9-10):2305-2309
Kato K, Nihon Univ, Sch Med, Dept Internal Med 3, Itabashi Ku, 30 1 Oyaguchi Kami Machi, Tokyo 173, JAPAN

WE investigated the role of Melatonin in the induction of gastric lesions induced by water immersion restraint stress or centrally administered thyrotropin-releasing hormone (TRH). Melatonin (0.1-1 ng) injected intracisternally (i.c.) 30 min prior to stress dose- dependently inhibited the induction of gastric lesions by water immersion restraint stress, while 100 mu g/kg, i.p. Failed to protect the gastric mucosa. Preadministration of Melatonin (1 ng, i.c.) significantly reduced (83%) the severity of gastric lesions induced by a TRH analogue (500 ng, i.c.). Serum Melatonin concentrations 30 min after administration of 1 ng Melatonin i.c. Did not differ from those of rats receiving i.c. Vehicle. These results suggest that Melatonin plays a protecti ve, anti-stress, role in the gastric mucosa via a mechanism involving the central nervous system.



Melatonin protects bovine cerebral endothelial
cells from hyperoxia-induced DNA damage and death.

Shaikh AY Xu J Wu YJ He L Hsu CY
Neurosci Lett 1997 JUL 4;229(3):193-197
Hsu CY, Washington Univ, Sch Med, Dept Neurol,
Box 8111,660 S Euclid Ave, St Louis,MO 63110 USA

Hyperoxia leads to excessive formation of reactive oxygen species (ROS). ROS cause damage to many cellular components, including DNA. Exposure of bovine cerebral endothelial cells to 95 or 100% oxygen resulted in an increase in DNA fragmentation, the appearance of DNA ladders, and cell death with morphological features suggestive of apoptosis. melatonin, an antioxidant, reduced hyperoxia-induced DNA fragmentation and cell death in a dose-dependent manner. Results from the present study support the contention that ROS play a major role in DNA damage and apoptotic death. Melatonin is an effective agent in reducing ROS-mediated DNA fragmentation and death in bovine cerebral endothelial cells. (C) 1997 Elsevier Science Ireland Ltd.



Hyperlipidemic nephropathy induced by
adriamycin: Effect of
Melatonin administration.

Montilla P Tunez I Munoz MC Lopez A Soria JV
Nephron 1997 JUL;76(3):345-350
Montilla P, Univ Cordoba, Sch Med, Dept Biochem;
Mol Biol, Avda Menendez Pidal S N, E 14004 Cordoba, SPAIN

The effect of Melatonin (MEL) on the nephropathy and the oxidative stress induced by a single and high dose of Adriamycin (AD) has been studied in Wistar male rats. MEL (50 mu g/kg/day) was injected intraperitoneally 3 and 7 days, respectively, before and after AD injection (20 mg/kg i.p.). Trunk blood was drawn and triglycerides, total cholesterol, phospholipids, high-density lipoprotein cholesterol, urea, creatinine, total protein, lipoperoxides, and reduced glutathione (GSH) levels and catalase activity (CAT) were determined in serum. In kidney homogenates, lipoperoxides, GSH, and CAT were measured as well as total protein in urine. AD administration resulted in hyperlipidemia and high-grade proteinuria and a marked increase in serum lipoperoxides, urea, and creatinine. In the kidney, the increase in lipoperoxides was accompanied by a significant decrease of GSH and CAT. The efficiency of MEL was specially remarkable in restoring GSH, CAT, and proteinuria to the levels of controls. These results confirm the involvement of free radicals in the pathogenesis of nephrotoxicity induced by AD. Likewise, they show the high antioxidative power of MEL and its marked effect on the prevention and suppression of this nephropathy.



A relationship between heat loss and sleepiness:
Effects of postural change and
Melatonin administration.

Krauchi K Cajochen C WirzJustice A
J Appl Physiol 1997 JUL;83(1):134-139
Krauchi K, Univ Basel, Psychiat Clin, Chronbiol;
Sleep Lab, Wilhelm Klein Str 27, CH 4025 Basel, SWITZERLAND

Both the pineal hormone Melatonin (Mel) and postural changes have thermoregulatory sequelae. The purpose of the study was to evaluate their relationship to subjective sleepiness. Eight healthy young men were investigated under the unmasking condit ions of a constant routine protocol. Heart rate, rectal temperature (T-re), skin temperatures (foot, T-fo; and stomach), and subjective sleepiness ratings were continuously recorded from 1000 to 1700. Mel (5 mg po) was administered at 1300, a time when Me l should not phase shift the circadian system. Both the postural change at 1000 from upright to a supine position (lying down in bed) and Mel administration at 1300 reduced T-re and increased T-fo in parallel with increased sleepiness. These findings sugg est that under comfortable ambient temperature conditions, heat loss via the distal skin regions (e.g., feet) is a key mechanism for induction of sleepiness as core body temperature declines.



Melatonin enhances IL-2, IL-6, and
IFN-gamma production by human
circulating CD4(+) cells - A possible nuclear
receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes.

Garcia Maurino S Gonzalez Haba MG Calvo JR
Rafii ElIdrissi M Sanchez Margalet V Goberna R
Guerrero JM
J Immunol 1997 JUL 15;159(2):574-581
Guerrero JM, Univ Seville, Sch Med, Dept Med Biochem;
Mol Biol, Avda Sanchez Pizjuan 4, Seville 41009, SPAIN

This paper shows that Melatonin is able to activate human Th1 lymphocytes by increasing the production of IL-2 and IFN-gamma in vitro. Th2 cells appear not to be affected by melatonin, since IL-4, which is mostly produced by Th2 cells, is not modified by the hormone. Melatonin also enhances IL-6 production by PBMCs. The activation by Melatonin of IL-6 production is apparently related to the presence of monocytes, rather than to Th2 cells, in the cell preparation, since PBMCs depleted of monocytes (CD14(+) cells) were not activated. Activation of PBMCs by Melatonin was dependent on the dose and, measured by cytokine production, was observed only when cells were either not activated or only slightly activated by low concentrations of PHA, or when cell activation was achieved by incubating the cells with previously irradiated cells. Using a different approach to identify what type of cells among the PBMC subsets was activated by melatonin, the expression of CD69, a marker of cell activation, was studied. Melatonin increased the percentage of cells expressing the CD69 Ag in CD4(+) but not in CD8(+) cells. We have also achieved enhanced production of IL-2 and IL-6 using CCP 52608, a specific ligand of the putative nuclear Melatonin receptor RZR/ROR, raising the possibility of direct effects of Melatonin on gene regulation in both Th1 cells and monocytes. The results suggest that Melatonin may be involved in the regulation of human immune functions by modulating the activity of Th1 cells and monocytes via nuclear receptor- mediated transcriptional control.



Melatonin in osteosarcoma: An effective drug?.

Panzer A
Med Hypotheses 1997 JUN;48(6):523-525
Panzer A, Univ Pretoria, Dept Physiol,
POB 2034, ZA 0002 Pretoria, SOUTH AFRICA

The pineal indole amine Melatonin has been shown to have oncostatic properties in a wide variety of neoplasms. Melatonin levels start to diminish before the onset of puberty and continue to decline during puberty. There appears to be a relationship between the rate of bone growth and the incidence of osteosarcoma (which was found to be highest in the long bones of the leg in the 10-14- year age group). It is hypothesized that the simultaneous decrease in Melatonin levels (with diminishing oncostatic protection), concurrent with the exponential increase In bone growth during puberty (i.e. Increased rate of cell proliferation), could be a factor in the typical age distribution of osteosarcoma. Melatonin is of value in combined chemotherapy, because it is non-toxic and can augment the anti-cancer action and decrease the side- effects of many other chemotherapeutic drugs. It is hoped that melatonin, as an adjunct to the routine chemotherapy of osteosarcoma, will help to improve the prognosis of this too often fatal disease.



Long term Melatonin treatment in blind
children and young adults with circadian
sleep-wake disturbances.

Palm L Blennow G Wetterberg L
Dev Med Child Neurol 1997 MAY;39(5):319-325
Palm L, Malmo Univ Hosp, Dept Paediat, S 20502 Malmo, SWEDEN

Oral Melatonin therapy was used to treat severe circadian sleep-wake disturbances in eight children and young adults in an open study, All patients were functionally blind, six of them because of defects in the anterior visual pathway. All mere mentally retarded. Baseline sleep diaries kept by the caregivers before treatment showed non- 24-hour sleep-wake syndrome, Diurnal variations in serum and urinary Melatonin were examined. Melatonin secretion peak time was delayed in seven patients, Body temperature variation was out of phase relative to sleep and Melatonin in five patients, and thus they had signs of internal desynchronisation, Melatonin given in the evening dramatically improved the sleep-wake pattern in all patients, The effect was maintained during long-term therapy for between I and 6 years in six patients. One patient fell back into the earlier sleep pattern after 6 to 8 months, and another had increasing sleep disturbance because of reflux oesophagitis, although the improvement regarding the circadian component remained, No side effects have been noted during the therapy, Oral Melatonin is promising as an efficient and seemingly safe alternative for treatment of severe circadian sleep disturbances.



Cataractogenesis and lipid peroxidation
in newborn rats treated with
buthionine sulfoximine:
Preventive actions of melatonin.

Li ZR Reiter RJ Fujimori O Oh CS Duan YP
J Pineal Res 1997 APR;22(3):117-123
Reiter RJ, Univ Texas, Hlth Sci Ctr, Dept Cellular;
Struct Biol, 7703 Floyd Curl Dr, San Antonio,TX 78284 USA

The purpose of this study was to examine the influence of exogenously administered Melatonin on cataract formation and lipid peroxidation in newborn rats treated with buthionine sulfoximine (BSO), a drug which inhibits the rate-limiting enzyme in glutathione (GSH) synthesis, gamma- glutamylcysteine synthase, thereby depleting animals of their stores of the important intracellular antioxidant, GSH. BSO (3 mmol/kg BW) was given for three consecutive days beginning on postnatal day 2; Melatonin (4 mg/kg) was injected daily beginning on postnatal day 2 and continuing until the animals were killed (either day 9 or day 17 after birth). None of the control animals (rats treated with neither BSO nor with melatonin) developed lenticular opacification during the observation period. In the BSO- treated rats, 16 of 18 animals (89%) had observable cataracts when they were examined. In rats that received both BSO and melatonin, the incidence of cataracts was highly significantly decreased, i.e., only 3 of 18 rats (7%) had observable cataracts. In addition to cataracts, the level of lipid peroxidation products (malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)) was examined in the lens, brain, liver, lung, and kidney of control and experimental animals. In BSO-treated rats, the lens, kidney, and lung exhibited increased levels of MDA plus 4- HDA relative to those measured in the control rats; these increases were reversed in the BSO-treated rats who were injected with Melatonin daily. While BSO administration did not increase basal levels of MDA plus 4-HDA in either the brain or liver, Melatonin reduced levels of lipid peroxidation products below those measured in the control rats (at 17 days after birth). The changes induced by Melatonin are consistent with the free-radical scavenging and antioxidative properties of this indole.



Melatonin and
N-tert-butyl-alpha-phenylnitrone block
60-Hz magnetic field-induced DNA single
and double strand breaks in rat brain cells.

Lai H Singh NP
J Pineal Res 1997 APR;22(3):152-162
Lai H, Univ Washington, Ctr Bioengn, Bioelectromagnet Res Lab,
Box 357962, Seattle,WA 98195 USA

In previous research, we have found an increase in DNA single- and double-strand breaks in brain cells of rats after acute exposure (two hours) to a sinusoidal 60-Hz magnetic field, The present experiment was carried out to investigate whether tre atment with Melatonin and the spin- trap compound N-tert-butyl-alpha-phenylnitrone (PEN) could block the effect of magnetic fields on brain cell DNA. Rats were injected with Melatonin (1 mg/kg, sc) or PEN (100 mg/kg, ip) immediately before and after two h ours of exposure to a 60-Hz magnetic field at an intensity of 0.5 mT. We found that both drug treatments blocked the magnetic field-induced DNA single- and double-strand breaks in brain cells, as assayed by a microgel electrophoresis method. Since melaton in and PEN are efficient free radical scavengers, these data suggest that free radicals may play a role in magnetic field-induced DNA damage.



Melatonin inhibits vasopastic
action of hydrogen peroxide in human
umbilical artery.

Okatani Y Watanabe K Hayashi K Wakatsuki A Sagara Y
J Pineal Res 1997 APR;22(3):163-168
Okatani Y, Kochi Med Sch, Dept Obstet;
Gynecol, Nanko Ku, Kochi 783, JAPAN

We evaluated the antioxidant property of Melatonin as it relates to the vasospastic effect of hydrogen peroxide (H2O2) on the human umbilical artery. Helical sections of umbilical arteries were obtained from healthy pregnant women who were delivered between weeks 37 and 39 of gestation. Changes in maximal potassium chloride (KCl)- induced tension were measured in arterial segments with intact endothelium. Segments were treated with H2O2 alone, or were pretreated either with an H2O2 scavenger (catalase, 2000 IU), a hydroxyl radical scavenger (mannitol, 10(-2)M), a nitric oxide-synthesis inhibitor (L- N-G-monomethyl arginine, LNMA, 2 x 10(-4)M), or Melatonin (10(-6)M to 10(-4)M). The effect of H2O2 (10(-4)M) on the relaxation induced by the calcium ionophore A23187 was also determined in arterial segments, with or without pretreatment with Melatonin (10(-6)M, 10(-4)M). H2O2 (10(- 6) M to 10(-4) M) potentiated vascular tension in a concentration-dependent manner (P 0.0001). Pretreatment with LNMA significantly suppressed the vasospastic effect of H2O2 (P 0.0001). Pretreatment with either catalase or mannitol significantly reduced the vasospastic effect of H2O2 (P 0.005, P 0.002, respectively). Melatonin also significantly reduced the vasospastic effect of H2O2 in a concentration-dependent manner (H2O2 10(-6) M, P 0.0001: H2O2 10(-5) M, P 0.0001: H2O2 10(-4)M, P 0.00001). Pretreatment with H2O2 significantly inhibited the relaxation induced by the calcium ionophore A23187 (P 0.005). Treatment with Melatonin prior to exposure to H2O2 significantly restored the relaxation induced by A23187 (P 0.005). Results suggest that H2O2 potentiates vascular tension in the human umbilical artery, perhaps by suppressing the endothelial synthesis of nitric oxide. Melatonin significantly suppressed the vasospastic effect of H2O2, possibly due to its ability to scavenge the hydroxyl radical..



Nocturnal plasma Melatonin profile
and Melatonin kinetics during
infusion in status migrainosus.

Claustrat B Brun J Geoffriau M Zaidan R Mallo C Chazot G
Cephalalgia 1997 JUN;17(4):511-517
Claustrat B, Hop Neurol, Serv Radiopharm;
Radioanal, 59 Blvd Pinel, F 69003 Lyon, FRANCE

The plasma Melatonin profile was significantly disturbed (phase-shift of the maximum Melatonin level) in four out of six female sufferers from status migrainosus, compared with nine healthy controls. The number of secretion peaks was similar in bo th groups. A nocturnal 20 mu g Melatonin infusion (from 21.00 to 01.00 h) evoked plasma Melatonin levels slightly higher than a physiological secretion peak. During infusion, the episodes of secretion were reinforced and the endogenous plasma profile was phase- advanced in two patients displaying a phase-delay. These data suggest impaired pineal function in migraine. In the absence of side effects of Melatonin infusion, the relief of certain migraine symptoms described by our patients might support a controlled trial of Melatonin in migraine.



Melatonin administration protects CA1
hippocampal neurons after transient
forebrain ischemia in rats.

Cho S Joh TH Baik HW Dibinis C Volpe BT
Brain Res 1997 MAY 2;755(2):335-338
Volpe BT, Cornell Univ, Coll Med, Burke Med Res Inst, Dept Neurol;
Neurosci, 785 Mamaroneck Ave, White Plains,NY 10605 USA

Melatonin administered at the beginning of cerebral reperfusion protected CA1 neurons against 10, 20 and 30 min of transient forebrain ischemia. Intraperitoneal injections of saline or Melatonin (10 mg/kg) were given after 0, 2 and 6 h, or 1, 2 an d 6 h of cerebral reperfusion, or 30 min prior to ischemia. One week later, quantitative histological analysis demonstrated that CAI neuronal density was significantly increased in the Melatonin groups that were treated at 0, 2, 6 h compared to the saline -treated controls. Ischemic protection of CA1 was lost in the animals in which the Melatonin treatment was delayed by 1 h, or given 30 min prior to the ischemia.



Retinal neurones containing kainate
receptors are influenced by exogenous
kainate and ischaemia while neurones
lacking these receptors are not
Melatonin counteracts the effect of
ischaemia and kainate.

Cazevieille C Osborne NN
Brain Res 1997 APR 25;755(1):91-100
Osborne NN, Univ Oxford, Nuffield Lab Ophthalmol,
Walton St, Oxford OX2 6AW, ENGLAND

The present experiments were carried out on three types of neurone in primary rabbit retinal cultures. One cell-type, bipolar neurones, have glutamate APB-type metabotropic receptors and can be identified by the presence of theta PKC-immunoreactivity. The other two cell-types are primarily amacrine cells and can be 'stained' for the localisation of GABA immunoreactivity or for serotonin taken up from the medium. Most of the serotonin- accumulating and GABA-containing neurones contain glutamate kainate-type receptors. Exposure of the cultures to treatment of kainate (50 mu M) or experimental ischaemia (8 h followed by 16 h reoxygenation) produced essentially similar findings. The serotonin-accumulating and GABA cells were affected as they were drastically reduced in numbers while the numbers of theta PKC- containing cells were unaffected. Inclusion of the kainate/AMPA antagonist CNQX (100 mu M) or Melatonin (100 mu M) to the medium during kainate or ischaemia treatments largely prevented the detrimental influences on the serotonin-accumulating and GABA cells. It is concluded that during experimental ischaemia excessive glutamate is released to influence cells which contain kainate and APE- type receptors. However, only the neurones containing the kainate receptors are negatively affected with the generation of free radicals. Melatonin or CNQX protects against this effect by scavenging free radicals or acting at the receptor level, respectively. (C) 1997 Elsevier Science B.V.



Suppressive effect of Melatonin administration
on ethanol- induced gastroduodenal
injury in rats in vivo.

Melchiorri D Sewerynek E Reiter RJ Ortiz GG Poeggeler B Nistico G
Br J Pharmacol 1997 MAY;121(2):264-270
Reiter RJ, Univ Texas, Hlth Sci Ctr, Dept Cellular;
Struct Biol, 7703 Floyd Curl Dr, San Antonio,TX 78284 USA

1 Melatonin protection against ethanol-induced gastroduodenal injury was investigated in duodenum-ligated rats. 2 melatonin, injected i.p. 30 min before administration of I mi of absolute ethanol. Given by gavage, significantly decreased ethanol-induced macroscopic, histological and biochemical changes in the gastroduodenal mucosa. 3 Ethanol-induced lesions were detectable as haemorrhagic streaks, Ethanol administration damaged 36% and 25% of the total gastric and duodenal surface, respectively. Melatonin treatment reduced ethanol-induced gastric and duodenal damage to 14% and 8%. Respectively When indomethacin was given together with ethanol, the gastric damaged area was 44% of the total surface, while the duodenal damaged area was 35%; Melatonin administration reduced the damage to only 13% of the total gastric surface and to 12% of total duodenal surface. 4 Both stomach and duodenum of ethanol-treated animals showed polymorphonuclear leukocyte (PMN) infiltration. The number of PMN increased more than 600 and 200 times in stomach and duodenum, respectively, following ethanol administration. Melatonin treatment reduced ethanol- induced PMN infiltration by 38% in the stomach and 20% in the duodenum. In indomethacin-ethanol-treated rats, the number of PMN increased by 875% compared to control group in the stomach and by 264% in duodenum. Melatonin administration reduced the indomethacin-ethanol-induced PMN rise by 57% in the stomach and 40% in the duodenum. 5 Gastroduodenal total glutathione (tGSH) concentration and glutathione reductase (GSSG-Rd) activity were significantly reduced following ethanol and indomethacin- ethanol administration. Melatonin ameliorated both the decrease in tGSH concentration as well as the reduction of GSSG-Rd activity elicited by ethanol both in the stomach and duodenum: Melatonin was effective ire against indomethacin-ethanol-induced damage only in the stomach. 6 Ethanol-induced gastroduodenal damage is believed to be mediated by the generation of free radicals. Recently. 3 number of in vivo and in vitro experiments have shown Melatonin to be an effective antioxidant and free radical scavenger; thus, we conclude that the protection by Melatonin against ethanol-induced gastroduodenal injury is due, at least in part, to its radical scavenging activity.