gastrointestinal melatonin; Th1 Th2; FMS CFS; clonidine ACTH cortisol; asthma; kynurenine; seizures

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10: Biol Signals Recept 2001 Nov-Dec;10(6):350-66

Localization, physiological significance and possible clinical implication of

gastrointestinal melatonin.

Bubenik GA.

Department of Zoology, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.

gbubenik@...

The gastrointestinal tract (GIT) is a major source of extrapineal melatonin. In

some animals, tissue concentrations of melatonin in the GIT surpass blood levels

by 10-100 times and the digestive tract contributes significantly to melatonin

concentrations in the peripheral blood, particularly during the day. Some

melatonin found in the GIT may originate from the pineal gland, as the organs of

the digestive system contain binding sites, which in some species exhibit

circadian variation. Unlike the production of pineal melatonin, which is under

the photoperiodic control, release of GI melatonin seems to be related to

periodicity of food intake. Melatonin and melatonin binding sites were localized

in all GI tissues of mammalian and avian embryos. Postnatally, melatonin was

localized in the GIT of newborn mice and rats. Phylogenetically, melatonin and

melatonin binding sites were detected in GIT of numerous mammals, birds and

lower vertebrates. Melatonin is probably produced in the serotonin-rich

enterochromaffin cells (EC) of the GI mucosa and can be released into the portal

vein postprandially. In addition, melatonin can act as an autocrine or a

paracrine hormone affecting the function of GI epithelium, lymphatic tissues of

the immune system and the smooth muscles of the digestive tube. Finally,

melatonin may act as a luminal hormone, synchronizing the sequential digestive

processes. Higher peripheral and tissue levels of melatonin were observed not

only after food intake but also after a long-term food deprivation. Such

melatonin release may have a direct effect on the various GI tissues but may

also act indirectly via the CNS; such action might be mediated by sympathetic or

parasympathetic nerves. Melatonin can protect GI mucosa from ulceration by its

antioxidant action, stimulation of the immune system and by fostering

microcirculation and epithelial regeneration. Melatonin may reduce the secretion

of pepsin and the hydrochloric acid and influence the activity of the

myoelectric complexes of the gut via its action in the CNS. Tissue or blood

levels of melatonin may serve as a marker of GI lesions or tumors. Clinically,

melatonin has a potential for a prevention or treatment of colorectal cancer,

ulcerative colitis, irritable bowel syndrome, children colic and diarrhea.

Copyright 2001 S. Karger AG, Basel

13: Life Sci 2001 Jun 22;69(5):543-51

Presence of melatonin in the human hepatobiliary-gastrointestinal tract.

Messner M, Huether G, Lorf T, Ramadori G, Schworer H.

Department of Psychiatry, University of Gottingen, Germany.

A variety of speculations about the possible origin and physiological role of

the neurohormone melatonin in the gastrointestinal tract exist. However, the

experimental evidence supporting any of these theories is not substantial and

are missing for humans. We studied the distribution of melatonin which was

measured with radioimmunoassay in the following compartments and organs of the

human hepatobiliary-gastrointestinal tract: bile (obtained by endoscopic

retrograde cholangiopancreaticography), peripheral venous and portal venous

blood (obtained from patients undergoing liver transplantation), endoscopically

derived biopsies (mainly consisting of mucosa and submucosa) of stomach,

duodenum, large intestine as well as in resected liver tissue. Melatonin

concentrations in gastrointestinal mucosa were between 136 +/- 27 pg/100 mg

(stomach) and 243 +/- 37 pg/100 mg (descending colon, each n = 5). Biliary

melatonin concentrations (85 +/- 45 pg/ml) correlated well with plasma

concentrations (55 +/- 38 pg/ml, each n = 14) and a considerable amount of

melatonin (about 51 ng/24 hours) appears to be excreted into the gut via the

bile duct. Melatonin concentrations were slightly higher in portal than in

peripheral venous blood and also the liver contained higher concentrations of

melatonin than the blood. In conclusion the presence and distribution of

melatonin in human gut, bile, liver and portal blood and the various reports on

modulatory actions of melatonin on gut and liver functions suggest that

melatonin may act as a mediator of inter-organ communication between gut and

liver.

16: J Neuroimmunol 2001 Jul 2;117(1-2):51-7

Melatonin modulation of lymphocyte proliferation and Th1/Th2 cytokine

expression.

Kuhlwein E, Irwin M.

Veterans Affairs San Diego Healthcare System, Department of Psychiatry,

University of California, San Diego, La Jolla, CA 92161, USA.

Melatonin is hypothesized to play a role in neuroimmunomodulation. This study

investigated the in vitro effects of melatonin (10(-12) - 10(-6) M) on human

peripheral blood mononuclear cell (PBMC) proliferation and T helper type 1 and T

helper type 2 (Th1/Th2) cytokine expression. In vitro doses of melatonin

significantly increased PBMC proliferation (p<0.05) and decreased IL-10

production in culture supernatants (p<0.05). However, there was no effect of

melatonin on the stimulated production of IFN-gamma or on the intracellular

accumulation of the activation antigen CD69, IFN-gamma, or IL-10 as measured by

flow cytometry. These data support the notion that physiologic doses of

melatonin increase lymphocyte proliferation possibly due to decreases in

production of the inhibitory cytokine IL-10.

18: Clin Physiol 2001 May;21(3):292-9

Effects of exogenous melatonin on pituitary hormones in humans.

Ninomiya T, Iwatani N, Tomoda A, Miike T.

Department of Child Development, Kumamoto University School of Medicine, Honjo,

Kumamoto, Japan.

The effects of melatonin on physiological function remain unclear, although the

therapeutic potential of melatonin is being increasingly recognized. The aim of

the present study is to investigate the effects of exogenous melatonin on the

spontaneous release of pituitary hormone in humans. A double blind

placebo-controlled protocol was designed to examine 12 adult healthy volunteers

and 12 sleep disorder patients who have been treating with low doses of

melatonin for 1 year. Either exogenous melatonin or placebo of 1 mg was given at

09:00 hours, followed by the collection of blood samples every 20 min for 4 h.

Each blood sample was examined for levels of serum melatonin, PRL, LH, FSH, GH

and TSH. LH levels were higher in sleep disorder patients compared with the

healthy volunteers. In other pituitary hormones, there were no significant

difference between healthy adults and sleep disorder patients. In all subjects,

PRL levels were stimulated by acute administration of 1 mg of exogenous

melatonin, while the levels of other pituitary hormones were not affected. These

results suggested that exogenous melatonin can affect the spontaneous release of

LH and PRL in humans. In addition, we demonstrated that 1-year oral melatonin

treatment did not affect the responses to the acute administration of melatonin.

28: J Clin Endocrinol Metab 2000 Oct;85(10):3690-2

High nocturnal melatonin in adolescents with chronic fatigue syndrome.

Knook L, Kavelaars A, Sinnema G, Kuis W, Heijnen CJ.

Department of Pediatric Immunology, Wilhelmina Children Hospital of the

University Medical Center Utrecht, The Netherlands.

Decreased quality of sleep is frequently reported by chronic fatigue syndrome

(CFS) patients. The pineal hormone melatonin is involved in regulation of sleep.

We analyzed the nocturnal rise in melatonin in 13 adolescent CFS patients and 15

healthy age-matched controls. Saliva samples were collected at hourly intervals

between 1700 and 0200 h. Nocturnal saliva melatonin levels were significantly

higher in CFS patients, compared with controls, at midnight, 0100 h, and 0200 h

(P < 0.001). No differences were observed in timing of melatonin increase in

saliva between patients and controls. Time of sleep onset and duration of sleep

did not differ significantly between patients and controls. However, all CFS

patients and only one of the controls in our study group reported unrefreshing

sleep. Our data demonstrate that sleep problems in adolescents with CFS are

associated with increased melatonin levels during the first part of the night.

Based on these data, we suggest that there is no indication for melatonin

supplementation in adolescents with CFS.

34: J Pineal Res 2000 Aug;29(1):48-53

Effect of clonidine on plasma ACTH, cortisol and melatonin in children.

Munoz-Hoyos A, Fernandez- JM, Molina-Carballo A, Macias M, Escames G,

Ruiz-Cosano C, Acuna-Castroviejo D.

Departamento de Pediatria, Hospital Universitario de Granada, Espana.

An interaction between melatonin and adrenocorticotropin (ACTH) seems to occur

in humans and both hormones respond to beta-adrenergic stimulation. As in lower

animal species, human pineal gland also contains alpha2-adrenergic receptors as

does the hypothalamus-pituitary axis. In this study the response of the pineal

gland and of the hypothalamus-pituitary-adrenal axis to alpha2-adrenergic

stimulation was assessed. Twenty-nine children (21 males, mean age 11.2 +/- 0.6

yr and eight females, mean age 9.1 +/- 1.1 yr) from the University of Granada

Hospital were studied. The children were diagnosed as having growth problems but

with a normal response of growth hormone (GH) to clonidine test. Changes in

plasma levels of ACTH, cortisol and melatonin were evaluated in these children

after oral administration of the alpha2-adrenoceptor agonist clonidine (100

microg/m2) or a placebo. Plasma ACTH, cortisol and melatonin were measured

before (basal) and at 30, 60 and 90 min after oral clonidine or placebo

administration. Hormonal determinations were carried out by commercial

radioimmunoassay kits, previously standardised in our laboratory. The results

show a significant decrease in plasma ACTH, cortisol and melatonin 30 min after

clonidine administration (P < 0.001), reaching lowest values at 90 min after the

drug was administered. The reduction in the levels of these hormones is

independent of their normal circadian decay since the control group showed a

significantly different pattern of behaviour. These data support the existence

of an inhibitory alpha2-adrenergic influence on both the pineal gland and the

hypothalamus-pituitary-adrenal in children and further support the presence of

alpha2-adrenoceptors in the human pineal gland.

40: J Rheumatol 1999 Dec;26(12):2675-80

Melatonin levels in women with fibromyalgia and chronic fatigue syndrome.

Korszun A, Sackett-Lundeen L, Papadopoulos E, Brucksch C, Masterson L, Engelberg

NC, Haus E, Demitrack MA, Crofford L.

Department of Psychiatry, University of Michigan Medical Center, Ann Arbor, USA.

akorszun@...

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are stress

associated disorders mainly affecting women. FM is characterized primarily by

widespread musculoskeletal pain, and CFS by profound debilitating fatigue, but

there is considerable overlap of clinical symptoms between these 2 syndromes.

Neuroendocrine abnormalities have been noted in both FM and CFS and

desynchronization of circadian systems has been postulated in their etiology.

The pineal hormone melatonin is involved in synchronizing circadian systems and

the use of exogenous melatonin has become widespread in patients with FM and

CFS. METHODS: We examined the characteristics and relationship of melatonin and

cortisol levels in premenopausal women with FM (n = 9) or CFS (n = 8), compared

to age and menstrual cycle phase matched controls. Blood was collected from an

indwelling intravenous catheter every 10 min over 24 h, and plasma melatonin and

cortisol were determined by radioimmunoassay at 60 and 10 min intervals,

respectively. RESULTS: Night time (23:00-06:50) plasma melatonin levels were

significantly higher in FM patients compared to controls (p<0.05), but there was

no significant difference in melatonin levels between CFS patients and controls.

No differences in the timing of cortisol and melatonin secretory patterns and no

internal desynchronization of the 2 rhythms were found in either patient group,

compared to controls. CONCLUSION: Raised plasma melatonin concentrations have

been documented in several other conditions that are associated with

dysregulation of neuroendocrine axes. Increased melatonin levels may represent a

marker of increased susceptibility to stress induced hypothalamic disruptions.

These data indicate that there is no rationale for melatonin replacement therapy

in patients with FM and CFS.

46: Eur J Clin Invest 1999 Jun;29(6):563-7

The role of melatonin in pathogenesis of aspirin-sensitive asthma.

Evsyukova HV.

The I. P. Pavlov Medical University, St sburg, Russia. otd_ned@...

BACKGROUND: Platelets are involved in the pathogenesis of bronchial asthma,

including aspirin-sensitive asthma (ASA). The pineal hormone melatonin (MT) has

been described as inhibiting several physiological processes in platelets. The

MT metabolite - N-acetyl-5-methoxy-kynurenamine - has a chemical structure

similar to that of acetylsalicylic acid. Because ASA patients usually suffer

from an active disease, despite the avoidance of aspirin and cross-reactive

drugs, it has been suggested that the MT synthesis may be lower and sensitivity

of platelet reception to MT may be higher in aspirin-sensitive asthmatic

subjects than in aspirin-tolerant ones. The objective of this study was to

investigate this hypothesis.

MATERIALS AND METHODS: We studied the urinary excretion of

6-sulphatoxymelatonin, the major metabolite of melatonin, and the effect of

different MT doses on ADP-induced platelet aggregation in vitro in 17 ASA

patients, 17 patients with aspirin-tolerant asthma (ATA) and 16 healthy

subjects.

RESULTS: The results of the study have revealed a lower level of daytime aMT6s

excretion in ASA patients (12.7 +/- 2.7 ng mL-1) than in ATA patients (32.7 +/-

9.9 ng mL-1, P < 0.05) and control subjects (19.9 +/- 5.8 ng mL-1, P < 0.05).

The preincubation of platelet-rich plasma with the MT in a dose of 0.01 pg mL-1

plasma results in an increase in the intensity and the rate of the first

platelet aggregation phase only in the ASA patients compared with the ATA

patients and control subjects.

CONCLUSION: We conclude that the reduction in MT production in ASA patients

defines the character of ADP-induced platelet aggregation and the change in its

first phase after the further addition of MT in vitro. The latter is associated

with the opening of some receptor-operated channels for Ca2+ or/and its

mobilization from the intracellular stores. The higher sensitivity of platelet

reception and a distorted reaction not only to MT but also to its metabolite may

be prerequisites for aspirin intolerance in ASA patients.

47: Psychoneuroendocrinology 1999 Feb;24(2):209-26

Normative melatonin excretion: a multinational study.

Wetterberg L, Bergiannaki JD, Paparrigopoulos T, von Knorring L, Eberhard G,

Bratlid T, Yuwiler A.

Department of Psychiatry, Karolinska Institute, St. Goran's Hospital, Stockholm,

Sweden.

The present study on overnight urinary melatonin was conducted on the most

geographically dispersed population to date, over a 1 year period, also covering

a broad age range (18-62 years). An inverse relationship between melatonin and

age, as well as between melatonin and weight was observed for both genders.

Females as a whole, had higher melatonin values than males. Furthermore, the

excretion of melatonin exhibited a bimodal distribution, distinguishing two

groups of individuals: low and high melatonin excretors. The cut-off point was

set at 0.25 nmol/l for ages up to 40 years and at 0.20 nmol/l for subjects above

this age. Since melatonin may be involved in several physiological and

pathological processes, it could be of importance to detect the type of

melatonin excretion that prevails in various conditions, using a simple

noninvasive procedure such as the overnight urinary measurement. For that

purpose, this large sample could serve as a worldwide reference databank across

different ages and locations.

48: J Child Neurol 1998 Oct;13(10):501-9

Melatonin's role as an anticonvulsant and neuronal protector: experimental and

clinical evidence.

Munoz-Hoyos A, -Forte M, Molina-Carballo A, Escames G, -Medina E,

Reiter RJ, Molina-Font JA, Acuna-Castroviejo D.

Departamento de Pediatria, Universidad de Granada, Espana.

The pineal gland classically has been considered as a vestigial and mystic

organ. In the last decades, and with the incorporation of new methodologic

procedures, it could be proved that it also has physiologic actions that vary

depending on the level of the phylogenetic scale. Its best-known secretion,

melatonin, has been related to many different actions, such as sleep promotion,

control of biologic rhythms, hormonal inhibition, and an inhibiting action on

central nervous system regulation mechanisms. In animal experimentation, there

are papers even accepting an anticonvulsant effect. In humans, evidence is

reduced to few experiences. In addition to this clinical experience, there is

other evidence that clearly relates melatonin to convulsive phenomena. This

relationship must be mediated by the following mechanisms attributed to

melatonin: altered brain GABAergic neurotransmission, its known interaction with

benzodiazepinic brain receptors, through tryptophan metabolite activity

(kynurenine, kynurenic acid), or even by its efficacy as a free-radical

scavenger.

55: J Pineal Res 1997 Sep;23(2):97-105

Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a

child with severe myoclonic epilepsy: two years' experience.

Molina-Carballo A, Munoz-Hoyos A, Reiter RJ, -Forte M, Moreno-Madrid F,

Rufo-Campos M, Molina-Font JA, Acuna-Castroviejo D.

Departamento de Pediatria, Hospital Clinico Universitario de Granada, Spain.

Recent data indicate that melatonin inhibits brain glutamate receptors and

nitric oxide production, thus suggesting that it may exert a neuroprotective and

antiexcitotoxic effect. Melatonin has been seen to prevent seizures in several

animal models and to decrease epileptic manifestations in humans. The lack of

response to conventional anticonvulsants in an epileptic child led us to use

melatonin in this case. A female child who began to have convulsive seizures at

the age of 1.5 months and was diagnosed as having severe myoclonic epilepsy was

unsuccessfully treated with different combinations of anticonvulsants, including

valproic acid, phenobarbital, clonazepam, vigabatrin, lamotrigin, and clobazam.

Melatonin was thus added to the treatment. Imaging studies (CT, SPECT, and MNR),

EEG recordings, blood biochemical, and hematological analyses, including

measures of the circadian rhythm of melatonin, were made. The child was

initially treated with various anticonvulsants. Severe neurological and

psychomotor deterioration combined with increased seizure activity showed a lack

of response to the treatment. At the age of 29 mon the patient was in a

pre-comatose stage at which time melatonin was added to treatment. After 1 month

of melatonin plus phenobarbital therapy and for a year thereafter, the child's

seizures were under control. On reducing the melatonin dose after this time,

however, seizures resumed and the patient's condition was re-stabilized after

restoring melatonin. Prior to our attempts to reduce melatonin, all analyses,

including EEG recordings and SPECT, were normal. As far as the results of

neurological examination are concerned, only mild hypotony without focalization

remained. Changes in the therapeutic schedules during the second year of

melatonin treatment, including the withdrawal of phenobarbital, did not result

in the same degree of seizure control, although progressively the child became

satisfactorily controlled. At the present moment the child continues to have

mild hypotony and shows attention disorder and irritability. Melatonin has

proven to be useful as adjunctive therapy in the clinical control of this case

of severe infantile myoclonic epilepsy. The results suggest that melatonin may

have a useful role in mechanisms of neuroprotection and also indicate its use in

other cases of untreatable epilepsy. Further studies using more patients and

placebo-treatment would be beneficial in understanding the potential use of

melatonin as a co-therapy in some cases of seizures.

PMID: 9392448 [PubMed - indexed for MEDLINE]