MELATONIN: Clinical Significance and
ORIGINAL ARTICLES 1Pawlikowski
et al | 2 Rimler et al | 3
Winczyk et al 4 Karasek et al |
5 Markowska et al | 6 Bortkiewicz et al
al | 8 Ostrowska
by Karasek, Reiter, Cardinali, Pawlikowski
Pawlikowski, M. Kolomecka, A. Wojtczak & M. Karasek: Effects of six months melatonin treatment on sleep quality and
"serum concentrations of estradiol, cortisol, dehydroepinadrosteron
sulfate, "and somatomedin C in elderly women 2002; 23 (suppl 1):17-19 pii:NEL230702A01 PMID:
October 10, 2001 Accepted: October 31, 2001
OBJECTIVES: The role of melatonin is aging is still under debate.
Therefore, an open pilot study on the effects of melatonin administration
on some sleep parameters, routine hematological and biochemical parameters,
and concentrations of hormones was performed in elderly women.
AND METHODS: The study was performed on 14 women (volunteers), aged
from 64 to 80 years (mean age 71±4.6 years). Melatonin (2 mg
daily at 19:00 h) was administered during 6 months. Before and after
melatonin treatment the peripheral venous blood samples were taken
in the morning (approx. at 08:00 h) after the overnight fast. The
total blood count, glucose, total cholesterol, LDL, HDL, and triglycerides
were estimated by routine laboratory methods. The serum concentrations
of the following hormones were determined: 17-beta-estradiol, dehydroepiandrosterone
sulfate (DHEAS), cortisol, and somatomedin C (IGF-I). Additionally,
before and after 6 months of melatonin therapy the investigated subjects
answered to a questionnaire dealing with sleep parameters and self-estimation
of general health status.
In 35.7% of investigated subjects an improvement in general sleep
quality and in such sleep parameters as sleep initiation, sleep latency,
number of awakenings episodes, wake time after sleep onset, was observed.
A significant decrease of estradiol concentrations was observed after
6 months of the melatonin treatment in comparison to initial levels.
IGF-I was found to be slightly but significantly increased after the
6 months melatonin therapy. Cortisol levels did not change significantly,
during the melatonin treatment. DHEAS concentrations increased after
melatonin therapy. Moreover, a tendency towards a higher DHEAS/cortisol
ratio was found after 6 months of treatment. Melatonin treatment did
not influence significantly either the parameters of total blood count
or glucose and serum lipids levels.
On the basis of this preliminary open study it seems that melatonin
administration may be beneficial for elderly subjects.
Although the role of melatonin in the aging process is still under
debate, there are some data suggesting that melatonin administration
may be beneficial in advanced age , especially in elderly insomniacs
[2, 3]. Melatonin secretion exhibit a clear circadian rhythm with
low values during the daytime and 8-15 fold increase at night [1,
4, 5]. This nocturnal peak in melatonin levels decrease significantly
with age [1, 5]. Recently melatonin received a great deal of attention
as therapeutic agent in various diseases. Moreover, safety of melatonin
treatment is discussed . Because the data on melatonin use in advanced
age are scarce we decided to perform an open pilot study on the effects
of melatonin administration on some sleep parameters, routine hematological
and biochemical parameters, and concentrations of hormones in elderly
Rimler, Z. Lupowitz & N. Zisapel: Differential regulation by melatonin of cell growth and androgen
receptor "binding to the androgen response element in prostate
2002; 23 (suppl 1):45-49 pii:NEL230702A02 PMID:
October 3, 2001 Accepted: October 15, 2001
words: melatonin; androgen; receptor; prostate; cancer
OBJECTIVES: The pineal hormone melatonin inhibits the growth of benign
human prostate epithelial cells and the androgen-dependent prostate
cancer LNCaP cells. In the androgen-nonresponsive prostate carcinoma
PC3 cells melatonin inhibits cell growth only at high but not low cell
density. We have recently found that melatonin causes nuclear exclusion
of the AR and attenuates it transcriptional activity in LNCaP cells
as well as PC3 cells stably transfected with a wild type AR expressing
vector (PC3-AR). The aim of this study was to investigate whether melatonin
inhibits effects of AR on cell growth in PC3-AR cells and whether inhibition
of AR DNA binding is involved.
The effects of androgen, melatonin and their combination on the growth
of the PC3-AR cells and on AR DNA binding in PC3-AR and LNCaP cells
DHT suppressed cell growth in the PC3-AR cells and enhanced AR binding
to the androgen responsive element (ARE). Melatonin had no effect on
cell growth in the absence of DHT but counteracted the androgen-induced
inhibition at low androgen concentrations. Melatonin did not suppress
and even slightly enhanced the capacity of AR binding to the ARE in
the PC3-AR as well as in LNCaP cells.
Attenuation by melatonin of AR activity in the prostate cancer cells
is not due to suppression of AR binding to the ARE, and is presumably
caused by its effects on AR protein interaction and intracellular trafficking.
Melatonin, the hormone secreted at night by the pineal gland, inhibits
the growth of human benign (BPH) and tumor (LNCaP) prostate epithelial
cells in vitro [1-4]. Melatonin inhibits growth of the prostatic carcinoma
PC3 cells which do not express the androgen receptor (AR) only at high
cell density and slightly enhances growth at low cell density . The
androgen receptor (AR) is an intracellular receptor that functions as
a ligand dependent transcription factor . The AR mediates all the
activities ascribed to androgens, including development, differentiation
and maintenance of male reproductive function, support of sexually dimorphic
non-reproductive functions and prostate cancer growth. In androgen target
tissues, the AR is localized within the nucleus . Upon ligand binding,
the AR binds to hormone response elements in the promoter region of
inducible genes thus controlling their transcription . Mutations
at the DNA binding domain of the AR, leading to nuclear exclusion of
the receptor and loss of androgen sensitivity, have recently been identified
in prostate cancer cells .
Winczyk, M. Pawlikowski, H. Lawnicka, J. Kunert-Radek, G. Spadoni,
G. Tarzia & M. Karasek: Effect of melatonin and melatonin receptors ligand
N-[(4-methoxy-1H-2-yl)methyl]propamide on murine Colon 38 cancer growth
in vitro and in vivo 2002; 23 (suppl 1):50-54 pii:NEL230702A03 PMID:
October 10, 2001 Accepted: November 8, 2001
words: melatonin; melatonin receptors; proliferation; apoptosis;
OBJECTIVES: Our previous study suggest that oncostatic action of melatonin
(MLT) depends mainly on nuclear RZR/ROR receptors. However, we cannot
exclude the involvement of membrane receptors in the control of tumor
growth. In the present study the effects of MLT and N-[(4-methoxy-1H-indol-2-yl)methyl]propanamide
(UCM 386 - antagonist of membrane MT1 receptor and partial agonist of
membrane MT2 receptor) on murine transplantable Colon 38 cancer were
investigated in vitro and in vivo conditions.
AND METHODS: The experiments were performed on adult male B6D2F1 mice
strain. In vitro the cell proliferation was measured using modified
Mosmann method. In the experiment performed in vivo, we assessed the
cell proliferation, apoptosis and proliferation/apoptosis ratio (P/A).
The incorporation of bromodeoxyuridine into tumor cell nuclei was used
as an index of cell proliferation (labeling index-LI). The labeling
of apoptotic cells according to TUNEL method was considered as an index
of apoptosis (AI).
In vitro MLT and UCM 386 decreased the cell proliferation, but administration
of MLT and UCM 386 together did not change the inhibitory effect of
MLT alone. In vivo MLT and UCM 386 alone decreased LI and the addition
of UCM 386 to MLT did not diminish the antiproliferative effect of MLT.
Melatonin and UCM 386 injected alone also increased the AI. Moreover,
both compounds given together exerted the additive effect on tumor apoptosis.
MLT and UCM 386 alone or together also significantly decreased P/A ratio
which is additional parameter confirming the inhibition of tumor growth.
The obtained data together with our earlier observations suggest that
oncostatic effect of MLT depends on acting via both MT2 and RZR/ROR
(MLT), the hormone of pineal gland, is a new candidate as anticancer
agent. Recently, the oncostatic action of melatonin on various experimental
cancers has been reported. The antitumor effect of melatonin is connected,
in part with antiproliferative and also proapoptotic activities. The
number of investigations confirmed the antiproliferative action of melatonin
[1, 2, 3]. The previous study conducted in our laboratory on murine
Colon 38 cancer shows that MLT causes not only the inhibition of tumor
cell proliferation, but also induces apoptosis . The mechanism by
which MLT exerts its antitumor effect is very complex and still not
clear. This pineal hormone may act indirectly via modulation of endocrine
and immune systems. Melatonin may also influence directly on tumor cells
through the specific binding sites. The best known melatonin binding
sites are two subtypes of receptors, named MT1 and MT2 . It was also
suggested that MLT is a natural ligand for the nuclear orphan receptors
RZR/ROR [6, 7]. Moreover, it was proposed that immunological and oncostatic
effects of melatonin depend mainly on nuclear signaling [8, 9]. ...
Karasek, A. Carrillo-Vico, J.M. Guerrero, K. Winczyk & M. Pawlikowski:
Expression of melatonin MT1 and MT2 receptors, and RORa1 receptor
in transplantable murine Colon 38 cancer
2002; 23 (suppl 1):55-60 pii:NEL230702A04 PMID:
January 23, 2002 Accepted: February 21, 2002
OBJECTIVES: There are some data suggesting that melatonin exerts oncostatic
action through membrane as well as nuclear receptors. In previous studies
we demonstrated the antiproliferative and proapoptotic action of melatonin
on transplantable murine Colon 38 adenocarcinoma cells. Therefore, the
aim of the present study was to determine whether the membrane melatonin
receptors MT1 and MT2 as well as the nuclear receptor RZR/RORa are expressed
in Colon 38 cells.
AND METHODS: Adult male B6D2F1 mice were used in this experiment. The
induction of tumor was conducted by subcutaneous injection of 0.2 mL
of a 33% suspension of Colon 38 cancer cells into axillary region. Expression
of mRNA encoding MT1 and MT2 melatonin membrane receptors was studied
by RT-PCR analysis, and expression of RORa1 nuclear receptor protein
was studied by Western blot analysis.
The expression of mRNA encoding both MT1 and MT2 melatonin receptors
was demonstrated in Colon 38 cancer cells. Moreover, immunodetection
revealed the expression of MT1 and RORa1 proteins in these cells.
Our studies on Colon 38 adenocarcinoma cells support the concept that
both membrane and nuclear receptors are involved in the oncostatic action
is substantial experimental evidence indicating inhibitory influence
of pineal hormone melatonin on the malignant tumor formation and/or
growth [1-4]. In the previous studies we demonstrated that in transplantable
murine Colon 38 adenocarcinoma melatonin exerts inhibitory effect on
the tumor cell proliferation and stimulatory effect on tumor cell apoptosis
[5-9]. Moreover, we suggested that melatonin decreases the tumor proliferation
acting through both membrane and nuclear receptors. On the other hand,
the induction of apoptosis by melatonin seems to depend mainly on its
action through RZR/RORa receptor [8, 9]. Therefore, the aim of the present
study was to determine whether membrane melatonin receptors MT1 and
MT2 as well as nuclear receptor RZR/RORa are expressed in Colon 38 cells.
Markowska, A. Mrozkowiak & K. Skwarlo-Sonta: Influence of melatonin on chicken lymphocyte in vitro:
involvement of membrane receptors
2002; 23 (suppl 1):67-72 pii:NEL230702A05 PMID:
October 21, 2001 Accepted: November 27, 2001
words: melatonin; signal transduction; proliferation; camp;
luzindole; chicken; splenocytes
Abstract OBJECTIVES: Time-dependent melatonin effects on chicken lymphocyte
proliferation in vitro and the involvement of cAMP in melatonin signal
transduction were examined.
AND METHODS: Splenocytes and peripheral blood mononuclear cells (PBMC)
were cultured in vitro in the presence of melatonin, phytohemagglutinin,
luzindole, dibutyrylcAMP (dbcAMP), forskolin and vasoactive intestine
peptide (VIP). Proliferation was measured by [3H]-thymidine incorporation
in cultures carried out for 24, 36, 48 and 72 h. Cyclic AMP formation
was assessed by radioimmunoassay in cells incubated for 30 min. or 24
Melatonin stimulated the spontaneous proliferation in short-term (36
and 48 h) splenocyte cultures and had no effect in 72 h cultures. It
inhibited mitogen-stimulated proliferation already in 24 h cultures
and this effect was observed regardless of the time of the culture.
Both melatonin effects were antagonized by luzindole - membrane-bound
melatonin receptor antagonist. Forskolin and dbcAMP caused a significant
inhibition of proliferation of splenocytes and PBMC cultured for 24
or 72 h, respectively. Melatonin inhibited the cAMP formation (30 min.
of incubation) stimulated by adenosine cyclase activators - forskolin
and VIP, but added alone failed to affect the cAMP concentration. In
mitogen-stimulated splenocytes cultured for 24 h Mel caused an increase
in cAMP correlated with the inhibition of cell proliferation.
Melatonin effects on chicken splenocytes appears time- and activation-dependent:
in short-term cultures it stimulates spontaneous and inhibits mitogen-activated
proliferation, probably via membrane-bound, luzindole-sensitive melatonin
receptors. Incubation with melatonin for 30 min. inhibits cAMP formation,
but in 24 h cultures it increases cAMP concentration leading to inhibition
A. Bortkiewicz, B. Pilacik, E. Gadzicka & W. Szymczak:
The excretion of 6-hydroxymelatonin sulfate in healthy young men
exposed to "electromagnetic fields emitted by cellular phone -
an experimental study
2002; 23 (suppl 1) 88-91 pii:NEL230702A06 PMID:
October 15, 2001 Accepted: November 12, 2001
words: melatonin; 6-hydroxymelatonin sulfate; magnetic field;
OBJECTIVES: It is quite likely that non-visible electromagnetic fields
(EMF) may affect melatonin production. Some studies confirmed this hypothesis
and showed that extremely low EMF altered pineal function in animals
and humans. Thus, it is reasonable to suppose that EMF emitted by cellular
phones may also influence secretion of melatonin. The present study
sought to evaluate possible effect of the exposure to EMF emitted by
cellular phone on 6-hydroxymelatonin sulfate (6-OHMS) excretion, which
reflects melatonin levels in blood.
AND METHODS: The examined group consisted of 9 healthy males aged 19-29
years. The experiment was performed under controlled conditions (the
light intensity-50 lx till midnight and 0 lx during night). Each person
was examined twice: on a day without exposure (control day, C-day) and
on a day with continuous exposure (60 min. exposure from cellular phone,
frequency 900 MHz, pulsed with 217 Hz, pulse with 576 µs, SAR
1.23 W/kg, E-day). From 7 p.m. to 8 p.m. they used a cellular phone.
The subjects did not know which day was E-day, and which was C-day.
From 8 p.m. till midnight the subjects listened to music and than they
slept till 7 a.m. next day. Urine samples were collected at 7 p.m.,
at midnight, and at 7 a.m. in the same way in C-day as in E-day. Sample
were frozen for later ELISA analysis of 6-OHMS. The 6-OHMS ELISA kit
from Immuno-Biological Laboratories (Hamburg) was used for measurement
of 6-OHMS. The data were analysed using Wilcoxon matched-pairs signed-ranks
test for each subject and for the whole group. We compared 6-OHMS level
on the E-day and on the C-day separately for 3 time-points - 7 p.m.,
midnight, 7 a.m.
Mean 6-OHMS level in both experiments did not differ significantly for
any of the respective time points. Circadian variations of 6-OHMS level
were detected in all subjects.
The results of our investigation has demonstrated that EMF emitted by
cellular phones has no distinct influence on the melatonin level.
increasing use of mobile phones has caused growing interest in possible
health effects of electromagnetic fields which they produce. Although
exposure caused by cellular phones does not exceed the admissible levels,
it is worth noting that the standards were developed on the basis of
expected thermal effects and do not consider possible effects of chronic,
non-thermal exposures. Studies on this subject are still sparse and
incomplete, some of them report disturbances in various physiological
functions associated with such exposure; non-specific neurovegetative
disorders, headaches, muscle pains, sleep disturbances, and increased
arterial blood pressure have been observed in the exposed subjects [1-5].
A lot of physiological and biochemical functions are influenced by melatonin.
Considering the significance of the effects of visible light on the
pineal function, theoretically it is quite likely that non-visible electromagnetic
fields may affect melatonin production. Some studies confirmed this
hypothesis and showed that extremely low electromagnetic fields altered
pineal function in animals and humans . Thus, it is reasonable to
suppose that radio frequency electromagnetic fields emitted by cellular
phones may also influence pineal production and secretion of melatonin.
However, either the experimental investigations on animals nor on humans
have brought a conclusive answer to this question. The objective of
this study was to determine whether 1-hour exposure to electromagnetic
fields emitted by cellular phone suppressed nocturnal melatonin production.
The present study sought to evaluate possible effects of the exposure
on 6-hydroxymelatonin sulfate (6-OHMS) excretion, which reflects melatonin
levels in blood.
Karasek, A. Szuflet, W. Chrzanowski, K. Zylinska & J. Swietoslawski: Circadian serum melatonin profiles in patients suffering from chronic
2002; 23 (suppl 1):97-102 pii:NEL230702A07 PMID:
November 20, 2001 Accepted: December 17, 2001
OBJECTIVES. In spite of broad interest, intensive studies on function
of melatonin have not yielded much information about relationships between
this hormone and kidneys in health, and particularity, in disease. Very
little is known about the circadian plasma melatonin concentrations
in patients with chronic renal failure (CRF). There are only a few studies
dealing with melatonin concentrations in renal diseases, mainly performed
in hemodialyzed patients with end-stage renal disease (ESRD). Moreover,
the most melatonin assays were performed during the daytime, and the
results are conflicting. Therefore, the aim of the present study was
to determine the circadian melatonin profiles in patients with different
stages of CRF.
AND METHODS. Twenty four patients (13 males and 11 females) with CRF
aged 35 to 58 years (mean±SEM: 47.0±1.6 years) were included
in the study. Patients were divided into two groups: group 1 - patients
with compensated CRF (serum creatinine: 2.0-5.0 mg/dL), group 2 - patients
with ESRD (serum creatinine: > 8,0 mg/dL). The control group consisted
of 20 healthy volunteers (10 males and 10 females) aged 35 to 55 years
(mean±SEM: 46.0±1.5 years) checked not to have renal failure
[serum creatinine: 0.8-1.4 mg/dL], and matched according to sex and
age. Blood samples were collected at 08:00, 12:00, 16:00, 20:00, 24:00,
02:00, 04:00, and 08:00 h. Melatonin concentration was measured by enzyme
In both groups of patients with chronic renal failure, i.e. in patients
with compensated disease and in patients with end-stage renal disease
melatonin nocturnal concentrations were significantly lower then those
in healthy volunteers. Moreover, in patients with compensated renal
failure also day-time melatonin concentrations were significantly depressed.
Area under curve was significantly lower in both groups of patients
in comparison with the control group.
The mechanism of depressed melatonin concentrations in CRF observed
in our study remains unclear. However, it seems possible that decline
in melatonin levels is due to impairment in adrenergic function that
occurs in CRF. Because the studies on the melatonin secretion in CRF
bring about conflicting results, the relationship between renal diseases
and melatonin secretion needs further investigations.
is a major secretory product of the pineal gland. This hormone received
recently great deal of interest due to its diversified action, including
regulation of biological rhythms [1, 2], free radicals scavenging [3,
4], modulation of the immune system [5, 6], influence on neoplastic
disease [7-9], and possible role in aging process [10, 11]. Although
the abolished melatonin circadian rhythm and amplitude have been demonstrated
in various diseases [12, 13], its precise role in different pathologies
is still unknown.
Melatonin secretion exhibits typical circadian rhythm with low concentrations
during the daytime (10-20 pg/mL) and high concentrations at night (70-120
pg/mL). The hormone is metabolized primarily in the liver and secondarily
in the kidney. It undergoes 6-hydroxylation to 6-hydroxymelatonin, followed
by sulfate or glucuronide conjugation to 6-hydroxymelatonin sulfate
(90-95%) or 6-hydroxymelatonin glucuronide (5-10%). Melatonin also forms
some minor metabolites. The main melatonin metabolite, 6-hydroxymelatonin
sulfate is excreted in urine [1, 13].
Melatonin synthesis may be influenced by drugs. It is strongly reduced
by b-blockers, whereas benzodiazepines, calcium antagonists, dexamethazone,
nonsteroidal anti-inflammatory drugs, and clonidine are somewhat less
active in this respect. Anti-depressive drugs stimulate melatonin secretion
In spite of broad interest, intensive studies on function of this hormone
have not yielded much information about relationships between melatonin
and kidneys in health, and particularity in disease. Very little is
known about the circadian plasma melatonin concentrations in patients
with chronic renal failure (CRF). There are only a few studies dealing
with melatonin concentrations in renal diseases, mainly performed in
hemodialyzed patients with end-stage renal disease (ESRD). Moreover,
the most melatonin assays were performed during the daytime, and the
results are conflicting [15-17].
Therefore, the aim of the present study was to determine the circadian
melatonin profiles in patients with different stages of CRF.
Ostrowska, B. Kos-Kudla, B. Marek, D. Kajdaniuk, P. Staszewicz,
B. Szapska & J. Strzelczyk:
The influence of pinealectomy and melatonin administration on "the
dynamic pattern of biochemical markers of bone metabolism in experimental
osteoporosis in the rat
2002; 23 (suppl 1):104-109 pii:NEL230702A08 PMID:
November 12, 2001 Accepted: January 10, 2002
words: pinealectomy; melatonin; bone metabolism; experimental
osteoporosis; female rats
BACKGROUND AND OBJECTIVES: There have been suggestions in literature
that characteristic changes of bone mass in osteoporosis may be related
to the melatonin (Mel): The aim of this study was to demonstrate whether
pinealectomy and Mel administration can affect postmenopausal osteoporosis
processes induced in female rats by way of ovariectomy.
The study included 198 animals; 6 remained intact (0), 96 were ovariectomized
(Ox), and the remaining ones underwent a sham operation (SOx). Two weeks
after surgery, the rats were divided into eight groups: 1) SOx + SPx,
2) SOx + SPx + Mel, 3) Ox + SPx, 4) Ox + SPx + Mel, 5) SOx + Px, 6)
SOx + Px + Mel, 7) Ox + Px, 8) Ox + Px + Mel. Animals from the 5th,
6th, 7th and 8th groups were pinealectomized (Px) while the remaining
ones underwent a sham operation (SPx). Two weeks after surgery Mel (50mg/100g
of bm) were administered intraperitoneally in rats in the 2nd, 4th,
6th and 8th groups while the remaining animals were administered with
solvent only (5% solution of ethyl alcohol in physiological saline).
Rats were administered the Mel solution or the solvent daily between
5 and 6 pm during a 4-week period. At the appropriate time, i.e. prior
to surgery (group 0) and after 6, 12, 18 and 24 weeks from Px or SPx
(time subgroups a, b, c and d) the animals were placed separately in
metabolic cages (from 6.30 until 9.30 am) in order to collect urine
aliquots for HYP and Ca determinations. The blood for the assay of ALP,
PICP and ICTP was collected within the next 24 hours at 8 am (rats killed
The study has shown that pinealectomy had inducing, while exogenous
Mel suppressing effect upon the level of investigated markers of bone
metabolism; these changes were more pronounced in ovariectomized rats.
Administration of Mel only partially levelled changes of bone metabolism
caused by pinealectomy. In rats with preserved pineal gland effect of
Mel on bone turnover markers was less pronounced. After discontinuing
administration of Mel distinct tendency to increase studied biochemical
markers of bone metabolism was shown.
Our findings suggest that Mel is an important modulator of experimental
osteoporosis processes induced in female rats by way of ovariectomy.
A few studies, particularly experimental, suggest that the main neurohormone
of pineal gland - melatonin (Mel) can influence bone tissue metabolism.
Our own studies performed previously on starved male rats have shown
a significant suppressive effect of Mel on processes of bone formation
and resorption . Furthermore, it has been found [unpublished data]
that illumination conditions, pinealectomy, and long-term Mel administration
influence the circadian metabolism of bone tissue in male rats, and
the changes in endogenous Mel concentrations seem to play an important
role in the mechanism of this dependence. In an experimental model of
postmenopausal osteoporosis, generated by ovariectomy in female rats,
a successive lowering of nocturnal Mel concentration was observed .
These changes correlated, in an inversely proportional manner, with
the values of biochemical markers of bone metabolism, particularly markers
of bone resorption. As a consequence of these studies it seems that
Mel deficiency, occurring probably as a result of switching off female
sex hormone function, may be a cofactor in inducing bone mass changes
in female rats with removed ovaries .
Clinical studies suggest that characteristic changes of bone mass in
postmenopausal osteoporosis, resulting from predominance of resorptive
processes over those leading to bone tissue formation, may be related
to the Mel . It has been suggested that pineal Mel is an anti-aging
hormone [2-6] and that the menopause is associated with a substantial
decline in Mel secretion and an increased rate of pineal calcification
[8-10]. ... ...
autoregulation of norepinephrine release from sympathetic nerve fibres
in the pineal gland of the domestic pig.
Pharmacological characterization of a2-adrenoceptors
mediating this process
2002; 23 (suppl 1):111-117 pii:NEL230702A09 PMID:
October 26, 2001 Accepted: November 14, 2001
BACKGROUND: Norepinephrine is the main neurotransmitter controlling
melatonin secretion in the mammalian pineal gland. Presynaptic autoregulation
of norepinephrine release from the sympathetic nerve fibers in the pineal
gland is poorly known.
Uptake and depolarization-evoked release of 3Hnorepinephrine were investigated
in vitro using pieces of the pig pineals. Specific antagonists and agonists
of a2adrenoceptors were employed for the characterization of a2-adrenoceptors
involved in the autoregulation of depolarization-evoked release of norepinephrine
in the pig pineal.
The level of neuronal uptake of norepinephrine in the pig pineal was
3.5±0.9 pmol/h/mg of wet tissue and represented about 77% of
the total tissue radioactivity. Potassium ions at concentration of 60
mM significantly evoked tritium release. This effect was abolished in
the absence of extracellular Ca2+ and was diminished in the presence
of Cd2+. Antagonists of a2-adrenoceptors increased depolarizationevoked
tritium release. The order of its potency (based on pED30) was rauwolscine
> phentolamine > BRL 44408 > WB 4101> RS 79948 = yohimbine
>> prazosin >> imiloxan. a2-agonists decreased K+evoked
release of tritium with the order of potency: UK14,304 > norepinephrine
= guanfacine > oxymetazoline.
The processes of neuronal uptake and depolarization-evoked release of
norepinephrine from the sympathetic nerve endings in the pig pineal
gland have been demonstrated. The studies with the use of adrenergic
antagonists and agonists indicate that the sympathetic nerve fibers
in the pig pineal gland possess functional presynaptic a2adrenoceptors,
which are involved in norepinephrine release inhibition. Due to the
pharmacological properties these receptors closely resemble the subtype
Norepinephrine released from the sympathetic nerve fibers is considered
as the main neurotransmitter regulating melatonin synthesis and therefore
responsible for the nocturnal increase in the secretion of this pineal
Majority of our knowledge about the adrenergic regulation of the mammalian
pinealocyte activity derives from the studies performed in the rat.
Norepinephrine acts on the melatonin synthesis pathway in the rat pinealocytes
via two postsynaptic adrenoceptors: a1 and b1 [1, 2]. The stimulation
of b1-adrenergic receptors leads to the increase in cyclic AMP production,
activation of transcription and translation of arylalkylamine Nacetyltransferase
(enzyme limiting melatonin synthesis and secretion) and the inhibition
of the proteosomal proteolysis of this enzyme [3, 4, 5]. The activation
of a1adrenoceptors, which by itself does not alter the activity of adenylate
cyclase and arylalkylamine N-acetyltransferase, potentiates b1-adrenergic
stimulation of cAMP and melatonin production [1, 2]. The presence of
postsynaptic a2-adrenoceptors functionally linked to membrane guanylate
cyclase has been also demonstrated in the rat pineal gland [6, 7].
Investigations performed in different mammalian species provided evidence
for species heterogeneity in the adrenergic regulation of melatonin
secretion in mammals [8, 9, 10, 11, 12]. The interspecies differences
concern both the adrenergic receptors involved in the regulation of
the pinealocyte activity at postsynaptic level [8, 9] as well as the
intracellular mechanisms, which control the rate of melatonin synthesis
[10, 11, 12]. ... ...
TABLE CONFERENCE REPORT
M. Karasek, R.J. Reiter,
D.P. Cardinali & M. Pawlikowski:
The future of melatonin as a
therapeutic agent pages: 118-121; pii:NEL230702X01; PMID:
Abstract Report of the round table conference summarizing the International
Symposium on "Melatonin: Clinical Significance and Therapeutic
Applications" is presented in this article. Some sleep disorders
and circadian rhythm disturbances are the widely accepted indications
for melatonin treatment. However, other possibilities for use of melatonin
in the therapy should be also taken into account, including a co-treatment
in cancer patients and free radical-related diseases. All aspects of
the possible therapeutic use of melatonin as well as its safety, dosage,
side effects and contraindications are discussed herein based on the
round table conference and they are presented in this paper.
Introduction A round table discussion on the future of melatonin in the therapy
was held at the end of the International Symposium in Polanica Zdroj
(Poland) devoted to clinical significance and therapeutic application
of melatonin. The authors were the active participants of this conference,
and this article summarizes the round table discussion.
Melatonin, the main secretory product of the pineal gland was discovered
by Lerner and coworkers  in 1958. Although the diversity of functions
of melatonin is still under debate, numerous investigations performed
since that time brought about significant progress in understanding
the relevance of this substance in animals and in humans. Moreover,
melatonin has become recently available in some countries (e.g. USA,
Argentina, Poland, China) as either an OTC drug or food supplement.
There are some widely accepted indications for therapeutic use of melatonin
but also perspectives for its broader use. Both the accepted indications
and further perspectives are discussed in this article.
accepted indications for therapeutic use of melatonin
Melatonin in sleep disorders ...
Melatonin in circadian clock disturbances ...
possibilities for therapeutic use of melatonin
Melatonin as free radical scavenger ....
Melatonin in aging and age-related diseases ...
Melatonin in clinical oncology ...
Melatonin in circulatory system diseases ...
of melatonin use ...
Contraindications ... Concluding
LETTERS (NEL) including Psychoneuroimmunology, Neuropsychopharmacology,
Reproductive Medicine, Chronobiology and
A peer-reviewed transdisciplinary Journal covering neuroendocrinology,
psychoneuroimmunology and chronobiology. A peer-reviewed transdisciplinary
Journal. RAPID publication of papers from basic and clinical research,
review articles and state-of the-art.
Science, Science Citation Index, (on the Internet), ISI, PA, USA
Alert (a current awareness service), ISI, PA, USA
Citation Index (on compact disk), ISI, PA, USA
/ Index Medicus