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PubMed1999

Pineal gland, melatonin and cancer. NEL Review.

Studies on the relationship between the pineal gland, melatonin and neoplastic disease have recently become one of the most fascinating aspects of pineal research. The first data suggesting a link between the pineal and cancer were published 70 years ago. However, the real progress in this area of research has been made in the last two decades. The bulk of the experimental evidence indicates the influence of the pineal gland on the malignant tumor formation and/or growth. The majority of reports point toward the oncostatic action of the pineal, exerted most probably by its hormone, melatonin, via different mechanisms, including modulation of endocrine and immune systems and direct antiproliferative action. The mechanisms of the oncostatic action of the pineal seem to be, however, very complex. There is some indication that the pineal gland may also play a role in human malignancy. Alterations in melatonin concentrations have been demonstrated in various tumor types including breast cancer, prostate cancer, colorectal carcinoma, and uterine cancer. Moreover, melatonin has been reported to be helpful in therapy of advanced cancer of various types. However, detailed 24h melatonin profiles must be studied in large numbers of patients with different types of tumors before determining whether melatonin concentrations have any diagnostic and/or prognostic values in cancer patients. Moreover, well designed clinical trials should be performed on the possible therapeutic significance of melatonin in neoplastic disease.

Journal Article↗
PubMed2004

Involvement of the pineal gland in diurnal cocaine reward in mice.

Contribution of circadian mechanisms to the psychostimulant-induced behaviors has been suggested. The pineal gland is important component of circadian mechanisms. Using pinealectomized mice and sham-operated controls, we tested the contribution of pineal gland to the rewarding effects of cocaine in conditioned place preference test. Experiments were performed both during the day and at night. Controls with intact pineal glands demonstrated significant decrease in cocaine-induced conditioned place preference at night compared to daytime, whereas pinealectomized mice did not show any diurnal differences. Circadian mechanisms regulated by the pineal gland thus appear critically involved in cocaine-induced reward.

Animals↗
PubMed1996

Calretinin immunoreactivity in pineal gland of different mammals including man.

Calretinin (CR) is a calcium-binding protein, found in a variety of organs and systems such as the central nervous system and the pineal gland. It was first thought to be a specific neuronal marker but this selectivity is now in question since CR has been demonstrated in avian thymus, rat ovary, rat and guinea pig inner ear, rat testis, and chicken and rat pineal gland. To contribute to the knowledge of the presence of CR-positive cells in the pineal parenchyma of rat and other mammalian including man, we performed immunocytochemistry on pineal glands of gerbils, rats, goats, cows, and humans, using a CR anti-serum. To confirm it was actually CR that was demonstrated, we performed Western Blot analyses. Finally, to precisely identify the nature of CR-positive cells we accomplished double-labelling immunofluorescence, using antisera against some nerve cell specific cytosquelettal proteins such as MAP-5, MAP-2, NF-L, NF-M, and NF-H. CR-positive cells were found in all pineal glands studied. These cells all possess a round, oval, or polygonal-shaped perikaryon sending one or more processes of different lengths into the glandular parenchyma. There is a lack of CR immunoreactivity in the nucleus and cell organelles while the cytosol contains a high concentration of this protein. Nevertheless, there are some slight differences between species, especially concerning the number of reactive cells and their relationships with different parenchymal structures such as blood vessels or acervuli. Among the CR-positive cells, only a few were actually nerve cells, contributing probably to an intrinsic innervation of the gland. The remaining CR-reactive cells seem to correspond mostly to pinealocytes in a specific histophysiological state and possibly to neuron-like cells. The significance of the CR-positive cells in the pineal glands remains to be elucidated.

Aged↗
PubMed1990

Interferon-gamma modulates melatonin production in rat pineal glands in organ culture.

The effect of interferon-gamma (IFN-gamma) on melatonin production was determined in rat pineal glands in organ culture. IFN-gamma enhanced the production of melatonin in the glands incubated with either 10 nM or 1,000 nM isoproterenol (ISO, a beta-adrenergic receptor agonist) but decreased the 100 nM ISO response. The enhanced melatonin production was accompanied by either unchanged or a lower level of N-acetyltransferase (NAT) activity, whereas the suppression was accompanied by a reduced NAT activity. IFN-gamma did not change the activity of the enzyme hydroxyindole-O-methyltransferase (HIOMT) in the ISO-stimulated pineal glands. The results indicate that IFN-gamma has a dual action on the pineal gland: One is to increase melatonin production through yet unknown mechanisms, and the other is to suppress NAT activity. These results also suggest that the pineal gland, under physiological stimulation, is modulated by IFN-gamma to increase melatonin production. A hypothetical model is proposed to explain the delicate regulation of pineal function by the immune system.

Acetylserotonin O-Methyltransferase↗
PubMed1985

Hamster and rat pineal gland beta-adrenoceptor characterization with iodocyanopindolol and the effect of decreased catecholamine synthesis on the receptor.

Rat and hamster pineal glands were used in binding studies to characterize their beta-adrenoceptors with a new specific antagonist ligand, iodocyanopindolol. The receptors were saturable, and the ligand was selective and demonstrated stereospecificity for both species. The rat pineal had a 20-fold greater density of beta-adrenoceptors, while the affinity was one-third that of the hamster pineal. utilizing this radioligand, we examined the effects of decreased sympathetic input to the pineal on beta-adrenergic receptors in both species. Decreased noradrenergic input to the pineal gland of the hamster was accomplished by superior cervical ganglionectomy, or by exposing the animals to continuous light for 36 hours. Parallel studies were conducted with hamster pineal gland in which catecholamine synthesis was measured. The results indicate that a selective decrease in catecholamine synthesis in the hamster pineal does not change the beta-adrenoceptor density or affinity. In contrast, a concomitant increase in beta-adrenoceptor density but not affinity occurs in the rat pineal gland after similar decreased sympathetic input.

Animals↗
PubMed1989

Morphology of the pig's pineal gland from 8th to 16th week of foetal life.

Pineal glands of the pig from the 8th to the 16th week of foetal life were examined by means of both light and electron microscopy, and changes in the pineal structure were observed. The pinealocyte structure manifests the secretory activity of the pineal gland at the time of examination.

Actin Cytoskeleton↗
PubMed1986

A clinical study on the relationship between the pineal gland and the opioid system.

Recent reports point to a link between the pineal gland and the opioid system. In order to investigate this relationship, two separate studies were performed on humans. Beta-endorphin plasma levels were determined after melatonin administration (0.2 mg/kg b.w. i.m. at 2 p.m.). Melatonin serum values were evaluated after administration of FK 33-824, a met-enkephalin analogue (0.3 mg i.v. infusion at 9 a.m.). A significant decrease of beta-endorphin plasma levels was observed 120 minutes after melatonin injection. Melatonin release was stimulated by FK 33-824, with a peak at 30 minutes. The present results provide evidence of the inhibitory effect of melatonin on beta-endorphin secretion and the stimulatory action of the opioid peptides on the pineal gland. However, further studies will be required to clarify the relationship between the opioid system and the pineal gland.

Adolescent↗
PubMed1991

The pineal gland in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology. Clinical, neurochemical, and neuroradiological data implicate the pineal gland in the pathophysiology of MS. To investigate the relationship of MS to the pineal gland further, we surveyed the prevalence of pineal calcification (PC) on CT scan in a cohort of 29 MS patients (7 men, 22 women, mean age: 40.1 years, SD = 8.9) who were admitted consecutively to a neurological service for acute exacerbation of symptoms. For the purpose of comparison, we also surveyed the prevalence of choroid plexus calcification (CPC) in the sample. Twenty-one age and sex-matched neurological patients served as controls (5 men, 16 women, mean age: 37.0, SD = 9.2). PC was seen in 100% of MS patients, while 72.4% patients (N = 21) had CPC. In the control sample, PC was found in 42.8% (N = 9) and CPC in 28.5% (N = 6). Thus, the strikingly high prevalence of PC in MS provides indirect support for an association between MS and abnormalities of the pineal gland. Moreover, since pineal melatonin is involved in neuroimmunomodulation, we propose, for the first time, that abnormalities of pineal melatonin functions are implicated in the pathophysiology of the disease.

Adult↗
PubMedDate not supplied

The antisteroid, antigonadotropic and metabolism-regulation activity of the pineal gland.

This is a synthetic presentation of the data accumulated along almost fourty years in the Institute of Endocrinology in Bucharest, on the biology of the pineal gland. Most of these were included in the book treating on the pineal gland as an organ of metabolic regulation. The works revealed hypoglycemic, anabolic, anticholesterolemic and glomerulotrophic action of the pineal peptides as opposed to the pinealectomy which induced completely opposite effects. It was also demonstrated that the pineal gland has an antisteroid action, being both anticorticosteroid and antiandrogenic; the antigonadotropic action was also revealed on the basis of the classical method in endocrinology in which two states of plus or of minus of the glandular secretions show diametrically opposed phenomena. Researches on the hormonology of the pineal gland led to the production of a biologically active peptide extract which was finally turned into a medicine under the name of Crinofizin. The therapeutic indications of this drug are also presented.

Adrenal Cortex Hormones↗
PubMed1998

Modulatory role of acetylcholine in the rat pineal gland.

The function of acetylcholine (ACh) in the mammalian pineal gland is unknown. To test the hypothesis that ACh exerts a modulatory role in this organ, in the present study electrophysiogical multiunit recordings were carried out in ex-vivo rat pineal glands superfused with different drugs. It was found that ACh (10(-7) M) as well as the cholinergic agonists oxotremorine (10(-7) M) and nicotine (10(-6) M) increased the discharge rates of most of the spontaneously active units and led to burst activity in previously regularly firing cells. It is concluded that ACh may play a modulatory role in the pineal by influencing the firing of a special population of pineal cells with perhaps receptor function.

Acetylcholine↗
PubMedDate not supplied

Neuropeptide Y in the mammalian pineal gland.

The present review describes the anatomy of the neuropeptide (NPY)ergic innervation of the mammalian pineal gland with emphasis on the rat. The proNPY-molecule is post-translationally processed by a single cleavage to neuropeptide Y (NPY) and a C-terminal peptide of NPY (CPON). NPY is C-terminally amidated, and the amidation is essential for binding of NPY to its corresponding receptor(s). Since no proNPY has been detected in rat pineal extracts, it is considered that proNPY is immediately processed to its final products in the gland. In the rat, numerous NPY- and CPON-immunoreactive (ir) nerve fibers are present in the capsule of the superficial pineal gland and in the pineal parenchyma, mostly related to the connective tissue spaces and the vasculature of the gland, but also present between the pinealocytes. Furthermore, a substantial number of fibers was observed in the deep pineal gland, the pineal stalk, and the underlying epithalamus. Occasionally, NPY- or CPON-immunoreactive fibers were found adjacent to the stria medullaris and in the posterior commissure, which could be followed to the adjacent deep pineal gland. At the ultrastructural level, the NPY-immunoreactivity was confined in boutons containing large granular vesicles (100-200 nm) as well as small (40-60 nm) granular vesicles. Some terminals were located in very close apposition to the pinealocyte cell membrane. Terminals were identified in perivascular spaces, but synaptic contacts between the immunoreactive terminals and pinealocytes were never observed. These data show that NPY is highly concentrated in nerve fibers throughout the rat pineal complex. Double-fluorescence histochemistry using tyrosine hydroxylase as marker for catecholaminergic fibers and NPY revealed that nearly all NPYergic fibers co-stored tyrosine hydroxylase in the superficial pineal gland. A minor portion of both immunoreactivities was not colocalized. In accordance, about 65% of the neurons in the superior cervical ganglion contained both CPON and tyrosine hydroxylase. In bilateral superior cervical ganglionectomized rats, a few NPY-ir nerve fibers remained mostly in the pineal capsule, but few fibers were also found in the superficial pineal parenchyma. Contrarily, only a moderate decrease was observed in the number of immunoreactive fibers in the deep pineal gland, and no reduction was observed in the adjacent epithalamus. In the ganglionectomised rats, co-localisation of tyrosine hydroxylase and NPY in intrapineal nerve fibers was not observed either in the superficial pineal gland, nor in the deep pineal gland. These results together with the available literature show that NPY is a sympathetic transmitter, and its actions in the pineal gland are, therefore, associated with the well-documented roles of noradrenaline. Possible roles of NPY in pineal biochemistry and physiology are discussed.

Animals↗
PubMed2001

Influence of sleep deprivation coupled with administration of melatonin on the ultrastructure of rat pineal gland.

The effects of sleep deprivation with or without melatonin treatment on the pineal morphology in rats were studied. Five days after sleep deprivation and using electron microscopy, many of the pinealocytes exhibited structural alterations including dilation of the cisternae of the rough/smooth endoplasmic reticulum, Golgi saccules and mitochondria, and an increase in the numbers of lipid droplets, vacuoles and dense-core vesicles. These features were considered as morphological evidence of increased synthesis or secretion by the pineal gland. In addition, numerous membranous profiles, considered to be degraded cellular organelles, were observed in some pinealocytes and sympathetic nerve terminals. It is suggested that the occurrence of degenerating organelles had resulted from the deleterious effect of sleep deprivation. This may be attributed to an overload of secretory activity of the pineal gland during stress elicited by the long-term sleep deprivation, leading to functional exhaustion and irreversible damage of the oxidation-related organelles. In sleep-deprived rats receiving a single injection of melatonin (10 mg/kg) for 5 consecutive days, the above features indicative of pinealocytic activation were attenuated. In fact, all signs of degeneration of cellular organelles were rarely found. These results suggest that the pineal gland is itself a target for exogenously administered melatonin. Thus, melatonin when administered systemically may be used as a potential neuroprotective drug against neuronal damage induced by sleep deprivation.

Animals↗
PubMed1989

Ethanol enhancement of isoproterenol-stimulated melatonin and cyclic AMP release from cultured pineal glands.

Norepinephrine stimulates the synthesis of melatonin in the pineal gland. The action of norepinephrine is believed to be mediated primarily by beta adrenergic receptors, and involves activation of adenylate cyclase. Ethanol, 25 to 50 mM, added to cultured pineal glands in vitro, enhanced isoproterenol-induced stimulation of cyclic AMP and melatonin production. The action of ethanol was observed only at doses of isoproterenol that produced a submaximal effect, and ethanol alone had no effect on cyclic AMP or melatonin release. Butanol, at a concentration of 2 mM, was as effective as 50 mM ethanol in increasing isoproterenol-stimulated cyclic AMP and melatonin release, indicating that the response to alcohols was not due simply to changes in osmolarity, and may reflect a hydrophobic interaction of the alcohols with the cell membrane. The effects of ethanol on pineal cyclic AMP and melatonin release were reversible after a 15-min preincubation, but not after a 2-hr preincubation, suggesting that, over a long incubation period, ethanol may sensitize the pineal beta adrenergic receptor-coupled adenylate cyclase system to isoproterenol. The findings in this study are consistent with earlier work showing that ethanol increases cerebral cortical beta adrenergic receptor-coupled adenylate cyclase activity, and demonstrate that the effect of ethanol on the receptor-effector system can result in an endocrinological response.

1-Butanol↗
PubMed1983

Evidence for pineal gland modulation of the neuroendocrine-thyroid axis.

Experiments with rats and hamsters have provided evidence for an inhibitory action of the pineal gland on the neuroendocrine-thyroid axis. While maintenance of these animals in short photoperiod results in reduced levels of circulating thyroxin (T4), pinealectomy restores the levels to normal. Recent studies suggest that an active pineal gland produces a substance which inhibits thyrotrophin-releasing hormone release from the hypothalamus. Several investigators have concluded that endogenous melatonin, produced in the pineal gland, could account for the inhibitory action of the pineal gland on blood T4 levels. Although melatonin administration has been reported to inhibit blood T4 levels in both rats and hamsters, under certain experimental conditions melatonin administration can be demonstrated to have a counter-antithyrotrophic effect resulting in increased blood levels of T4 and thyrotrophin. Assay of blood levels of melatonin of rats and hamsters under various experimental conditions will be necessary to distinguish physiological from pharmacological effects of melatonin. Lesion studies as well as studies with melatonin implants in the brain, suggest that the site of action is in the anterior hypothalamus. The effects of melatonin on the neuroendocrine-thyroid axis are similar to its effects on the neuroendocrine-gonadal axis, leading to the hypothesis of a common site of action for the thyroid and gonadal effects of melatonin. Although many pineal 'factors' have been postulated to account for the action of this gland, an action of melatonin on the serotonergic system of the brain stem could account for the data.

Animals↗
PubMed1978

Estimation of the methylating capacity of the pineal gland. With special reference to indole metabolism.

In order to obtain more information on the methylating capacity of the pineal gland, a method determining the formation of different 5-methoxyindoles in the pineal gland was developed. The method depends on measuring the incorporation of labelled methyl groups into the various hydroxyindoles present in the pineal gland, after incorporation of pineal tissue with labelled S-adenosyl methionine. Hydroxyindoles were not added to the incubation medium. After incubation thin-layer chromatography was performed with pineal tissue together with the incubation medium; the spots were scraped and counted.

Animals↗
PubMed1979

Norepinephrine turnover in pineal gland and superior cervical ganglia. Changes after gonadotrophin administration to castrated rats.

The effects of FSH and LH on norepinephrine (NE) turnover in pineal gland and superior cervical ganglia of castrated female rats were examined by measuring the decline of [3H]NE concentration in the organ 30--120 min after a single i.v. injection of the labeled amine. Both FSH and LH treatment significantly decreased [3H]NE turnover in the pineal gland whereas only FSH accelerated it in the ganglia. As compared to controls, the initial uptake of [3H]NE was lower in the pineal gland of FSH- and LH-treated animals, and higher in the superior cervical ganglia of rats injected with FSH. Neither FSH nor LH modified [3H]NE turnover in heart or adrenal gland, nor changed their endogenous catecholamine content. Pineal monoamine oxidase (MAO) activity type B (assaying by using beta-phenylethylamine as substrate) was decreased by FSH or LH injection. Only FSH modified MAO activity in the ganglia by increasing significantly type A enzyme (assaying by using serotonin as substrate). These results suggest that FSH and LH affect significantly NE metabolism in pineal gland and superior cervical ganglia of spayed rats.

Adrenal Glands↗
PubMed2004

Arterial supply of the pineal gland of Akkaraman sheep.

Arterial vascularisation of the ovine pineal gland was investigated by latex injection preparations of the common carotid artery in 20 adult Akkaraman sheep brains under stereo light microscope. It was observed that the arterial supply comes exclusively from branches of the caudal cerebral artery. The pineal gland was found to contain a rich vascular network. This network also received a few branches from the caudal choroid rami.

Animals↗