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The role of pineal gland in breast cancer development.

The role of the modulation of the pineal gland function in development of breast cancer is discussed in this review. An inhibition of the pineal function with pinealectomy or with the exposure to the constant light regimen stimulates mammary carcinogenesis, whereas the light deprivation inhibits the carcinogenesis. Epidemiological observations on increased risk of breast cancer in night shift workers, flight attendants, radio and telegraph operators and on decreased risk in blind women are in accordance with the results of experiments in rodents. Treatment with pineal indole hormone melatonin inhibits mammary carcinogenesis in pinealectomized rats, in animals kept at the standard light/dark regimen (LD) or at the constant illumination (LL) regimen. Pineal peptide preparation Epithalamin and synthetic tetrapeptide Epitalon (Ala-Glu-Asp-Gly) are potent inhibitors of mammary carcinogenesis in rodents and might be useful in the prevention of breast cancer in women at risk.

Animals↗

Presence of isorenin in human pineal gland.

A renin-like enzyme was identified in adult human pineal gland preserved post mortem in acetone. The mean value of the isorenin content was equivalent to 470 +/- 75.4 ng. ang II/g Pt/h.

Adult↗

Adenosine analogs elevate N-acetylserotonin and melatonin in rat pineal gland.

Adenosine, S-adenosyl-L-homocysteine, adenosine analogs such as 5'-N-ethylcarboxamidoadenosine and mioflazine, a nucleoside transport inhibitor, injected intraperitoneally at 09.00 h during the light period increased melatonin levels in the pineal gland of the rat. The largest increase occurred with 1 mg/kg 5'-N-ethylcarboxamidoadenosine. A representative time-response curve with 5'-N-ethylcarboxamidoadenosine (1 mg/kg) showed a maximal peak of N-acetylserotonin and melatonin 2 and 4 h after injection, respectively. These results are discussed in relation with the possible modulation through A2 receptors of melatonin synthesis in the pineal gland.

Adenosine↗

The vascularization of the pineal gland (epiphysis cerebri) of the rat.

The vascularization of the rat pineal gland was investigated with, respectively, latex and resin injection preparations of the cephalic blood vessels in adult Wistar rats. From the dissection of the latex-injected and aldehyde-fixed rat brains under the stereo light microscope it was found that the arterial supply comes exclusively from separate branches of the posterior cerebral artery. The pineal area was dissected out from the resin injected and corroded specimens under the stereo light microscope and was inspected in the SEM. The supplying arteries, identified on the basis of their endothelial cell imprint patterns, were 4 to 6 in number with a diameter of 20 to 40 micron. The venous drainage consisted of 12 to 16 short veins with a diameter of 40 to 60 micron, all draining directly into the great cerebral vein and thereafter via the sinus influens immediately into the systemic venous circulation.

Animals↗

Ultrastructure of the pineal gland after gamma-irradiation under conditions of inhibition of adrenocortical function.

Electron microscopy showed that whole-body gamma-irradiation in sublethal doses led to the appearance of injuries in pinealocytes, glial cells, and vessels of the pineal gland in rats. Limitation of the nonspecific effect of gamma-irradiation via inhibition of adrenocortical function with metopirone in physiological doses reduced the radiation-induced ultrastructural damage to the pineal gland.

Adrenal Cortex↗

Principal neurons projecting to the pineal gland in close association with small intensely fluorescent cells in the superior cervical ganglion of rats.

The localization in the superior cervical ganglia (SCG) of small, intensely fluorescent (SIF) cells and of principal nerve (PN) cells innervating the pineal gland was examined in adult male Sprague-Dawley rats. PN cells were demonstrated by means of the retrograde neuron-tracing method using the fluorescent tracer Fluoro-Gold (FG) injected into the pineal gland. SIF cells were visualized by the formaldehyde-induced fluorescence method. Twenty-nine percent of the FG-labeled PN cells were found closely associated with SIF cells. In the rostral half of the ganglion, 43% of the SIF cells were situated in juxtaposition to one or several labeled neurons. The possible influence of SIF cells on the regulation of pineal metabolism is discussed with respect to their role as both local endocrine cells and interneurons.

Animals↗

Scientific research on the pineal gland and melatonin: a bibliometric study for the period 1966-1994.

By means of teledischarge techniques from the database MEDLINE we selected those documents that contained in their title one or several of the following descriptors: pineal*, epiphys*, or melatonin*, in addition to the descriptor pineal-body in the MESH (Medical Subject Headings) section. A total of 7,617 original documents published between 1966 and 1994 were extracted that dealt with any aspect related with the pineal gland or its main secretary product, melatonin. The main bibliometric laws were applied: Price's Law on the increase in scientific literature, Bradford's Law on the dispersion of the scientific literature, and Lotka's Law on the author's productivity. Furthermore, we have analyzed the participation index (PaI) of the main countries within the global production, the productivity index of the authors (PI), and the number of authors/paper index. Our results demonstrate an exponential increase of the scientific literature on the pineal gland ("r" value = 0.983, in contrast with a "r" value = 0.966 after the linear adjustment). The number of publications on melatonin was less than those on other aspects of pineal research until 1991, when this situation was reversed. The journal with the largest number of original papers is Journal of Pineal Research (1st Bradford's zone) with 533 articles, followed by Journal of Neural Transmission (258) and Neuroendocrinology (221), which constituted the 2nd Bradford's zone. The total number of authors is 9,140, responsible for 23,524 authorships. 3.8% of the authors present a PI > or = 1 (large producers), and 64.9% a PI = 0 (occasional authors). Lotka's Law was widely fulfilled in this material since 10.3% of the authors are responsible of 50.2% of all the papers. The average number of authors per paper has changed from 2.29 in 1966 to 3.85 in 1994. The most productive country (during the interval between 1988-1994) was USA (PaI = 30.6), followed by Japan (7.15), United Kingdom (6.45), Germany (6.37), France (6.26), Italy (6.15) and Spain (5.34). Of the total number articles published, 86.9% are in English.

Bibliometrics↗

Absence of acetylcholinesterase-positive nerve structure in the superficial part of the pineal gland of adult albino rats.

Application of the histochemical method for testing acetylcholiesterase (AChE, EC 3.1.1.7) combined with silver impregnation of the nervous tissue showed the absence of AChE-positive nerve structures in the superficial part of the pineal gland in adult male albino rats. It was carried out at the level of the light microscope. If it is assumed that the test for the presence of AChE is a form of indirect conclusion concerning the cholinergic nature of given nerve structures, then in the case of the superficial innervation of the pineal gland, the outcome of the test is negative.

Acetylcholinesterase↗

Id-1 expression defines a subset of vimentin/S-100beta-positive, GFAP-negative astrocytes in the adult rat pineal gland.

Id proteins are dominant negative members of the helix-loop-helix (HLH) transcription factor family which are involved in the differentation of many cell types, including glia. We have recently identified the adult rat pineal gland as a major site of Id-1 and Id-3 expression. In the present study, double fluorescence immunocytochemical analysis was used to examine the co-localization of Id-1 and Id-3 with both neuronal (synaptophysin, betaIII-tubulin) and astrocytic markers (GFAP, vimentin, S-100beta) in the rat pineal. In addition to localizing Id-1 and Id-3 protein to the melatonin-producing pinealocytes, we have also made the novel observation that Id-1, but not Id-3, is highly expressed in a population of vimentin-positive/S-100beta-positive/GFAP-negative astrocytes. Surprisingly, Id-1 was primarily cytoplasmic in these cells, and expression extended throughout the cellular processes. The pineal has been recognized previously as a unique region of the central nervous system in which a vimentin-positive/GFAP-negative glial phenotype is maintained in adult mammals. The exclusion of Id-1 from GFAP-positive cells, and expression in a population of vimentin-positive pineal astrocytes is evidence of a role for Id-1 in the adult stabilization of one form of astrocyte. These results identify the rat pineal gland as a model system for the functional analysis of Id-1.

Animals↗

The mechanism of modification by propranolol of the metabolism of phosphatidyl-CMP (CDP-diacylglycerol) and other lipids in the rat pineal gland.

The mechanism underlying the alteration of phospholipid metabolism in rat pineal gland in vitro produced by propranolol and tertiary amine local anesthetics was investigated. 0.1 mM propranolol did not affect either the levels or specific activity of [32P]ATP in glands. In the presence of the drug, the incorporation of cytidine, but not of inorganic phosphate, into phosphatidyl-CMP (CDP-diacylglycerol) was dependent on the cytidine concentration. The incorporation of glycerol into phosphatidyl-CMP, phosphatidylinositol and phosphatidylglycerol was enhanced by propranolol, whereas labeling of phosphatidylcholine was decreased. When both 1 mM propranolol and 1 mM inositol were present, labeling of phosphatidylinositol was further increased, stimulation of phosphatidyl-CMP and phosphatidylglycerol labeling was reduced and incorporation into phosphatidylcholine and triacylglycerol was depressed. The incorporation of [3H]inositol into pineal lipids was also enhanced by propranolol. 10 microM propranolol inhibited rat liver phosphatidic acid phosphohydrolase by 50%, while local anesthetics were less potent in the decreasing order: dibucaine greater than tetracaine greater than lidocaine greater than procaine. The propranolol-induced accumulation of phosphatidyl-CMP was prevented by supplying adequate freely diffusible inositol in the medium. The phosphatidyl-CMP which accumulated was not utilized for the enhanced formation of phosphatidylinositol brought about by norepinephrine. The results indicate that propranolol and local anesthetics redirect pineal phospholipid metabolism in part by inhibition of phosphatidic acid phosphohydrolase.

Adenosine Triphosphate↗

Photoperiodic control of body weight and energy metabolism in Syrian hamsters (Mesocricetus auratus): role of pineal gland, melatonin, gonads, and diet.

The effects of photoperiod and the pineal hormone melatonin on the regulation of body weight and energy metabolism were examined in Syrian hamsters, Mesocricetus auratus. Short photoperiod-housed female and male hamsters showed increases in body weight gain, feed efficiency, carcass lipid, brown adipose tissue mass, and thermogenic capacity. These effects of short photoperiods were mimicked by afternoon melatonin injections to hamsters in long-day photoperiods and were exaggerated in hamsters fed high fat diets. To determine the role of the gonads in these effects, ovariectomized hamsters were treated similarly and found to exhibit changes in body weight and energy metabolism that were 80-90% of those in gonadally intact hamsters. The role of the pineal gland in short photoperiod-induced body weight gain was examined in sham-pinealectomized and pinealectomized hamsters. Short photoperiod-induced increases in body weight were seen in both pinealectomized and sham-pinealectomized hamsters. Thus, pinealectomy blocks the effects of short photoperiods on reproductive function and thyroid activity, but not on body weight regulation. These results suggest that the effects of short photoperiods on body weight and energy metabolism are mediated by multiple, redundant mechanisms involving decreases in gonadal hormone secretion, changes in melatonin secretion, and gonad- and pineal-independent changes. All of the effects of short photoperiods are exaggerated in hamsters fed a high fat diet. These changes may represent adaptive preparatory responses that enhance winter survival in Syrian hamsters.

Adipose Tissue, Brown↗

Influence of maternal pineal gland on the developmental pattern of neurokinin A (NKA) and substance P (SP) in male-rat-offspring: relationship to the season of the year.

The present study examines the influence of maternal pineal gland on the frontal cortex, striatal and testicular concentrations of the tachykinins, neurokinin A (NKA) and substance P (SP). Control, pinealectomized (PIN-X) and PIN-X plus melatonin-treated (PIN-X + MEL) mother rats were prepared. Male offspring rats were studied at 21, 31 and 60 days of age, during the four seasons of the year. In control-offspring tachykinin concentrations in frontal cortex were found at their highest levels in 21-day-old rats with a moderate decrease up to 60 days of age. This developmental pattern was season-dependent, observed only during summer and fall. Maternal PIN-X or PIN-X + MEL resulted in alterations in the offspring, showing during spring and summer significantly higher concentrations (P < 0.01) and during fall significantly lower concentrations of tachykinins in the frontal cortex (P < 0.05, P < 0.01) as compared to control-offspring. The tachykinin concentration in the striatum of control-offspring showed no major modifications throughout the ages studied in the four seasons of the year. With very few exceptions, PIN-X- and PIN-X + MEL did not alter tachykinin concentrations in striatum. Testicular SP concentrations showed a decrease from 21 to 60 days of age. PIN-X or PIN-X + MEL only caused minor and inconsistent modifications in testicular SP levels. In conclusion, our data clearly indicate for the first time that the maternal pineal gland participates in the regulation of the postnatal tachykinin development in some areas of the central nervous system. This effect was more evident in the frontal cortex than in the striatum and testes.

Animals↗

The pineal gland is very large and active in newborn antarctic seals.

The pineal gland of newborn elephant seals and Weddell seals is larger than in adult females. The gland is considerably larger at birth in Weddell seals than in elephant seals. The former experience greater extremes of temperature. Plasma melatonin concentrations in excess of 2000 pg/ml were recorded in the first days of life, compared with 20-50 pg/ml in adults.

Animals↗

Factors regulating sterol biosynthesis in the rat pineal gland in vitro.

The effects of hormones, feeding and photoperiod on pineal sterol biosynthesis were studied in rat pineal glands incubated with 1-14C acetate. The rate of sterol biosynthesis was 7.1 nmol/g/2 h. A high synthesis rate was observed during mid-dark of a 12:12 LD cycle and under constant light. Melatonin, testosterone, and glucagon had no effect on sterol synthesis whereas estradiol increased it and insulin and norepinephrine treatments decreased it. Increased cAMP levels resulting from dibutyryl cAMP and theophylline were also found to be inhibitory. Dietary cholesterol did not alter the rate of sterol biosynthesis but 24 h fasting depressed sterol synthesis significantly. It can be concluded that hormones and substrate availability may be involved in the regulation of pineal sterol biosynthesis.

Animals↗

Dynamics of noradrenergic circadian input to the chicken pineal gland.

To analyze the dynamics of sympathetic input to the chicken pineal the concentrations of catecholamines, indoleamines and some of their metabolites were determined by high performance liquid chromatography with electrochemical detection (HPLC-EC) in the pineal glands of young chickens killed at different times of day. Rhythmic variations over 24 h were observed in tissue levels of dopamine (DA), 5-hydroxytryptamine (5-HT), N-acetylserotonin (NAS) and 5-hydroxyindoleacetic acid (5-HIAA), while norepinephrine (NE) concentrations exhibited no significant change. DA content peaked 2 h after onset of darkness and NAS was detectable only during the night. A bimodal pattern of 5-HT and 5-HIAA levels was observed with peak tissue levels occurring at dawn and dusk. To determine the possible differential effects of light on these biogenic amines, birds were sacrificed at midday, midnight and at midnight following a 1 h exposure to light, and their pineals processed for HPLC-EC. NE, DA and 5-HT levels were similar at midday and midnight, while 5-HIAA and NAS were elevated during the night. Midnight illumination decreased NE and NAS levels, increased 5-HT and 5-HIAA levels and had no effect on DA levels. Temporal variations in NE turnover were determined by pretreating young chickens with alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, and measuring the rates of decline in NE content over 2 h at midday and midnight in birds held on light cycles and at mid-subjective day in birds held in constant darkness (DD).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

(+)-N-allylnormetazocine enhances N-acetyltransferase activity and melatonin synthesis: preliminary evidence for a functional role of sigma receptors in the rat pineal gland.

In the present study, to evaluate the role that sigma receptors play in the physiology of the pineal gland, we assessed the effects of the sigma receptor ligand (+)-N-allylnormetazocine on the gland activity during either the day or the night. As compared to saline, (+)-N-allylnormetazocine enhanced the physiological increases in both pineal N-acetyltransferase (NAT) activity and melatonin content at night, but it did not affect the biosynthetic activity of the gland during the day. Moreover, (+)-N-allylnormetazocine potentiated the enhancement of NAT activity and pineal melatonin content induced by isoproterenol administration during the day. The nocturnal stimulation of pineal NAT activity and melatonin levels by (+)-N-allylnormetazocine was prevented by pretreatment with rimcazole, a specific sigma receptor antagonist. These results demonstrate that sigma receptor activation by (+)-N-allylnormetazocine is not able, by itself, to stimulate pineal melatonin production, whereas it potentiates the biosynthetic activity of the pineal gland when this is stimulated noradrenergically.

Animals↗