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PubMed1993

Differential intracellular mechanisms mediate the co-ordinate induction of c-fos and jun-B in the rat pineal gland.

In the rat pineal gland the immediate early genes c-fos and jun-B are co-ordinately induced in vivo following the onset of darkness, and in vitro following treatment with adrenergic drugs. An extensive in vitro analysis of the mechanisms which regulate the induction of these two genes has revealed that, although there are common pathways of control, c-fos and jun-B exhibit differential regulation by adrenoceptor types, second messenger pathways and protein kinase C. The presence of differential intracellular mechanisms of regulation provides precise control over the expression pattern of immediate early genes, a pattern which is crucial for cellular response since the combinatorial actions of the products of these genes are a determinant of target gene activation. The pineal gland is a unique experimental model in which the molecular pharmacology of immediate early gene regulation can be investigated.

Adrenergic Agonists↗

PubMed1992

Involvement of cyclic guanosine monophosphate (cGMP) and cytosolic guanylate cyclase in the regulation of synaptic ribbon numbers in rat pineal gland.

In the rat pineal gland N-acetyltransferase (NAT) activity and synaptic ribbon (SR) numbers display a circadian rhythm. It is well-known that NAT activity is regulated by adrenergic mechanisms involving cyclic adenosine monophosphate (cAMP) as a second messenger. However, the mechanism involved in the regulation of SR numbers has not been established so far. In the present in vitro study, we have investigated the effects of 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP), a cyclic guanosine monophosphate (cGMP) analog, and stimulation of guanylate cyclase on SR numbers. Incubation with 8-bromo-cGMP increased SR numbers in a dose- and time-dependent manner. Further, stimulation of the cytosolic guanylate cyclase also resulted in increased SR numbers. Adrenergic agonists stimulated cGMP but did not alter SR numbers. These findings suggest that cGMP is involved as a second messenger in the regulation of SR numbers. Since the adrenergically stimulated increase in cGMP did not influence SR numbers, a non-adrenergic cGMP metabolic pathway seems to be involved in the regulation of SR numbers in the rat pineal gland.

Animals↗

PubMed1990

Hypothalamic regulation of circadian noradrenergic input to the chick pineal gland.

While the avian pineal gland contains circadian oscillators and photoreceptors capable of producing circadian rhythms of the hormone melatonin, it is extensively innervated by post-ganglionic fibers of the superior cervical ganglia which release norepinephrine (NE) rhythmically. Norepinephrine turnover is higher during subjective day than during subjective night. In mammals, this rhythmic input, which is higher in subjective night than subjective day, derives from the hypothalamic suprachiasmatic nuclei (SCN) and is essential for rhythmic melatonin production. The present study was designed to determine whether one of two candidates for the avian homologue of the mammalian SCN is necessary for rhythmic NE turnover in the chick pineal gland. Either electrolytic lesions or sham lesions were delivered to the periventricular preoptic nuclei (PPN) or to the visual suprachiasmatic nucleus (vSCN). After recovery, the rates of decline in [NE] were determined following pretreatment with alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, at mid-subjective day or at mid-subjective night. Birds receiving sham surgeries in either PPN or vSCN and birds receiving lesions of the PPN exhibited rhythmicity in NE turnover. No rhythm of NE turnover could be determined in birds with ablated vSCN.

Animals↗

PubMed1989

Melatonin secretion from goldfish pineal gland in organ culture.

Pineal glands were removed from goldfish reared under 12L-12D at 25 degrees for 2 weeks. These were incubated for 6 days under (1) normal 12L-12D (lights on 0600-1800 hr), (2) reversed 12L-12D (lights on 1800-0600 hr), (3) continuous dark, or (4) continuous light condition at 25 degrees. The incubation medium was changed at 12-hr intervals (0600-1800 and 1800-0600 hr) and secreted melatonin (MLT) was measured by RIA. Under 12L-12D or reversed 12L-12D, MLT secretion was active in the dark phase and was suppressed in the light phase of a given photoperiod. Under a continuous dark condition, a large amount of MLT was secreted into the medium, although the amount gradually decreased. The MLT secretion was more active in the period corresponding to the dark phase of the acclimatory photoperiod than in the period corresponding to the light phase. This pattern in secretion remained for 4 days. Under a continuous light condition, MLT secretion was suppressed, but the secretion was rapidly increased after changing the photoperiod from the light to the dark condition. These findings clearly indicate that MLT secretion in the organ-cultured pineal gland is photosensitive. It is active under dark and inactive under light conditions. The existence of a circadian rhythm in MLT secretion is also suggested.

Animals↗

PubMed2007

Transcriptional regulation of arylalkylamine-N-acetyltransferase-2 gene in the pineal gland of the gilthead seabream.

Pineal serotonin-N-acetyltransferase (arylalkylamine-N-acetyltransferase; AANAT) is considered the key enzyme in the generation of circulating melatonin rhythms; the rate of melatonin production is determined by AANAT activity. In all the examined species, AANAT activity is regulated at the post-translational level and, to a variable degree, also at the transcriptional level. Here, the transcriptional regulation of pineal aanat (aanat2) of the gilthead seabream (Sparus aurata) was investigated. Real-time polymerase chain reaction quantification of aanat2 mRNA levels in the pineal gland collected throughout the 24-h cycle revealed a rhythmic expression pattern. In cultured pineal glands, the amplitude was reduced, but the daily rhythmic expression pattern was maintained under constant illumination, indicating a circadian clock-controlled regulation of seabream aanat2. DNA constructs were prepared in which green fluorescent protein was driven by the aanat2 promoters of seabream and Northern pike. In vivo transient expression analyses in zebrafish embryos indicated that these promoters contain the necessary elements to drive enhanced expression in the pineal gland. In the light-entrainable clock-containing PAC-2 zebrafish cell line, a stably transfected seabream aanat2 promoter-luciferase DNA construct exhibited a clock-controlled circadian rhythm of luciferase activity, characteristic for an E-box-driven expression. In NIH-3T3 cells, the seabream aanat2 promoter was activated by a synergistic action of BMAL/CLOCK and orthodenticle homeobox 5 (OTX5). Promoter sequence analyses revealed the presence of the photoreceptor conserved element and an extended E-box (i.e. the binding sites for BMAL/CLOCK and OTX5 that have been previously associated with pineal-specific and rhythmic gene expression). These results suggest that seabream aanat2 is a clock-controlled gene that is regulated by conserved mechanisms.

Animals↗

PubMed1977

A histochemical study of aldehyde fuchsin-positive material and "high-esterase cells" in the pineal gland of the Mongolian gerbil.

The pineal gland of the Mongolian gerbil consists of a superficial gland, stalk and deep pineal. The deep pineal differentiates postnatally. Histochemical studies of the superficial pineal gland indicate that it may be involved in the secretion of protein. Presumptive secretory material visualized by aldehyde fuchsin (AF) and chrome hematoxylin was observed along the course of blood vessels and among the pinealocytes. The distribution and texture of the AF-positive material was distinctive. It did not correspond to the pattern and texture of material stained with PAS, Sudan Black or acid orcein. Staining with AF was markedly reduced after incubation with trypsin, indicating that the AF-positive material is at least partially protein. The amount of stainable material increased with age. The AF-positive material was observed in what appeared to be interstitial or glial cells and processes, and in the processes of perivascular cells. Cells and fibrous processes with high non-specific esterase activity ("high-esterase cells") were observed among the pinealocytes and along the course of blood vessels. The distribution of the "high-esterase cells" and the morphology and texture of their esterase-containing processes were remarkably similar to the morphology and distribution of the material that stained with AF. It may be that the "high-esterase cells" contain AF-positive material. The "high-esterase cells" hydrolyzed both alpha-naphthyl acetate and alpha-naphthyl butyrate. The pinealocytes hydrolyzed only alpha-naphthyl acetate. The "high-esterase cells" appear to form a distinct class of cells within the superficial pineal gland. They are tentatively identified as a type of glial cell.

Acid Phosphatase↗

PubMed1983

Involvement of the pineal gland in rats with experimental autoimmune uveitis.

Pineal glands of rats with experimentally induced autoimmune uveitis (EAU) were studied histologically. Inflammatory changes, characterized by mononuclear infiltration, were found in the pineal glands of one-third of the Lewis rats that developed EAU by active immunization with S-antigen. No changes in the pineal gland were observed in AVN rats which are "low responders" for EAU and did not develop ocular disease. Frequency and severity of both pineal gland and ocular involvement clearly were elevated by intravenous injection of Bordetella pertussis along with the S-antigen immunization; all B. pertussis-treated rats of both Lewis and AVN strains developed pineal and ocular changes. Inflammatory changes of the pineal gland also were found in rats in which EAU was induced passively by transfer of lymphocytes from S-antigen-immunized donors. The frequency of involvement of the pineal gland was found to be lower than that of the retinas in rats where EAU was induced by active immunization or by adoptive transfer of lymphocytes.

Animals↗

PubMed2005

Posthatching developmental changes in noradrenaline content in the chicken pineal gland.

Noradrenaline (NA) levels in pineal gland of chickens at various posthatching stages (P2, P4, P8, P15, P30 and P57) were determined by high-performance liquid chromatography with electrochemical detection. Pineal NA content markedly increased between P2 and P30. P30 and P57 chickens, kept from the day of hatching under a 12:12 hr light-dark (LD) illumination cycle, exhibited rhythmic changes in pineal NA, with levels in the dark period being markedly higher than in the light period. In younger birds pineal NA concentrations did not show pronounced daily variations. In 4-wk-old chickens (P28-30) kept under constant darkness (DD), the rhythmic pattern of pineal NA persisted for 1 day (with higher values during the subjective dark phase than during the subjective light phase), but this disappeared 24 hr after the introduction of DD. In contrast, NA content in pineal glands isolated from birds maintained for 2 days under continuous light was similar to that found during the light phase of the LD cycle, and did not exhibit significant rhythmicity. In P30 chickens, pretreated with alpha-methyl-p-tyrosine (AMPT, an inhibitor of tyrosine hydroxylase, the key regulatory enzyme in the biosynthesis of catecholamines), pineal NA content declined slowly and monophasically during the light phase. During the dark phase the AMPT-induced decay of NA was biphasic--namely an initial rapid decline over the first 15 min which was followed by a slow-rate decline--an observation indicating that NA turnover was higher in the dark. Acute exposure of the dark-adapted P30 and P57 chickens to light significantly decreased pineal NA content, but did not affect pineal NA concentrations in younger birds. Our results suggest that the NA rhythm in the chicken pineal gland and its sensitivity to light regulation progressively develop during the first month of life.

Aging↗

PubMed2002

Vasopressinergic innervation of the pig pineal gland.

An immunohistochemical study of the pineal gland of the domestic pig was carried out using the antisera raised against vasopressin (VP). The pineal glands were taken from the newborn, 21-day- and 7-month old female pigs. The pig pineal gland is moderately innervated by VP-immunoreactive nerve fibers. They run from the habenular commissure into the connective tissue septa and further into the pineal parenchyma. In the subependymal tissue as well as in the connective tissue septa, the fibers are smooth or with small varicosities and in the parenchyma with large ones. The obtained results point to extrapineal and extraepithalamic source of the fibers. The density of VP-immunoreactive fibers in the pineal gland of 7-month old pigs is higher than in the younger animals.

Aging↗

PubMed1996

The chemical neuroanatomy of the mammalian pineal gland: neuropeptides.

The mammalian pineal gland contains multiple afferent peptidergic nerve fibres. Sympathetic nerve fibres, with their origin in the superior cervical ganglia, contain neuropeptide Y colocalized with norepinephrine. Other pinealopetal nerve fibres, probably originating in the pterygopalatine ganglion, contain vasoactive intestinal peptide and peptide histidine isoleucine. Fibres containing substance P and calcitonin gene-related peptide have also been demonstrated in pinealopetal nerve fibres. These fibres might originate in the trigeminal ganglion. The neurotransmitter content of the fibres of the central innervation, innervating the gland from the brain via the pineal stalk, has not been elucidated. However, strong indications for the presence of neuropeptide Y, substance P, somatostatin, and vasopressin in these fibres have been presented. Recent immunohistochemical studies have further shown the presence of subtypes of pinealocytes containing neuropeptides. Thus, pinealocytes containing beta-endorphin, leu-enkephalin, and somatostatin have been demonstrated in the gland. Immunohistochemistry at the electron microscopical level has shown, that in some species, leu-enkephalin containing pinealocytes make synaptic contacts with other pinealocytes indicating of paracrine regulation of the pineal gland. It must however be emphasized that large interspecies variations exist with regard to the peptidergic pineal innervation and its content of peptidergic cells.

Animals↗

PubMed2000

Adrenergic and cholinergic regulation of in vitro melatonin release during ontogeny in the pineal gland of Long Evans rats.

Melatonin, produced by the pineal gland, plays an important role in a great variety of neuroendocrine functions. The rhythmic release of melatonin by the mammalian pineal gland is regulated by norepinephrine (NE) acting via alpha- and beta-adrenergic receptors utilizing distinct signal transduction pathways. Acetylcholine has been demonstrated to exert various effects in the mammalian pineal gland, including an inhibitory action on the NE-induced stimulation of melatonin production. However, data obtained by different laboratories on the interaction of adrenergic receptors are not consistent and whether muscarinic and/or nicotinic receptors participate in the various effects of acetylcholine is still contradictory. To investigate noradrenergic as well as cholinergic mechanisms during ontogeny, we have investigated in vitro melatonin release from isolated pineal glands of Long Evans rats of different ages. NE as well as the beta-adrenergic receptor agonist isoproterenol (ISO) significantly elevated the melatonin release in pineal glands from postnatal week 2 on. In pineal glands originating from 2- to 4-week-old rats, simultaneous activation of alpha- and beta-adrenergic receptors by ISO and the alpha-adrenergic receptor agonist methoxamine (MET) or NE resulted in significantly weaker stimulation of melatonin production than beta-receptor activation alone. Acetylcholine evoked a significant increase in melatonin release in pineal glands from 2- to 4-week-old rats. In pineal glands from 8- to 20-week-old animals, ISO, ISO + MET or NE stimulated pineal melatonin release to comparable maxima, whereas acetylcholine was without effect. Our data indicate (1) that the adrenergic stimulation of pineal melatonin production in Long Evans rats is dominated by a beta-adrenergic mechanism, (2) that additional alpha-adrenergic receptor activation is inhibitory and (3) dependent on the developmental status of the animal, and (4) that acetylcholine acting via muscarinic receptors has the capacity to stimulate melatonin release during early ontogeny. These data suggest that the melatonin-generating system of the pineal gland of Long Evans rats undergoes substantial functional changes during early postnatal development, including adrenergic as well as cholinergic mechanisms.

Acetylcholine↗

PubMed1983

Light-induced decrease of serotonin N-acetyltransferase activity and melatonin in the chicken pineal gland and retina.

In the pineal gland and retina of chickens, light exposure at night when serotonin N-acetyltransferase (NAT) activity levels are high causes a 4--5-fold decrease in NAT activity. The t1/2 of NAT inactivation is 10 min and the kinetics of inactivation are similar in the pineal gland and retina. A brief pulse of light can initiate the process of NAT inactivation which continues in the dark for 30 min before a partial recovery of NAT activity occurs. In blinded chicks, there is less inactivation of pineal NAT by light than in intact chicks, indicating that the eyes are involved in the pineal's response to light. In chicks that have had their superior cervical ganglia removed inactivation of pineal NAT by light is intermediate between that of intact and blind chicks, indicating that ganglionectomy does not completely mimic the effects of blinding. The pineal gland itself is light-sensitive in culture. Light causes a 4--5-fold decrease in NAT activity in static organ culture, and inhibits melatonin release in flow-through organ culture. Drugs that increase cyclic nucleotide levels in cells (cholera toxin, RO 20-1724, monobutyryl cyclic AMP, monobutyryl cyclic GMP) block the NAT decrease by light, whereas high potassium or EGTA do not block this light-induced NAT inactivation.

Acetyltransferases↗

PubMed1989

Kinetic study of melatonin release from rat pineal glands using a perifusion technique.

In previous studies, noradrenaline was found to elicit a rise of melatonin secretion through activation of typical beta-adrenergic receptors. In the present study, a perifusion system was developed to characterize the kinetics of melatonin release from rat pineal glands. Isolated pineal glands from adult male rats were continuously perifused for 15 h in a Krebs-Ringer solution, and the concentration of melatonin in the effluent perifusate was monitored using a specific radioimmunoassay. The rate of release of melatonin declined during the first 3-4 h of perifusion and then remained fairly stable for at least 11 h. The spontaneous release of melatonin was around 20 pg per min and per gland. When pineal glands were stimulated with isoproterenol, melatonin release output linearly increased for at least 2 h after the stimulation. The increase in melatonin release depended on the isoproterenol concentration and on the duration of the stimulation. The analysis of the pattern of melatonin secretion by a single rat pineal gland showed that the secretion was irregular but did not present a clear feature of pulsatile or oscillatory release over a 11 h-long study. The perifusion system was found useful in order to follow the characteristics of melatonin release from pineal glands and should allow investigations of neuronal or hormonal control of pineal gland activities.

Animals↗

PubMed2003

Bidirectional communication between the pineal gland and the immune system.

The pineal gland is a vertebrate neuroendocrine organ converting environmental photoperiodic information into a biochemical message (melatonin) that subsequently regulates the activity of numerous target tissues after its release into the bloodstream. A phylogenetically conserved feature is increased melatonin synthesis during darkness, even though there are differences between mammals and birds in the regulation of rhythmic pinealocyte function. Membrane-bound melatonin receptors are found in many peripheral organs, including lymphoid glands and immune cells, from which melatonin receptor genes have been characterized and cloned. The expression of melatonin receptor genes within the immune system shows species and organ specificity. The pineal gland, via the rhythmical synthesis and release of melatonin, influences the development and function of the immune system, although the postreceptor signal transduction system is poorly understood. Circulating messages produced by activated immune cells are reciprocally perceived by the pineal gland and provide feedback for the regulation of pineal function. The pineal gland and the immune system are, therefore, reciprocally linked by bidirectional communication.

Animals↗

PubMed1990

Norepinephrine suppresses both photoreceptor and neuron-like properties expressed by cultured rat pineal glands.

Our previous study showed that pineal glands of the newborn rat express properties of both photoreceptors and endocrine cells, when transferred to cell culture conditions, whereas opsin was not detected in cells of the intact pineal glands of the postnatally developing or mature rats (Araki et al., 1988). In the present study we asked a question why photoreceptor-like cells do not differentiate in vivo, although the pineal cells have the potency as revealed in cell culture conditions. Our hypothesis was that norepinephrine (NE) may suppress the differentiation of cells with photoreceptor properties. This was proved by adding NE into the culture medium, and only few opsin-like immunoreactive cells, if any, were differentiated in the presence of 10(-6) M NE. NE also suppresses the extension of neurite-like processes by serotonin-like immunoreactive (endocrine) cells, another property expressed in cultures. Other aminergic neurotransmitters, such as dopamine and serotonin, did not have such effects. These results imply that the massive innervations of the pineal gland by the sympathetic ganglion may suppress both photoreceptor and neuron-like properties of the mammalian pineal gland in vivo.

Animals↗

PubMed2001

Distribution of growth associated protein (GAP-43) immunoreactivity in nerve fibers supplying the pig pineal gland.

An immunohistochemical study of the pig pineal gland was carried out using monoclonal mouse antiserum against growth-associated protein GAP-43. The pineal glands were obtained from the 3, 5, 8 weeks old piglets. The immunopositive nerve fibers were observed in the pineal gland as well as in the habenular and the posterior comissural areas. They formed a dense network in the habenular area and the proximal part of the pineal gland. In the comissural area and in the apical part of the gland. single positive fibers were observed. The obtained results may suggest a difference in the plasticity of innervation between the particular regions of the pineal gland.

Animals↗

PubMed1992

Somatostatin and prosomatostatin immunoreactive nerve fibers in the bovine pineal gland.

An immunohistochemical study of the bovine pineal gland was performed by using polyclonal rabbit antisera raised against synthetic peptide fragments corresponding to the amino acid sequences of somatostatin-14, somatostatin-28, somatostatin-28 (1-12), and prosomatostatin (20-36). Immunoreactive nerve fibers were demonstrated in the pineal gland with all four antisera. The nerve fibers were located throughout the gland, both perivascularly and intraparenchymally, with the highest density of fibers in the proximal part, close to the pineal stalk. A number of immunoreactive nerve fibers were also found in the habenular area and stria medullaris projections. Some of the fibers in the stria medullaris projections could be followed into the pineal gland via the rostral part of the pineal stalk. A few immunoreactive nerve fibers were present in posterior commissure, in the subcommissural organ and pretectal area. Thus, the present study shows that the bovine pineal gland is innervated by nerve fibers containing all four sequences of prosomatostatin. The anatomical location of the somatostatin-immunoreactive nerve fibers in the bovine pineal gland indicates that the perikarya of some of these nerve fibers are located in the brain.

Animals↗

PubMed1999

Melatonin: an endogenous negative modulator of 12-lipoxygenation in the rat pineal gland.

Major biochemical activities of the pineal gland include melatonin biosynthesis and 12-lipoxygenation. In this paper, we provide evidence in vivo that melatonin regulates 12-lipoxygenation via 12-lipoxygenase (LOX) expression. The relationship between these two biochemical activities was established by monitoring levels of endogenous melatonin and a 12-LOX metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), in the rat pineal gland both during the light-dark cycle and after isoproterenol injection using GC/MS with negative ion chemical ionization. As pineal melatonin production reflected a typical diurnal variation, 12-HETE levels showed an off-phase diurnal pattern in relation to melatonin levels. Intravenous administration of isoproterenol, which has been shown to elevate melatonin production, decreased the 12-HETE level significantly. The reduction of 12-HETE levels during the dark phase and after isoproterenol injection was accompanied by decreases in 12-LOX mRNA and protein levels. Direct administration of melatonin to rats by intravenous injection decreased pineal 12-LOX protein levels significantly, indicating that melatonin plays a role in down-regulating 12-LOX expression. When pineal glands were incubated with exogenous melatonin in culture, time-dependent reduction of 12-LOX protein levels was observed. The melatonin-induced reduction in 12-LOX protein was abolished in the presence of the melatonin receptor antagonist luzindole, establishing further the role of melatonin in this process. Incubation of pineal homogenates with exogenous melatonin partially inhibited 12-LOX activity. Taken together, an inverse relationship exists in the endogenous production of 12-HETE, 12-LOX mRNA and protein with respect to melatonin production in the rat pineal gland. Melatonin decreased both 12-LOX mRNA and protein levels in addition to 12-LOX enzyme activity, indicating that melatonin is an endogenous modulator of pineal 12-lipoxygenation.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗