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Delta-sleep-inducing peptide and two of its analogs reduce nocturnal increase of N-acetyltransferase activity in rat pineal gland.

Serotonin N-acetyltransferase, an enzyme of the pineal gland, converts serotonin to N-acetylserotonin. The activity of this enzyme is induced by norepinephrine in the evening to reach high levels during the dark phase. Delta-sleep-inducing peptide, a humoral sleep factor, also seems to affect circadian rhythms. Intravenous injection of this peptide or either of two of its analogs in the evening significantly reduced the increase of N-acetyltransferase 4 h later. The dose-response relationship of the peptides showed an inverted U-shaped pattern with the active dose about 30 nmol/kg. The effect appears to be dependent on the time of day of administration, as injections in the morning did not change the enzymatic activity. These findings indicate that delta-sleep-inducing peptide (and two of its analogs) can affect enzymatic activities and that these influences probably vary throughout a time period of 24 h.

Acetyltransferases↗

Inverse correlation between "synaptic" ribbon number and the density of adrenergic nerve endings in the pineal gland of various mammals.

The number of "synaptic" ribbons was inversely correlated with the density of the adrenergic nerve endings of the pineal gland compared among a diverse group of species including the fox, cat, rat, cotton rat, white-footed mouse, Djungarian hamster, ground squirrel, and chipmunk. The concentration of norepinephrine paralleled the number of adrenergic nerve terminals in the pineal glands of the cotton rat, rat, and ground squirrel, the only species in which norepinephrine concentrations were measured. The number of ribbon fields paralleled numbers of "synaptic" ribbons in all species examined. Adrenergic nerve endings were observed primarily within the perivascular spaces, although some endings also were found among parenchymal cells. Adrenergic nerve endings forming synaptic junctions with pinealocytes were not observed in any of these species, nor was there any physical association between these nerve endings and "synaptic" ribbons.

Animals↗

Identification of A and B forms of monoamine oxidase in the iris-ciliary body, superior cervical ganglion, and pineal gland of albino rabbits.

The properties of monoamine oxidase activity in homogenates of the iris-ciliary body, superior cervical ganglion, and pineal gland of albino rabbits have been studied. Inhibition curves using specific inhibitors support the concept of A and B enzyme forms, with the following ratios of A/B activity: iris-ciliary body, 40/60; superior cervical ganglion, 90/10; pineal gland, 13/87. Experiments on enzymes from animals with superior cervical ganglionectomy indicate that both A and B forms in the iris-ciliary body have a predominantly extraneuronal location. No significant differences in activity were observed between iris-ciliary body preparations from normal and denervated animals with substrates specific for A or B forms, or with substrates deaminated by both A and B forms. With tryptamine as substrate the iris enzyme can be inhibited by a variety of common monoamine oxidase inhibitors. Topical application of the inhibitor pargyline lowers intraocular pressure in the normal rabbit eye but not in the sympathetically denervated eye. This observation and in vitro data suggest that the mechanism of action of pargyline is through the adrenergic system and not dependent upon intrinsic activity.

Animals↗

Lysosomal enzyme activities are decreased in the retina and their circadian rhythms are different from those in the pineal gland of rats fed an alpha-linolenic acid-restricted diet.

The retinal rod outer segment (ROS) is shed and digested daily by phagosomes in retinal pigment epithelial (RPE) cells. We previously observed significantly fewer large phagosomes in rats fed an alpha-linolenic acid (ALNA)-deficient diet. Rats fed a safflower oil diet (ALNA-restricted) or a perilla oil diet (ALNA-sufficient) through two generations were adapted to a 24-h cycle with light from 0700 to 1900 h. They were killed at 0500, 0900, 1300 and 1700 h to determine the activities of four lysosomal enzymes in retina, including beta-glucosidase, beta-glucuronidase, hexosaminidase and acid phosphatase. The enzyme activities at 0500 h were the lowest and then increased gradually until 1700 h, exhibiting similar circadian rhythms in the two dietary groups. However, the activities at each time point were significantly lower in the safflower group. In the pineal gland, the activities were maximum at 1300 h, except for beta-glucosidase, and were not different between groups. These diets had qualitatively similar but quantitatively different effects on the fatty acid compositions of the retina and the pineal gland. These results indicate that decreased amplitudes in electroretinogram and altered size distribution of phagosomes, as induced by a restricted intake of ALNA, are associated with decreased lysosomal enzyme activities in the retina but not in the pineal gland.

Acid Phosphatase↗

The influence of the pineal gland on migraine and cluster headaches and effects of treatment with picoTesla magnetic fields.

For over half a century the generally accepted views on the pathogenesis of migraine were based on the theories of Harold Wolff implicating changes in cerebral vascular tone in the development of migraine. Recent studies, which are based on Leao's concept of spreading depression, favor primary neuronal injury with secondary involvement of the cerebral circulation. In contrast to migraine, the pathogenesis of cluster headache (CH) remains entirely elusive. Both migraine and CH are cyclical disorders which are characterised by spontaneous exacerbations and remissions, seasonal variability of symptoms, and a relationship to a variety of environmental trigger factors. CH in particular has a strong circadian and seasonal regularity. It is now well established that the pineal gland is an adaptive organ which maintains and regulates cerebral homeostasis by "fine tuning" biological rhythms through the mediation of melatonin. Since migraine and CH reflect abnormal adaptive responses to environmental influences resulting in heightened neurovascular reactivity, I propose that the pineal gland is a critical mediator in their pathogenesis. This novel hypothesis provides a framework for future research and development of new therapeutic modalities for these chronic headache syndromes. The successful treatment of a patient with an acute migraine attack with external magnetic fields, which acutely inhibit melatonin secretion in animals and humans, attests to the importance of the pineal gland in the pathogenesis of migraine headache.

Adult↗

Effects of near-ultraviolet light on the nocturnal serotonin N-acetyltransferase activity of rat pineal gland.

Effects of near-ultraviolet (UV-A; 325-390 nm, peak at 365 nm) light on the activity of the pineal serotonin N-acetyltransferase (NAT; a penultimate and key regulatory enzyme in melatonin biosynthesis) were examined in rats. Acute exposure of dark-adapted animals to UV-A radiation produced a marked suppression of NAT activity of the pineal gland, the effect being dependent on exposure time. The decrease in the night-time NAT activity evoked by a 1-min pulse of UV-A light (as well as by a 15-s pulse of broad-band visible light) gradually deepened during the first 40 min of treatment of animals with constant darkness, then the enzyme activity began to rise reaching control values by 3 h. Treatment of rats with a protein synthesis inhibitor, cycloheximide, attenuated this night-driven reactivation of the pineal NAT activity. The presented results provide evidence that UV-A light is a powerful signal capable of controlling melatonin biosynthesis in rat pineal gland.

Animals↗

Gas chromatographic analysis of free amino acids in the hyaloplasm of the hypophysis, pineal gland, thyroid gland, spinal cord, thymus and lymph nodes of the cow.

Studies of the qualitative and quantitative composition of free amino acids in the hyaloplasm of the hypophysis, pineal gland, thyroid gland, spinal cord, thymus and lymph nodes of the cow are described. The following findings are reported: the highest levels of alanine, valine, glycine, isoleucine, histidine, leucine, threonine, serine, phenylalanine, tyrosine and lysine are found in the thyroid gland, methionine and aspartic acid in the spinal cord, tryptophan and hydroxyproline in the pineal gland, and proline and glutamic acid in the thymus gland. The highest level by weight is that of glutamic acid in all tissues. The presence of alpha-aminobutyric acid combined with sarcosine and 4-aminoisobutyric acid with 2-AOA and citrulline with cystine was demonstrated. alpha-Aminoisobutyric acid and isovaline were found in the spinal cord.

Amino Acids↗

Adenosine effects on the rat pineal gland in vitro: cyclic adenosine monophosphate levels, N-acetyltransferase, and thyroxine type II 5'-deiodinase activities and melatonin production.

The presence of adenosine and its receptors in the pineal gland suggests that they could have a regulatory influence on pineal physiology. Rat pineal glands cultured in the presence of the adenosine analog 5'-N-ethylcarboxamido adenosine (NECA) promoted a significant increase in pineal adenosine 3'5'-monophosphate (cAMP) content, similar to that caused by the beta-adrenergic receptor agonist isoproterenol (ISO). A potentiation of the cAMP response occurred when the glands were simultaneously stimulated with both NECA and ISO. Whereas high cAMP levels induced by ISO were associated with an increased N-acetyltransferase (NAT) activity and rise in the melatonin production and release, the NECA-induced rise in cAMP concentration failed to promote an increase in the activity of either NAT or another pineal enzyme thyroxine 5'-deiodinase type II; likewise, pineal melatonin levels did not rise.

Adenosine↗

Effects of photoperiod, melatonin, and the pineal gland on compensatory gonadal hypertrophy during postnatal development in the marsh rice rat (Oryzomys palustris).

The roles of photoperiod, melatonin, and the pineal gland in regulating the magnitude of compensatory gonadal hypertrophy (CGH) and other reproductive and non-reproductive organ growth during post-weaning development were examined in the marsh rice rat Oryzomys palustris. Juvenile rice rats of both sexes were left gonadally intact (control group) or unilaterally castrated (ULC) and housed on 12L:12D, 14L:10D, or 16L:8D. Within a photoperiod (14L:10D and 16L:8D, but not 12L:12D), growth of the remaining testis, but not the remaining ovary, as well as several additional organs in both sexes were significantly affected, suggesting that the compensatory hypertrophy of the testis is photoperiod-dependent. There was no effect of testis asymmetry on CGH as ULC of either testis in rice rats housed on 14L:10D resulted in a comparable increase of CGH. Melatonin implants in rice rats maintained on 16L:8D had little to no effect (CGH included) on most parameters examined. Both melatonin implants and pinealectomy (separate experiments) in rice rats transferred to 12L:12D prevented short photoperiod-induced effects on CGH, the growth of the reproductive organs and the Harderian glands. Evening melatonin injections had a significant inhibitory effect on the growth of the remaining testis (no CGH was observed) and all other parameters measured. Lastly, ULC did not alter the percentage of males which successfully mated compared to intact animals. Taken together, these data suggest that photoperiod, melatonin, and the pineal gland can affect and regulate reproductive (e.g., CGH in some cases) and non-reproductive growth during postnatal development in the marsh rice rat.

Animals↗

Effects of either forskolin, the 1,9-dideoxy derivative of forskolin, or 8-bromocyclic AMP on cyclic AMP and melatonin production in the Syrian hamster pineal gland in organ culture.

The possible involvement of cyclic AMP in the regulation of melatonin production was investigated in cultured Syrian hamster pineal glands. Addition of forskolin, an adenylate cyclase activator, to the incubation medium caused marked increases in both cyclic AMP and melatonin levels in glands collected in the second half of the dark period. 8-Bromocyclic AMP, an analogue of cyclic AMP, also increased melatonin production. The 1,9-dideoxy derivative of forskolin, which is unable to activate the cyclase, was ineffective in stimulating either cyclic AMP levels or melatonin production. These results support a primary role for cyclic AMP in the nocturnal increase of melatonin production in the Syrian hamster pineal gland.

8-Bromo Cyclic Adenosine Monophosphate↗

Purinergic and noradrenergic cotransmission in the rat pineal gland.

ATP is coreleased with noradrenaline in several noradrenergic synapses, and P2-like receptors were shown to be present in rat pineal glands. A new method of functional investigation was developed to assess the importance of both transmitters (noradrenaline and ATP) in eliciting the synthesis of melatonin and its precursor N'-acetyl-5-hydroxytryptamine (N'-acetyl-5-HT) through transmural electrical field stimulation of cultured pineal glands. Incubation with the beta-adrenoceptor antagonist propranolol (>10(-7) M) blocked almost completely the production of N'-acetyl-5-HT, whilst the P2 receptor antagonists pyridoxalphosphate-6 azophenyl-2',4'-disulfonic acid (PPADS, >3x10(-6) M) and suramin (>10(-6) M) blocked it partially. These findings indicate a physiologically relevant role for the purinergic cotransmission in this system.

Adenosine Triphosphate↗

The pineal gland in wild-type and two zebrafish mutants with retinal defects.

Light and transmission electron microscopy were used to characterize the ultrastructural features of the pineal glands of wild-type and two mutant zebrafish strains that have retinal defects. Particular attention was given to the pineal photoreceptors. Photoreceptors in the pineal gland appear quite similar to retinal cone photoreceptors, having many of the same structural characteristics including outer segment disk membranes often confluent with the plasma membrane, calycal processes surrounding the outer segments, and classic connecting cilia. The pineal photoreceptor terminals differ from photoreceptor terminals in the retina in that they have short synaptic ribbons and make dyad synapses which may or may not be invaginated. Pineal photoreceptors in two zebrafish mutants with abnormal retinal photoreceptors were also studied. Pineal photoreceptors in the niezerka (nie) mutant degenerate, as they do in the retina, indicating that pineal and retinal photoreceptors share at least some genes. However, the synaptic terminals of no optokinetic response c (nrc) pineal photoreceptors are normal, suggesting that this mutation is specific to the retina.

Animals↗

Large glial cyst of the pineal gland: a possible growth mechanism. Case report.

The authors report on a patient who presented with a large symptomatic glial cyst of the pineal gland communicating with the third ventricle. The hole between the ventricle and the cyst, suspected on magnetic resonance images, was found at surgery. The to-and-fro flow mechanism is considered to be involved in the pathogenesis of growth in this unusual large glial cyst of the pineal gland, although this mechanism cannot be applied universally.

Adult↗

The role of pineal gland in circadian rhythms regulation.

In the presented article we try to find a synthesis of the current knowledge on circadian rhythms. We pick up the most prominent oscillations in human physiology and review the current knowledge of their regulation. Circadian oscillations in the parameters of internal environment are driven by the pineal gland. A biochemical pathway in the pineal transforms tryptophan through serotonin to the final product--the indolamine melatonin. Its plasma level is high at night and low during the day. Melatonin, easily penetrating through biological barriers, thus carries phase of day information to all peripheral tissues. Light exposure of retina alters (via neural pathways connecting retina to pineal gland) the amount of serotonin metabolized to melatonin. This physiological mechanism of adjustment of the endogenous clock to the solar day can be altered in some circumstances, leading to pathologic symptoms. The best known diseases caused by breakdown in circadian regulation are seasonal affective disorders and jet-lag syndrome. (Fig. 2, Ref. 71.)

Circadian Rhythm↗

'Synaptic' bodies in the pineal glands of the cow, sheep and pig.

The present results show that 'synaptic' bodies (SB) are a heterogeneous group of organelles in the pineal glands of Artiodactyla. Basically, rod-like (ribbons) and sphere-like (spherules) SB can be distinguished. In the pig small numbers of both 'synaptic' ribbons (SR) and 'synaptic' spherules (SS) are found. In bovine and ovine pineal glands few SS but no SR were seen. The same results were obtained from animals of the same species but from different continents. This suggests that the numbers of SB are species specific rather than influenced by the different lighting conditions in Europe and in equatorial Africa.

Africa↗

Time of origin of the rat pineal gland cells. A bromodeoxyuridine immunohistochemical study.

The immunohistochemical detection of bromodeoxyuridine (BrdU) was used to study the time of origin of the cells in the pineal gland of the rat. A study was made involving 17 groups of 4 rats each, administered with a single dose of bromodeoxyuridine (BrdU, 25 mg/kg) in 7 phases of the embryonic period (E15 to E21) and in 10 postnatal phases (between P0 and P30), followed by determination in each rat of the number of visible immune-labeled cells in the pineal gland 60 days after birth. The results show that approximately 60% of the pineal cells underwent the last division(s) prior to differentiation in the prenatal period between E18 and E21. The rest of the pineal cells originated after birth, particularly in the first 5 postnatal days.

Animals↗

Regional heterogeneity in immunoreactive macrophages/microglia in the rat pineal gland.

Using specific macrophage antibodies (OX-42, OX-6, ED-1 and ED-2), this study examined the distribution of macrophages/microglia in the pineal gland of adult rats. Except for ED-2, all antibodies labeled distinct subpopulations of macrophages/microglia in the gland; ED-2 labeling was hardly detectable. The quantitative study showed that the pineal macrophages/microglia (PMM) expressing complement type 3 receptors (OX-42) were more numerous than those expressing the major histocompatibility complex class II antigen (OX-6) or unknown cytoplasmic/lysosomal antigens (ED-1). The PMM were ubiquitous, especially the OX-42 labeled cells which were distributed from the dorsal to the ventral aspect of the gland. The macrophages/microglia labeled with OX-6 or ED-1 were localized mainly in the intermediate portion of the pineal gland. Immunolabeled cells were sparsely distributed in the distal portion of the pineal gland. A notable feature was that the OX-6 labeled macrophages/microglia showed a proximal-distal gradient in cell density. Another interesting feature was the occurrence of prominent cell aggregations around the larger blood vessels. These cells were mostly round and exhibited different immunoreactivity. Confocal microscopic study with triple immunolabeling further revealed that individual PMM cell possessed two or more different antigens (ED-1+/OX-6+, OX-42+/OX-6+ or OX-42+/ED-1+). Remarkably, a large population co-expressed ED-1+/OX-6+/OX-42+. The present results show that the expression of immunoreactive molecules in PMM varies in topographical distribution of the cells. It is suggested that this may be linked to their immunoregulatory functions in the gland.

Animals↗

Variation of melatonin and serotonin content in rat pineal gland with sex and oestrous phase difference determined by high-performance liquid chromatography with fluorimetric detection.

Simultaneous determination of melatonin and serotonin in rat pineal gland is described using reversed-phase high-performance liquid chromatography with fluorimetric detection. These indoles were analysed isocratically within 15 min. In this work, veratric acid (3,4-dimethoxybenzoic acid), which has fluorescence characteristics (lambda ex = 290 nm, lambda em = 350 nm) around the wavelength of native fluorescence of melatonin (lambda ex = 285 nm, lambda em = 345 nm), was used as an internal standard. This method was applied to the determination of melatonin and serotonin in male and female rat pineal gland. No significant differences between the two groups were observed in the pineal melatonin and serotonin contents. The pineal melatonin and serotonin contents were compared with the oestrous and the di-oestrous phases of female rats. They were not widely different from each other.

Animals↗