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Pineal Gland Abstracts: 2004

Note: the following is a limited selection of abstracts available at PubMed, Science Direct, and Toxnet.

Abstracts on the Pineal Gland by Year
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2005
(Jan-June)
2004
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http://news.independent.co.uk/uk/health_medical/story.jsp?story=535733

The Independent (UK)

28 June 2004

Watching TV 'blocks sleep hormone in children'

By Philip Willan in Rome

Exposure to television can influence melatonin levels in children and possibly contribute to the premature onset of puberty, according to a study by scientists from the University of Florence.

The study found a 30 per cent increase in levels of the sleep-regulating hormone in children who had abstained from watching television for a week, the Rome daily La Repubblica reported yesterday.

The findings are based on a study of 74 children from the Tuscan town of Cavriglia who volunteered to forego television, video games and computers for a week last month in the interests of science. Aged between six and 12, the children normally watched an average of three hours' television a day. Urine samples taken at the beginning and end of the experiment showed a significant rise in melatonin levels, particularly among the younger children, by the end of the television-less week. As well as blacking out the video screens, parents were asked to reduce the intensity of artificial lighting in their homes during the experiment.

Melatonin is a hormone produced by the pineal gland, a pea-sized organ just above the middle of the brain. Exposure to light during the day inhibits its production, which normally begins around 9pm, with rising levels of melatonin in the blood making people feel sleepy. Scientists are less certain about the role of the hormone in regulating the onset of puberty, an issue the Florence researchers intend to pursue. In Western societies, the arrival of puberty has advanced by about a year since the 1950s, when television became common.


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15308302

Neurosci Lett. 2004 Aug 26;367(1):79-84.

Vesicular inhibitory amino acid transporter is expressed in gamma-aminobutyric acid (GABA)-containing astrocytes in rat pineal glands.

Echigo N, Moriyama Y.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tshushima-naka, Okayama 700-8530, Japan.

gamma-Aminobutyric acid (GABA) is an inhibitory amino acid and acts as an intercellular transmitter in the central nervous system and peripheral tissues. In pineal glands, GABA is supposed to be a paracrine-like modulator of secretion of melatonin, although its mode of action, especially the sites of GABA signal appearance, is unknown. Vesicular inhibitory amino acid transporter (VIAAT) is a potential marker for the GABAergic phenotype. Here we presented evidence that VIAAT is expressed in GFAP-expressing astrocytes and a subpopulation of OX42-expressing microglia, but not in pinealocytes in cultured cells of rat pineal glands. The VIAAT-expressing cells also exhibit GABA immunoreactivity. Essentially the same results were obtained for pineal glands. These results suggest that GABA is stored and secreted from astrocytes and a subpopulation of microglia in pineal glands.

PMID: 15308302 [PubMed - in process]


August 5, 2004
Register News, Burlington County NJ 08505
http://www.zwire.com/site/news.cfm?BRD=1091&dept_id=456077&newsid=12620973&PAG=461&rfi=9

Golf tourney
   Thursday, Aug. 19 — Friends of Jenna Golf Tournament will begin with a shotgun start at 12:30 p.m. at the Gambler Ridge Golf Club, Burlington Path Road, Cream Ridge. Cost is $95 per golfer and the deadline is Monday, Aug. 16. Hole sponsorship is available for $125.
   Proceeds will help defray medical expenses for Fieldsboro/Bordentown resident Jenna Carroll, 15, who has been fighting an illness for about 18 months. She was recently diagnosed with a rare cancer (pineal) which affects the lining of her brain and spine. This illness has left her legally blind and as a result of her recent surgery she has to learn how to walk again. Jenna will go through chemotherapy and faces more surgeries.
   Call Jean or Phil Horner at 298-1393 for details or e-mail mommadukes716@aol.com.


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15364404

Neurosci Lett. 2004 Sep 30;368(3):243-8.

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.

Vazquez Moreno N, Debeljuk L, Diaz Rodriguez E, Fernandez Alvarez C, Diaz Lopez B.

Dpto. Biologia Funcional, Area Fisiologia, Facultad de Medicina, Universidad de Oviedo, C/Julian Claveria 6, 33006 Oviedo, Spain.

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.

PMID: 15364404 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15350827

Life Sci. 2004 Sep 24;75(19):2291-302.

The profile of melatonin production in tumour-bearing rats.

Ferreira AC, Martins E Jr, Afeche SC, Cipolla-Neto J, Costa Rosa LF.

Laboratory of Metabolism, Department of Histology and Embryology, University of Sao Paulo, Brazil.

The pineal gland is involved in the regulation of tumour growth through the anticancer activity of melatonin, which presents immunomodulatory, anti-proliferative and anti-oxidant effects. In this study we measured melatonin content directly in the pineal gland, in an attempt to clarify the modulation of pineal melatonin secretory activity during tumour growth. Different groups of Walker 256 carcinosarcoma bearing rats were sacrificed at 12 different time points during 24h (12h:12h light/dark cycle) on different days during the tumour development (on the first, seventh and fourteenth day after tumour inoculation). Melatonin content in the pineal gland was determined by high-performance liquid chromatography with electrochemical detection. During tumour development the amount of melatonin secreted increased from 310.9 ng/mg of protein per day from control animals, to 918.1 ng/mg of protein per day 14 days after tumour implantation, and there were changes in the pineal production profile of melatonin. Cultured pineal glands obtained from tumour-bearing rats turned out to be less responsive to noradrenaline, suggesting the existence, in vivo, of putative factor(s) modulating pineal melatonin production. The results demonstrated that during tumour development there is a modification of pineal melatonin production daily profile, possibly contributing to cachexia, associated to changes in pineal gland response to noradrenaline stimulation.

PMID: 15350827 [PubMed - in process]

Note from FAN:
Definition of Cachexia - A profound and marked state of constitutional disorder, general ill health and malnutrition. The loss of body weight and muscle mass frequently seen in patients with advanced diseases. Synonyms: cachexy, wasting


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15349080

Neuro Endocrinol Lett. 2004 Jun;25(3):173-5.

Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis?

Dickerman RD, Stevens QE, Steide JA, Schneider SJ.

Department of Neurosurgery, North Shore University-Long Island Jewish Medical Center, New Hyde Park, NY 11004, USA. drrdd@yahoo.com

Accelerated development of secondary sexual characteristics or sexual precocity is a well-known entity. Most authors recognize two groups of patients, those described as having central precocious puberty (CPP) and those with precocious pseudopuberty. CPP results from premature activation of the hypothalamic-pituitary-gonadal axis and pseudopuberty is caused by lesions that secrete gonadotropin-like substances or hormones. The onset of CPP is usually before age 8 in females and age 9 in males; however, there is contention that the age of onset is much earlier and also differs depending on the patients' race. Previously reported causes of CPP include intracranial neoplasm, infection, trauma, hydrocephalus and Angelman's syndrome. Pineal cysts are usually asymptomatic incidental findings, but have been associated with CPP. We present an interesting case of a patient with CPP and an associated pineal cyst. We review the literature on the pathogenesis of CPP and associated pineal cyst, the neuroendocrine relationship between the pineal gland and puberty and the neurosurgical role in these cases.

PMID: 15349080 [PubMed - in process]

 

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15681810

Ann N Y Acad Sci. 2004 Dec;1035:216-30.
 
Melatonin, metals, and gene expression: implications in aging and neurodegenerative disorders.

Lahiri DK, Chen D, Lahiri P, Rogers JT, Greig NH, Bondy S.

Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202. dlahiri@iupui.edu.

Melatonin is a hormone secreted by the pineal gland, mostly in the dark period of the light/dark cycle, with corresponding fluctuations reflected in the plasma melatonin levels. This hormone plays a critical role in the regulation of various neural and endocrine processes that are synchronized with daily change in photoperiod. Abnormal melatonin levels are associated with metabolic disturbances and other disorders. Melatonin potentially plays an important role in aging, prolongation of life span, and health in the aged individual. It may exert a beneficial action on neurodegenerative conditions in those with debilitating diseases. It interacts with metals and, in some cases, neutralizes their toxic effects. Levels of melatonin decrease with aging in mice. Its dietary supplementation has recently been shown to result in a significant rise in levels of endogenous melatonin in serum as well as all other tissue samples tested. The effects of dietary melatonin have been studied in the brain of mice with regard to nitric oxide synthase, synaptic proteins, and amyloid beta peptides (Abeta), which are involved in amyloid deposition and plaque formation in Alzheimer's disease (AD). Melatonin supplementation has no significant effect on cerebral cortical levels of nitric oxide synthase or synaptic proteins, such as synaptophysin and SNAP-25. Notably, however, elevated brain melatonin levels resulted in a significant reduction in levels of toxic cortical Abeta of both 40- and 42-amino-acid forms. Taken together, these results suggest that dietary melatonin supplementation may slow the neurodegenerative changes associated with brain aging and that the depletion of melatonin in the brain of aging mice may, in part, account for this adverse change.

PMID: 15681810 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15589268

Front Neuroendocrinol. 2004 Sep;25(3-4):177-95.
 
Human pineal physiology and functional significance of melatonin.

Macchi MM, Bruce JN.

New York State Psychiatric Institute, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, Unit 50, New York, NY 10032, United States.

Descriptions of the pineal gland date back to antiquity, but its functions in humans are still poorly understood. In both diurnal and nocturnal vertebrates, its main product, the hormone melatonin, is synthesized and released in rhythmic fashion, during the dark portion of the day-night cycle. Melatonin production is controlled by an endogenous circadian timing system and is also suppressed by light. In lower vertebrates, the pineal gland is photosensitive, and is the site of a self-sustaining circadian clock. In mammals, including humans, the gland has lost direct photosensitivity, but responds to light via a multisynaptic pathway that includes a subset of retinal ganglion cells containing the newly discovered photopigment, melanopsin. The mammalian pineal also shows circadian oscillations, but these damp out within a few days in the absence of input from the primary circadian pacemaker in the suprachiasmatic nuclei (SCN). The duration of the nocturnal melatonin secretory episode increases with nighttime duration, thereby providing an internal calendar that regulates seasonal cycles in reproduction and other functions in photoperiodic species. Although humans are not considered photoperiodic, the occurrence of seasonal affective disorder (SAD) and its successful treatment with light suggest that they have retained some photoperiodic responsiveness. In humans, exogenous melatonin has a soporific effect, but only when administered during the day or early evening, when endogenous levels are low. Some types of primary insomnia have been attributed to diminished melatonin production, particularly in the elderly, but evidence of a causal link is still inconclusive. Melatonin administration also has mild hypothermic and hypotensive effects. A role for the pineal in human reproduction was initially hypothesized on the basis of clinical observations on the effects of pineal tumors on sexual development. More recent data showing an association between endogenous melatonin levels and the onset of puberty, as well as observations of elevated melatonin levels in both men and women with hypogonadism and/or infertility are consistent with such a hypothesis, but a regulatory role of melatonin has yet to be established conclusively. A rapidly expanding literature attests to the involvement of melatonin in immune function, with high levels promoting and low levels suppressing a number of immune system parameters. The detection of melatonin receptors in various lymphoid organs and in lymphocytes suggests multiple mechanisms of action. Melatonin has been shown to be a powerful antioxidant, and has oncostatic properties as well, both direct and indirect, the latter mediated by its effects on reproductive hormones. Finally, there are reports of abnormal daily melatonin profiles in a number of psychiatric and neurological disorders, but the significance of such abnormalities is far from clear.

PMID: 15589268 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15580172

Neuro Endocrinol Lett. 2004 Oct;25(5):368-72.

The hypothalamic-pituitary-thyroid axis and melatonin in humans: possible interactions in the control of body temperature.

Mazzoccoli G, Giuliani A, Carughi S, De Cata A, Puzzolante F, La Viola M, Urbano N, Perfetto F, Tarquini R.

Department of Internal Medicine, Regional General Hospital Casa Sollievo della Sofferenza, Opera di Padre Pio da Pietrelcina, Cappuccini Av., 71013 S.Giovanni Rotondo (FG), Italy.

OBJECTIVE: Melatonin plays a role in the regulation of biological rhythms, body temperature presents circadian variations with lower levels during nighttime, when melatonin levels are very high, and thyroid hormones influence shiver independent thermogenesis. We have investigated on possible interactions between the hypothalamic-pituitary-thyroid axis and melatonin in the control of body temperature in humans.

METHODS: Peripheral blood samples for thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), free-thyroxine (FT4), melatonin levels determination and body temperature measurements were obtained every four hours for 24-hours starting at 0600 h in a controlled temperature and light-dark environment from ten healthy males, aged 38-65 (mean age +/-s.e. 57.4+/-3.03, mean body mass index +/-s.e. 25.5+/-0.75). We calculated fractional variation and correlation on single time point hormone serum levels and tested whether the time-qualified data series showed consistent pattern of circadian variation.

RESULTS: A statistically significant difference was evidenced for the fractional variation of daytime TSH serum levels (0600 h-1000 h vs. 1000 h-1400 h, p=0.01, 1000 h-1400 h vs. 1400 h-1800 h, p=0.0001, 1400 h-1800 h vs. 1800 h-2200 h, p=0.001) and for the fractional variation of FT4 serum levels at 1800 h-2200 h vs. 2200 h-0200 h (p=0.02). FT4 serum levels correlated positively with TRH serum levels at 1000 h (r=0.67, P=0.03) and at 1400 h (r=0.63, p=0.04), negatively with TSH serum levels at 2200 h (r=-0.67, p=0.03), negatively with melatonin serum levels at 2200 h (r=-0.64, p=0.04) and at 0200 h (r=-0.73, p=0.01). TRH serum levels correlated positively with TSH serum levels at 0200 h (r=0.65, p=0.04) and at 0600 h (r=0.64, p=0.04). Body temperature correlated positively with FT4 serum levels at 1000 h (r=0.63, p=0.04) and negatively with melatonin serum levels at 0200 h (r=-0.64, p=0.04). A clear circadian rhythm was validated for body temperature (with acrophase in the morning) and melatonin, TRH and TSH secretion (with acrophase at night), while FT4 serum level changes presented ultradian periodicity (with acrophase in the morning).

CONCLUSION: Changes of TSH serum levels are smaller and those of FT4 are greater at night, when melatonin levels are higher, so that the response of anterior pituitary to hypothalamic TRH and of thyroid to hypophyseal TSH may be influenced by the pineal hormone that may modulate the hypothalamic-pituitary-thyroid axis function and influence the circadian rhythm of body temperature.

PMID: 15580172 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15597771

J Neurosurg. 2004 Dec;101(6):1061-4.

Primary extraskeletal osteosarcoma in the pineal region. Case report.

Saesue P, Chankaew E, Chawalparit O, Na Ayudhya NS, Muangsomboon S, Sangruchi T.

Division of Neurosurgery, Department of Surgery, Siriraj Hospital, Mahidol University, Bangkok, Thailand. sipas@mucc.mahidol.ac.th

Primary extraskeletal osteosarcoma occurring in the brain parenchyma is distinctly uncommon, with only five cases having been reported. The authors describe the case of a 45-year-old man who presented with progressive headache and diplopia. Computerized tomography scanning and magnetic resonance imaging results revealed a pineal region tumor with obstructive hydrocephalus. The patient underwent partial resection of the tumor. The histological examination showed large pleomorphic tumor cells embedded in osteoid matrix. Immunohistochemical analysis was negative for various antibodies and thus excluded a glial, germ cell, epithelial, and lymphoid tumor origin. Only vimentin showed strong positivity in most of the tumor cells. Ultrastructurally, the tumor cells were rich in dilated rough endoplasmic reticula. Clear zones between tumor cells and osteoid matrix were observed. The osteoid matrix was made up of small collagen fibrils and hydroxyapatite deposits. The tumor was not attached to the bone structure of the skull. These findings are consistent with the features of extraskeletal osteosarcoma. Data from complete medical and radiological studies excluded a metastatic origin for this tumor. Partial resection and postoperative radiotherapy had provided tumor control at 11 months after the onset of symptoms. This is the first reported case of a primary extraskeletal osteosarcoma occurring in the pineal region.

PMID: 15597771 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15605771

Vopr Onkol. 2004;50(4):454-8.

[Diethylstilbestrol-induced uterine sarcoma in mice]

[Article in Russian]

[No authors listed]

Female mice of CBA strain received diethylstilbestrol (DES) 1 g body weight intraperitoneally. High incidence of histiocytic uterine sarcoma was observed in parents (25%), first generation (F1), descendants (10.9%), and generation F2m (through F1 males mated with females in control) (17.8%). Morphologically, tumor cells examined through light and electron microscopy were referred to as histiocyte-like elements. Half of the animals had metastases in the liver, kidneys, lungs, spleen, pineal and adrenal glands and stomach. The development of tumors in generation F2m, which was not exposed to DES, might be accounted for by "transgeneration" carcinogenesis, i.e. passage of carcinogenic effect through a generation.

PMID: 15605771 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15581421

Curr Drug Targets CNS Neurol Disord. 2004 Dec;3(6):515-33.

The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia.

Benitez-King G, Ramirez-Rodriguez G, Ortiz L, Meza I.

Instituto Nacional de Psiquiatria, Departamento de Neurofarmacologia, Subdireccion de Investigaciones Clinicas, Mexico, D.F., Mexico. bekin@imp.edu.mx.

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.

PMID: 15581421 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15582681

Pharmacol Biochem Behav. 2004 Dec;79(4):733-7.
 
Melatonin inhibits the development of tolerance to U-50,488H analgesia via benzodiazepine-GABA(A)ergic mechanisms.

Dhanaraj E, Nemmani KV, Ramarao P.

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Phase-X, S.A.S. Nagar-160 062 (Pb), India.

Melatonin, a primary secretory product of pineal gland, is known to produce many of its pharmacological actions via benzodiazepine-gamma-aminobutyric acid(A) (GABA(A))ergic mechanisms. Recently, we showed that benzodiazepine-GABA(A)ergic mechanisms play an important role in U-50,488H (U50) analgesia and its tolerance. Hence, in the present study, the effect of melatonin on U50 analgesia and its tolerance was investigated. Furthermore, the possible role of benzodiazepine-GABA(A)ergic mechanisms in the actions of melatonin on U50 analgesia was investigated. All experiments were performed using the radiant tail-flick test for mice. Melatonin [0.2, 1 and 5 mg/kg, intraperitoneal (i.p.)] neither produced analgesia nor affected the acute U50 (40 mg/kg, i.p.) analgesia. Tolerance to U50 analgesia was induced by administering U50 (40 mg/kg, i.p.) twice daily over 6 days. Treatment with melatonin (1 and 5 mg/kg, i.p) 15 min prior to each dose of U50 inhibited the development of tolerance, whereas a low dose of melatonin (0.2 mg/kg, i.p.) did not. The inhibition of U50 tolerance by melatonin was reversed by the chronic treatment with flumazenil (0.1 mg/kg), a benzodiazepine receptor antagonist and picrotoxin (1 mg/kg), a GABA(A)-gated chloride channel blocker. Flumazenil and picrotoxin neither affected tail-flick latencies nor altered acute U50 analgesia and its tolerance. Interestingly, chronic 6-day melatonin treatment in a vehicle (U50-naive) group did not alter U50 analgesia measured on day 7. Together, these findings suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to U50 analgesia. The inhibition of U50 tolerance by melatonin was reversed by flumazenil and picrotoxin treatment, suggesting that benzodiazepine-GABA(A)ergic mechanisms play an important role in the development of tolerance to U50 analgesia and that melatonin inhibits the development of U50 tolerance via benzodiazepine-GABA(A)ergic mechanisms.

PMID: 15582681 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15616152

Drug Metab Dispos. 2004 Dec 22; [Epub ahead of print]
 
METABOLISM OF MELATONIN BY HUMAN CYTOCHROMES P450.

Ma X, Idle JR, Krausz KW, Gonzalez FJ.

National Cancer Institute.

In humans, the pineal hormone melatonin (MEL) is principally metabolized to 6-hydroxymelatonin (6-HMEL), which is further conjugated with sulfate and excreted in urine. MEL O-demethylation represents a minor reaction. The exact role of individual human cytochromes P450 in these pathways has not been established. We used a panel of 11 recombinant human P450 isozymes to investigate for the first time the 6-hydroxylation and O-demethylation of MEL. CYP1A1, CYP1A2 and CYP1B1 all 6-hydroxylated MEL, with CYP2C19 playing a minor role. These reactions were NADPH-dependent. CYP2C19, and to some extent CYP1A2, O-demethylated MEL. The Km (microM) and Vmax (kcat, pmol min-1 pmol-1 P450) for 6-hydroxylation were estimated as 19.2+/-2.01, 6.46+/-0.22 (CYP1A1); 25.9+/-2.47, 10.6+/-0.32 (CYP1A2); 30.9+/-3.76, 5.31+/-0.21 (CYP1B1). These findings confirm the suggestion of others that CYP1A2 is probably the foremost hepatic P450 in the 6-hydroxylation of MEL and a single report that CYP1A1 is also able to mediate this reaction. However, this is the first time that CYP1B1 has been shown to 6-hydroxylate MEL. The IC50 for the CYP1B1 selective inhibitor TMS was estimated to be 30 nM for MEL 6-hydroxylation by recombinant human CYP1B1. Comparison of brain homogenates from wild-type and cyp1b1-null mice, revealed that MEL 6-hydroxylation was clearly mediated to a significant degree by CYP1B1. CYP1B1 is not expressed in the liver but has a ubiquitous extrahepatic distribution and is found at high levels in tissues that also accumulate either MEL or 6-HMEL, such as intestine and cerebral cortex, where it may assist in regulating levels of MEL and 6-HMEL.

PMID: 15616152 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15608359

J Physiol Pharmacol. 2004 Jul;55 Suppl 2:33-46.
 
Modulation of pancreatic enzyme secretion by melatonin and its precursor: L-tryptophan. Role of CCK and afferent nerves.

Leja-Szpak A, Jaworek J, Nawrot-Porabka K, Palonek M, Mitis-Musiol M, Dembinski A, Konturek SJ, Pawlik WW.

Dept Med Physiol Faculty of Health Care, Jagiellonian University Collegium Medicum, Cracow, Poland. mpjawore@cyf-kr.edu.pl.

Melatonin, a pineal hormone, is also produced in the gastrointestinal tract. Melatonin receptors have been detected in the stomach, intestine and pancreas. This indole inhibits insulin secretion but its role in the physiological modulation of exocrine pancreatic function is yet unknown. The aim of this study was to evaluate the pancreatic secretory effect of melatonin and its precursor; L-tryptophan given intraduodenally (i.d.) to the conscious rats with intact or capsaicin deactivated sensory nerves. CCK(1) receptor antagonist; tarazepide, was used in the part of the study to determine the involvement of CCK in the secretory effects of melatonin. The secretory studies were performed on awaken rats surgically equipped with silicone catheters, one of them was inserted into pancreato-biliary duct, the other one - into duodenum. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) were administered i.d. Samples of pancreatic juice were collected in 15 minutes aliquots. Tarazepide (2,5 mg/kg i.p.) was given to the rats 15 min prior to the administration of melatonin or L-tryptophan. Neurotoxic dose of capsaicin (100 mg/kg s.c.) was used to deactivate afferent nerves and thus to assess the role of these nerves in the melatonin-induced pancreatic enzyme secretion. Administration of melatonin (1, 5 or 25 mg/kg i.d.) or L-tryptophan (10, 50 or 250 mg/kg i.d.) significantly increased pancreatic amylase outputs. Deactivation of sensory nerves by capsaicin or administration of CCK(1) - receptor antagonist; tarazepide, reversed the stimulatory effects of melatonin or L-tryptophan on pancreatic secretory function. Administration of melatonin or its amino-acid precursor to the rats resulted in the significant and dose-dependent rises of melatonin and CCK plasma levels. We conclude that melatonin or its precursor; L-tryptophan stimulates pancreatic enzyme secretion via stimulation of CCK release and activation of duodeno-pancreatic reflexes.

PMID: 15608359 [PubMed - in process]


Note: full free paper is available by going to: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15550511

Endocrinology. 2004 Nov 18; [Epub ahead of print]
 
DAILY VARIATIONS IN TYPE II IODOTHYRONINE DEIODINASE ACTIVITY IN THE RAT BRAIN AS CONTROLLED BY THE BIOLOGICAL CLOCK.

Kalsbeek A, Buijs RM, van Schaik R, Kaptein E, Visser TJ, Zandieh Doulabi B, Fliers E.

Netherlands Institute for Brain Research (A.K, R.L.V.S.), Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine III (E.K., T.J.V.), Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands; Academic Medical Center (B.Z.D, E.F.), Department of Endocrinology and Metabolism, F5-171, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Type II deiodinase (D2) plays a key role in regulating thyroid-hormone dependent processes in, among others, the central nervous system (CNS), by accelerating the intracellular conversion of thyroxine (T4) into active thyroid hormone, T3. Just like the well-known daily rhythm of the hormones of the hypothalamo-pituitary-thyroid (HPT) axis, D2 activity also appears to show daily variations. However, the mechanisms involved in generating these daily variations, especially in the CNS, are not known. Therefore, we decided to investigate the role the master biological clock, located in the hypothalamus, plays with respect to D2 activity in the rat CNS, as well as the role of one of its main hormonal outputs, i.e. plasma corticosterone. D2 activity showed a significant daily rhythm in the pineal and pituitary gland, as well as in hypothalamic and cortical brain tissue, albeit with a different timing of its acrophase in the different tissues. Ablation of the biological clock abolished the daily variations of D2 activity in all 4 tissues studied. The main effect of the knock-out of the suprachiasmatic nuclei (SCN) was a reduction of nocturnal peak levels in D2 activity. Moreover, contrary to previous observations in SCN-intact animals, in SCN-lesioned animals the decreased levels of D2 activity are accompanied by decreased plasma levels of the thyroid hormones, suggesting that the SCN separately stimulates D2 activity as well as the HPT-axis.

PMID: 15550511 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15556393

Comp Biochem Physiol A Mol Integr Physiol. 2004 Nov;139(3):365-9.

Seasonal changes in brain melatonin concentration in the three-spined stickleback (Gasterosteus aculeatus): towards an endocrine calendar.

Sokolowska E, Kalamarz H, Kulczykowska E.

Department of Genetics and Marine Biotechnology, Institute of Oceanology of Polish Academy of Sciences, sw. Wojciecha 5 Str., 81-347 Gdynia, Poland.

Pineal organ and its hormone melatonin (N-acetyl-5-methoxytryptamine) is likely involved in timing and synchronisation of many internal processes, such as reproduction, with annual changes in environmental cues, i.e., photoperiod and water temperature. The seasonal changes in melatonin profile in stickleback brains related to the following reproductive phases were examined, and the link between melatonin concentrations and the stages of spawning cycle was analysed. Two wild populations of sticklebacks were exposed to annual environmental changes in their natural habitats. Brains, gonads, kidneys and livers were collected over 2 years. Melatonin was measured using RIA and the indices, gonadosomatic (GSI), nephrosomatic (NSI) and hepatosomatic (HSI), were calculated. The role of melatonin, as a component of internal calendar engaged in the control of seasonal breeding in this species, is discussed. The extremely high melatonin levels observed in early spring (March) and autumn (October) seem to mark out a time frame for spawning in sticklebacks. The seasonal pattern of melatonin production and identified development stages of gonads suggests the potential inhibitory effect of the hormone on stickleback reproduction in shortening photoperiod and stimulatory effect in lengthening photoperiod.

PMID: 15556393 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15559508

Adv Gerontol. 2004;14:105-13.

[The influence of substances revealing geroprotective of spontaneous carcinogenesis in mice]

[Article in Russian]

[No authors listed]

The review presents the results of experimental studies conducted by the author. CBA, SHR, HER-2/neu and SAM mice revealed inhibition of age-related alterations in estrus function and spontaneous tumour development and showed life span extension under the influence of the pineal gland hormone Melatonin, synthetic peptide bioregulator Epitalon, delta-sleep-inducing peptide Deltaran, enterosorbent Aqualen and succinic acid containing preparation Neuronol (Noogam). The observed effect depended on the dose and conditions of administration, as well as genetic predisposition of the particular mice strains to tumour development.

PMID: 15559508 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15562014

J Clin Endocrinol Metab. 2004 Nov 23; [Epub ahead of print]
 
Human lymphocyte-synthesized melatonin is involved in the regulation of the IL-2/IL-2 receptor system.

Carrillo-Vico A, Lardone PJ, Fernandez-Santos JM, Martin-Lacave I, Calvo JR, Karasek M, Guerrero JM.

Department of Medical Biochemistry and Molecular Biology and Department of Normal and Pathological Cytology and Histology, The University of Seville School of Medicine and Virgen

Macarena Hospital, Seville, Spain. Laboratory of Electron Microscopy, Chair of Pathology, Medical University of Lodz, Lodz, Poland.

Since melatonin was first isolated in 1958 up to the last few years, this substance was considered a hormone exclusive to the pineal gland. Although melatonin has lately been identified in a large number of extrapineal sites, its potential biological actions have not yet been studied. This paper shows that human lymphocyte-synthesized melatonin plays a crucial role modulating IL-2/IL-2 receptor system, since when blocking melatonin biosynthesis by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, both IL-2 and IL-2 receptor levels fell, restoring them by adding exogenous melatonin. Moreover, we demonstrated this endogenous melatonin interfered with the exogenous melatonin effect on IL-2 production. Melatonin exerted these effects by a receptor-mediated action mechanism, because both IL-2 and IL-2 receptor expressions significantly decreased when lymphocytes were incubated in the presence of the specific membrane and/or nuclear melatonin receptor antagonists, luzindole and/or CGP 55644, respectively. Finally, we made the real significance of the membrane melatonin receptors in this process clear, so prostaglandin E2-induced inhibition on IL-2 production increased when we blocked the membrane receptors using luzindole. In conclusion, these data show that endogenous melatonin is an essential part for an accurate response of human lymphocytes through the modulation of IL-2/IL-2 receptor system.

PMID: 15562014 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15547321

Biogerontology. 2004 Oct;5(5):339-345.
 
Pineal graft in old rats improves erythrocyte resistance to peroxyl radical-induced hemolysis.

Moroni F, Marcheselli F, Recchioni R, Fattoretti P, Bertoni-Freddari C.

INRCA Research Department, Centre of Cytology, Via Birarelli 8, Italy.

Pineal graft from young to old rats was performed and red blood cell hemolysis, induced by the water-soluble radical initiator 2,2'-azobis (2-amidino-propane) dihydrochloride (AAPH), was evaluated 6 months after graft. Pineal graft modified the hemolysis curve kinetic profile in grafted rats versus age-matched controls, the 50% hemolysis time as well as the lag time were longer, whereas the maximal amount of hemolysis was lower, and it occurred over a longer period of time. Thiobarbituric acid reactive substances production was lower in pineal-grafted rats than in controls and the age-related decrease of erythrocyte membrane fluidity was prevented by pineal graft. The present findings support an important physiological role of pineal gland in preventing age-related alterations of erythrocyte membranes and suggest a possible antioxidant action of melatonin.

PMID: 15547321 [PubMed - as supplied by publisher]


Micron , Volume 35, Issue 8 , December 2004, Pages 655-670
   
Bizarre alterations of the morphology of pineal synaptic bodies under constant light and an evaluation of suitable 3D-reconstruction software

Holger Jastrow (a), Dirk Schmanke (b) and Jörg Weinert (c)

a Department of Anatomy, University of Mainz, Becherweg 13, D-55128, Mainz, Germany
b University Clinic Central Network Group, Langenbeckstr. 1, D-55101, Mainz, Germany
c ConVis Medizinische Datenverarbeitung GmbH & Co. KG, Robert-Bosch-Str. 23, 55129, Mainz, Germany

Received 10 May 2004;  Revised 7 June 2004;  accepted 8 June 2004.  Available online 2 July 2004.

Abstract - Three dimensional (3D) reconstruction and modelling software was evaluated to find a procedure suitable for visualization of small subcellular structures in transmission electron microscope images. The method applied in this study demonstrates bizarre alterations of the structure of synaptic bodies (SBs) in pinealocytes of the guinea-pig pineal gland caused by constant illumination. It can, in general, be used for any 3D reconstruction from serial sections.
Pineal glands of five guinea-pigs (two kept under a LD cycle of 12:12 h; three kept in constant light, for 4 months) were investigated. SBs consist of an electron-dense centre with attached vesicles. Under normal lighting conditions most SBs are flat plates (about 35 nm in thickness), which eventually may be bent. The proteins comprising the molecular basis of SBs, mainly RIBEYE A and B are polymerised in a regular manner in these plates. This is not the case in other SBs, which appear as spheres or irregular lumps. SBs lie in groups in which usually some of the plates are arranged in parallel arrays
Constant illumination caused different changes in morphology: many of the SBs lie in ‘paired fields’, i.e. appear in groups attached to the cell membranes of two pinealocytes directly opposite to each other. Some of the SBs in such groups are strongly bent, showing blebs and irregular thickened areas, others seem to aggregate and show inclusions of cytoplasm. Further goblet-like, shield-like and other bizarre forms of SBs occurred and the relative number of spheroid and lump-like SBs increased. Protrusions on larger SBs suggest detachment or fusion of SB material to a greater extent than in the control animals. There is a reduction of areas in which the polymerisation of the SB proteins remains well ordered, i.e. where the typical thickness of 35 nm is maintained. It remains unclear why this polymerisation pattern is only partly affected by constant light.


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15450952

Biochem Pharmacol. 2004 Nov 1;68(9):1869-78.
 
Oxidative DNA damage induced by a melatonin metabolite, 6-hydroxymelatonin, via a unique non-o-quinone type of redox cycle.

Sakano K, Oikawa S, Hiraku Y, Kawanishi S.

Department of Environmental and Molecular Medicine, Mie University School of Medicine, Mie 5148507, Japan.

Melatonin, an indolic pineal hormone, is produced primarily at night in mammals and is important in controlling biological rhythms. Although melatonin is known to be effective as a free radical scavenger and has an anti-cancer effect, carcinogenic properties have also been reported. In relation to its carcinogenic potential, we have examined whether 6-hydroxymelatonin, a major melatonin metabolite, can induce DNA damage in the presence of metal ion using [(32)P]-5'-end-labeled DNA fragments obtained from genes relevant to human cancer. 6-Hydroxymelatonin induced site-specific DNA damage in the presence of Cu(II). Formamidopyrimidine-DNA glycosylase treatment induced cleavage sites mainly at G residues of the 5'-TG-3' sequence, whereas piperidine treatment induced cleavage sites at T mainly of 5'-TG-3'. Interestingly, 6-hydroxymelatonin strongly damaged G and C of the 5'-ACG-3' sequence complementary to codon 273 of the p53 gene. These results suggest that 6-hydroxymelatonin can cause double-base lesions. DNA damage was inhibited by both catalase and bathocuproine, Cu(I)-specific stabilizer, suggesting that reactive species derived from the reaction of H(2)O(2) with Cu(I) participate in DNA damage. Cytochrome P450 reductase efficiently enhanced 6-hydroxymelatonin-induced oxidative DNA damage and oxygen consumption, suggesting the formation of redox cycle. It is noteworthy that 6-hydroxymelatonin can efficiently induce DNA damage via non-o-quinone type of redox cycle. Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in calf thymus DNA was significantly increased by 6-hydroxymelatonin in the presence of Cu(II). Furthermore, 6-hydroxymelatonin significantly increased the formation of 8-oxodG in human leukemia cell line HL-60 but not in HP100, a hydrogen peroxide (H(2)O(2))-resistant cell line derived from HL-60. The 6-hydroxymelatonin-induced 8-oxodG formation in HL-60 cells significantly decreased by the addition of bathocuproine or o-phenanthroline. Therefore, it is concluded that melatonin may exhibit carcinogenic potential through oxidative DNA damage by its metabolite.

PMID: 15450952 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15530547

Acta Histochem. 2004 Nov 25;106(5):331-336.
 
Efficacy of melatonin as protectant against oxidative stress and structural changes in liver tissue in pinealectomized rats.

Sahna E, Parlakpinar H, Vardi N, Cigremis Y, Acet A.

Department of Pharmacology, Faculty of Medicine, Firat University, Elazig, Turkey.

Previous observations demonstrated that physiological levels of melatonin, the pineal secretory product, are important in protecting against oxidative stress-induced tissue damage. We investigated the effects of pinealectomy and administration of exogenous melatonin on liver tissue in rats. Pinealectomized (Px) and sham-operated (non-Px) rats were used. We evaluated structural changes, reduced glutathione (GSH) levels and malondialdehyde (MDA) levels. Rats were divided into three groups (10 rats in each group): control (non-Px), Px+vehicle and Px+melatonin (4mg/kg given daily intraperitoneally for 10 days). Liver GSH levels were significantly lower in Px rats than in the control group. Melatonin administration significantly increased GSH levels (p<0.05). Px caused a significant increase in MDA levels as compared with the control group and melatonin administration to Px rats significantly reduced MDA levels in the liver (p<0.05). Sinusoidal dilatation to a varying degree developed in all Px rats. Severity of mononuclear cell infiltration and sinusoidal congestion were lower in Px+melatonin group than in the Px group. These findings suggest that a significant increase in oxidative and structural changes occur in rat livers after pinealectomy, which can be diminished by melatonin treatment.

PMID: 15530547 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15378522

Prostate. 2004 Sep 17 [Epub ahead of print]
 
Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism.

Sainz RM, Mayo JC, Tan DX, Leon J, Manchester L, Reiter RJ.

Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas.

BACKGROUND: Melatonin, the main secretory product of the pineal gland, inhibits the growth of several types of cancer cells. Melatonin limits human prostate cancer cell growth by a mechanism which involves the regulation of androgen receptor function but it is not clear whether other mechanisms may also be involved.
METHODS: Time-course and dose-dependent studies were performed using androgen-dependent (LNCaP) and independent (PC3) prostate cancer cells. Cell number, cell viability, and cell cycle progression were studied. Neuroendocrine differentiation of these cells was evaluated by studying morphological and biochemical markers. Finally, molecular mechanisms including the participation of melatonin membrane receptors, intracellular cAMP levels, and the PKA signal transduction pathway were also analyzed. RESULTS: Melatonin treatment dramatically reduced the number of prostate cancer cells and stopped cell cycle progression in both LNCaP and PC3 cells. In addition, it induced cellular differentiation as indicated by obvious morphological changes and neuroendocrine biochemical parameters. The role of melatonin in cellular proliferation and differentiation of prostate cancer cells is not mediated by its membrane receptors nor related to PKA activation.
CONCLUSIONS: The treatment of prostate cancer cells with pharmacological concentrations of melatonin influences not only androgen-sensitive but also androgen-insensitive epithelial prostate cancer cells. Cell differentiation promoted by melatonin is not mediated by PKA activation although it increases, in a transitory manner, intracellular cAMP levels. Melatonin markedly influences the proliferative status of prostate cancer cells. These effects should be evaluated thoroughly since melatonin levels are diminished in aged individuals when prostate cancer typically occurs. Copyright 2004 Wiley-Liss, Inc.

PMID: 15378522 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15384069

J Comp Neurol. 2004 Oct 25;478(4):379.
 
Distribution of transcription factor inducible cyclicAMP early repressor (ICER) in rodent brain and pituitary.

Kell CA, Dehghani F, Wicht H, Molina CA, Korf HW, Stehle JH.

Dr. Senckenbergische Anatomie, Institute of Anatomy II, University of Frankfurt, 60590 Frankfurt, Germany.

In morphogenetic dynamics of neurons, and in adaptive physiology of brain function, transcription factors of the cyclicAMP signaling pathway, such as activator cyclicAMP responsive element binding protein (CREB) and inhibitor inducible cyclicAMP early repressor (ICER), play an important role. In particular, the presence of the transcription factor ICER in neurons or neuroendocrine cells suggests the need for the gating of an up-regulated gene expression. Little is known, however, about the natural distribution of the inhibitory transcription factor ICER. We, therefore, mapped the rodent brain and pituitary for an ICER immunoreaction and found a nuclear staining for this transcription factor. ICER-positive glial cells were found throughout the brain. ICER-positive neurons were found in sensory input centers, like the olfactory bulb, or sensory brain stem nuclei, and in hypothalamic nuclei involved in central neuroendocrine control. In addition, neuroendocrine/endocrine transducers, like the pituitary and the pineal gland showed a high basal presence of ICER. Our data show that a basic ICER level is required by many cell systems and can be seen as an anticipatory and/or a protective measure in systems with superior reactive dynamics.

PMID: 15384069 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15379450

Acta Vet Hung. 2004;52(3):361-7.

Effect of melatonin on biochemical variables of the blood in dairy cows.

Darul K, Kruczynska H.

Department of Animal Nutrition and Feed Management, August Cieszkowski Agricultural University, ul Wolynska 33, 60-637 Poznan, Poland.

In order to examine the effect of exogenous melatonin on selected biochemical variables of the blood in ruminants, dairy cows were given the pineal gland hormone in the dose of 0.1 mg/kg body weight. One and four hours after melatonin administration blood samples were collected from the cows in the control and the treated group in order to determine the levels of glucose, insulin, total cholesterol, triglycerides, free fatty acids, as well as the activities of alanine and aspartate aminotransferase. The pineal gland hormone caused a significant increase in the levels of total cholesterol and triglycerides, slight increases in glucose and insulin levels, and a significant decrease in the concentration of free fatty acids. Melatonin did not exert an effect on the activity of liver enzymes.

PMID: 15379450 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15375761

Histol Histopathol. 2004 Oct;19(4):1187-92.
 
Melatonin-like immunoreactivity in the pineal gland of the cow: an immunohistochemical study.

Carvajal JC, Gomez-Esteban MB, Carbajo S, Munoz-Barragan L.

Department of Human Anatomy and Histology, Faculty of Medicine, University of Salamanca, Spain.

With a view to checking the presence of melatonin in the pineal gland of the cow, in the present work we used six adult animals, ranging in age from one to six years, which were sacrificed at dawn. Sections of 6 micro m thickness of Bouin-fixed and paraffin-embedded pineal glands were incubated in an anti-melatonin serum, which was provided by the Institute for Molecular and Cellular Recognition, Gunma University, Maebshi, Japan. After incubation and successive washings in PBS, some of the sections were treated with the avidin-biotin-peroxidase complex (ABC) technique using antisera from Sigma, and developed with the method of Graham and Karnovsky (which employs 3,3'-diaminobenzidine and H2O2 as developer). Other sections were incubated in a goat-anti-rabbit IgG (H+L) bound to fluorochrome Cy5 for immunofluorescence studies. An intense reaction for melatonin was observed in the cytoplasm but not in the nucleus of melatonin secreting pinealocytes located in peripheral and intermediate zones of the pineal gland. Immunoabsorption of the antimelatonin primary antibody with melatonin at a dilution of 10 mM per 0.1 ml of serum prevented the reaction, as happened when any of the antisera used in the procedure were used. Immunoabsorption of anti-melatonin serum with different amounts of bovine albumin (ranging between 1/5 to 1/50) failed to inhibit the immunoreactivity. When a bovine anti-albumin antibody was employed, working with the above methods, no immunoreaction was detected. Our data suggest that the pinealocytes of cows sacrificed at dawn contain immunoreactive melatonin.

PMID: 15375761 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15447706

Headache. 2004 Oct;44(9):929-30.
 
Headaches and pineal cyst: a (more than) coincidental relationship?

Peres MF, Zukerman E, Porto PP, Brandt RA.

Pineal cysts are common findings in neuroimaging studies. The cysts are more frequent in women in their third decade of life. Pineal cysts can be symptomatic, headache is the most common symptom. The pineal gland has important physiological implications in humans, but little is known about the impact of pineal cysts in human physiology. We report 5 headache patients with pineal cyst, 4 women, 1 man, mean age 37.6, mean cyst diameter 10.1 mm. Two patients had migraine without aura, 1 migraine with aura, 1 chronic migraine, and 1 hemicrania continua. Three patients had strictly unilateral headaches. We hypothesize pineal cysts may be not incidental in headache patients, inducing an abnormal melatonin secretion.

PMID: 15447706 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15465605

J Neuroimmunol. 2004 Nov;156(1-2):146-52.
 
Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release.

Silva SO, Rodrigues MR, Ximenes VF, Bueno-da-Silva AE, Amarante-Mendes GP, Campa A.

Departamento de Analises Clinicas e Toxicologicas, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Sao Paulo CEP 05508-900, SP, Brazil.

A growing body of evidence suggests that the pineal hormone, melatonin, has immunomodulatory properties, although very little is known about its effect on leukocytes. Therefore, we aimed to investigate the effect of melatonin and its oxidation product N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) on cytokine production by neutrophils and peripheral blood mononuclear cells (PBMCs). AFMK (0.001-1 mM) inhibits the lipopolysaccharide (LPS)-mediated production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) more efficiently in neutrophils than PBMCs. Moreover, the inhibitory activity of AFMK is stronger than that of melatonin. Interestingly, monocytes efficiently oxidize melatonin to AFMK. We conclude that neutrophils are one of the main targets for melatonin and that at least part of the effects described for melatonin on immune cells may be due to its oxidation product, AFMK. We also consider that the oxidation of melatonin may be an important event in the cross-talking between neutrophils and monocytes.

PMID: 15465605 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15449681

Arkh Patol. 2004 Jul-Aug;66(4):13-6.

[Human epiphyseal concrements in schizophrenia]

[Article in Russian]

[No authors listed]

The epiphysis is a gland containing firm extracellular bodies (brain sand) the number of which increases with age. Microscopy and roentgen microtomography showed that in some cases of schizophrenia the amount of brain sand decreases. In parallel, cytoplasm of pinealocytes appears to contain concrements of a new type--irregular hollow spheres of 0.1-1.5 microm in size. They may contain fluoride. Typical hydroxyapatite retaining organic stroma may dissolve starting from the center both in health and schizophrenia.

PMID: 15449681 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15455095

Bull Exp Biol Med. 2004 Jun;137(6):597-600.

Effects of pineal peptides on circadian dynamics of spermatogonia proliferation in albino rats.

[Article in English, Russian]

Arav VI, Sych VF, Zheleznyak EV, Slesarev SM.

Department of Common Biology, Ul'yanovsk State University. bio@ulsu.ru

Mitotic index of type B spermatogonia in intact animals is characterized by a circadian rhythm. Mitotic index increased and its circadian rhythm disappeared after pinealectomy. Treatment with Epithalamin for 14 days restored the circadian rhythm. The circadian biorhythm of spermatogonia proliferation suggests the presence of circadian rhythm of spermatogenesis in general and its regulation by the pineal gland.

PMID: 15455095 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15469089

Sheng Li Ke Xue Jin Zhan. 2004 Jul;35(3):210-4.

[Advances in study on molecular mechanism of circadian clock in pineal gland]

[Article in Chinese]

Wang GQ, Tong J.

Department of Physiology, Medical School, Soochow University, Suzhou 215007.

The pineal gland functions as a central circadian oscillator in a variety of nonmammalian vertebrates. More recently, clock genes such as Per, Cry, Clock, and Bmal have been found in a variety of vertebrate clock structures including the avian pineal gland. The profiles of the temporal change of the clock gene expression in the avian pineal gland are more similar to those in the mammalian suprachiasmatic nucleus (SCN) of the hypothalamus. Avian pineal gland and mammalian SCN seem to share a fundamental molecular framework of the clock oscillator composed of a transcription/translation-based autoregulatory feedback loop. Some products of the clock genes serve as positive or negative regulators influencing the clock oscillation. The circadian time-keeping mechanism is also involved in several post-translational events. The above-mentioned processes play a quite important role in the stability of the oscillator and/or the photic-input pathway for entrainment of the clock.

PMID: 15469089 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15357659

J Pineal Res. 2004 Oct;37(3):153-60.

Protective effect of N-acetyl-serotonin on the nonenzymatic lipid peroxidation in rat testicular microsomes and mitochondria.

Gavazza MB, Catala A.

Catedra de Bioquimica, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata, Argentina.

N-acetyl-serotonin, the immediate precursor of melatonin in the tryptophan metabolic pathway in the pineal gland, has been reported to be an antioxidant. The aim of this study was to test the in vitro protective effect of N-acetyl-serotonin on the ascorbate-Fe(++) induced lipid peroxidation of polyunsaturated fatty acids (PUFAs) located in testis microsomes and mitochondria. We assayed increasing concentrations (0-10 mm) of N-acetyl-serotonin in testis microsomes and (0-1 mm) of N-acetyl-serotonin in testis mitochondria. Control experiments were performed by incubating microsomal and mitochondrial membranes with N-acetyl-serotonin in the absence of lipid peroxidation-inducing drugs. Special attention was paid to the changes produced on the highly PUFAs C20:4 n6 and C22:5 n6. The light emission (chemiluminescence) used as a marker of lipid peroxidation was similar in both organelles when the control and peroxidized groups were compared. N-acetyl-serotonin reduced lipid peroxidation in testicular microsomes or mitochondria for both C20:4 n6 and C22:5 n6. Both long chain PUFAs were protected when N-acetyl-serotonin was incorporated either into microsomes or mitochondria. The N-acetyl-serotonin concentration required to inhibit by approximately 70% lipid peroxidation process was 10 mm in microsomes and between 0.50 and 1 mm in mitochondria. IC 50 values calculated from the inhibition curve of N-acetyl-serotonin on the chemiluminescence rates were higher in microsomes (4.50 mm) than in mitochondria (0.25 mm). In these experimental conditions, N-acetyl-serotonin was about 18 times more potent in testicular mitochondria in inhibiting the oxidative processes than it was in testicular microsomes. These results suggest that the protective role of N-acetyl-serotonin in preserving the long PUFAs may be related to its ability to reduce lipid peroxidation.

PMID: 15357659 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15357143

Rev Neurosci. 2004;15(3):209-30.

Genetic aspects of melatonin biology.

Anisimov SV, Popovic N.

Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Lund, Sweden. Sergey.Anisimov@mphy.lu.se

For decades, the important physiological roles of the pineal hormone have inspired scientific investigations. Research efforts have generated a broad amount of information relevant to various genetic aspects of melatonin biology. Nevertheless, our understanding of the effect of genetic factors upon melatonin biosynthesis and the mechanisms of gene expression regulation by melatonin in target tissues is far from complete. The present review makes an effort to summarize and systematize the existing information on the subject, sequentially discussing
(i) the effect of genetic factors upon melatonin biosynthesis,
(ii) melatonin receptor expression profiles, and
(iii) the effect of melatonin upon expression of genes in target tissues.

PMID: 15357143 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15356035

J Clin Endocrinol Metab. 2004 Sep;89(9):4388-90.
 
Increase in 6-Hydroxymelatonin Excretion in Humans during Ascent to High Altitudes.

Frisch H, Waldhauser F, Waldhor T, Mullner-Eidenbock A, Neupane P, Schweitzer K.

Department of Pediatrics, University Hospital Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. herwig.frisch@meduniwien.ac.at

Melatonin (MLT), the pineal gland hormone involved in the regulation of circadian rhythms, shows characteristic diurnal variation. Its physiological role in humans is not clear. Exposure to high altitudes may disrupt the circadian rhythm and lead to various endocrine changes. MLT in humans has not been studied under these conditions. Urinary 6-hydroxy-MLT sulfate (aMT6s) excretion was analyzed during the day (0700-2200 h) and night (2200-0700 h) phases. A cohort of 33 healthy volunteers, aged 19-65 yr, was studied during an ascent to a high altitude in the Himalayas on three occasions (at a lower altitude, at 3400 m, and after reaching maximal altitudes of 5600-6100 m). aMT6s excretion during the daytime remained unchanged during exposure to high altitudes. As expected, nocturnal values were higher than diurnal values at each point in time. However, there was a significant increase in nocturnal MLT excretion after the ascent to high altitudes. Ascent to high altitudes is associated with increased nocturnal excretion of aMT6s. The mechanism and physiological significance of this MLT increase are unclear.

PMID: 15356035 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15352385

J Physiol Biochem. 2004 Mar;60(1):61-72.

Physiological and metabolic functions of melatonin.

Barrenetxe J, Delagrange P, Martinez JA.

Dpt. Physiology and Nutrition, University of Navarra, C/Irunlarrea, s/n, Pamplona, Spain.

Melatonin is a lipophilic hormone, mainly produced and secreted at night by the pineal gland. Melatonin synthesis is under the control of postganglionic sympathetic fibers that innervates the pineal gland. Melatonin acts via high affinity G protein-coupled membrane receptors. To date, three different receptor subtypes have been identified in mammals: MT1 (Mel 1a) and MT2 (Mel 1b) and a putative binding site called MT3. The chronobiotic properties of the hormone for resynchronization of sleep and circadian rhythms disturbances has been demonstrated both in animal models or in clinical trials. Several other physiological effects of melatonin in different peripheral tissues have been described in the past years. In this way, it has been demonstrated that the hormone is involved in the regulation of seasonal reproduction, body weight and energy balance. This contribution has been focused to review some of the physiological functions of melatonin as well as the role of the hormone in the regulation of energy balance and its possible involvement in the development of obesity.

PMID: 15352385 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15352165

J Cell Biochem. 2004 Sep 1;93(1):83-92.
 
Extremely low frequency electromagnetic fields as effectors of cellular responses in vitro: Possible immune cell activation.

Simko M, Mattsson MO.

Division of Environmental Physiology, Institute of Cell Biology and Biosystems Technology, University of Rostock, Albert-Einstein-Strasse 3, D-18059 Rostock, Germany.

There is presently an intense discussion if electromagnetic field (EMF) exposure has consequences for human health. This include exposure to structures and appliances that emit in the extremely low frequency (ELF) range of the electromagnetic spectrum, as well as emission coming from communication devices using the radiofrequency part of the spectrum. Biological effects of such exposures have been noted frequently, although the implication for specific health effects is not that clear. The basic interaction mechanism(s) between such fields and living matter is unknown. Numerous hypotheses have been suggested, although none is convincingly supported by experimental data. Various cellular components, processes, and systems can be affected by EMF exposure. Since it is unlikely that EMF can induce DNA damage directly, most studies have examined EMF effects on the cell membrane level, general and specific gene expression, and signal transduction pathways. In addition, a large number of studies have been performed regarding cell proliferation, cell cycle regulation, cell differentiation, metabolism, and various physiological characteristics of cells. Although 50/60 Hz EMF do not directly lead to genotoxic effects, it is possible that certain cellular processes altered by exposure to EMF indirectly affect the structure of DNA causing strand breaks and other chromosomal aberrations. The aim of this article is to present a hypothesis of a possible initial cellular event affected by exposure to ELF EMF, an event which is compatible with the multitude of effects observed after exposure. Based on an extensive literature review, we suggest that ELF EMF exposure is able to perform such activation by means of increasing levels of free radicals. Such a general activation is compatible with the diverse nature of observed effects. Free radicals are intermediates in natural processes like mitochondrial metabolism and are also a key feature of phagocytosis. Free radical release is inducible by ionizing radiation or phorbol ester treatment, both leading to genomic instability. EMF might be a stimulus to induce an "activated state" of the cell such as phagocytosis, which then enhances the release of free radicals, in turn leading to genotoxic events. We envisage that EMF exposure can cause both acute and chronic effects that are mediated by increased free radical levels:
(1) Direct activation of, for example macrophages (or other cells) by short-term exposure to EMF leads to phagocytosis (or other cell specific responses) and consequently, free radical production. This pathway may be utilized to positively influence certain aspects of the immune response, and could be useful for specific therapeutic applications.
(2) EMF-induced macrophage (cell) activation includes direct stimulation of free radical production.
(3) An increase in the lifetime of free radicals by EMF leads to persistently elevated free radical concentrations. In general, reactions in which radicals are involved become more frequent, increasing the possibility of DNA damage.
(4) Long-term EMF exposure leads to a chronically increased level of free radicals, subsequently causing an inhibition of the effects of the pineal gland hormone melatonin.
Taken together, these EMF induced reactions could lead to a higher incidence of DNA damage and therefore, to an increased risk of tumour development. While the effects on melatonin and the extension of the lifetime of radicals can explain the link between EMF exposure and the incidence of for example leukaemia, the two additional mechanisms described here specifically for mouse macrophages, can explain the possible correlation between immune cell system stimulation and EMF exposure. Copyright 2004 Wiley-Liss, Inc.

PMID: 15352165 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15344912

J Neuroendocrinol. 2004 Sep;16(9):741-9.

Activation of arylalkylamine N-acetyltransferase by phorbol esters in bovine pinealocytes suggests a novel regulatory pathway in melatonin synthesis.

Schomerus C, Laedtke E, Korf HW.

Dr Senckenbergische Anatomie, Institut fur Anatomie II, Johann Wolfgang Goethe-Universitat Frankfurt, Frankfurt, Germany.

In all mammalian species investigated, noradrenaline activates a beta-adrenoceptor/cAMP/protein kinase A-dependent mechanism to switch on arylalkylamine N-acetyltransferase and melatonin biosynthesis in the pineal gland. Other compounds which are known to influence the melatonin-generating system are phorbol esters. The effect of phorbol esters on regulation of melatonin synthesis has been mainly investigated in rat pinealocytes. In these cells, phorbol esters do not increase cAMP levels and arylalkylamine N-acetyltransferase on their own; however, phorbol esters potentiate the effects on cAMP and AANAT activity induced upon beta-adrenoceptor stimulation. In the present study, we investigated the effect of phorbol esters on the regulation of melatonin synthesis in bovine pinealocytes. We show that, in these cells, the phorbol esters 4beta-phorbol 12-myristate 13-acetate (PMA) or phorbol 12,13-dibutyrate have a direct stimulatory effect and induced 4-10-fold increases in AANAT protein levels, AANAT activity and melatonin production. The extent of these effects was similar to those induced by noradrenaline. Notably, responses to PMA were not accompanied by increases in cAMP levels. Northern blot analysis showed that Aanat mRNA levels did not change upon PMA treatment indicating that phorbol esters control AANAT at a post-transcriptional level. The effects on AANAT and melatonin production were reduced by use of protein kinase C inhibitors, but not by blockade of the cyclic AMP/protein kinase A pathway. Our results point towards a novel mechanism in the regulation of melatonin production that is cAMP-independent and involves protein kinase C. The study is of particular interest because regulation of melatonin biosynthesis in bovines may resemble that in primates more closely than that in rodents.

PMID: 15344912 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15357664

J Pineal Res. 2004 Oct;37(3):193-7.

Melatonin increases cell proliferation in the dentate gyrus of maternally separated rats.

Kim MJ, Kim HK, Kim BS, Yim SV.

Department of Obesity Management, Graduate School of Obesity Science, Dongduk Women's University, Seoul, South Korea.

Melatonin in mammals, produced by the pineal gland and elsewhere, has shown antioxidant and neuroprotective properties in neuronal cells. We investigated whether melatonin would increase newly born cells (cell proliferation) in the dentate gyrus of maternally separated rats. To examine the effect of melatonin on cell proliferation of the dentate gyrus in maternally separated rats, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry was performed. Rat pups were separated from their mothers and socially isolated on postnatal day 14. Melatonin (10 mg/kg, i.p.) and BrdU (50 mg/kg, i.p.) were given to them for 7 days. The number of BrdU-positive cells was significantly increased in the dentate gyrus of maternally separated pups with melatonin administration (P < 0.001). In addition, the expression of glucocorticoid receptor was significantly decreased in the dentate gyrus compared with maternally separated pups not given melatonin (P < 0.001). This is the first report that melatonin increases cell proliferation in the dentate gyrus of maternally separated rats.

PMID: 15357664 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15357831

Pigment Cell Res. 2004 Oct;17(5):454-60.

Melatonin, melatonin receptors and melanophores: a moving story.

Sugden D, Davidson K, Hough KA, Teh MT.

Division of Reproductive Health, Endocrinology and Development, School of Biomedical Sciences, Kings College London, London, UK.

Melatonin (5-methoxy N-acetyltryptamine) is a hormone synthesized and released from the pineal gland at night, which acts on specific high affinity G-protein coupled receptors to regulate various aspects of physiology and behaviour, including circadian and seasonal responses, and some retinal, cardiovascular and immunological functions. In amphibians, such as Xenopus laevis, another role of melatonin is in the control of skin coloration through an action on melanin-containing pigment granules (melanosomes) in melanophores. In these cells, very low concentrations of melatonin activate the Mel(1c) receptor subtype triggering movement of granules toward the cell centre thus lightening skin colour. Mel(1c) receptor activation reduces intracellular cAMP via a pertussis toxin-sensitive inhibitory G-protein (Gi), but how this and other intracellular signals regulate pigment movement is not yet fully understood. However, melanophores have proven an excellent model for the study of the molecular mechanisms which coordinate intracellular transport. Melanosome transport is reversible and involves both actin- (myosin V) and microtubule-dependent (kinesin II and dynein) motors. Melanosomes retain both kinesin and dynein during anterograde and retrograde transport, but the myosin V motor seems to be recruited to melanosomes during dispersion, where it assists kinesin II in dominating dynein thus driving net dispersion. Recent work suggests an important role for dynactin in coordinating the activity of the opposing microtubule motors. The melanophore pigment aggregation response has also played a vital role in the ongoing effort to devise specific melatonin receptor antagonists. Much of what has been learnt about the parts of the melatonin molecule required for receptor binding and activation has come from detailed structure-activity data using novel melatonin ligands. Work aiming to devise ligands specific for the distinct melatonin receptor subtypes stands poised to deliver selective agonists and antagonists which will be valuable tools in understanding the role of this enigmatic hormone in health and disease.

PMID: 15357831 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15325001

Med Hypotheses. 2004;63(4):588-96.
 
Lighting for the human circadian clock: recent research indicates that lighting has become a public health issue.

Pauley SM.

P.O. Box 3759, Ketchum, ID 83340, USA.

The hypothesis that the suppression of melatonin (MLT) by exposure to light at night (LAN) may be one reason for the higher rates of breast and colorectal cancers in the developed world deserves more attention. The literature supports raising this subject for awareness as a growing public health issue. Evidence now exists that indirectly links exposures to LAN to human breast and colorectal cancers in shift workers. The hypothesis begs an even larger question: has medical science overlooked the suppression of MLT by LAN as a contributor to the overall incidence of cancer? The indirect linkage of breast cancer to LAN is further supported by laboratory rat experiments by David E. Blask and colleagues. Experiments involved the implanting of human MCF-7 breast cancer cell xenografts into the groins of rats and measurements were made of cancer cell growth rates, the uptake of linoleic acid (LA), and MLT levels. One group of implanted rats were placed in light-dark (12L:12D) and a second group in light-light (12L:12L) environments. Constant light suppressed MLT, increased cancer cell growth rates, and increased LA uptake into cancer cells. The opposite was seen in the light-dark group. The proposed mechanism is the suppression of nocturnal MLT by exposure to LAN and subsequent lack of protection by MLT on cancer cell receptor sites which allows the uptake of LA which in turn enhances the growth of cancer cells. MLT is a protective, oncostatic hormone and strong antioxidant having evolved in all plants and animals over the millennia. In vertebrates, MLT is normally produced by the pineal gland during the early morning hours of darkness, even in nocturnal animals, and is suppressed by exposure to LAN. Daily entrainment of the human circadian clock is important for good human health. These studies suggest that the proper use and color of indoor and outdoor lighting is important to the health of both humans and ecosystems. Lighting fixtures should be designed to minimize interference with normal circadian rhythms in plants and animals. New discoveries on blue-light-sensitive retinal ganglion cell light receptors that control the circadian clock and how those receptors relate to today's modern high intensity discharge (HID) lamps are discussed. There is a brief discussion of circadian rhythms and light pollution. With the precautionary principle in mind, practical suggestions are offered for better indoor and outdoor lighting practices designed to safeguard human health.

PMID: 15325001 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15311999

Physiol Res. 2004;53(4):403-8.
 
Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study.

Kus I, Sarsilmaz M, Colakoglu N, Kukne A, Ozen OA, Yilmaz B, Kelestimur H.

Department of Physiology, Medical School, Firat University, 23119 Elazig, Turkey. e-mail: hkelestimur@firat.edu.tr

Melatonin, the main hormone of the pineal gland, informs the body about the environmental light and darkness regimen, which in turn contributes to the photoperiodic adaptation of several physiological functions. Leptin, the hormone secreted mainly by adipocytes and some other tissues including the pituitary, informs the brain about the mass of adipose tissue, which plays an important role in energy homeostasis. Melatonin has been shown to decrease circulating leptin levels. It is currently not known whether melatonin has an effect on leptin synthesis in the pituitary. The aim of this study was to immunohistochemically examine the effects of pinealectomy and administration of melatonin on leptin production in the rat anterior pituitary. The pituitary samples obtained from 18 male Wistar rats including sham-pinealectomized, pinealectomized and melatonin-injected pinealectomized groups were immunohistochemically evaluated. Immunostaining of leptin was moderate (3+) in sham-pinealectomized rats, heavy (5+) in pinealectomized rats and low (1+) in melatonin-treated pinealectomized rats, respectively. The present results indicate that pinealectomy induces leptin secretion in anterior pituitary cells, and this increase of leptin synthesis can be prevented by administration of melatonin. Thus, melatonin seems to have both physiological and pharmacological effects on leptin production in the anterior pituitary of male rats.

PMID: 15311999 [PubMed - in process]


http://www.fluoridealert.org/pesticides/pineal.aug.20.2004.york.pa.htm

August 20, 2004

News article published by the York Dispatch (Pennsylvania)

Relief from darkness. Brain surgery at 13.

By Megan Shirey

A 15 year old girl "suffered from a symptomatic pineal brain lesion since age 9. She had severe headaches and vision problems and was very sensitive to light ..."


http://www.fluoridealert.org/pesticides/pineal.nih.aug.12.2004.htm

August 12, 2004.

Press Release from US National Institutes of Health

Pineal Gland Evolved To Improve Vision, According To Theory By NICHD Scientist. Theory May Increase Understanding of Eye Disease, Sleep Disorders.

The pineal gland — which regulates the cycles of sleep and waking — appears to have evolved as an indirect way to improve vision, by keeping toxic compounds away from the eye, according to a new theory by a researcher at the National Institute of Child Health and Human Development at the National Institutes of Health. The theory has implications for understanding macular degeneration, a condition causing vision loss in people age 60 and older. The theory is described in the August Journal of Biological Rhythms and represents the work of David Klein, Ph.D., Chief of NICHD's Section on Neuroendocrinology. Dr. Klein studies melatonin, the pineal hormone that regulates sleep and wake cycles ... Briefly, the theory holds that melatonin was at first a kind of cellular garbage, a by-product created in cells of the eye when normally toxic substances were rendered harmless. Roughly 500 million years ago, however, the ancestors of today's animals became dependent on melatonin as a signal of darkness. As the need for greater quantities of melatonin grew, the pineal gland developed as a structure separate from the eyes, to keep the toxic substances needed to make melatonin away from sensitive eye tissue ...


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15302263

Gen Comp Endocrinol. 2004 Sep;138(2):139-47.

Duality of serotonin-N-acetyltransferase in the gilthead seabream (Sparus aurata): molecular cloning and characterization of recombinant enzymes.

Zilberman-Peled B, Benhar I, Coon SL, Ron B, Gothilf Y.

Department of Zoology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

Serotonin-N-acetyltransferase (arylalkylamine-N-acetyltransferase, AANAT) is the key enzyme in the biosynthesis of melatonin in the pineal gland and retinal photoreceptors. Rhythmic AANAT activity drives rhythmic melatonin production in these tissues. The presence of two AANATs, AANAT1 and AANAT2, has been previously demonstrated in three fresh water teleosts. This duality, the result of early gene duplication, is unique to teleost species. In this study, the cDNAs encoding for AANAT1 and AANAT2 were cloned from a marine fish, the gilthead seabream (sb, Sparus aurata). Northern blot hybridization analysis indicates that sbAANAT1 and sbAANAT2 are exclusively expressed in the retina and pineal gland, respectively. Bacterially expressed recombinant sbAANATs exhibit differential enzyme kinetics. Recombinant retinal sbAANAT1 has relatively high substrate affinity and low activity rate; it is inhibited by high substrate and product concentrations. In contrast, recombinant pineal sbAANAT2 exhibits low substrate affinity and high activity rate and is not inhibited by substrates or products. The two recombinant enzymes also exhibit differential substrate preference. Retinal sbAANAT1 acetylates a range of arylalkylamines while pineal sbAANAT2 preferentially acetylates indoleethylamines, especially serotonin. The different spatial expression patterns, enzyme kinetics, and substrate preferences of the two sbAANATs support the hypothesis that, as a consequence of gene duplication, teleosts have acquired two AANATs with different functions. Pineal AANAT2 specializes in the production of large amounts of melatonin that is released into the circulation and exerts an endocrine role. Retinal AANAT1, on the other hand, is involved in producing low levels of melatonin that execute a paracrine function. In addition, retinal AANAT1 may carry out an as yet unknown function that involves acetylation of arylalkylamines other than serotonin.

PMID: 15302263 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15266411

Pediatr Blood Cancer. 2004 Sep;43(3):261-6.
 
Pineal gland abnormalities in Langerhans cell histiocytosis.

Grois N, Prosch H, Waldhauser F, Minkov M, Strasser G, Steiner M, Unger E, Prayer D.

Children's Cancer Research Institute, St. Anna Children's Hospital, Vienna, Austria.

BACKGROUND: The most common types of central nervous system (CNS) disease in Langerhans cell histiocytosis (LCH) comprise involvement of the hypothalamic-pituitary region (HPR) and neurodegenerative changes in the cerebellum, basal ganglia or pons. In the review process of magnetic resonance images (MRI) from 129 LCH patients a high frequency of cysts within or large pineal glands was noted by chance.
PROCEDURE: To prove whether this observation was specific for LCH or not, we compared MRI findings of the HPR in LCH patients with a control group of 55 non-LCH patients with the same age and sex distribution.
RESULTS: In LCH patients, the pineal gland was significantly larger and also the number of pineal cysts was significantly higher as compared to the control group. No difference was found regarding the size or frequency of cystic changes between patients who had received chemotherapy prior to the MRI and untreated patients. In the LCH patients, we further found a significant correlation of pineal gland enlargement with involvement of the HPR, but not with neurodegenerative changes. Analysis of melatonin (the principal hormone of the pineal gland) levels in 24 hr urine in 14 LCH patients did not reveal a melatonin deficiency or overproduction in the LCH group as compared to 6 normal controls.
CONCLUSIONS: The pineal gland is another site of possible CNS involvement in LCH. LCH CNS patients did not show an overt disturbance in melatonin levels. The role of the pineal gland in CNS LCH remains to be defined. Copyright 2004 Wiley-Liss, Inc.

PMID: 15266411 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15255933

J Neurochem. 2004 Aug;90(3):559-66.

In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus.

Anhe GF, Caperuto LC, Pereira-Da-Silva M, Souza LC, Hirata AE, Velloso LA, Cipolla-Neto J, Carvalho CR.

Departamento de Fisiologia e Biofisica, ICB, USP, Sao Paulo, Brazil.

Melatonin is the pineal hormone that acts via a pertussis toxin-sensitive G-protein to inhibit adenylate cyclase. However, the intracellular signalling effects of melatonin are not completely understood. Melatonin receptors are mainly present in the suprachiasmatic nucleus (SCN) and pars tuberalis of both humans and rats. The SCN directly controls, amongst other mechanisms, the circadian rhythm of plasma glucose concentration. In this study, using immunoprecipitation and immunoblotting, we show that melatonin induces rapid tyrosine phosphorylation and activation of the insulin receptor beta-subunit tyrosine kinase (IR) in the rat hypothalamic suprachiasmatic region. Upon IR activation, tyrosine phosphorylation of IRS-1 was detected. In addition, melatonin induced IRS-1/PI3-kinase and IRS-1/SHP-2 associations and downstream AKT serine phosphorylation and MAPK (mitogen-activated protein kinase) phosphorylation, respectively. These results not only indicate a new signal transduction pathway for melatonin, but also a potential cross-talk between melatonin and insulin.

PMID: 15255933 [PubMed - in process]


Full free report available at http://endo.endojournals.org/cgi/rapidpdf/en.2004-0864v1

Endocrinology. 2004 Aug 5 [Epub ahead of print]
 
ADRENERGIC REGULATION AND DIURNAL RHYTHM OF p38 MITOGEN-ACTIVATED PROTEIN KINASE PHOSPHORYLATION IN THE RAT PINEAL GLAND.

Chik CL, Mackova M, Price D, Ho AK.

Department of Physiology and Department of Medicine (C.L.C.), Faculty of Medicine and Dentistry, University of Alberta, 7-26 Medical Sciences Building, Edmonton, Alberta T6G 2H7, CANADA.

In this study, we investigated adrenergic and photoneural regulation of p38MAPK phosphorylation in the rat pineal gland. Norepinephrine (NE), the endogenous neurotransmitter, dose-dependently increased the levels of phosphorylated MAPK kinase 3/6 (MKK3/6) and p38MAPK in rat pinealocytes. Time-course studies showed a gradual increase in MKK3/6 and p38MAPK phosphorylation that peaked between 1 and 2 h and persisted for 4 h post NE-stimulation. In cells treated with NE for 2 and 4 h, the inclusion of prazosin or propranolol reduced NE-induced MKK3/6 and p38MAPK phosphorylation, indicating involvement of both alpha- and beta-adrenergic receptors for the sustained response. Whereas treatment with (Bu)2cAMP or ionomycin mimicked the NE-induced MKK3/6 and p38MAPK phosphorylation, neither (Bu)2cGMP nor 4beta-phorbol 12-myristate 13-acetate had an effect. The NE-induced increase in MKK3/6 and p38MAPK phosphorylation was blocked by KT5720 (a protein kinase A inhibitor) and KN93 (a Ca(2+)/calmodulin-dependent kinase inhibitor), but not by KT5823 (a protein kinase G inhibitor) or calphostin C (a protein kinase C inhibitor). In animals housed under a lighting regimen with 12 h of light, MKK3/6 and p38MAPK phosphorylation increased in the rat pineal gland at zeitgeber time 18. The nocturnal increase in p38MAPK phosphorylation was blocked by exposing the animal to constant light and reduced by treatment with propranolol, a beta-adrenergic blocker. Together, our results indicate that activation of p38MAPK is under photoneural control in the rat pineal gland and that protein kinase A and intracellular Ca(2+) signaling pathways are involved in NE regulation of p38MAPK.

PMID: 15297444 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15288644

Micron. 2004;35(8):655-70.
 
Bizarre alterations of the morphology of pineal synaptic bodies under constant light and an evaluation of suitable 3D-reconstruction software.

Jastrow H, Schmanke D, Weinert J.

Department of Anatomy, University of Mainz, Becherweg 13, D-55128 Mainz, Germany.

Three dimensional (3D) reconstruction and modelling software was evaluated to find a procedure suitable for visualization of small subcellular structures in transmission electron microscope images. The method applied in this study demonstrates bizarre alterations of the structure of synaptic bodies (SBs) in pinealocytes of the guinea-pig pineal gland caused by constant illumination. It can, in general, be used for any 3D reconstruction from serial sections. Pineal glands of five guinea-pigs (two kept under a LD cycle of 12:12 h; three kept in constant light, for 4 months) were investigated. SBs consist of an electron-dense centre with attached vesicles. Under normal lighting conditions most SBs are flat plates (about 35 nm in thickness), which eventually may be bent. The proteins comprising the molecular basis of SBs, mainly RIBEYE A and B are polymerised in a regular manner in these plates. This is not the case in other SBs, which appear as spheres or irregular lumps. SBs lie in groups in which usually some of the plates are arranged in parallel arrays Constant illumination caused different changes in morphology: many of the SBs lie in 'paired fields', i.e. appear in groups attached to the cell membranes of two pinealocytes directly opposite to each other. Some of the SBs in such groups are strongly bent, showing blebs and irregular thickened areas, others seem to aggregate and show inclusions of cytoplasm. Further goblet-like, shield-like and other bizarre forms of SBs occurred and the relative number of spheroid and lump-like SBs increased. Protrusions on larger SBs suggest detachment or fusion of SB material to a greater extent than in the control animals. There is a reduction of areas in which the polymerisation of the SB proteins remains well ordered, i.e. where the typical thickness of 35 nm is maintained. It remains unclear why this polymerisation pattern is only partly affected by constant light.

PMID: 15288644 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15287450

J Neurosurg Spine. 2004 May;100(5):430-6.

Neuroendoscopic findings in patients with intracranial germinomas correlating with diabetes insipidus.

Wellons JC 3rd, Reddy AT, Tubbs RS, Abdullatif H, Oakes WJ, Blount JP, Grabb PA.

Section of Pediatric Neurosurgery, and Divisions of Pediatric Hematology/Oncology and Pediatric Endocrinology, Children's Hospital, Birmingham, Alabama 35233, USA.

OBJECT: Intracranial germinomas commonly occur in the pineal region, the floor of the third ventricle (hypothalamus), or both, and they are often associated with diabetes insipidus (DI). The authors conducted a study to correlate preoperative DI with the endoscopic and magnetic resonance (MR) imaging evidence of tumor on the third ventricle floor.
METHODS: The authors reviewed hospital records, office charts, and MR imaging studies obtained in patients in whom a biopsy sampling procedure was performed with or without endoscopic third ventriculostomy (ETV) at Children's Hospital, Birmingham, Alabama between May 1998 and July 2002. Ten patients with the pathological diagnosis of pure germinoma were identified. Preoperative MR imaging findings and presenting symptoms were correlated with intraoperative neuroendoscopic findings. Seven patients presented with symptomatic hydrocephalus and underwent concomitant ETV. Six patients presented with DI and MR imaging evidence of involvement of the third ventricle floor. Two patients presented with DI and no initial MR imaging evidence of neoplastic involvement of the third ventricle floor; in both there was endoscopic evidence of neoplastic involvement of the floor of the third ventricle. In two children without DI, neither MR imaging nor endoscopic evidence of involvement of the third ventricle floor was observed.
CONCLUSIONS: In the authors' experience with intracranial germinoma, endoscopic tumor biopsy sampling, and ETV provide an effective, safe, and minimally invasive means of obtaining diagnostic tissue and treating any concomitant hydrocephalus. The authors found that preoperative DI is an absolute predictor of neoplastic involvement of the hypothalamus regardless of MR imaging findings. Therefore, in the setting of DI and intracranial germinoma without neuroimaging evidence of hypothalamic involvement, germinomatous involvement of the hypothalamus should be assumed present, if not confirmed endoscopically at the time of biopsy sampling or third ventriculostomy, when devising adjuvant treatment plans for such patients.

PMID: 15287450 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15280413

J Clin Pathol. 2004 Aug;57(8):882-4.
 
Pineal yolk sac tumour with a solid pattern: a case report in a Chinese adult man with Down's syndrome.

Tan HW, Ty A, Goh SG, Wong MC, Hong A, Chuah KL.

Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore.

Intracranial germ cell tumours are rare. The incidence of primary intracranial yolk sac tumour is even more uncommon, with only two reported cases being associated with Down's syndrome in the English literature. This report details the findings of yolk sac tumour in the pineal region affecting a 22 year old Chinese man with Down's syndrome. Histology revealed yolk sac tumour with only a solid pattern, potentially mimicking the more common germinoma in the pineal region. No other germ cell components were identified. This is the third report of intracranial yolk sac tumour manifesting in a patient with trisomy 21. The pathology of this tumour and its differential diagnoses are discussed.

PMID: 15280413 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15247319

Mol Pharmacol. 2004 Jul 9 [Epub ahead of print]
 
The Nicotinic Receptor in the Rat Pineal Gland is an {alpha}3 {beta}4 Subtype.

Hernandez SC, Vicini S, Xiao Y, Davila-Garcia MI, Yasuda R, Wolfe BB, Kellar KJ.

Georgetown University School of Medicine.

The rat pineal gland contains a high density of neuronal nicotinic receptors (nAChRs). We characterized the pharmacology of the binding sites and function of these receptors, measured the nAChR subunit mRNA and used subunit-specific antibodies to establish the receptor subtype as defined by subunit composition. In ligand binding studies, [(3)H]epibatidine binds with an affinity of approximately 100 pM to nAChRs in the pineal, and the density of these sites is approximately 5-times that in rat cerebral cortex. The affinities of nicotinic drugs for binding sites in the pineal gland are similar to those at alpha3 beta4 nAChRs heterologously expressed in HEK293 cells. In functional studies, the potencies and efficacies of nicotinic drugs to activate or block whole cell currents in dissociated pinealocytes match closely their potencies and efficacies to activate or block (86)Rb(+) efflux in the cells expressing heterologous alpha3 beta4 nAChRs. Measurements of mRNA indicated the presence of transcripts for alpha3, beta2 and beta4 nAChR subunits but not those for alpha2, alpha4, alpha5, alpha6, alpha7, or beta3 subunits. Immunoprecipitation with subunit-specific antibodies showed that virtually all [(3)H]EB-labeled nAChRs contained alpha3 and beta4 subunits associated in one complex. The beta2 subunit was not associated with this complex. Taken together, these results indicate that virtually all of the nAChRs in the rat pineal gland are the alpha3 beta4 nAChR subtype, and that the pineal gland can therefore serve as an excellent and convenient model in which to study the pharmacology and function of these receptors in a native tissue

PMID: 15247319 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15230869

J Pineal Res. 2004 Aug;37(1):55-70.
 
Visualization of the antioxidative effects of melatonin at the mitochondrial level during oxidative stress-induced apoptosis of rat brain astrocytes.

Jou MJ, Peng TI, Reiter RJ, Jou SB, Wu HY, Wen ST.

Department of Physiology and Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.

Oxidative stress-induced mitochondrial dysfunction has been shown to play a crucial role in the pathogenesis of a wide range of diseases. Protecting mitochondrial function, therefore, is vital for cells to survive during these disease processes. In this study, we demonstrate that melatonin, a chief secretory product of the pineal gland, readily rescued mitochondria from oxidative stress-induced dysfunction and effectively prevented subsequent apoptotic events and death in rat brain astrocytes (RBA-1). The early protection provided by melatonin in mitochondria of intact living cells was investigated by the application of time-lapse conventional, confocal, and multiphoton fluorescent imaging microscopy coupled with noninvasive mitochondria-targeted fluorescent probes. In particular, we observed that melatonin effectively prevented exogenously applied H(2)O(2)-induced mitochondrial swelling in rat brain astrocytes at an early time point (within 10 min) and subsequently reduced apoptotic cell death (150 min later). Other early apoptotic events such as plasma membrane exposure of phosphatidyl serine and the positive YOPRO-1 staining of the early apoptotic nucleus were also prevented by melatonin. A mechanistic study at the mitochondrial level related to the early protection provided by melatonin revealed that the indole molecule significantly reduced mitochondrial reactive oxygen species (ROS) formation induced by H(2)O(2) stress. Melatonin also prevented mitochondrial ROS generation caused by other organic hydroperoxides including tert-butyl hydroperoxide and cumene hydroperoxide. This antioxidative effect of melatonin is more potent than that of vitamin E. Via its ability to reduce mitochondrial ROS generation, melatonin prevented H(2)O(2)-induced mitochondrial calcium overload, mitochondrial membrane potential depolarization, and the opening of the mitochondrial permeability transition (MPT) pore. As a result, melatonin blocked MPT-dependent cytochrome c release, the downstream activation of caspase 3, the condensation and karyorrhexis of the nucleus and apoptotic fragmentation of nuclear DNA. Thus, the powerful mitochondrial protection provided by melatonin reinforces its therapeutic potential to combat a variety of oxidative stress-induced mitochondrial dysfunctions as well as mitochondria-mediated apoptosis in various diseases.

PMID: 15230869 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15230865

J Pineal Res. 2004 Aug;37(1):26-35.
 
Estrogen modulation of adrenoceptor responsiveness in the female rat pineal gland: differential expression of intracellular estrogen receptors.

Sanchez JJ, Abreu P, Gonzalez-Hernandez T, Hernandez A, Prieto L, Alonso R.

Department of Physiology (Laboratory of Cellular Neurobiology), University of La Laguna School of Medicine and Institute of Biomedical Technologies, La Laguna, Sta Cruz de Tenerife, Spain.

The effect of different doses of 17beta-estradiol (E(2)) on the pineal response to beta-adrenoceptor stimulation in female rats was examined. Pinealocytes from 21-day-old ovariectomized rats were exposed to different estrogen doses and treated with beta-adrenergic agonists. Estrogen treatment produced a dose-dependent, biphasic response to beta-adrenoceptor-induced accumulation of cAMP. This effect was inhibitory at estrogen doses up to 0.1 nm and fitted to a negative exponential curve, while at doses from 0.1 to 100 nm the effect was stimulatory and fitted to a standard positive hyperbola. For in vivo studies, ovariectomized rats were treated with equivalent estrogen concentrations plus a single dose of progesterone (250 microg per rat), and their pineals exposed in vitro to beta-adrenergic agonists. Low doses of E(2) (0.1-100 ng per rat) reduced both pineal cAMP accumulation and N-acetyltransferase activity after beta-adrenoceptor stimulation, while a high dose (10 microg per rat) induced the opposite response. Apparently, the final estrogen target was the pineal beta-adrenergic receptor, as a low dose of E(2) (which had diminished cAMP accumulation after beta-adrenoceptor stimulation) also reduced its maximal binding capacity (B(max)) and its dissociation constant (K(d)). We also found that the female rat pineal gland contains two different ER subtypes, alpha and beta, which respond to estrogen exposure with nucleocytoplasmic shuttling. These results indicate that, in the female rat, estrogen directly modulates pineal sensitivity to adrenergic stimulation in a complex, dose-dependent manner that may be related to differential expression and activity of two estrogen receptor subtypes within pineal cells.

PMID: 15230865 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15203247

Peptides. 2004 Jun;25(6):997-1004.
 
Seasonal changes of SP and NKA in frontal cortex, striatum and testes in the rat. Role of maternal pineal gland.

Vazquez Moreno N, Debeljuk L, Diaz Rodriguez E, Fernandez Alvarez C, Diaz Lopez B.

Dpto. Biologia Funcional, Area Fisiologia, Facultad de Medicina, Universidad de Oviedo, C/Julian Claveria, No. 6, 33006 Oviedo, Spain.

The concentrations of neurokinin A (NKA) and substance P (SP), members of tachykinins family, have been studied in all seasons of the year in frontal cortex, striatum and testes of male offspring 21-, 31-, or 60 days old of mother Wistar rats: control, pinealectomized (PIN-X) and pinealectomized + melatonin during pregnancy (PIN- [Formula: see text] ) kept under 12h:12h L:D. Control-offspring: in spite of having been kept under constant environmental conditions throughout the year, had marked differences in tachykinin concentrations. The highest tachykinin concentrations in the frontal cortex were found in summer and fall and the lowest in winter and spring. Maternal PIN-X resulted in alterations of this developmental pattern, mainly in PIN-X- and PIN- [Formula: see text] -offspring in which the highest tachykinin concentrations at 21 and 31 days of age were only observed during summer. The alterations were observed up to 60 days of age for both tachykinins, when at this age control-offspring showed similar NKA concentrations. Seasonal variations were still observed in PIN-X- and PIN- [Formula: see text] -offspring. In striatum and testes no mayor modifications throughout the four seasons of the year were found, with very few exceptions. PIN-X did not alter tachykinin concentrations, neither treatment with melatonin did it. In conclusion, our data clearly indicate for the first time that NKA and SP do indeed have seasonal rhythms in frontal cortex and that the maternal pineal gland plays a role in their entrainment already during fetal life.

PMID: 15203247 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15183467

Int J Radiat Oncol Biol Phys. 2004 Jul 1;59(3):639-53.
 
Melatonin as a radioprotective agent: a review.

Vijayalaxmi, Reiter RJ, Tan DX, Herman TS, Thomas CR Jr.

Department of Radiation Oncology, The University of Texas Health Science Center, San Antonio, Texas, USA.

Melatonin (N-acetyl-5-methoxytryptamine), the chief secretory product of the pineal gland in the brain, is well known for its functional versatility. In hundreds of investigations, melatonin has been documented as a direct free radical scavenger and an indirect antioxidant, as well as an important immunomodulatory agent. The radical scavenging ability of melatonin is believed to work via electron donation to detoxify a variety of reactive oxygen and nitrogen species, including the highly toxic hydroxyl radical. It has long been recognized that the damaging effects of ionizing radiation are brought about by both direct and indirect mechanisms. The direct action produces disruption of sensitive molecules in the cells, whereas the indirect effects ( approximately 70%) result from its interaction with water molecules, which results in the production of highly reactive free radicals such as (.)OH, (.)H, and e(aq)(-) and their subsequent action on subcellular structures. The hydroxyl radical scavenging ability of melatonin was used as a rationale to determine its radioprotective efficiency. Indeed, the results from many in vitro and in vivo investigations have confirmed that melatonin protects mammalian cells from the toxic effects of ionizing radiation. Furthermore, several clinical reports indicate that melatonin administration, either alone or in combination with traditional radiotherapy, results in a favorable efficacy:toxicity ratio during the treatment of human cancers. This article reviews the literature from laboratory investigations that document the ability of melatonin to scavenge a variety of free radicals (including the hydroxyl radical induced by ionizing radiation) and summarizes the evidence that should be used to design larger translational research-based clinical trials using melatonin as a radioprotector and also in cancer radiotherapy. The potential use of melatonin for protecting individuals from radiation terrorism is also considered.

PMID: 15183467 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15183204

J Chem Neuroanat. 2004 Jun;27(3):193-200.
 
Immunolocalisation of endothelin-1 in human brain.

Naidoo V, Naidoo S, Raidoo DM.

Department of Pharmacology, Nelson R Mandela School of Medicine, University of Natal, South Africa.

The potent vasoconstrictor endothelin-1 (ET-1) may function as a neuropeptide and be a contributing factor in some neurological disorders, e.g. Alzheimer's dementia. The presence of ET-1 has been studied more extensively in the rat and porcine nervous systems than in the human brain. Also, the recent description of the extensive ET-1 mRNA localisation in human neural tissue supports expression in regions of human brain not previously investigated. Using specific anti-ET-1 polyclonal antiserum, we immunolocalised ET-1 in 24 regions of human brain autopsy tissues, and correlated this with ET-1 mRNA distribution. ET-1 immunoreactivity was observed within some cells of all the 24 areas examined. Neuronal staining for ET-1 was demonstrated within the diencephalon, brainstem, basal nuclei, cerebral cortex, cerebellar hemisphere, amygdala and hippocampus. In addition, ET-1 immunolabelling was visualised in the pituitary gland as well as in the choroid plexus. The primary sensory cortex and pineal gland also contained immunoreactive ET-1, although ET-1 mRNA had never been detected in these regions previously. The localisation of ET-1 and its subsequent correlation with ET-1 mRNA in most of the regions investigated suggest a more extensive distribution of the ET system in the human brain than was previously identified.

PMID: 15183204 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15214647

Clin Oncol (R Coll Radiol). 2004 Jun;16(4):244-7.

Pineal parenchymal tumours: II. On the aggressive behaviour of pineoblastoma in patients with an inherited mutation of the RB1 gene.

Plowman PN, Pizer B, Kingston JE.

Department of Clinical Oncology, St Bartholomew's Hospital, London, UK.
NickPlowman@Bartsandthelondon.nhs.uk

This report relates to a retrospective analysis of two non-randomised cohorts of patients with pineoblastoma, with some differences in presenting features and treatment characteristics. We have identified a large difference in survival depending on the possession or otherwise of the mutated RB (retinoblastoma) gene in the genome/karyotype. Eight children with familial retinoblastoma (non-metastatic at presentation) developed pineoblastoma and were treated by chemotherapy and radiotherapy. The survival of these patients was compared with the survival of nine non-metastatic sporadic cases of pineoblastoma similarly staged and treated. One out of eight children having the RB mutation in the genome survived compared with seven out of nine in the group with sporadic pineoblastoma (P = 0.002). It is suggested that the inheritance of the mutated retinoblastoma gene is not only causal in the generation of this tumour type but, in a way that is yet to be defined, renders such tumours more aggressive or less responsive to therapy. With the current interest in the role of RB mutations in other cancers (where the prognostic import of single genes is less easily identified), this observation may have wider relevance.

PMID: 15214647 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15193530

Brain Res. 2004 Jul 9;1013(2):204-11.
 
Signal transmission from the suprachiasmatic nucleus to the pineal gland via the paraventricular nucleus: analysed from arg-vasopressin peptide, rPer2 mRNA and AVP mRNA changes and pineal AA-NAT mRNA after the melatonin injection during light and dark periods.

Isobe Y, Nishino H.

Department of Neuro-physiology and Brain Sciences, Nagoya City University, Graduate School of Medical Sciences, Mizuho, Nagoya 467-8601, Japan.

Arg-vasopressin (AVP) containing neurons are one of the output paths from the suprachiasmatic nucleus (SCN), the center of the biological clock. AVP mRNA transcription is controlled by a negative feedback loop of clock genes. Circadian rhythm of melatonin release from the pineal gland is regulated by the SCN via the paraventricular nucleus (PVN). To clarify the transduction system of circadian signals from the SCN to the pineal gland, we determined the effects of melatonin injection (1 mg/kg, i.p.) during light and dark periods on Per2 and AVP mRNAs in the SCN and PVN, in addition to arylalkylamine N-acetyltransferase (AA-NAT) and inducible cAMP early repressor (ICER) mRNAs in the pineal gland of rats using RT-PCR. AVP peptide contents were also measured in the SCN and PVN. AVP content in the SCN decreased during the light period, while no changes were observed in the PVN. In the SCN, Per2 mRNA increased during both light and dark periods. In the PVN, Per2 decreased during the light period and increased during the dark period at 180 min after melatonin injection. In the pineal gland, Per2 mRNA increased between 60 and 180 min after the melatonin injection during the light period, while it did not significantly change during the dark period. The AA-NAT mRNA varied similar to the Per2 mRNA changes. These results might suggest that the different responses to melatonin in the pineal gland during the light and dark periods was originated in the changes of Per2 in the PVN via SCN.

PMID: 15193530 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15217395

Eur J Neurosci. 2004 Jun;19(12):3382-8.

Clock gene mRNA and protein rhythms in the pineal gland of mice.

Karolczak M, Burbach GJ, Sties G, Korf HW, Stehle JH.

Dr Senckenbergische Anatomie, Institute of Anatomy II, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.

In vertebrates, the rhythmic transcription of clock genes, regulated by their own gene products, provides the basis for self-sustaining circadian clockworks. These endogenous clocks are lost in most mammalian tissues, but not in the central pacemaker of the hypothalamic suprachiasmatic nucleus (SCN). An interesting model system to understand this phylogenetic shift in function of clock gene products is the rodent pineal gland, as its intrinsic clockwork was replaced during evolution by an input-dependent oscillator. By means of immunohistochemistry, immunoblotting and real time PCR, we investigated the day/night expression profiles of all major clock genes and their products in the pineal gland of one melatonin-proficient and one melatonin-deficient mouse strain. All clockwork elements known to be indispensable for a sustained rhythm generation in the SCN were also found in the pineal organ of both mouse strains. Only mPer1 mRNA and PER1 protein accumulation coincides with timecourses of many other pineal genes and their products, which are cyclicAMP inducible. Here, presented data together with the known mechanisms for regulation of the mPer1 gene in the rodent pineal gland forward the idea that in this tissue PER1 may have a trigger function for initiating the cycles of the clockwork's transcriptional/translational feedback loops.

PMID: 15217395 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15170901

Pediatr Blood Cancer. 2004 Jul;43(1):95.
 
Pineal dysfunction in Langerhans cell histiocytosis?

Imashuku S, Morimoto Y, Yamamoto T, Morimoto A, Hibi S, Todo S.

No abstract available

Kyoto City Institute of Health, and Environmental Sciences, Kyoto, Japan.

PMID: 15170901 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14967883

Clin Hemorheol Microcirc. 2004;30(1):47-52.
 
Hemorheology, melatonin and pinealectomy. What's the relationship? An experimental study.

Berker M, Dikmenoglu N, Bozkurt G, Ergonul Z, Ozgen T.

Department of Neurosurgery, Hacettepe University School of Medicine, Ankara, Turkey. mberker@hacettepe.edu.tr

The circadian rhythm of stroke and myocardial infarction (MI) may be related to the circadian rhythm of melatonin, and erythrocyte deformability may be the key mechanism in this relationship. Therefore, this study has been performed to determine if there is a relationship between the pineal gland and melatonin and red cell deformability. Twenty-eight rats underwent pinealectomy, pinealectomy plus melatonin administration (200 mg/kg), or no treatment (n=7 in each group). Erythrocyte deformability was determined using the filtration technique. The results are reported in mean (+/-SD) seconds: control: 1.45+/-0.44; pinealectomy (A): 1.55+/-0.16; pinealectomy (B): 1.34+/-0.26 and pinealectomy and melatonin: 2.56+/-0.69. Pinealectomy by itself did not cause any statistically significant change in erythrocyte deformability but the addition of melatonin significantly decreased it. These results suggest a relationship between melatonin and erythrocyte deformability. Further investigations may uncover the causes of the circadian rhythm of stroke and MI, which may help improve chronobiological therapies.

PMID: 14967883 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14985420

J Neurosci. 2004 Feb 25;24(8):1803-11.
 
Gating of the cAMP signaling cascade and melatonin synthesis by the circadian clock in mammalian retina.

Fukuhara C, Liu C, Ivanova TN, Chan GC, Storm DR, Iuvone PM, Tosini G.

Neuroscience Institute and National Science Foundation Center for Behavioral Neuroscience, Morehouse School of Medicine, Atlanta, Georgia 30310-1495, USA.

Melatonin is synthesized in retinal photoreceptor cells and acts as a neuromodulator imparting photoperiodic information to the retina. The synthesis of melatonin is controlled by an ocular circadian clock and by light in a finely tuned mechanism that ensures that melatonin is synthesized and acts only at night in darkness. Here we report that the circadian clock gates melatonin synthesis in part by regulating the expression of the type 1 adenylyl cyclase (AC1) and the synthesis of cAMP in photoreceptor cells. This gating is effected through E-box-mediated transcriptional activation of the AC1 gene, which undergoes robust daily fluctuations that persist in constant illumination. The circadian control of the cAMP signaling cascade indicates that the clock has a more general and profound impact on retinal functions than previously thought. In addition, rhythmic control of AC1 expression was observed in other parts of the central circadian axis, the suprachiasmatic nucleus and pineal gland, but not in other brain areas examined. Thus, clock control of the cAMP signaling cascade may play a central role in the integration of circadian signals that control physiology and behavior.

PMID: 14985420 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14986306

J Comp Neurol. 2004 Mar 29;471(2):113-27.
 
Demonstration of an orexinergic central innervation of the pineal gland of the pig.

Fabris C, Cozzi B, Hay-Schmidt A, Naver B, Moller M.

Department of Experimental Veterinary Science, University of Padua, I-35020 Legnaro, Italy. chiara.fabris@unipd.it

Orexins/hypocretins, two isoforms of the same prepropeptide, are widely distributed throughout the brain and are involved in several physiological and neuroendocrine regulatory patterns, mostly related to feeding, sleep, arousal, and cyclic sleep-wake behaviors. Orexin-A and orexin-B bind with different affinities to two G-protein-coupled transmembrane receptors, orexin-1 and orexin-2 receptors (OR-R1 and OR-R2, respectively). Because of the similarities between the human and the swine brain, we have studied the pig to investigate the orexinergic system in the diencephalon, with special emphasis on the neuroanatomical projections to the epithalamic region. By using antibodies against orexin-A and orexin-B, immunoreactive large multipolar perikarya were detected in the hypothalamic periventricular and perifornical areas at the light and electron microscopic levels. In the region of the paraventricular nucleus, the orexinergic neurons extended all the way to the lateral hypothalamic area. Immunoreactive nerve fibers, often endowed with large varicosities, were found throughout the hypothalamus and the epithalamus. Some periventricular immunoreactive nerve fibers entered the epithalamic region and continued into the pineal stalk and parenchyma to disperse among the pinealocytes. Immunoelectron microscopy confirmed the presence of orexinergic nerve fibers in the pig pineal gland. After extraction of total mRNA from the hypothalamus and pineal gland, we performed RT-PCR and nested PCR using primers specific for porcine orexin receptors. PCR products were sequenced, verifying the presence of both OR-R1 and OR-R2 in the tissues investigated. These findings, supported by previous studies on rodents, suggest a hypothalamic regulation of the pineal gland via central orexinergic nervous inputs. Copyright 2004 Wiley-Liss, Inc.

PMID: 14986306 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15032620

Curr Drug Targets Immune Endocr Metabol Disord. 2004 Mar;4(1):1-10.

Melatonin role in experimental arthritis.

Cardinali DP, Garcia AP, Cano P, Esquifino AI.

Departamento de Fisiologia, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. cardinal@mail.retina.ar

Our perception of the function of the pineal gland and its hormone melatonin has attained a new dimension during the last decade. Through melatonin, the pineal becomes a principal organ present in vertebrates involved in the control of rhythmic adaptations to daily and seasonal cycles. Melatonin is synthesized and secreted during the dark period of the light/dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system than can "read" the message. Melatonin acts as an arm of the circadian clock, giving a time-related signal to a number of body functions; one of them is the circadian organization of the immune response. This review discusses melatonin role in rheumatoid arthritis. Animal studies employing Freund's complete mycobacterial adjuvant (FCA) as a model of rheumatoid arthritis are described. Immune and neuroendocrine circadian rhythms were examined in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-h organization of immune and neuroendocrine responses becomes altered. Significant effects of immune response on diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented alteration of 24-h rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin treatment prevented alteration of the 24-h variation in hypothalamic monoamine transmitter turnover during the preclinical phase of Freund's adjuvant arthritis in rats. A comparison between the inflammatory and immune responses elicited by physiological and pharmacological doses of melatonin in FCA arthritis is reported. Pinealectomized rats exhibited a significantly less pronounced inflammatory response, which was restored to normal by a low melatonin dose (0.3 microg/ml of drinking water), whereas a high melatonin dose (30 microg/ml) that resulted in a 50-60-fold increase in plasma melatonin, augmented the inflammatory and immune response. These results should be considered in the light of recent reports that rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin and that their synovial macrophages respond to melatonin with an increased cytokine production.

PMID: 15032620 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15032326

Acta Histochem. 2004 Feb;106(1):29-36.

Effects of pinealectomy and exogenous melatonin on rat hearts.

Mizrak B, Parlakpinar H, Acet A, Turkoz Y.

Department of Pathology, Faculty of Medicine, T. Ozal Medical Center, Inonu University, 44069, Malatya, Turkey. bmizrak@inonu.edu.tr

The effects of pinealectomy and administration of melatonin, the major secretory product of the pineal gland, which is a direct free radical scavenger and an indirect antioxidant, were studied in rat hearts on the basis of cardiac morphology and biochemical findings. Three groups of Wistar rats were used: one group was the sham-operated control, one group consisted of pinealectomized rats and one group consisted of pinealectomized rats that were treated with melatonin. Serum cholesterol, tissue levels of malondialdehyde (MDA) and reduced glutathione (GSH), and heart weight were determined. Histochemical staining with the Van Gieson, PAS/Alcian blue at pH 2.5 and Masson's trichrome methods were performed in addition to hematoxylin-eosin staining. Levels of serum cholesterol and tissue MDA, and heart weight were increased in pinealectomized rats whereas GSH levels did not change. Melatonin administration reversed these effects. Microscopically, myocardial fibrosis and myxomatous degeneration of cardiac valves were detected in all pinealectomized rats. It can be concluded that pinealectomy of rats causes morphological changes in rat hearts, and short-term application of melatonin does not reverse these changes.

PMID: 15032326 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15009512

J Pineal Res. 2004 Apr;36(3):204-211.

MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells.

Kadekaro AL, Andrade LN, Floeter-Winter LM, Rollag MD, Virador V, Vieira W, Castrucci AM.

Departamento de Fisiologia, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo Departamento de Parasitologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brasil Department of Anatomy and Cell Biology, Uniformed Services University of the Health Sciences, Bethesda, MD Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Melatonin, a derivative of tryptophan that is present in all vertebrates, was first described in bovine pineal gland. It is known that melatonin is a highly conserved molecule, present also in unicellular organisms and plants. Several effects of melatonin have been described, including receptor- and non-receptor-mediated actions. Herein, we studied the effects of melatonin on in vitro and in vivo cell proliferation of Cloudman S-91 murine melanoma cells. We demonstrated that melatonin treatment significantly inhibits S-91 melanoma cell proliferation in vitro (EC50 = 10-7 m) as well as reduces tumor growth in vivo. We also demonstrated that melatonin directly increases the activity of the antioxidant enzymes catalase and glutathione peroxidase. These effects are most likely triggered through the direct intracellular action of melatonin, since the presence of receptors could not be demonstrated in this cell line. Expression of MT-1 melatonin receptor by stable transfection, mediated a dramatic antiproliferative melatonin effect (EC50 = 10-10 m) in S-91 cells. The expressed receptor is negatively coupled to the adenylyl cyclase/cyclic AMP signaling pathway via Gi protein. These results suggest that expression of the MT-1 melatonin receptor in melanoma cells is a potential alternative approach to specifically target cells in cancer therapeutic treatment.

PMID: 15009512 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15009505

J Pineal Res. 2004 Apr;36(3):155-64.

Melatonin and its precursor, L-tryptophan: influence on pancreatic amylase secretion in vivo and in vitro.

Jaworek J, Nawrot K, Konturek SJ, Leja-Szpak A, Thor P, Pawlik WW.

Chair of Physiology Pathology, Jagiellonian University Collegium Medicum, Krakow, Poland.

Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from l-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or l-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or l-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or l-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK1 receptor antagonists (tarazepide or l-364,718). Pretreatment with luzindole, an antagonist of melatonin MT2 receptor failed to affect melatonin- or l-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or l-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or l-tryptophan used at doses of10-8-10-5 m. We conclude that exogenous melatonin, as well as that produced endogenously from l-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or l-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.

PMID: 15009505 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15033929

FASEB J. 2004 Mar 19 [Epub ahead of print]
 
Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin.

Andrabi SA, Sayeed I, Siemen D, Wolf G, Horn TF.

Melatonin, the secretory product of the pineal gland, is known to be neuroprotective in cerebral ischemia, which is so far mostly attributed to its antioxidant properties. Here we show that melatonin directly inhibits the mitochondrial permeability transition pore (mtPTP). mtPTP contributes to the pathology of ischemia by releasing calcium and cytochrome c (cyt c) from mitochondria. Consistently, NMDA-induced calcium rises were diminished by melatonin in cultured mouse striatal neurons, similar to the pattern seen with cyclosporine A (CsA). When the mouse striatal neurons were subjected to oxygen-glucose deprivation (OGD), melatonin strongly prevented the OGD-induced loss of the mitochondrial membrane potential. To assess the direct effect of melatonin on the mtPTP activity at the single channel level, recordings from the inner mitochondrial membrane were obtained by a patch-clamp approach using rat liver mitoplasts. Melatonin strongly inhibited mtPTP currents in a dose-dependent manner with an IC50 of 0.8 microM. If melatonin is an inhibitor of the mtPTP, it should prevent mitochondrial cyt c release as seen in stroke models. Rats underwent middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. Melatonin (10 mg/kg ip) or vehicle was given at the time of occlusion and at the time of reperfusion. Indeed, infarct area in the brain sections of melatonin-treated animals displayed a considerably decreased cyt c release along with less activation of caspase-3 and apoptotic DNA fragmentation. Melatonin treatment diminished the loss of neurons and decreased the infarct volume as compared with untreated MCAO rats. Our findings suggest that the direct inhibition of the mtPTP by melatonin may essentially contribute to its anti-apoptotic effects in transient brain ischemia. tracellular calcium * TMRM * NMDA * apoptosis * fluo-4

PMID: 15033929 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15045699

Metabolism. 2004 Apr;53(4):500-6.
 
Pinealectomy alters adipose tissue adaptability to fasting in rats.

Alonso-Vale MI, Anhe GF, Borges-Silva Cd CN, Andreotti S, Peres SB, Cipolla-Neto J, Lima FB.


This study investigated the effects of pinealectomy and fasting on rat adipose tissue metabolism, as well as on profiles of the hormones directly involved in its regulation (insulin, leptin, and corticosterone). Pinealectomized (PINX) and sham-operated (CONTROL) adult male Wistar rats were killed 6 weeks after surgery, in either fed or fasted (12 and 36 hours) states. Blood samples (for glucose and hormone determinations) and peri-epididymal adipocytes (for in vitro insulin-stimulated glucose uptake, oxidation, and incorporation into lipids) were collected. Pineal ablation decreased insulin-stimulated glucose uptake in adipocytes of both fed and fasted animals without affecting insulin-binding capacity. Pinealectomy attenuated the reduction in the ability to oxidize glucose in both basal and insulin-stimulated states during fasting. This alteration in the ability of adipocytes to oxidize glucose appeared together with a decrease in insulin-induced glucose incorporation into lipids in PINX animals. Additionally, pinealectomized rats showed higher corticosterone levels in both fed and fasted states, and a lower leptinemia with 36 hours of fasting, in comparison to CONTROLs. In conclusion, our data reinforce the hypothesis that the pineal gland has a role in the modulation of adipocyte metabolism, and its absence alters metabolic adaptation to fasting in rats.

PMID: 15045699 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15081831

Gen Comp Endocrinol. 2004 May 1;136(3):322-327.
 
Social stress affects circulating melatonin levels in rainbow trout.

Larson ET, Winberg S, Mayer I, Lepage O, Summers CH, OVerli O.

Department of Comparative Physiology, Evolutionary Biology Centre, Norbyvagen 18A, Uppsala University, SE-75236 Uppsala, Sweden.

In salmonid fishes there are indications that socially subordinate individuals avoid competition with larger, dominant fish by adjusting daily feeding and activity cycles. As in other vertebrates, the pineal organ and its hormone melatonin act as synchronizers of daily rhythms to the external light/dark cycle in salmonids. Social defeat may act as a potent stressor; inducing elevated glucocorticoid secretion and a general behavioral inhibition. Here, we show that social stress also affects circulating melatonin levels in rainbow trout, a species known to display strong dominance hierarchies both in the wild and under captive rearing. Subordinate individuals had significantly higher nighttime melatonin levels than dominant fish or controls. There was no effect of social rank on the much lower melatonin levels observed in animals sampled during the day. Correlations between circulating glucocorticoids and melatonin depended on circadian cycles as well as social context. This study suggests that altered melatonin production contributes to the physiological and behavioral profile of subordinate animals. Social status, and other determinants of the stress level of experimental animals, therefore should be taken into consideration as potential factors influencing the results from in vivo research on this hormone.

PMID: 15081831 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15053978

Gene Expr Patterns. 2004 May;4(3):297-301.

Pcp4l1, a novel gene encoding a Pcp4-like polypeptide, is expressed in specific domains of the developing brain.


Bulfone A, Caccioppoli C, Pardini C, Faedo A, Martinez S, Banfi S.

Stem Cell Research Institute (SCRI), Istituto Scientifico San Raffaele (HSR), Via Olgettina 58, Milan 20132, Italy.

We report the cloning of a novel mouse gene (Pcp4l1) that encodes a polypeptide with significant sequence similarity to the Purkinje cell protein 4 gene (Pcp4) and describe its expression pattern during mouse development. Similar to Pcp4, the Pc4l1 gene product is characterized by the presence of an IQ domain and is highly conserved across evolution. RNA in situ hybridization reveals instead that Pcp4l1 has a distinct pattern of expression: it is only expressed in the central nervous system (CNS), and is first detected at E9.5 in the mesencephalic and metencephalic roof plate as well as in the isthmus, in a region that overlaps the expression domains of Pax2, Fgf8 and Wnt1. Thus, the early Pcp4l1 expression pattern coincides with the regional expression of well-characterized patterning molecules in the organizing centers of the developing brain. Starting at midgestation, Pcp4l1 is mainly expressed in the structures of the circumventricular organs, including the subcommissural organ, the rhombencephalic and telencephalic choroid plexi, and the pineal gland. In the adult brain, this transcript is also detected in laminar as well as in several nuclear structures of the CNS.

PMID: 15053978 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14962065&dopt=Abstract

J Pineal Res. 2004 Mar;36(2):132-139.

Pinealectomy induces malformation of the spine and reduces the mechanical strength of the vertebrae in Atlantic salmon, Salmo salar.

Fjelldal PG, Grotmol S, Kryvi H, Gjerdet NR, Taranger GL, Hansen T, Porter MJ, Totland GK.

Department of Aquaculture, Institute of Marine Research, Matre Aquaculture Research Station, Matredal Departments of Zoology Odontology Biomaterials, University of Bergen, Bergen, Norway Tasmanian Aquaculture and Fisheries Institute, University of Tasmania, Hobart, Tasmania, Australia.

This study describes the long-term effects of surgical ablation of the pineal gland on the spine of 3-yr-old Atlantic salmon (Salmo salar L.) with a mean weight of 3.2 kg. Radiographic examinations showed that 82% of the pinealectomized fish developed marked lateral (scoliosis) and dorso-ventral spinal curvatures. The proportions of the individual vertebral bodies and their mechanical properties were also altered. The stiffness, yield limit and resilience of the vertebral bodies, as measured by compression in the cranio-caudal direction, were significantly lower in the pinealectomized than in the sham-pinealectomized group. Calcium, phosphorous and total mineral content of the vertebral bodies were also significantly lower in the pinealectomized fish, while these parameters were similar in scales in the two groups. Alterations of the spinal curve accompanied by changes in the proportions, mechanical strength and mineral content of the vertebral bodies of the pinealectomized salmon indicate that melatonin has several functions related to vertebral bone growth. As the lesions found in salmon are similar to the spinal malformations observed in avian species and mammals after pinealectomy, this study strengthens the hypothesis of a phylogenetically conserved function of the pineal gland related to skeletal development.

PMID: 14962065 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14960297&dopt=Abstract

Biol Psychiatry. 2004 Feb 15;55(4):428-33.
 
Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland.

Patel PD, Pontrello C, Burke S.

Mental Health Research Institute, University of Michigan Medical Center, C560 MSRB II, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0669, USA.

BACKGROUND: Regulation of raphe serotonergic cells is fundamental to the prevailing hypothesis of major depression pathophysiology. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis, but brainstem TPH mRNA expression has been difficult to measure and study. Recently, a novel paralog of TPH, TPH2 (or neuronal TPH), was described, but its anatomic expression is unknown.
METHODS: In situ hybridization histochemical survey was conducted across Sprague-Dawley rat brain for TPH1 and TPH2 mRNA. Semiquantitative techniques were used to estimate relative mRNA levels in individual cells.
RESULTS: Almost exclusively, TPH2 mRNA is expressed in raphe, in a pattern overlapping the histologically defined raphe nuclei. In sharp contrast, TPH1 (the previously known TPH) is expressed predominantly in pineal gland. There is no appreciable overlap in the expression of these paralogs. The level of TPH2 mRNA expression in individual raphe cells is approximately 2.5-fold greater than the level of TPH1 expression in pinealocytes.
CONCLUSIONS: TPH2 mRNA has an anatomic expression pattern consistent with brainstem raphe nuclei and is likely to be the gene giving rise to the majority of TPH activity in these cells. The robust expression of TPH2 in brainstem should facilitate studies on the transcriptional regulation of raphe serotonin biosynthesis.

PMID: 14960297 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14702181&dopt=Abstract

Histol Histopathol. 2004 Jan;19(1):137-42.
 
Time of origin of the rat pineal gland cells. A bromodeoxyuridine immunohistochemical study.

Calvo JL, Boya J, Carbonell AL, Garcia-Maurino JE.

Department of Histology, Faculty of Medicine, Complutense University, Madrid, Spain.

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.

PMID: 14702181 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14675126&dopt=Abstract

J Pineal Res. 2004 Jan;36(1):18-24.

Melatonin suppresses cerebral edema caused by middle cerebral artery occlusion/reperfusion in rats assessed by magnetic resonance imaging.

Torii K, Uneyama H, Nishino H, Kondoh T.

Institute of Life Sciences, Ajinomoto Co., Inc., Kawasaki Department of Physiology, Nagoya City University Medical School, Nagoya, Japan.

Melatonin, a pineal secretory product synthesized from tryptophan, has been found to be effective against neurotoxicity. The present study was aimed at demonstrating the effectiveness of melatonin in vivo in reducing ischemia-induced cerebral edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.) just prior to 1 hr of MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. In the saline-treated control rats, increases in T2-weighted signals (water content) were clearly observed in the striatum and in the cerebral cortex. In the melatonin-treated group, total volume of edema was reduced by 51.6% compared with control group (P < 0.01). The protective effect of melatonin against edema was more clearly observed in the cerebral cortex (reduced by 59.8%, P < 0.01) than in the striatum (reduced by 34.2%, P < 0.05). Edema volume in a coronal slice was the greatest at the level of the bregma. Suppression of cerebral edema by melatonin was more effective posterior than anterior to the bregma. Melatonin appeared to reduce the volume of the edematous sites rather than to shift the signal intensity distribution. The present MRI study clearly demonstrates the effectiveness of melatonin against cerebral edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments associated with ischemic stroke.

PMID: 14675126 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14717709&dopt=Abstract

Eur J Biochem. 2004 Jan;271(2):418-28.

New substrate analogues of human serotonin N-acetyltransferase produce in situ specific and potent inhibitors.

Ferry G, Ubeaud C, Mozo J, Pean C, Hennig P, Rodriguez M, Scoul C, Bonnaud A, Nosjean O, Galizzi JP, Delagrange P, Renard P, Volland JP, Yous S, Lesieur D, Boutin JA.


Pharmacologie Moleculaire et Cellulaire, Institut de Recherches SERVIER, Croissy-sur-Seine Physico-Chimie Analytique, Institut de Recherches SERVIER, Suresnes Institut de Recherches Internationales SERVIER, Courbevoie Faculte de Pharmacie, Lille, France.

Melatonin is synthesized by an enzymatic pathway, in which arylalkylamine (serotonin) N-acetyltransferase catalyzes the rate-limiting step. A previous study [Khalil, E.M., De Angelis, J., Ishii, M. & Cole, P.A. (1999) Proc. Natl Acad. Sci. USA96, 12418-12423] reported the discovery of bromoacetyltryptamine (BAT), a new type of inhibitor of this enzyme. This compound is the precursor of a potent bifunctional inhibitor (analogue of the transition state), capable of interfering with both the substrate and the cosubstrate binding sites. This inhibitor is biosynthesized by the enzyme itself in the presence of free coenzyme A. In the present report, we describe the potency of new N-halogenoacetyl derivatives leading to a strong in situ inhibition of serotonin N-acetyltransferase. The new concept behind the mechanism of action of these precursors was studied by following the biosynthesis of the inhibitor from tritiated-BAT in a living cell. The fate of tritiated-phenylethylamine (PEA), a natural substrate of the enzyme, in the presence or absence of [3H]BAT was also followed, leading to their incorporation into the reaction product or the inhibitor (N-acetyl[3H]PEA and coenzyme A-S[3H]acetyltryptamine, respectively). The biosynthesis of this bifunctional inhibitor derived from BAT was also followed by nuclear magnetic resonance during its catalytic production by the pure enzyme. In a similar manner we studied the production of another inhibitor generated from N-[2-(7-hydroxynaphth-1-yl)ethyl]bromoacetamide. New derivatives were also screened for their capacity to inhibit a purified enzyme, in addition to enzyme overexpressed in a cellular model. Some of these compounds proved to be extremely potent, with IC50s of approximately 30 nm. As these compounds, by definition, closely resemble the natural substrates of arylalkylamine N-acetyltransferase, we also show that they are potent ligands at the melatonin receptors. Nevertheless, these inhibitors form a series of pharmacological tools that could be used to understand more closely the inhibition of pineal melatonin production in vivo.

PMID: 14717709 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14698909&dopt=Abstract

Comp Biochem Physiol B Biochem Mol Biol. 2004 Jan;137(1):43-7.
 
Influence of exogenous thyroxine on plasma melatonin in juvenile Atlantic salmon (Salmo salar).

Kulczykowska E, Sokolowska E, Takvam B, Stefansson S, Ebbesson L.

Department of Genetics and Marine Biotechnology, Institute of Oceanology of Polish Academy of Sciences, Sw. Wojciecha 5 Str., 81-347 Gdynia, Poland. ewakulcz@cbmpan.gdynia.pl

One of the most clearly defined endocrine changes during the parr-smolt transformation of anadromous salmonids is an increase in plasma levels of thyroid hormones. The role of pineal hormone melatonin in timing and synchronisation of smoltification is widely discussed. The effect of administration of exogenous thyroxine (T4) on plasma melatonin was investigated in juvenile Atlantic salmon (Salmo salar) at the early stages of parr-smolt transformation. Fish were kept in fresh water under simulated-natural photoperiod and exposed to exogenous T4. Fish were sampled at 12.00 and 24.00 h from treatment and control tanks, 2 and 14 days after treatment started. Plasma melatonin and L-thyroxine were measured using RIA and competitive enzyme immunoassay, respectively. After 2 days of T4 treatment, marked difference in plasma melatonin concentration measured at 12.00 and 24.00 h was still observed in both groups. However, 2-week exposure to T4 caused a reduction in night-time plasma melatonin level and thus, probably, inhibited melatonin related time-keeping system in juvenile salmon. Additional studies are needed to clarify the mechanism of the described phenomenon.

PMID: 14698909 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14715696&dopt=Abstract

FASEB J. 2004 Jan 8 [Epub ahead of print].
 
Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance.

Carrillo-Vico A, Calvo JR, Abreu P, Lardone PJ, Garcia-Maurino S, Reiter RJ, Guerrero JM.

It has been historically assumed that the pineal gland is the major source of melatonin (N-acetyl-5-methoxytryptamine) in vertebrates. Melatonin plays a central role in fine-tuning circadian rhythms in vertebrate physiology. In addition, melatonin shows a remarkable functional versatility exhibiting antioxidant, oncostatic, antiaging, and immunomodulatory properties. Melatonin has been identified in a wide range of organisms from bacteria to human beings. Its biosynthesis from tryptophan involves four well-defined intracellular steps catalyzed by tryptophan hydroxylase, aromatic amino acid decarboxylase, serotonin-N-acetyltransferase, and hydroxyndole-O-methyltransferase. Here, for the first time, we document that both resting and phytohemagglutinin-stimulated human lymphocytes synthesize and release large amounts of melatonin, with the melatonin concentration in the medium increasing up to five times the nocturnal physiological levels in human serum. Moreover, we show that the necessary machinery to synthesize melatonin is present in human lymphocytes. Furthermore, melatonin released to the culture medium is synthesized in the cells, because blocking the enzymes required for its biosynthesis or inhibiting protein synthesis in general produced a significant reduction in melatonin release. Moreover, this inhibition caused a decrease in IL-2 production, which was restored by adding exogenous melatonin. These findings indicate that in addition to pineal gland, human lymphoid cells are an important physiological source of melatonin and that this melatonin could be involved in the regulation of the human immune system, possibly by acting as an intracrine, autocrine, and/or paracrine substance

PMID: 14715696 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14702181&dopt=Abstract

Histol Histopathol. 2004 Jan;19(1):137-42.
 
Time of origin of the rat pineal gland cells. A bromodeoxyuridine immunohistochemical study.

Calvo JL, Boya J, Carbonell AL, Garcia-Maurino JE.

Department of Histology, Faculty of Medicine, Complutense University, Madrid, Spain.

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.

PMID: 14702181 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14698909&dopt=Abstract

Comp Biochem Physiol B Biochem Mol Biol. 2004 Jan;137(1):43-47.
 
Influence of exogenous thyroxine on plasma melatonin in juvenile Atlantic salmon (Salmo salar).

Kulczykowska E, Sokolz shtsls;owska E, Takvam B, Stefansson S, Ebbesson L.

Department of Genetics and Marine Biotechnology, Institute of Oceanology of Polish Academy of Sciences, Sw. Wojciecha 5 Str., 81-347, Gdynia, Poland

One of the most clearly defined endocrine changes during the parr-smolt transformation of anadromous salmonids is an increase in plasma levels of thyroid hormones. The role of pineal hormone melatonin in timing and synchronisation of smoltification is widely discussed. The effect of administration of exogenous thyroxine (T4) on plasma melatonin was investigated in juvenile Atlantic salmon (Salmo salar) at the early stages of parr-smolt transformation. Fish were kept in fresh water under simulated-natural photoperiod and exposed to exogenous T4. Fish were sampled at 12.00 and 24.00 h from treatment and control tanks, 2 and 14 days after treatment started. Plasma melatonin and L-thyroxine were measured using RIA and competitive enzyme immunoassay, respectively. After 2 days of T4 treatment, marked difference in plasma melatonin concentration measured at 12.00 and 24.00 h was still observed in both groups. However, 2-week exposure to T4 caused a reduction in night-time plasma melatonin level and thus, probably, inhibited melatonin related time-keeping system in juvenile salmon. Additional studies are needed to clarify the mechanism of the described phenomenon.

PMID: 14698909 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14694429&dopt=Abstract

Mol Reprod Dev. 2004 Feb;67(2):145-53.
 
Transition from embryonic to adult transcription pattern of serotonin N-acetyltransferase gene in avian pineal gland.

Oblap R, Olszanska B.

Institute of Genetics and Animal Breeding, Polish Academy of Science, Jastrzebiec n/Warsaw, Poland.

The study reports the change of transcription pattern of serotonin N-acetyltransferase gene and melatonin receptor genes during ontogenesis of the avian pineal gland. The RT-PCR technique was used to investigate the expression of the arylalkylamine N-acetyltransferase (AA-NAT) and melatonin receptor genes during development of the pineal glands isolated from Japanese quail (Coturnix coturnix japonica) embryos incubated from 3 days on until hatching (17 days), and in some organs (pineal, brain hemisphere, eye, leg, heart) of the 3-day-old quail embryo. It was shown that two phases of AA-NAT expression are observed during pineal gland development. The first, embryonic-type phase, lasts from the beginning until 7-10 days of incubation, and is marked by the presence of two RT-PCR products for AA-NAT: the shorter mature form without intron (238 bp), and the longer form (323 bp) containing an unprocessed intron of 85 bp. The second, adult-type phase is characterized by the presence of a single mature transcript, containing no intron; it starts from 7 to 10 days of incubation and lasts until hatching and in the adult pineal. The duration of this transition time from the embryonic to the adult transcription pattern in the quail pineal gland from 7 to 10 days of incubation we attribute to asynchronic embryo development, because quail chicks usually hatch between the 16th and 19th day of incubation. Analysis of the AA-NAT protein sequences for chick and quail (GeneBank accession no. U 46 502 and AF 007 068, respectively) revealed their perfect homology with the part of protein read from the sequence present in the adult-type phase of the pineal gland (the RT-PCR product of 238 bp). The presence of the intron (in the 323 bp RT-PCR product, accession no. AY 197 460) in the embryonic-phase of the pineal gland changes the reading frame of the mRNA sequence and the hypothetical resulting protein loses its homology with the chick and quail AA-NAT enzyme starting with 105th amino acid of the complete chick AA-NAT protein comprising 205 amino acids (accession no. U 46 502). In the whole embryos at stages 1-8 (according to the Hamburger-Hamilton classification) both RT-PCR products with and without intron were consistently found, and individual tissues from 3-day-old embryos also produced two AA-NAT products, i.e., the expression was of the embryonic-type. At the time of transition from the embryonic to the adult AA-NAT transcription pattern, in 7-11-day-old embryos, all three melatonin receptor transcripts (mel-1a, mel-1b, and mel-1c) were observed in the pineals, without consistent modifications of the band intensity. In the adult pineal, a single mature AA-NAT transcript was present as well as all three melatonin receptor transcripts, usually with preferential expression of the mel-1a band. The transition time from the embryonic to adult AA-NAT expression pattern coincides well with the acquisition of functional activity and the appearance of melatonin synthesis in the embryonic pineal reported for chicken, as related to quail. We suggest that the change in transcription pattern of the AA-NAT gene may reflect another, still unknown mechanism of regulating AA-NAT activity during ontogenesis, at the level of mRNA processing, whose specificity (or not) for embryonic development we wish to establish in the future. Mol. Reprod. Dev. 67:145-153, 2004. Copyright 2004 Wiley-Liss, Inc.

PMID: 14694429 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15094477

Neuroreport. 2004 Mar 22;15(4):691-4.
 
The pineal gland and anxiogenic-like action of fluoxetine in mice.

Uz T, Dimitrijevic N, Akhisaroglu M, Imbesi M, Kurtuncu M, Manev H.

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, IL 60612, USA.

Fluoxetine produces initial paradoxical anxiogenic effect in some patients. In an elevated plus-maze (EPM), fluoxetine triggers an anxiogenic-like effect in rodents. Behavioral responses to psychoactive drugs can be modified by the pineal gland. We assessed the actions of fluoxetine in the EPM in melatonin-proficient C3H mice, melatonin-deficient C57BL6 mice, and in sham-operated and pinealectomized mice. Mice were assayed 30 min after the first injection and on day 14. Protracted fluoxetine treatment reduced the time on the anxiogenic open arms and increased the entries into the safe closed arms in sham-operated C3H mice. Fluoxetine was ineffective in pinealectomized C3H or C57BL6 mice. It is possible that the pineal system contributes to the previously observed anxiogenic action of fluoxetine in humans.

PMID: 15094477 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14686914&dopt=Abstract

Eur J Biochem. 2004 Jan;271(1):1-13.
 
Glutamate signaling in peripheral tissues.

Hinoi E, Takarada T, Ueshima T, Tsuchihashi Y, Yoneda Y.

Laboratory of Molecular Pharmacology, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa, Japan.

The hypothesis that l-glutamate (Glu) is an excitatory amino acid neurotransmitter in the mammalian central nervous system is now gaining more support after the successful cloning of a number of genes coding for the signaling machinery required for this neurocrine at synapses in the brain. These include Glu receptors (signal detection), Glu transporters (signal termination) and vesicular Glu transporters (signal output through exocytotic release). Relatively little attention has been paid to the functional expression of these molecules required for Glu signaling in peripheral neuronal and non-neuronal tissues; however, recent molecular biological analyses show a novel function for Glu as an extracellular signal mediator in the autocrine and/or paracrine system. Emerging evidence suggests that Glu could play a dual role in mechanisms underlying the maintenance of cellular homeostasis - as an excitatory neurotransmitter in the central neurocrine system and an extracellular signal mediator in peripheral autocrine and/or paracrine tissues. In this review, the possible Glu signaling methods are outlined in specific peripheral tissues including bone, testis, pancreas, and the adrenal, pituitary and pineal glands.

PMID: 14686914 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14678827&dopt=Abstract

Gene Expr Patterns. 2004 Jan;4(1):47-51.
 
Bsx, an evolutionary conserved Brain Specific homeoboX gene expressed in the septum, epiphysis, mammillary bodies and arcuate nucleus.

Cremona M, Colombo E, Andreazzoli M, Cossu G, Broccoli V.

Stem Cell Research Institute, DIBIT, San Raffaele Science Park Via Olgettina 58, 20132, Milan, Italy

Shaping and orchestrating the genetic program involved in embryonic modelling of brain structures is a major function played by homeobox containing genes. Recently, analysis of conditional mouse mutants has pointed out additional roles in supporting adult brain functional activities. During a search for novel homeobox genes in the public released genomic sequences derived by the Human and Mouse genome projects, we were able to identify the mouse homologue of the Drosophila brain specific homeobox gene. We named it Bsx and characterized its expression in embryonic and post-natal mouse brain. Interestingly, Bsx shows an expression pattern restricted to a few specific developing brain structures. Pineal gland, telencephalic septum, hypothalamic pre-mammillary body and arcuate nucleus are the only brain structures where we detected Bsx transcriptional activity, which is maintained also after birth. In particular, Bsx might be considered an important molecular marker for early embryonic stages of epiphysis development, being specifically expressed in this neural structure from E9.5 onwards.

PMID: 14678827 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14675130&dopt=Abstract

J Pineal Res. 2004 Jan;36(1):49-57.
 
Melatonin attenuates rat carotid chemoreceptor response to hypercapnic acidosis.

Tjong YW, Chen Y, Liong EC, Ip SF, Tipoe GL, Fung ML.

Departments of Physiology Anatomy, University of Hong Kong, Hong Kong, China.

Respiratory activity is under circadian modulation and the physiological mechanisms may involve the pineal secretory product, melatonin, and the carotid chemoreceptor. We hypothesized that melatonin modulates the carotid chemoreceptor response to hypercapnic acidosis. To determine whether the effect of melatonin on the chemoreceptor response to hypercapnic acidosis is mediated by melatonin receptors in the chemosensitive cells, cytosolic calcium ([Ca2+]i) was measured by spectrofluorometry in fura-2-loaded glomus cells dissociated from rat carotid bodies. Melatonin (0.01-10 nm) per se did not change the [Ca2+]i levels of the glomus cells but it concentration-dependently attenuated the peak [Ca2+]i response to hypercapnic acidosis in the glomus cells. In addition, the [Ca2+]i response was attenuated by 2-iodomelatonin, an agonist of melatonin receptors. The melatonin-induced attenuation of the [Ca2+]i response to hypercapnic acidosis was abolished by pretreatment with an non-selective mt1/MT2 antagonist, luzindole, and by MT2 antagonists, 4-phenyl-2-propionamidotetraline or DH97. In situ hybridization study with antisense mt1 and MT2 receptor mRNA oligonucleotide probes showed an expression of mt1 and MT2 receptors in the rat carotid body. Also, melatonin attenuated the carotid afferent response to hypercapnic acidosis in single- or pauci-fibers recorded from the sinus nerve in isolated carotid bodies superfused with bicarbonate-buffer saline. Results suggest that an activation of the melatonin receptors expressed in the glomus cells of the rat carotid body reduces the chemoreceptor response to hypercapnic acidosis. This modulation may play a physiological role in the influence of the circadian rhythms on the chemoreflex.

PMID: 14675130 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14634822&dopt=Abstract

Pflugers Arch. 2004 Jan;447(4):405-7. Epub 2003 Nov 21.
 
Melatonin reduces noradrenaline-induced vasoconstriction in the uterine artery of pregnant hooded seals ( Cystophora cristata).

Stokkan KA, Aarseth JJ.

Department of Arctic Biology and Institute of Medical Biology, University of Tromso, 9037, Tromso, Norway, Karl-Arne.Stokkan@fagmed.uit.no

In pregnant seals the dive-associated constriction of the uterine artery is inhibited for unknown reasons. The seal fetus has an extremely large and active pineal gland, not found in any other mammals. We have investigated if the pineal hormone melatonin affects fetal blood supply during diving. Using isolated ring segments of the uterine artery from pregnant hooded seals (Cystophora cristata), we measured the change in isometric tension caused by noradrenaline (NA) with and without physiological concentrations of melatonin. Melatonin alone had no effects while NA increased the tension in a dose-dependent manner. The NA-induced tension was about 70% reduced by melatonin, but was completely recovered after washout of melatonin. These results indicate that the large and active pineal gland of the fetal seal may be involved in upholding maternal uterine blood flow during diving.

PMID: 14634822 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14597558&dopt=Abstract

FASEB J. 2004 Jan;18(1):149-51. Epub 2003 Nov 03.
 
Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1.

Beni SM, Kohen R, Reiter RJ, Tan DX, Shohami E.

Department of Pharmacology, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Traumatic brain injury (TBI) is followed by massive production of reactive oxygen species (ROS), which mediate secondary cellular damage. Low molecular weight antioxidants (LMWA) constitute one of the defense mechanisms of the brain, and their levels correlate with post-TBI outcome. Melatonin, the main pineal hormone, possesses antioxidant properties. We investigated the effects of melatonin on neurobehavioral recovery, brain LMWA, and activation of the redox-sensitive transcription factors nuclear factor-kappaB (NF-kappaB) and AP-1 in mice subjected to closed head injury (CHI). Given 1 h after CHI, melatonin facilitated recovery during at least 1 wk (P<0.05) and decreased lesion size by approximately twofold (P<0.01). The dose response displayed a bell-shape, i.e., neuroprotection was achieved with 5 but not 1 or 10 mg/kg. At the neuroprotective dose, melatonin treatment was associated with sustained (4 days) elevation of brain LMWA, including ascorbic acid (P<0.05). In contrast, LMWA were unaffected by the administration of the neuroprotective endocannabinoid 2-arachidonoyl glycerol. Furthermore, melatonin did not alter early phase (24 h) CHI-induced activation of NF-kappaB and AP-1; however, it blocked the robust late-phase (8 days) activation of NF-kappaB and decreased that of AP-1 to below basal levels. Our results demonstrate that melatonin induces neuroprotection, presumably via potentiation of brain antioxidants and attenuation of NF-kappaB and AP-1 activation.

PMID: 14597558 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15055442

J Neuropathol Exp Neurol. 2004 Mar;63(3):185-92.

Cenacchi G, Giangaspero F.

Department of Radiology and Pathology, University of Bologna, Bologna, Italy.

Since the appearance in 2000 of the World Health Organization (WHO) classification for central nervous system (CNS) neoplasms, numerous descriptions of new entities or variants have appeared in the literature. In the group of neuronal and mixed glioneuronal neoplasms are lesions with distinctive morphological features that are still not included in a precise classification, including extraventricular neurocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal of the fourth ventricle, glioneuronal with neuropil-like rosette, and DNT-like tumor of the septum pellucidum. The glioneuronal tumor with neuropil-like rosette and oligodendroglioma with neurocytic differentiation represent morphological variants of genetically proven diffuse gliomas. The lipoastrocytoma and the pilomixoid astrocytoma enlarge the group of astrocytic lesions. Rare, low-grade gliomas of the spinal cord with extensive leptomeningeal dissemination associated with unusual neuroimaging are described. The chordoid glioma of the third ventricle and the papillary tumor of the pineal region seem to be correlated by a common histogenesis from the specialized ependyma of the subcommissural organ. An embryonal tumor with neuropil and true rosettes combining features of neuroblastoma and ependymoblastoma is discussed. These new, recently described lesions indicate that the complex morphologic spectrum of CNS tumors is far from being completely delineated.

PMID: 15055442 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15046865

Brain Res Mol Brain Res. 2004 Apr 7;123(1-2):45-55.
 
Rat pineal arylalkylamine-N-acetyltransferase: cyclic AMP inducibility of its gene depends on prior entrained photoperiod.

Engel L, Mathes A, Schwerdtle I, Heinrich B, Pogorzelski B, Holthues H, Vollrath L, Spessert R.

Department of Anatomy, Johannes Gutenberg University, Saarstrasse 19-21 D-55099, Mainz, Germany.

The nocturnal biosynthesis of melatonin in the rat pineal depends on strongly enhanced expression of the enzyme N-acetyltransferase [arylalkylamine N-acetyltransferase (AA-NAT); EC 2.3.1.87]. AA-NAT transcription is stimulated during darkness by adrenergic inputs to the pineal from the suprachiasmatic nucleus (SCN). Nocturnal activation of the AA-NAT promotor following stimulation of pinealocyte adrenoceptors involves cAMP-dependent stimulation of protein kinase A (PKA). The nocturnal rise in AA-NAT depends on the lighting conditions. As compared with light/dark (LD) 12:12, the delay between dark onset and the nocturnal rise in AA-NAT is shortened under long photoperiods and prolonged under short photoperiods. Here, we report that the rapidity of nocturnal AA-NAT induction depends on cAMP inducibility of the gene. Accordingly, cAMP produces a strong AA-NAT response in pineals obtained from rats housed under long photoperiods and a weak AA-NAT response under short photoperiods. Changes in AA-NAT inducibility are fully developed not earlier than after seven cycles. This observation suggests that long-term changes in the photoperiod are necessary to achieve full adjustment of cAMP inducibility of the gene. A direct relationship was found between cAMP-dependent AA-NAT inducibility and the pineal protein kinase A (PKA) activity. As compared to LD 12:12, PKA activity was increased under LD 20:4 and attenuated under LD 4:20. On the basis of the present findings, we suggest that the photoperiod determines the effectiveness of nocturnal AA-NAT induction by long-term modulation of the intrapineal pathway that transmits the cAMP signal to the AA-NAT gene.

PMID: 15046865 [PubMed - in process]


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15184510

J Exp Biol. 2004 Jun 15;207(Pt 14):2379-87.
 
Pineal organs of deep-sea fish: photopigments and structure.

Bowmaker JK, Wagner HJ.

Division of Visual Science, Institute of Ophthalmology, University College London, London EC1V 9EL, UK.

We have examined the morphology and photopigments of the pineal organs from a number of mesopelagic fish, including representatives of the hatchet fish (Sternoptychidae), scaly dragon-fish (Chauliodontidae) and bristlemouths (Gonostomidae). Although these fish were caught at depths of between 500 and 1000 m, the morphological organisation of their pineal organs is remarkably similar to that of surface-dwelling fish. Photoreceptor inner and outer segments protrude into the lumen of the pineal vesicle, and the outer segment is composed of a stack of up to 20 curved disks that form a cap-like cover over the inner segment. In all species, the pineal photopigment was spectrally distinct from the retinal rod pigment, with lambda(max) displaced to longer wavelengths, between approximately 485 and 503 nm. We also investigated the pineal organ of the deep demersal eel, Synaphobranchus kaupi, caught at depths below 2000 m, which possesses a rod visual pigment with lambda(max) at 478 nm, but the pineal pigment has lambda(max) at approximately 515 nm. In one species of hatchet fish, Argyropelecus affinis, two spectral classes of pinealocyte were identified, both spectrally distinct from the retinal rod photopigment.

PMID: 15184510 [PubMed - in process]