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      Blockade of Estrogen Receptors Decreases CNS and Pituitary Prostaglandin Synthase Expression in Fetal Sheep

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          Background/Aims: Both prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) and estradiol stimulate fetal ACTH secretion and augment fetal ACTH responses to stress. We have reported that estradiol increases prostaglandin endoperoxide synthase-2 (PGHS-2), and we have proposed that there is a positive feedback relationship between estrogen and fetal hypothalamus-pituitary-adrenal (HPA) axis activity that is dependent upon PGHS activity in the fetal brain. The present study was designed to test the hypothesis that blockade of estrogen receptors in the fetal brain decrease PGHS-2 expression and reduces fetal HPA axis activity. Methods: In study 1, six time-dated pregnant ewes with chronically-catheterized twin fetuses were used. In each pregnancy, one twin was treated intracerebroventricularly (icv) with the estrogen receptor antagonist ICI 182,780 (25 µg/day; n = 6) while the other twin served as an age-matched control. In study 2, plasma samples were drawn from 10 singleton chronically-catheterized fetuses on alternating days until the time of spontaneous parturition. Results: ICI infusion caused significantly decreased PGHS-2 mRNA abundance in fetal central nervous system and pituitary, with the greatest decreases occurring in hippocampus and pituitary. There were no statistically significant changes in PGHS-1 mRNA. ICI infusion did not significantly change fetal plasma concentrations of pro-opiomelanocortin (POMC), ACTH, or cortisol in fetuses 130–134 days ges- tation (study 1) but did decrease the preparturient rise in plasma pro-opiomelanocortin concentrations in study 2. Conclusion: We conclude that PGHS-2 expression in the late-gestation fetal brain is in part stimulated by circulating estrogens in fetal plasma. Blockade of CNS estrogen receptors reduces preparturient plasma concentrations of POMC, but does not reduce fetal HPA axis activity in 130–134 day fetal sheep.

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          Most cited references 21

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          Characterization of inducible cyclooxygenase in rat brain.

          Considerable debate exists regarding the cellular source of prostaglandins in the mammalian central nervous system (CNS). At least two forms of prostaglandin endoperoxide synthase, or cyclooxygenase (COX), the principal enzyme in the biosynthesis of these mediators, are known to exist. Both forms have been identified in the CNS, but only the distribution of COX 1 has been mapped in detail. In this study, we used Western blot analysis and immunohistochemistry to describe the biochemical characterization and anatomical distribution of the second, mitogen-inducible form of this enzyme, COX 2 in the rat brain. COX 2-like immunoreactive (COX 2-ir) staining occurred in dendrites and cell bodies of neurons, structures that are typically postsynaptic. It was noted in distinct portions of specific cortical laminae and subcortical nuclei. The distribution in the CNS was quite different from COX 1. COX 2-ir neurons were primarily observed in the cortex and allocortical structures, such as the hippocampal formation and amygdala. Within the amygdala, neurons were primarily observed in the caudal and posterior part of the deep and cortical nuclei. In the diencephalon, COX 2-ir cells were also observed in the paraventricular nucleus of the hypothalamus and in the nuclei of the anteroventral region surrounding the third ventricle, including the vascular organ of the lamina terminalis. COX 2-ir neurons were also observed in the subparafascicular nucleus, the medial zona incerta, and pretectal area. In the brainstem, COX 2-ir neurons were observed in the dorsal raphe nucleus, the nucleus of the brachium of the inferior colliculus, and in the region of the subcoeruleus. The distribution of COX 2-ir neurons in the CNS suggests that COX 2 may be involved in processing and integration of visceral and special sensory input and in elaboration of the autonomic, endocrine, and behavioral responses.
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            Molecular mechanisms involved in the regulation of prostaglandin biosynthesis by glucocorticoids.

            The anti-inflammatory properties of glucocorticoids are attributed in part, to their interference with prostaglandin synthesis. Phospholipases A2 and cyclooxygenases, the key enzymes of prostaglandin biosynthesis, are targets of glucocorticoid action; the molecular mechanisms, however, are not yet understood in detail. Obviously, glucocorticoids can act at different levels of gene regulation depending on cell type and inducing stimulus. The current knowledge of glucocorticoid interference with phospholipase A2 and cyclooxygenase expression is summarized. In comparison with other nonsteroidal anti-inflammatory drugs, glucocorticoids are unique inasmuch as they also inhibit cytokine synthesis and expression of other inflammation-related enzymes. Based on a more detailed understanding of glucocorticoid action, it may be possible to therapeutically exploit the anti-inflammatory effects and at the same time avoid the unwanted metabolic actions of these steroids.
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               J KITAY (1963)

                Author and article information

                S. Karger AG
                December 2007
                09 October 2007
                : 87
                : 2
                : 121-128
                aDepartment of Physiology and Functional Genomics, University of Florida College of Medicine and bDepartment of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, Fla., USA
                109664 PMC2793319 Neuroendocrinology 2008;87:121–128
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 3, References: 36, Pages: 8
                Hormone Actions in the Brain


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