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      Brain Allopregnanolone in the Fetal and Postnatal Rat in Response to Uteroplacental Insufficiency

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          Abstract

          Background/Aims: Allopregnanolone suppresses central nervous system activity and has neuroprotective actions in hypoxia-induced brain injury. In pregnant sheep allopregnanolone concentrations are high during fetal life and decline rapidly after birth. We investigated brain allopregnanolone concentrations of fetal and postnatal rats derived from normal and growth restricted pregnancies. Methods: Bilateral uterine vessel ligation (or sham) was performed at gestation day 18 to induce uteroplacental insufficiency in WKY rats (n = 7–8 per group). Brain allopregnanolone was measured by radioimmunoassay at 2 study ages, gestation day 20 (n = 6 per group) and postnatal day 6 (n = 6–8 per group), from control and growth-restricted pups. Results: Fetal brain allopregnanolone concentrations were higher in growth-restricted fetuses compared to control (p < 0.05). Allopregnanolone concentrations decreased at birth with a greater decline in growth restriction (p < 0.05). Postnatal day 6 brain allopregnanolone concentrations were lower in growth restriction (p < 0.05). Conclusions: Growth restriction is a potent stimulus for neurosteroid synthesis in the fetal brain in late pregnancy. The low concentrations of allopregnanolone in the growth-restricted postnatal brain suggest a delay in the capacity of the adrenal gland or brain to synthesize pregnane steroids or their precursors and may render the postnatal brain vulnerable to hypoxia-induced injury.

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          Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain.

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            Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery.

            The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of gamma-aminobutyric acid type A (GABAA) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3, and gamma2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5alpha-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36Cl- uptake and the decrease of gamma2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.
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              Time-Dependent Changes in Rat Brain Neuroactive Steroid Concentrations and GABA A Receptor Function after Acute Stress

              The time courses of changes in rat brain neuroactive steroid concentrations and γ-aminobutyric acid type A (GABA A ) receptor function elicited by acute stress were investigated in animals exposed to CO 2 for 1 min, a treatment known to induce stress in rats and panic attacks in humans. Inhalation of CO 2 induced increases in cerebral cortical steroid concentrations, the time dependence of which varied with the steroid examined. Thus, progesterone and deoxycorticosterone showed maximal increases (10- and 4-fold, respectively) 10 min after CO 2 inhalation and had returned to basal values by 30 and 60 min, respectively. In contrast, pregnenolone and 3 α -hydroxy-5 α -pregnan-20-one (allopregnanolone) concentrations showed maximal increases (+174 and +200%, respectively) at 30 min, were still higher than control at 60 min and returned to control values 120 min after stress. Inhalation of CO 2 also resulted in increases in plasma steroid concentrations, most of which peaked at 30 min and had returned to control values by 60 min. A parallel analysis of the stress-induced changes in GABA A receptor function, assessed either biochemically by t-[ 35 S]butylbicyclophosphorothionate ([ 35 S]TBPS) binding to cerebral cortical membranes or behaviorally by the punished responding score in Vogel’s test, showed that the effects of CO 2 inhalation on both parameters were maximal (+51 and –40%, respectively) after 10 min; the behavioral reaction returned to normal after 60 min, whereas [ 35 S]TBPS binding had returned to control values 120 min after stress. The results show that: (a) the maximal increase in the brain concentrations of allopregnanolone, a potent and efficacious positive modulator of GABA A receptors, occurred at a time (30 min) when both conflict behavior and [ 35 S]TBPS binding begun to decrease, and (b) both allopregnanolone concentrations and [ 35 S]TBPS binding had returned to control values 120 min after CO 2 inhalation. The data are thus consistent with a physiological role of neuroactive steroids in restoring GABAergic tone after stress.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2008
                November 2008
                13 June 2008
                : 88
                : 4
                : 287-292
                Affiliations
                aDepartment of Physiology, The University of Melbourne, Melbourne, Vic., bMothers and Babies Research Centre, University of Newcastle, Newcastle, N.S.W., cDepartment of Physiology, Monash University, Clayton, Vic., Australia
                Article
                139771 Neuroendocrinology 2008;88:287–292
                10.1159/000139771
                18552483
                6fd72c38-803d-470d-a47a-3eb70d4838c2
                © 2008 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.

                History
                : 20 December 2007
                : 18 March 2008
                Page count
                Figures: 2, Tables: 1, References: 27, Pages: 6
                Categories
                Neurotoxicity and Neuroprotection

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Uteroplacental insufficiency,Allopregnanolone,Brain,Growth restriction

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