PEPTIDE AND AMINO ACID TRANSPORT MECHANISMS IN THE CENTRAL NERVOUS SYSTEM PEPTIDE AND AMINO ACID TRANSPORT MECHANISMS IN THE CENTRAL NERVOUS SYSTEM Edited by Lj. Rakić Professor of Neurobiology and Biochemistry, Faculty of Medicine, University of Belgrade D.J. Begley Dept. of Physiology, King's College, London H. Davson Professor of Physiology, St. Thomas's Hospital, London B.V. Zloković Associate Professor of Medical Physiology, Faculty of Medicine, University of Belgrade M S TOCKTON P R E S S © The contributors 1988 Softcover reprint of the hardcover 1st edition 1988 978-0-333-45600-2 All rights reserved. No reproduction, copy or transmission of this publication may be made without written permission. No paragraph of this publication may be reproduced, copied or transmitted save with written permission or in accordance with the provisions of the Copyright Act 1956 (as amended), or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 33-4 Alfred Place, London WC1E 7DP. Any person who does any unauthorised act in relation to this publication may be liable to criminal prosecution and civil claims for damages. First published 1988 Published by THE MACMILLAN PRESS LTD Houndmills, Basingstoke, Hampshire RG21 2XS and London Companies and representatives throughout the world Published in the United States and Canada by STOCKTON PRESS 15 East 26th Street, New York, NY 10010 ISBN 978-0-935859-52-2 or British Library Cataloguing in Publication Data Peptide and amino acid transport mechanisms in the central nervous system. 1. Vertebrates. Nervous system. Amino acids and peptides. Transport I. Rakić, Lj. (Ljubiša) 596'.0188 ISBN 978-1-349-09929-0 ISBN 978-1-349-09927-6 (eBook) DOI 10.1007/978-1-349-09927-6 CONTENTS Preface Acknowledgements Peptide interactions with the blood-brain-CSF interfaces Neuropeptide transport mechanisms in the central nervous system B. V. Zlokovic, D. 1. Begley, M. B. Segal, H. Davson, Lj Rakic, M. N. Lipovac, D. M. Mitrovic and R. M. Jankov 3 Peptides and the blood-brain barrier W A. Banks and A. 1. Kastin 21 Peptides and cerebral microvessels M. Spatz, H. Yamamoto, D. W Lust, B. Wroblewska, N. Merkel and 1. Bembry 33 Peptide receptors of the cerebral capillary endothelium and the transport of amino acids across the blood-brain barrier A. Ermisch, R. Landgraf, P. Brust, R. Kretzschamr and 1. Hess 41 Transport of encephalins from the cerebrospinal fluid of the rabbit D. J. Begley and D. G. Chain 55 The uptake by chorotd plexus and passage into CSF of 1251-prolactin in preterm rabbits A. V. Lorenzo, K. R. Winston and 1. Adler 67 Insulin as a regulatory peptide in tne CNS D. G. Baskin, D. M. Dorsa, D. P. Figlewicz, E. S. Corp, B. 1. Wilcox, B. 1. Wallum and S. C. Woods 79 Protein transport mechanisms in the central nervous system Structural aspects of the blood-brain and blood-CSF barriers with respect to endo,genous proteins K. Mol/gard, Y. Ba/slev and N. R. Saunders 93 The origins and functions of proteins in CSF in the developing brain K. M. Dziegliewska and N. R. Saunders 103 Cyclic nucleotide-mediated regulation of albumin transport in brain microvessels F. 1o6 119 Immunocytochemical screening of natural antibodies against glia and ependyma A. V. Sakharova, L. Z. Jakubov, N. V. Romanova, S. M. Lozhnikova and 0. V. Rokhlin 129 Peptide effects on the central nervous system Delta sleep promoting effect of a delta sleep-inducing peptide v. Susie 141 The effects of vasopressin and related peptides on tolerance to ethanol P. L. Hoffman, G. Szabo and B. Tabakoff 147 The effect of enkephalins and of enkephalinase inhibttors on the central cholinergic mechanisms participating in the peripheral adrenergic activation V. M. Varagic, V. Stojanovic and E. Dioljic 157 Peptides and brain disorders Experimental psychosis and transport of amino acids and peptides across the blood-brain barrier Lj. Rakic, B. V. Zlokovic, H. Davson, D. J. Begley, M. B. Segal, M. N. Lipovac, D. M. Mitrovic, J. B. Mackie and R. Veskov 169 Parkinson's disease and depression: possible role for neuropeptides of the hypothalamic-pituitary axis V. S. Kostic, M. Stojanovic and D. Pavlovic 183 Amino acid transport mechanisms in the central nervous system Amino acid uptake in synaptosomal preparations E. A. Debler and A. Lajtha 195 Exchange diffusion of large neutral amino acids between blood and brain A. Gjedde 209 Kinetic analysis of carrier mediated blood-brain barrier transport with reference to amino acids V. J. Cunningham and R. J. Hargreaves 219 Factors which intluence the concentration of amino acids in cerebrospinal fluid M. B. Segal and B. V. Zlokovic 229 Amino acid transport by a glial blood-brain barrier: studies in an elasmobranch fish J. N. Abbott, B. V. Zlokovic, M. Taylor, J. Hart and Lj. Rogac 241 A comparative view of amino acid transport across the blood-brain barrier (endothelium) and the placenta (trophoblast) D. L. Yudilevich, C. P. D. Wheeler and J. C. Bustamante 245 Enzymatic aspects of the blood-brain and blood-CSF barriers Transport and barrier systems of the cerebral microvasculature: enzymatic aspects B. M. Djuricic and B. B. Mrsulja 269 The effects of cAMP and adenylate cyclase activators on cerebrospinal fluid formation S. Hyman, J. G. McComb, E. Stephanian and M. H. Weiss 279 Techniques for investigating the blood-brain barrier Techniques for the study of blood-brain barrier in non-mammalian species N. J. Abbott, A. M. Butt and B. V. Zlokovic 289 Is pulsation important for the brain R. Deane and M. W B. Bradbury 305 A supravital brain perfusion technique for the study of the blood-brain barrier: with special reference to leucine transport J. Greenwood, P. J. Luthert, 0. E. Pratt, A. S. Hazel and C. C. Hughes 317 Index 333 PREFACE While reading the proofs of this book I have been struck by the gold mine of information about peptide function in the central nervous system that has been opened up. Little did I think, when I asked my colleague Dr David Begley, to measure the clearance of an artifi cial dipeptide, glycyl-leucine, from the rabbit's ventricles, that I should have opened the lid of this Pandora's box, a lid that might have been held down, so far as I was concer ned, but for a meeting with Dr Berislav Zlokovic at Queen Elizabeth College, where he was working with Professor David Yudilevich. Against all the rules, Berislav came to work with me at King's College on peptide transport, and by a fortunate chance I asked my friend in the Wellcome Trust, Dr Edda Hannington, if they had funds for supporting research projects involving other countries. It was through her, and her successor, Dr Michael Morgan, that the funding of a cooperative research programme, involving Pro fessor Rakic and Dr Zlokovic on the one hand, and myself and my colleagues Drs Segal, Begley and Abbott, on the other, was initiated. The result of this cooperation is the pre sent volume which, I think, contains a wealth of information regarding the role of pepti des in the central nervous system and, more importantly, their transport within this sys tem. Thus, quite apart from the pleasure I have had from]ugoslav hospitality during the three-to-four years during which this cooperative programme has been functioning, it gi ves me enormous pleasure to realize that, in this accidental manner, I have been the "fir st cause" of an excellent book that, I am sure, will grace the shelves of many an experi mental neurologist. Although the primary impetus for this cooperative programme is to be attributed to the Wellcome Trust, whom I cannot thank too heartily, its implementati on depended on the valuable support of the British Council, whose representatives Dr Richard Phillips and Nastasi a Braun I am happy to count among my very good friends, and Branka Maricic from the Federal Yugoslav Zavod for the International Cooperation. London Hugh Davson December 1987 ACKNOWLEDGEMENTS This book had its origin in the international symposium under the auspices of the Serbian Academy of Sciences and Arts which was supported by generous contributions from: The British Council, The Wellcome Trust and The Republicka Zajednica Nauke SR Srbiie. We thank all these donors for their sponsorship. Skilful technical editorial help of Voja Glavonjic and assistance of Dr Milo Lipovac in preparing the index of the book are gratefully acknowledged. We thank Drs Radmila Mileusnic, Dusan Mitrovic, Jasmina Mackie and Ksenija Jovanovic for their help during organization of the Symposium. The Publisher and Editors wish to thank Her Majesty The Queen for kindly authorizing the reproduction on the front cover of the anatomical drawing by Leonardo da Vinci, from the collection of The Royal Library, Windsor Castle. PEPTIDE INTERACTIONS WITH THE BLOOD-BRAIN-CSF INTERFACES 1 Neuropeptide transport mechanisms in the central nervous system B. V. Zlokovic1, D. J. Begley, M. B. SegaP, H. Davsonv, Lj Rakif34, M. N. Lipovac1, D. M. Mitrovic1 and R. M. JankovS 1 Institute of Medical Pnys1010gy, Faculty of Medicine Belgrade, Yugoslavia 2 Department of Physiology, King's College London, U.K. 3 Sherrington School of Physiology, St. Thomas's Hospital, London, U.K. 4 Department of Biochemistry, Faculty of Medicine Belgrade, Yugoslavia 5 Department of Chemistry, Faculty of Science Belgrade, Yugoslavia INTRODUCTION In the last fifteen years a number of studies have demonstrated a variety of be havioural and electrophysiological effects of peptides in mammals when given either systemically (intravenously, intraperitoneally), intracerebroventricularly, intrathecally and/ or applied locally into different nervous structures by ionto phoresis (Kastin et al., 1979; Zadina et al., 1986). In parallel with these studies, by means of immuno-cytochemical techniques, different central nervous system (CNS) peptidergic pathways have been visualized (Kreiger et al., 1983). The role of neuropeptides in CNS function is multiple, underlying the basic physiologi cal phenomena such as: neurotransmission and/ or neuromodulation, regulation of cerebral blood flow and cerebrospinal fluid (CSF) secretion, regulation of the neuroendocrine axis, the organization of the integrity of the blood-brain barrier, and modulation of blood-brain barrier permeability to nutrients and other mole cules (Pardndge, 1986; Davson et a!., 1987). Metabolic steps that are involved in the synthesis, enzymatic degradation and/ or metabolic transformation of brain-derived peptides have also been identified in many cases (Davson et al., 1987). However, the role of specialized cellular systems, including the blood-brain and blood-cerebrospinal fluid harri ers, in neuropeptide homeostasis of the CNS "milieu interieur" seems to be still only partially understood, and for some neuropeptides regarded as a passive one (Banks and Kastin, 1985, 1987). This is in contrast with the highly developed metabolic and regulatory activities of the endothelial and ependymal sheets in CNS homeostasis of ions, nutrients, hormones and some neurotransmitters (Bradbury. 1979; Davson et al.. 1987). In this respect, of particular mterest, both from the physiological and medi cal point of view, is a correct understanding of exchange kinetics for neuropep tides between the brain cells, brain extracellular fluid and its circulating com- 3