An Introduction to the Blood-Brain Barrier PDF
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An Introduction to the Blood-Brain Barrier An Introduction to the Blood-Brain Barrier HughDavson Emeritus Professor, Sherrington School of Physiology UMDS, Guy' sand St Thomas' s Hospitals, London Berislav ZIokovic Associate Professor ofNeurosurgery, Physiology and Biophysics, USC School of Medicine, Los Angeles Ljubisa Rakic Professor of Neurobiology and Biochemistry, School ofMedicine, Belgrade and Maleolm B. SegaI Reader in Physiology, Sherrington School ofPhysiology UMDS, Guy' sand St Thomas' s Hospitals, London M MACMILLAN © The authors 1993 Softcover reprint of the hardcover 1s t edition 1993 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, Designs and Patents Act 1988, or under the terms of any licence permiuing limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London WIP 9HE. 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 1993 by THE MACMILLAN PRESS L TD Houndmills, Basingstoke, Hampshire RG21 2XS andLondon Companies and representatives throughout the world ISBN 978-1-349-11884-7 ISBN 978-1-349-11882-3 (eBook) DOI 10.1007/978-1-349-11882-3 A catalogue record for this book is available from the British Library. Typeset by Wearset Boldon, Tyne and Wear Contents Preface vii 1. History and basic concepts 1 Classical experiments 1 The extracellular space of the brain 3 The cerebrospinal fluid 4 Permeability of the blood-brain barrier 11 Permeability: definition and measurement 14 Michaelis-Menten kinetics 23 Active transport 40 Application to the blood-brain barrier 56 The cerebrospinal fluid and the blood-CSF barrier 80 Transposition to the blood-brain barrier 101 Enzymatic contributions to the blood-brain barrier 109 Breakdown of the blood-brain barrier 110 Penetration of carrier-bound hormones 112 Penetration oflarge molecules 114 The broken-down barrier 121 Steady-state CSF concentrations 126 Complete morphology of the blood-brain barrier 128 2. Transport of glucose and amino acids in the central nervous system 146 Glucose 146 Amino acids 170 3. Peptides and proteins 195 Peptides in the central nervous system 195 Functions of peptides in the brain 201 Peptide and protein interactions at the blood-brain barrier 218 Regulation of protein transport 242 Modulation of peptide transport 243 Enzymatic degradation of peptides 244 Peptide receptors in non-barrier regions 245 Therapeutic applications 249 Peptides and proteins in the CSF 253 4. Transport of some precursors of nucleotides and some vitamins 273 Nucleotide precursors 273 Vitamins 285 v vi Contents 5. Experimental models in the study of the pathology of the blood-brain barrier 293 Introduetion 293 Amphetamine experimental psyehosis 294 Experimental allergie eneephalomyelitis 305 Cortieallesions 309 Subjea Index 323 Preface The possibility of producing a short introduction to the physiology of the blood-brain barrier was both discussed and agreed by the authors after a small symposium on the subject had been held at the Serbian Academy of Arts and Science in 1989. The present volume is the result; in it we have tried to present lucidly the physical factors goveming transport from blood into the central nervous tissue and the ccrebrospinal fluid, and then to describe some studies on specific aspects, notably the transport of amino acids, sugars and peptides. Finally, in view of the suspicion that some neurological diseases have as their basis a faHure or impairment of the blood-brain barrier, we have included an account of some attempts to establish animal preparations that might serve as experimental models mimicking human pathology. If the reading of this book stimulates research on the pathology of some central nervous diseases, it will have achieved its main purpose; in addition, we trust that workers in the life sciences will find it a useful introduction to a field that has expanded explosively since the early prejudices against the concept of a blood-brain barrier were dispelled. We must conclude by thanking the Wellcome Trust, the British Council and the Federal Yugoslav Zavod for their financial help in promoting the co-operation between workers in Britain and Yugoslavia that has culminated in the writing of this book. June, 1991 H.D. B.Z. L.R. M.B.S. VIi Chapter 1 History and Basic Concepts Classical Experiments Intravital Staining The concept of the blood-brain barrier derives from the classical studies of the pioneers in chemotherapy, such as Ehrlich, who administered dyestuffs parenter ally in the hope that they would attack infective organisms. Thus Ehrlich observed that many dyes, after intravenous injection, stained the tissues of practically the whole body, while the brain was spared. Later, Lewandowsky (1900) showed that the Prussian blue reagents (iron sah and potassium ferrocyanide) did not pass from blood to brain, and he formulated clearly the concept of the blood-brain barrier (Bluthirnschranke). The more definitive demonstration of the bafrier we owe to Goldmann, who showed (1909) that, after intravenous injection with trypan blue, the brain was unstained; the dye did not enter the cerebrospinal fluid (CSF), although the choroid plexuses and meninges were stained. In a second paper (Goldmann, 1913), he described experiments in which trypan blue was injected into the CSF; in this event, the brain tissue was strongly stained, so that Goldmann rightly concluded that there was, indeed, a barrier between blood, on the one hand, and brain tissue on the other. Any argument that the failure to stain the brain with trypan blue after intravenous injection was due to a peculiar staining feature of the nervous tissue was negated by this fundamental 'second experiment', the first experiment being the demonstration that nervous tissue was unstained after intravenous injection. Penetration ofOther Solutes The blood-brain barrier, as initially revealed by studies on dyestuffs, was shown not to be peculiar to these organic molecules, and, in general, it proved that substances that usually failed to cross cell membranes also failed to cross the blood-brain barrier (Krogh, 1946). Now, it was early demonstrated that penetra tion into cells was govemed by the lipid-solubility of the compound being studied measured by its oil-water partition coefficient, concentration in oil B=------- concentration in water Figure 1.1, for example, from the classical study ofCollander and Barlund (1933) on single plant cells, shows that ease of penetration through the cell membrane, measured by the molecule's permeability coefficient (p. 14), was directly related to 1 2 An Introduction to the Blood-Brain Barrier 10 ! Water ! Water • MRo < 15 ® MRo 15-2 ({g) MRo 22-3 ~ MRo >30 0.0001 0.001 0.01 0.1 Figure 1.1 Permeability of Chara cells plotted against oiVwater partition coefficient. Ordinates: permeability in cm/h XMI/2. Abscissae: oiVwater partition coefficient. From Collander, Physiol. Plant. (1949) its partition coefficient, relatively lipid-insoluble substances, such as sucrose and glycerol, with partition coefficients in the region of 1 x 10-4-1 X 10-5, barely, if at all, penetrating cells; when the partition coefficient was in the region of 0.01, there was significant penetration, as with thiourea; with a partition coefficient of, say, 0.1, as with ethyl alcohol, penetration was very rapid. Early semiquantitative studies of passage of solutes into the brain from blood showed that the barrier was high for substances such as sucrose or mannitol but low for substances such as ethyl alcohol or propyl thiourea. Thus, as Krogh emphasized in 1946, the capillaries of the brain, or other lining membranes separating blood from the brain tissue, behaved like single cells, in marked contrast to the capillaries of most other tissues of the body, where it is found that passage from blood to the extracellular space is rapid and virtually independent of the partition coefficient. Early Objections to the Concept If we look back on the subject now over the period, say, 1920 to 1960, it becomes evident that Goldmann's second experiment was ignored, and it was repeatedly argued that the blood-brain barrier, as described by Goldmann's first experiment, History and Basic Concepts 3 was an artefact resulting from the failure of the dyestuff to be taken up by the tissue after leaving the blood vessels. The strongest argument adduced in support of this position was the appearance of the brain in electron-microscopical sections; previously the histology of the brain had been examined by two basic procedures that stained either the neurons (Golgi technique) or the glia. Pictures obtained by either technique left room for the assumption that the nervous tissue had a considerable extracellular space, comparable with that of other tissues. However, the osmium-stained preparations of the electron microscope revealed both glia and neurons, so tightly packed that it was argued that the extracellular space was negligible, so that if trypan blue and other acidic dyestuffs passed out of the capillaries, the staining would not be intense enough for observation in the light-microscope. There is no need to recapitulate in detail the experimental studies that these claims stimulated. Since it was apparently insufficient to emphasize Goldmann's second experiment and its significance, more direct experimental proof of a barrier between blood, on the one hand, and the extracellular fluid of the central nervous system, on the other, was necessary. First, it was important to determine the actual size of the extracellular space; although the electron-microscopical studies suggested that this would be very smalI, compared with that in muscle and other connective tissues, nevertheless it must have an experimentally determinable magnitude. The Extracellular Space of the Brain Experimental Measurement The basis for determination of the extracellular space of a tissue, such as muscle, has been the measurement of the concentrations of an 'extracellular marker' in the tissue and in the medium surrounding the cells when the system is in diffusional equilibrium with the marker. If the experiment is performed in vivo, the concentration in the extracellular fluid may be equated with that in the blood plasma, provided that there is readyequilibration between the two fluids. If the experiment is carried out in vitro, then the concentration in the bathing medium will be compared with that in the tissue. The requirement of the marker is that it should not penetrate cells, being confined to the extracellular space. In this case the extracellular space is given by: concentration in tissue (mmoVg-tissue) ------------------~----~--~----xl00 concentration in plasma-water or saline (mmoVg-HzO) With the in vivo experiment some of the marker will remain in the blood vessels, but allowance for this may be made by measuring the 'blood-space' by infusing labelIed red cells.
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