Physiology and Pharmacology of. the Blood-Brain Barrier

Transcription

1 Physiology and Pharmacology of. the Blood-Brain Barrier Contributors N.J. Abbott, D. Barnes, D.J. Begley, A.L. Betz M.W.B. Bradbury, M.W. Brightman, D.J. Brooks, H.F. Cserr P.A. Fraser, A. Gjedde, G.W. Goldstein, J. Greenwood N.H. Greig, M.K. Gumerlock, J.J. Laterra J.-M. Lefauconnier, P.J. Luthert, D.K. Male, E.A. Neuwelt C.S. Patlak, O.E. Pratt, S.I. Rapoport, P.J. Robinson N.R. Saunders, G.P. Schielke, Q.R. Smith Editor Michael W.B. Bradbury Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

2 Contents CHAPTER 1 Ultrastructure of Brain Endothelium M.W. BRIGHTMAN. With 5 Figures 1 A. Endothelium as a Blood-Brain Barrier 1 B. Astroglia as a Blood-Brain Barrier 2 C. Blood-Brain Access 6 I. Vascularization of Grafts to the Brain 6 1. Grafts of Peripheral Tissues 6 2. Similarity Between Ventricle and Anterior Chamber of the Eye 6 3. CNS Versus Peripheral Tissue Grafts 9 II. Immunological Aspects of the Endothelium 9 III. Circumventricular Organs Fenestrae Pits and Vesicles Tubules : 13 D. Ontogeny 14 E. Astrocytic Modulation of the Barrier 15 F. Constituents of Barrier Cell Membranes 18 References 19 CHAPTER 2 Methods of Study Q.R. SMITH 23 A. Introduction 23 B. Morphologic Techniques 24 I. Organic Dye Tracers 24 II. Electron Microscopy 24 III. Quantitative Morphometry 25 C. In Vivo Transport Methods 25 I. Intravenous Administration/Compartmental Analysis 26 II. Brain Perfusion 30

3 XII Contents III. Indicator Dilution 32 IV. Brain Uptake Index 33 V. Other Techniques 34 D. New Dimensions 36 I. Evaluation of Barrier Transport and Permeability in Humans Positron Emission Tomography Magnetic Resonance Imaging 37 II. Autoradiography 37 III. Brain Vasculature/Perfused Capillaries 38 IV. Other Barrier Sites Choroid Plexus Epithelium Blood-Nerve Barrier Blood-Retinal Barrier 40 V. In Vivo Microdialysis 41 VI. Single Capillary Studies 41 E. Molecular/Cellular Biology 42 I. Isolated Microvessels/Endothelial Monolayers 42 II. Identification of Barrier Transporters and Enzymes 43 III. Expression of Barrier Characteristics 43 F. Summary and Perspectives 44 References 44 CHAPTER 3 Diffusional and Osmotic Permeability to Water P.A. FRASER. With 3 Figures 53 A. Introduction 53 B. The Nature of Permeability 54 C. Water Permeability of the Blood-Brain Barrier 55 I. Diffusive Permeability 56 II. Osmotic Permeability 59 D. Conclusion 62 References 63 CHAPTER 4 Blood-Brain Glucose Transfer A. GJEDDE. With 8 Figures 65 A. Brief History 65 B. Brain Endothelial Glucose Transporter 66 I. Molecular Biology 66 II. Molecular Kinetics 68 III. Structural Requirements of Glucose Transport 69

4 Contents XIII C. Theory of Blood-Brain Glucose Transfer 70 I. Apparent Permeability and Flux 71 II. Facilitated Diffusion Michaelis-Menten Equation Michaelis-Menten Constants Partition Volume 75 III. Multiple Membranes Endothelial Membranes Glial and Neuronal Cell Membranes 78 D. Evidence of Blood-Brain Glucose Transfer 79 I. Methods Operational Equations Experimental Procedures The Blood-Brain Barrier In Vitro 83 II. Normal Values in Awake Subjects Permeability and Flux in Normoglycemia Michaelis-Menten Constants Non-Saturable Glucose Transfer Metabolism-Flux Ratio and the Lumped Constant 90 III. Acute Changes of Glucose Transport Activation and Deactivation Carbon Dioxide and Spreading Depression Anoxia and Ischaemia 96 IV. Chronic Changes Pre- and Postnatal Development Dementia Hypo- and Hyperglycaemia 98 References 103 CHAPTER 5 Transport of Amino Acids J.-M. LEFAUCONNIER. With 3 Figures 117 A. Amino Acid Transport Systems in Animal Cells 117 B. Neutral and Cationic Amino Acids 118 I. Influx Quantification of Influx Summary of the Results Obtained 120 II. Efflux Efflux in the Capillaries Passive Efflux Via the Arachnoid Villi Efflux Via the Choroid Plexus and Arachnoid Membrane III. Net Uptake 128 C. Anionic Amino Acids 129

5 XIV Contents D. Metabolism in the Endothelial Cells of Some Transported Amino Acids 129 E. Regulation of Blood-Brain Amino Acid Transport 130 I. Availability of Amino Acids: Plasma Amino Acid Concentration 131 II. Proportions and Rate of Transport of the Amino Acids Between Blood and Brain 131 III. Is Amino Acid Transport Modified by Hormones? 132 IV. Can Amino Acid Transport Be Modified by Neurotransmitters? 133 F. Physiological and Pathological Modifications 134 I. Blood-Brain Amino Acid Transport During Development Technical Problems How Many Blood-Brain Transport Systems Have Been Found in Immature Animals? Coexistence of Higher Blood-Brain Transport with a Lower Density of Capillaries When Does the Asymmetry of Transport Between the Two Membranes of the Endothelial Cells Appear? 136 II. Effect of Drugs on Blood-Brain Transport of Amino Acids III. Pathological Modifications of Amino Acid Transport Hepatic Encephalopathies Uraemia Diabetes Aminoaciduria Intoxications Depressive States 141 References 142 CHAPTER 6 Peptides and the Blood-Brain Barrier D.J. BEGLEY. With 1 Figure 151 A. Introduction: Central Actions of Peripherally Administered Peptides 151 B. Uptake of Peptides at the Blood-Brain Interfaces 153 I. Intracarotid Bolus Injection Studies (Brain Uptake Index) II. Intravenous Bolus Injection Studies 158 III. Brain Perfusion Studies 164 IV. Choroid Plexus Perfusion Studies 171 V. Isolated Cerebral Microvessels 174 VI. Cultured Cerebral Endothelial Cells 178 C. Evidence for Transport Into Brain Extracellular Fluid 181 D. The Influence of Peptides on Blood-Brain Barrier Permeability to Specific Solutes 189

6 Contents XV E. General Conclusions 194 References 196 CHAPTER 7 The Movement of Vitamins Into the Brain O.E. PRATT. 1 With 1 Figure 205 A. Routes 205 I. The Trans-Capillary Route 205 II. Other Possible Routes 205 B. Mechanisms 207 I. Passive Diffusion 207 II. Carrier-Mediated Transport 207 III. Binding Proteins 208 IV. Covalently Bound Carriers 208 C. The Individual Vitamins 208 I. Thiamine 208 II. Ascorbic Acid 211 III. Pyridoxine 212 IV. Folates 213 V. Vitamin B, VI. Nicotinamide, Nicotinic Acid 214 VII. Choline 214 VIII. Nucleosides and Purine Bases 214 IX. Other B-Vitamins 215 X. Lipophilic Vitamins 215 D. Clinical Implications 215 E. Homeostasis 216 F. Conclusions 217 References 218 CHAPTER 8 Electrolyte Transport G.P. SCHIELKE and A.L. BETZ. With 3 Figures 221 A. Brain Electrolyte Homeostasis 221 I. Stability of the Extracellular Potassium Concentration 221 II. Spatial Buffering of Potassium 222 III. Extracellular Sodium and Chloride Concentrations 222 IV. Pathologic Conditions 223 B. Blood-Brain Barrier Permeability to Electrolytes 224 I. Measurements of Electrolyte Permeability 224 II. Route of Electrolyte Passage Across the BBB Passive Permeability Pathways 226

7 XVI Contents 2. Evidence for Active Transport Pathways 228 III. Epithelial Properties of the Brain Capillary Endothelium 229 IV. Mechanisms of Ion Transport Across the BBB Luminal Entry Mechanisms Abluminal Transport Systems 233 V. Regulation of BBB Permeability to Ions Regulation by Electrolytes and Glucose Regulation by Nerves Regulation by Hormones 237 References 238 CHAPTER 9 Secretion and Bulk Flow of Interstitial Fluid H.F. CSERR and C.S. PATLAK. With 4 Figures 245 A. Introduction 245 B. Factors Governing Extracellular Fluid Exchanges Within the Brain 246 I. Blood-Brain Barrier 246 II. Cerebral ISF and CSF 246 III. Pathways of Flow Between Brain and CSF 247 C. Bulk Flow of ISF 248 I. Methods of Study 248 II. Drainage of ISF from Brain to CSF Historical Perspectives Recent Studies 250 III. Retrograde Flow of CSF Into Brain 252 IV. Studies Using Horseradish Peroxidase as Tracer 253 D. Secretion of ISF by the Cerebral Endothelium: An Hypothesis 254 E. Outflow of ISF to Blood and Deep Cervical Lymph 255 F. Functions of ISF Flow 256 I. Clearance 256 II. Brain Volume Regulation 256 III. Immune Function 258 References 258 CHAPTER 10 Trace Metal Transport at the Blood-Brain Barrier M.W.B. BRADBURY. With 4 Figures 263 A. Introduction 263 B. Theoretical and Experimental Approach 264 C. Intravenous Administration in Intact Rat 264

8 Contents XVII D. Short Vascular Perfusion of the Brain etc 266 E. Solutions for Brain Perfusion etc 266 F. Uptake of Various Trace Metals Into Brain After Radiotracer Infusions 268 I. Lead 270 II. Zinc 271 III. Iron 273 IV. Gallium 274 G. Conclusions 275 References 276 CHAPTER 11 Transport of Drugs P.J. ROBINSON and S.I. RAPOPORT. With 4 Figures 279 A. Introduction 279 B. Protein Binding and Drug Uptake 282 I. Kinetics of Protein Binding 283 II. Measurable Quantities 284 III. Limiting Cases Restrictive Elimination Instantaneous Equilibration Dissociation-Limited Uptake 287 IV. Implications and Examples 288 V. Additional Factors 289 C. Modification of the Blood-Brain Barrier 290 I. Osmotic Blood-Brain Barrier Opening 290 II. Tumor Chemotherapy 294 D. Conclusions 295 References 297 CHAPTER 12 Clinical Assessment of Blood-Brain Barrier Permeability: Magnetic Resonance Imaging D. BARNES. With 1 Figure 301 A. Introduction 301 B. Multiple Sclerosis 302 C. Tumours 305 D. Cerebrovascular Disease 306 E. Other Cerebral Diseases 307 F. Quantification of BBB Permeability 307 References 309

9 XVIII Contents CHAPTER 13 Clinical Assessment of the Blood-Brain Barrier: Positron Emission Tomography D.J. BROOKS. With 1 Figure 313 A. Introduction 313 B. Rb + Transport 314 C. Ga-EDTA Transport 318 D. Glucose Transport 319 E. Albumin Diffusion and Microvascular Haematocrit 320 F. Amino Acid Transport 321 G. Conclusions 322 References 323 CHAPTER 14 Ontogenetic Development of Brain Barrier Mechanisms N.R. SAUNDERS. With 12 Figures 327 A. Introduction 327 B. Barriers to Dyes and Proteins in the Developing Brain 330 C. Formation of the Fundamental Blood-Brain and Blood-CSF Barriers in the Embryonic and Fetal Brain 332 D. Ultrastructure of Tight Junctions in Embryonic and Fetal Brain E. Cerebral Endothelial Cells In Vitro 335 F. Suitable Preparations for Studies of Barrier Mechanisms in the Developing Brain In Vivo 337 G. Barrier Permeability to Lipid Insoluble Molecules in the Fetal/Neonatal Brain 339 H. CSF-Brain Barrier in the Immature Brain 341 I. CSF Secretion and Pressure 345 J. Electrolytes in CSF in the Developing Brain 348 K. Glucose and Amino Acid Transport in the Developing Brain 351 L. Proteins in CSF in the Fetus and Neonate 353 M. Trace Metals and Brain-Liver Glycoproteins in the Developing Brain :. 358 N. Drugs and Barriers in the Developing Brain 360 O. Conclusions 361 References 362

10 Contents XIX CHAPTER 15 Comparative Physiology of the Blood-Brain Barrier N.J. ABBOTT. With 9 Figures 371 A. Introduction 371 I. History of Blood-Brain Barrier Studies 371 II. Value of Comparative Studies Comparisons Between Animal Groups Selection of Convenient Experimental Preparation Preparations Offering Unique Advantages 373 B. Evolutionary Pressures Leading to Development of a Blood-Brain Barrier 373 I. Why Do We Need a Blood-Brain Barrier? 373 II. Ionic Homeostasis and Neural Function 374 III. Isolation for Chemical Signalling 375 IV. Regulation of the Periaxonal Environment 376 C. Site of the Barrier Layer 378 I. Endothelial Barrier of Vertebrates 378 II. Glial Barriers in Higher Invertebrates 378 III. Transitional Glial/Pericyte Barrier of Cephalopod Molluscs IV. Apparently Anomalous Glial Blood-Brain Barrier of Elasmobranch Fish 379 V. Residual Barrier-Forming Properties of Vertebrate Glia and Ependyma 380 VI. Role of Pericytes in Barrier Function 381 D. Inductive Signals in Barrier Formation 381 I. Grafting Studies: Brain Versus Non-Brain 381 II. Implanted Astrocytes 382 III. Induction in Culture Differences Between Cultured and In Situ Endothelial Cells Effects of Astrocytes on the Endothelium Effects of Endothelial Cells on Astrocytes 383 IV. Induction in Development 383 V. Global Hypothesis of Induction 384 E. Comparative Approach in Developmental Studies 384 I. Maturity at Birth 384 II. Blood-Brain Barrier Development and Ion Homeostasis 385 III. Relation of Ontogeny and Phlyogeny 385 F. Permeability and Transport Properties of Barrier Layers 387 I. The Vertebrate Endothelial Barrier 387 II. The Vertebrate Choroid Plexus 387 III. The Elasmobranch Glial Barrier 388 IV. The Cephalopod Glial Barrier 389 V. Crustacean and Insect Glial Barriers 389

11 XX Contents VI. Comparison of Endothelial and Glial Barriers Properties Common to Barrier Layers Differences of Endothelial and Glial Barriers 389 G. Relation of Interstitial Fluid and Cerebrospinal Fluid 390 I. Vertebrate Brain 390 II. Cephalopod Brain 391 H. Summary and Conclusions 391 References 391 CHAPTER 16 Immunology of Brain Endothelium and the Blood-Brain Barrier D.K. MALE. With 4 Figures 397 A. Introduction 397 B. Molecular Permeability 398 I. Antibodies 398 II. Routes of Molecular Movement 399 C. Movement of Antigens out of the CNS 401 D. Antigen Presentation by Brain Endothelial Cells 401 I. MHC Expression and Induction 402 II. Stimulation of T-Cell Proliferation 404 E. Cellular Migration Across Brain Endothelium 405 I. The Role of Lymphocytes 405 II. Control by Brain Endothelium 408 III. Molecules Controlling Cell Migration into Brain 409 F. Summary and Synthesis 412 References 412 CHAPTER 17 The Blood-Brain Barrier In Vitro and in Culture J.J. LATERRA and G.W. GOLDSTEIN. With 6 Figures 417 A. Introduction 417 B. Isolated Microvessels 418 C. Transport 418 I. Glucose 421 II. Amino Acids 423 III. Potassium 425 D. The Blood-Brain Barrier in Cell Culture 425 E. Microvessel Morphogenesis In Vitro 427 F. Conclusion 432 References 434

12 Contents XXI CHAPTER 18 Opening of the Barrier in Cerebral Pathology P.J. LUTHERT. With 2 Figures 439 A. Introduction 439 B. Demonstration of Barrier Breakdown in Pathological States 440 I. Technical Aspects 440 II. Barrier Breakdown in Cerebral Tumours 440 III. Barrier Breakdown in Alzheimer's Disease 441 IV. Barrier Breakdown in Other Pathological States 441 C. An Anatomical Approach to Barrier Opening in Cerebral Pathology 442 I. Luminal Factors Loss of Autoregulation Circulating Factors 443 II. Reorganisation of Angioarchitecture Angioarchitecture of Cerebral Tumours Angioarchitecture in Alzheimer's Disease 445 III. The Endothelial Cell Ultrastructural Correlates of Barrier Breakdown 445 IV. The Basement Membrane 447 V. Pericytes. 448 VI. Astrocytes The Role of the Astrocyte in Barrier Maintenance Astrocyte Reactions to Cerebral Injury 448 VII. Blood-Brain Barrier Innervation 449 VIII. Immune Aspects 450 IX. Parenchymal Factors 450 D. Consequences of Barrier Opening 451 I. Benefits of Barrier Opening 451 II. Complications of Barrier Opening 451 E. Manipulation of the Pathologically Disturbed Barrier 452 F. Conclusions 452 References 453 CHAPTER 19 Experimental Manipulation of the Blood-Brain and Blood-Retinal Barriers J. GREENWOOD. With 4 Figures 459 A. Introduction 459 B. Manipulation of the Blood-Brain and Blood-Retinal Barriers 461 I. Disruptive Agents of Non-Pathological Origin Hyperosmolar Solutions Bile Salts 464

13 XXII Contents 3. Drugs and Anaesthetics Enzymes Cations and Endothelial Cell Surface Charge 469 II. Disruptive Agents of Pathological Origin Arachidonic Acid and the Eicosanoids Histamine Bradykinin Hydroxytryptamine Cytokines, Platelet Activating Factor and Complement Tumour Secreted Vascular Permeability Factor 476 III. Miscellaneous Techniques 477 C. Cellular Mechanisms of Increased Barrier Permeability and Route of Leakage 478 References 479 CHAPTER 20 Drug Entry Into the Brain and Its Pharmacologic Manipulation N.H. GREIG. With 18 Figures 487 A. Introduction 487 B. The Presence and Function of a Blood-Brain Barrier 488 I. The Structural Barrier 488 II. The Enzymatic Barrier III. Barrier Permeability 491 C. Factors Determining Time-Dependent Brain Drug Levels 493 I. Ionization. ~ 493 II. Drug Binding to Plasma Proteins 494 III. Time-Dependent Plasma Concentration 495 IV. Cerebral Blood Flow 498 D. Strategies for Increasing the Brain Concentration of Drugs 499 I. Development of Lipophilic Analogues and Prodrugs 499 II. Carrier-Mediated Transport 510 E. Summary 515 References 516 CHAPTER 21 Therapeutic Opening of the Blood-Brain Barrier in Man M.K. GUMERLOCK and E.A. NEUWELT. With 2 Figures 525 A. Introduction 525 B. Chemotherapy for Malignant Brain Tumors 527 I. Published Clinical Series 527 II. Malignant Glioma 532

14 Contents XXIII III. Cerebral Lymphoma 534 IV. Metastatic Tumors to the Brain 535 C. Imaging BBB Disruption 535 D. Complications of BBB Disruption/Chemotherapy 536 E. Tumor-Specific Monoclonal Antibody Infusion after BBB Disruption 537 F. Treatment of Fungal Brain Abscess with BBB Disruption/ Chemotherapy 538 G. Conclusion 539 References 540 Subject Index 543