Physiology and Pharmacology of the Blood-Brain Barrier

ISBN-13: 9783642768965 / Angielski / Miękka / 2011 / 549 str.

N.J. Abbott;D. Barnes;D.J. Begley

Opis

The blood-brain barrier is still not completely understood and therefore the subject of fascinating study. How are endogenous substances transported through the blood-brain barrier? What are the known therapeutic and toxic agents? How are they transported across cerebral microvessels? The discussion of these and other questions with far-reaching consequences for all neuroscientists can be found in this volume. This authoritative and up-to-date review of the blood-brain barrier gives a proper understanding of the topic. The experimental principles, the results of very recent research, as well as the implications that experimental research has for clinical treatment are thoroughly covered. Information is given on: - new findings based on classical physiological and pharmacological techniques, - results obtained from brain capillaries in vitro and in culture, - results obtained from the new scanning techniques (PET and MRI), - the immunology of the blood-brain barrier, - trace metal transport, - the pathological breakdown of the barrier and - the modification of drugs to increase their entry into the brain. Here is a source of information that is invaluable to specialists concerned with basic research in the neurosciences, with the design of neuropharmacological agents, with the radiological diagnosis of cerebral pathology or with the treatment of cerebral lesions!

Spis treści

1 Ultrastructure of Brain Endothelium.- A. Endothelium as a Blood-Brain Barrier.- B. Astroglia as a Blood-Brain Barrier.- C. Blood-Brain Access.- I. Vascularization of Grafts to the Brain.- 1. Grafts of Peripheral Tissues.- 2. Similarity Between Ventricle and Anterior Chamber of the Eye.- 3. CNS Versus Peripheral Tissue Grafts.- II. Immunological Aspects of the Endothelium.- III. Circumventricular Organs.- 1. Fenestrae.- 2. Pits and Vesicles.- 3. Tubules.- D. Ontogeny.- E. Astrocytic Modulation of the Barrier.- F. Constituents of Barrier Cell Membranes.- References.- 2 Methods of Study.- A. Introduction.- B. Morphologic Techniques.- I. Organic Dye Tracers.- II. Electron Microscopy.- III. Quantitative Morphometry.- C. In Vivo Transport Methods.- I. Intravenous Administration/Compartmental Analysis.- II. Brain Perfusion.- III. Indicator Dilution.- IV. Brain Uptake Index.- V. Other Techniques.- D. New Dimensions.- I. Evaluation of Barrier Transport and Permeability in Humans.- 1. Positron Emission Tomography.- 2. Magnetic Resonance Imaging.- II. Autoradiography.- III. Brain Vasculature/Perfused Capillaries.- IV. Other Barrier Sites.- 1. Choroid Plexus Epithelium.- 2. Blood-Nerve Barrier.- 3. Blood-Retinal Barrier.- V. In Vivo Microdialysis.- VI. Single Capillary Studies.- E. Molecular/Cellular Biology.- I. Isolated Microvessels/Endothelial Monolayers.- II. Identification of Barrier Transporters and Enzymes.- III. Expression of Barrier Characteristics.- F. Summary and Perspectives.- References.- 3 Diffusional and Osmotic Permeability to Water.- A. Introduction.- B. The Nature of Permeability.- C. Water Permeability of the Blood-Brain Barrier.- I. Diffusive Permeability.- II. Osmotic Permeability.- D. Conclusion.- References.- 4 Blood-Brain Glucose Transfer.- A. Brief History.- B. Brain Endothelial Glucose Transporter.- I. Molecular Biology.- II. Molecular Kinetics.- III. Structural Requirements of Glucose Transport.- C. Theory of Blood-Brain Glucose Transfer.- I. Apparent Permeability and Flux.- II. Facilitated Diffusion.- 1. Michaelis-Menten Equation.- 2. Michaelis-Menten Constants.- 3. Partition Volume.- III. Multiple Membranes.- 1. Endothelial Membranes.- 2. Glial and Neuronal Cell Membranes.- D. Evidence of Blood-Brain Glucose Transfer.- I. Methods.- 1. Operational Equations.- 2. Experimental Procedures.- 3. The Blood-Brain Barrier In Vitro.- II. Normal Values in Awake Subjects.- 1. Permeability and Flux in Normoglycemia.- 2. Michaelis-Menten Constants.- 3. Non-Saturable Glucose Transfer.- 4. Metabolism-Flux Ratio and the Lumped Constant.- III. Acute Changes of Glucose Transport.- 1. Activation and Deactivation.- 2. Carbon Dioxide and Spreading Depression.- 3. Anoxia and Ischaemia.- IV. Chronic Changes.- 1. Pre- and Postnatal Development.- 2. Dementia.- 3. Hypo- and Hyperglycaemia.- References.- 5 Transport of Amino Acids.- A. Amino Acid Transport Systems in Animal Cells.- B. Neutral and Cationic Amino Acids.- I. Influx.- 1. Quantification of Influx.- 2. Summary of the Results Obtained.- II. Efflux.- 1. Efflux in the Capillaries.- 2. Passive Efflux Via the Arachnoid Villi.- 3. Efflux Via the Choroid Plexus and Arachnoid Membrane.- III. Net Uptake.- C. Anionic Amino Acids.- D. Metabolism in the Endothelial Cells of Some Transported Amino Acids.- E. Regulation of Blood-Brain Amino Acid Transport.- I. Availability of Amino Acids: Plasma Amino Acid Concentration.- II. Proportions and Rate of Transport of the Amino Acids Between Blood and Brain.- III. Is Amino Acid Transport Modified by Hormones?.- IV. Can Amino Acid Transport Be Modified by Neurotransmitters?.- F. Physiological and Pathological Modifications.- I. Blood-Brain Amino Acid Transport During Development.- 1. Technical Problems.- 2. How Many Blood-Brain Transport Systems Have Been Found in Immature Animals?.- 3. Coexistence of Higher Blood-Brain Transport with a Lower Density of Capillaries.- 4. When Does the Asymmetry of Transport Between the Two Membranes of the Endothelial Cells Appear?.- II. Effect of Drugs on Blood-Brain Transport of Amino Acids.- III. Pathological Modifications of Amino Acid Transport.- 1. Hepatic Encephalopathies.- 2. Uraemia.- 3. Diabetes.- 4. Aminoaciduria.- 5. Intoxications.- 6. Depressive States.- References.- 6 Peptides and the Blood-Brain Barrier.- A. Introduction: Central Actions of Peripherally Administered Peptides.- B. Uptake of Peptides at the Blood-Brain Interfaces.- I. Intracarotid Bolus Injection Studies (Brain Uptake Index).- II. Intravenous Bolus Injection Studies.- III. Brain Perfusion Studies.- IV. Choroid Plexus Perfusion Studies.- V. Isolated Cerebral Microvessels.- VI. Cultured Cerebral Endothelial Cells.- C. Evidence for Transport Into Brain Extracellular Fluid.- D. The Influence of Peptides on Blood-Brain Barrier Permeability to Specific Solutes.- E. General Conclusions.- References.- 7 The Movement of Vitamins Into the Brain.- A. Routes.- I. The Trans-Capillary Route.- II. Other Possible Routes.- B. Mechanisms.- I. Passive Diffusion.- II. Carrier-Mediated Transport.- III. Binding Proteins.- IV. Covalently Bound Carriers.- C. The Individual Vitamins.- I. Thiamine.- II. Ascorbic Acid.- III. Pyridoxine.- IV. Folates.- V. Vitamin B12.- VI. Nicotinamide, Nicotinic Acid.- VII. Choline.- VIII. Nucleosides and Purine Bases.- IX. Other B-Vitamins.- X. Lipophilic Vitamins.- D. Clinical Implications.- E. Homeostasis.- F. Conclusions.- References.- 8 Electrolyte Transport.- A. Brain Electrolyte Homeostasis.- I. Stability of the Extracellular Potassium Concentration.- II. Spatial Buffering of Potassium.- III. Extracellular Sodium and Chloride Concentrations.- IV. Pathologic Conditions.- B. Blood-Brain Barrier Permeability to Electrolytes.- I. Measurements of Electrolyte Permeability.- II. Route of Electrolyte Passage Across the BBB.- 1. Passive Permeability Pathways.- 2. Evidence for Active Transport Pathways.- III. Epithelial Properties of the Brain Capillary Endothelium.- IV. Mechanisms of Ion Transport Across the BBB.- 1. Luminal Entry Mechanisms.- 2. Abluminal Transport Systems.- V. Regulation of BBB Permeability to Ions.- 1. Regulation by Electrolytes and Glucose.- 2. Regulation by Nerves.- 3. Regulation by Hormones.- References.- 9 Secretion and Bulk Flow of Interstitial Fluid.- A. Introduction.- B. Factors Governing Extracellular Fluid Exchanges Within the Brain.- I. Blood-Brain Barrier.- II. Cerebral ISF and CSF.- III. Pathways of Flow Between Brain and CSF.- C. Bulk Flow of ISF.- I. Methods of Study.- II. Drainage of ISF from Brain to CSF.- 1. Historical Perspectives.- 2. Recent Studies.- III. Retrograde Flow of CSF Into Brain.- IV. Studies Using Horseradish Peroxidase as Tracer.- D. Secretion of ISF by the Cerebral Endothelium: An Hypothesis.- E. Outflow of ISF to Blood and Deep Cervical Lymph.- F. Functions of ISF Flow.- I. Clearance.- II. Brain Volume Regulation.- III. Immune Function.- References.- 10 Trace Metal Transport at the Blood-Brain Barrier.- A. Introduction.- B. Theoretical and Experimental Approach.- C. Intravenous Administration in Intact Rat.- D. Short Vascular Perfusion of the Brain etc..- E. Solutions for Brain Perfusion etc..- F. Uptake of Various Trace Metals Into Brain After Radiotracer Infusions.- I. Lead.- II. Zinc.- III. Iron.- IV. Gallium.- G. Conclusions.- References.- 11 Transport of Drugs.- A. Introduction.- B. Protein Binding and Drug Uptake.- I. Kinetics of Protein Binding.- II. Measurable Quantities.- III. Limiting Cases.- 1. Restrictive Elimination.- 2. Instantaneous Equilibration.- 3. Dissociation-Limited Uptake.- IV. Implications and Examples.- V. Additional Factors.- C. Modification of the Blood-Brain Barrier.- I. Osmotic Blood-Brain Barrier Opening.- II. Tumor Chemotherapy.- D. Conclusions.- References.- 12 Clinical Assessment of Blood-Brain Barrier Permeability: Magnetic Resonance Imaging.- A. Introduction.- B. Multiple Sclerosis.- C. Tumours.- D. Cerebrovascular Disease.- E. Other Cerebral Diseases.- F. Quantification of BBB Permeability.- References.- 13 Clinical Assessment of the Blood-Brain Barrier: Positron Emission Tomography.- A. Introduction.- B. 82Rb+Transport.- C. 68Ga-EDTA Transport.- D. Glucose Transport.- E. Albumin Diffusion and Microvascular Haematocrit.- F. Amino Acid Transport.- G. Conclusions.- References.- 14 Ontogenetic Development of Brain Barrier Mechanisms.- A. Introduction.- B. Barriers to Dyes and Proteins in the Developing Brain.- C. Formation of the Fundamental Blood-Brain and Blood-CSF Barriers in the Embryonic and Fetal Brain.- D. Ultrastructure of Tight Junctions in Embryonic and Fetal Brain.- E. Cerebral Endothelial Cells In Vitro.- F. Suitable Preparations for Studies of Barrier Mechanisms in the Developing Brain In Vivo.- G. Barrier Permeability to Lipid Insoluble Molecules in the Fetal/Neonatal Brain.- H. CSF-Brain Barrier in the Immature Brain.- I. CSF Secretion and Pressure.- J. Electrolytes in CSF in the Developing Brain.- K. Glucose and Amino Acid Transport in the Developing Brain.- L. Proteins in CSF in the Fetus and Neonate.- M. Trace Metals and Brain-Liver Glycoproteins in the Developing Brain.- N. Drugs and Barriers in the Developing Brain.- O. Conclusions.- References.- 15 Comparative Physiology of the Blood-Brain Barrier.- A. Introduction.- I. History of Blood-Brain Barrier Studies.- II. Value of Comparative Studies.- 1. Comparisons Between Animal Groups.- 2. Selection of Convenient Experimental Preparation.- 3. Preparations Offering Unique Advantages.- B. Evolutionary Pressures Leading to Development of a Blood-Brain Barrier.- I. Why Do We Need a Blood-Brain Barrier?.- II. Ionic Homeostasis and Neural Function.- III. Isolation for Chemical Signalling.- IV. Regulation of the Periaxonal Environment.- C. Site of the Barrier Layer.- I. Endothelial Barrier of Vertebrates.- II. Glial Barriers in Higher Invertebrates.- III. Transitional Glial/Pericyte Barrier of Cephalopod Molluscs.- IV. Apparently Anomalous Glial Blood-Brain Barrier of Elasmobranch Fish.- V. Residual Barrier-Forming Properties of Vertebrate Glia and Ependyma.- VI. Role of Pericytes in Barrier Function.- D. Inductive Signals in Barrier Formation.- I. Grafting Studies: Brain Versus Non-Brain.- II. Implanted Astrocytes.- III. Induction in Culture.- 1. Differences Between Cultured and In Situ Endothelial Cells.- 2. Effects of Astrocytes on the Endothelium.- 3. Effects of Endothelial Cells on Astrocytes.- IV. Induction in Development.- V. Global Hypothesis of Induction.- E. Comparative Approach in Developmental Studies.- I. Maturity at Birth.- II. Blood-Brain Barrier Development and Ion Homeostasis.- III. Relation of Ontogeny and Phlyogeny.- F. Permeability and Transport Properties of Barrier Layers.- I. The Vertebrate Endothelial Barrier.- II. The Vertebrate Choroid Plexus.- III. The Elasmobranch Glial Barrier.- IV. The Cephalopod Glial Barrier.- V. Crustacean and Insect Glial Barriers.- VI. Comparison of Endothelial and Glial Barriers.- 1. Properties Common to Barrier Layers.- 2. Differences of Endothelial and Glial Barriers.- G. Relation of Interstitial Fluid and Cerebrospinal Fluid.- I. Vertebrate Brain.- II. Cephalopod Brain.- H. Summary and Conclusions.- References.- 16 Immunology of Brain Endothelium and the Blood-Brain Barrier.- A. Introduction.- B. Molecular Permeability.- I. Antibodies.- II. Routes of Molecular Movement.- C. Movement of Antigens out of the CNS.- D. Antigen Presentation by Brain Endothelial Cells.- I. MHC Expression and Induction.- II. Stimulation of T-Cell Proliferation.- E. Cellular Migration Across Brain Endothelium.- I. The Role of Lymphocytes.- II. Control by Brain Endothelium.- III. Molecules Controlling Cell Migration into Brain.- F. Summary and Synthesis.- References.- 17 The Blood-Brain Barrier In Vitro and in Culture.- A. Introduction.- B. Isolated Microvessels.- C. Transport.- I. Glucose.- II. Amino Acids.- III. Potassium.- D. The Blood-Brain Barrier in Cell Culture.- E. Micro vessel Morphogenesis In Vitro.- F. Conclusion.- References.- 18 Opening of the Barrier in Cerebral Pathology.- A. Introduction.- B. Demonstration of Barrier Breakdown in Pathological States.- I. Technical Aspects.- II. Barrier Breakdown in Cerebral Tumours.- III. Barrier Breakdown in Alzheimer’s Disease.- IV. Barrier Breakdown in Other Pathological States.- C. An Anatomical Approach to Barrier Opening in Cerebral Pathology.- I. Luminal Factors.- 1. Loss of Autoregulation.- 2. Circulating Factors.- II. Reorganisation of Angioarchitecture.- 1. Angioarchitecture of Cerebral Tumours.- 2. Angioarchitecture in Alzheimer’s Disease.- III. The Endothelial Cell.- 1. Ultrastructural Correlates of Barrier Breakdown.- IV. The Basement Membrane.- V. Pericytes.- VI. Astrocytes.- 1. The Role of the Astrocyte in Barrier Maintenance.- 2. Astrocyte Reactions to Cerebral Injury.- VII. Blood-Brain Barrier Innervation.- VIII. Immune Aspects.- IX. Parenchymal Factors.- D. Consequences of Barrier Opening.- I. Benefits of Barrier Opening.- II. Complications of Barrier Opening.- E. Manipulation of the Pathologically Disturbed Barrier.- F. Conclusions.- References.- 19 Experimental Manipulation of the Blood-Brain and Blood-Retinal Barriers.- A. Introduction.- B. Manipulation of the Blood-Brain and Blood-Retinal Barriers.- I. Disruptive Agents of Non-Pathological Origin.- 1. Hyperosmolar Solutions.- 2. Bile Salts.- 3. Drugs and Anaesthetics.- 4. Enzymes.- 5. Cations and Endothelial Cell Surface Charge.- II. Disruptive Agents of Pathological Origin.- 1. Arachidonic Acid and the Eicosanoids.- 2. Histamine.- 3. Bradykinin.- 4. 5-Hydroxytryptamine.- 5. Cytokines, Platelet Activating Factor and Complement.- 6. Tumour Secreted Vascular Permeability Factor.- III. Miscellaneous Techniques.- C. Cellular Mechanisms of Increased Barrier Permeability and Route of Leakage.- References.- 20 Drug Entry Into the Brain and Its Pharmacologic Manipulation.- A. Introduction.- B. The Presence and Function of a Blood-Brain Barrier.- I. The Structural Barrier.- II. The Enzymatic Barrier.- III. Barrier Permeability.- C. Factors Determining Time-Dependent Brain Drug Levels.- I. Ionization.- II. Drug Binding to Plasma Proteins.- III. Time-Dependent Plasma Concentration.- IV. Cerebral Blood Flow.- D. Strategies for Increasing the Brain Concentration of Drugs.- I. Development of Lipophilic Analogues and Prodrugs.- II. Carrier-Mediated Transport.- E. Summary.- References.- 21 Therapeutic Opening of the Blood-Brain Barrier in Man.- A. Introduction.- B. Chemotherapy for Malignant Brain Tumors.- I. Published Clinical Series.- II. Malignant Glioma.- III. Cerebral Lymphoma.- IV. Metastatic Tumors to the Brain.- C. Imaging BBB Disruption.- D. Complications of BBB Disruption/Chemotherapy.- E. Tumor-Specific Monoclonal Antibody Infusion after BBB Disruption.- F. Treatment of Fungal Brain Abscess with BBB Disruption/ Chemotherapy.- G. Conclusion.- References.