Implications of the Blood-Brain Barrier and Its Manipulation : Volume 1 Basic Science Aspects

Understanding the structure and function of the blood-brain barrier (BBB) and recogniz­ ing its clinical relevance require a concert of scientific disciplines applied from a view­ point of integrative physiology rather than from only molecular or analytical approaches. It is this broad scope that is emphasized in this book. In my opinion, four original contributions define the field as it exists today. The first, a monograph by Broman,1 entitled The Permeability of the Cerebrospinal Vessels in Normal and Pathological Conditions, was the model for many subsequent clinical and 3 experimental studies on BBB pathology. Second, experiments by Davson, summarized in his book entitled Physiology of the Ocular and Cerebrospinal Fluids, indicated that passive entry of nonelectrolytes into brain from blood is governed largely by their lipid 4 solubility. This research supported the original suggestion by Gesell and Hertzman that cerebral membranes have the semipermeability properties of cell membranes. The modem era of the barrier was introduced with the 1965 paper by Crone,2 entitled "Facilitated transfer of glucose from blood to brain tissue. " This paper identified stereospecific, facilitated transport of glucose as part of a system of regulatory barrier properties at a time when only a barrier to passive diffusion had been contemplated. Finally, the 1967 paper by Reese and Kamovsky, 11 entitled "Fine structural localization of a blood-brain barrier to exogenous peroxidase," sited the barrier at the continuous layer of cerebrovascular endothelial cells, which are connected by tight junctions.

1. The Challenge of the Blood-Brain Barrier.- 1. Introduction.- 2. Do Monocytes Stream across the Blood-Brain Barrier in Response to Brain Injury?.- 3. Effects of Injury to the Blood-Brain Barrier by Mass Lesions in the CNS: Neuroradiologic Characteristics.- 4. Encephalopathy Associated with Cryoprecipitable Australia Antigen.- 5. Adoptive Immunotherapy as a Means to Circumvent the Blood-Brain Barrier and the Immunologic Privilege of the CNS.- 6. The Dramatic Effect of Corticosteroids on Vasogenic Cerebral Edema.- 7. The Role of Blood-Brain Barrier Modification in the Treatment of Primary Brain Tumors.- 8. Competition at the Blood-Brain Barrier by Dietary Amino Acids Causing Fluctuations in the Motor Performance of Patients with Parkinson Disease Who Are Receiving Levodopa Therapy.- 9. Conclusion.- References.- 2. History of the Blood-Brain Barrier Concept.- 1. Studies with Dyestuffs.- 2. The Stern-Gautier Hypothesis.- 3. Selectivity of the Barrier.- 4. Lipid Solubility.- 5. Sink Action of the Cerebrospinal Fluid.- 6. Morphology of the Blood-Brain Barrier.- 6.1. Brain Capillary Endothelial Cell End-Feet.- 6.2. Electron Microscopists’ Heresy.- 7. The Extracellular Space of the Brain.- 8. The Barriers and Homeostasis.- 8.1. Brain Extracellular Fluid.- 8.2. Cerebral Edema.- 9. Ontogeny of the Blood-Brain Barrier.- 9.1. Rate of Protein Exchange.- 9.2. Concentrations of Individual Proteins.- 10. Comparative Aspects.- 10.1. Elasmobranchs.- 10.2. Holocephalans.- 10.3. Cyclostomes.- 10.4. The Invertebrate Barrier.- 10.5. Value of Comparative Studies.- 11. The Present Era.- 11.1. Perfused Brain.- 11.2. Isolated Choroid Plexus.- 11.3. Isolated Brain Microvessels.- 12. Summary.- References.- 3. The Anatomic Basis of the Blood-Brain Barrier.- 1. Intercellular Tight Junctions.- 1.1. Structure and Permeability.- 1.2. Glial Modulation.- 2. Pits, Vesicles, and Channels.- 2.1. Vesicle Translocation.- 2.2. Most Vesicles May Be Pits.- 2.3. Vesicle Fusion and Fission.- 2.4. Cryofixation and Chemical Fixation.- 3. Receptors.- 3.1. Insulin.- 3.2. Low-Density Lipoprotein.- 3.3. Transferrin.- 4. Electric Charge.- 4.1. Charge and Endocytosis.- 4.2. Charge and Lectin Binding.- 5. Circumventing the Barrier.- 5.1. Retrograde Axonal Transport.- 5.2. Endothelial Alteration.- 5.3. Transplants.- 6. Extravascular Spread of Peroxidase.- 6.1. Perivascular Basement Membrane.- 6.2. Interstitial Compartment.- 6.3. Clearance via Basement Membranes.- 7. Enzymes.- 8. Conclusions.- References.- 4. Quantitation of Blood-Brain Barrier Permeability.- 1. Introduction.- 2. Two Methodologic Approaches.- 3. Continuous Uptake.- 3.1. Intravenous Administration.- 3.2. Brain-Perfusion Technique.- 4. Single-Pass Uptake.- 4.1. Indicator Diffusion.- 4.2. Brain Uptake Index.- 4.3. Single Injection-External Registration.- 5. Summary.- References.- 5. Transport across the Blood-Brain Barrier.- 1. Physicochemical Factors Influencing Permeability.- 1.1. Solute Transport.- 1.2. Water.- 1.3. Influence of Protein Binding.- 1.4. Convection in Cerebral Interstitial Fluid.- 2. Specific Transport.- 2.1. Monosaccharides.- 2.2. Monocarboxylic Acids.- 2.3. Amino Acids.- 2.4. Vitamins, Cofactors, and Nucleic Acid Precursors.- 2.5. Peptides.- 3. Factors Modifying Permeability.- 3.1. Blood Flow and Permeability.- 3.2. Modulation of Transport Mechanisms.- 4. Conclusions.- References.- 6. Pharmacology of the Blood-Brain Barrier.- 1. Introduction.- 2. Methods of Measuring Drug Transfer.- 3. Capillary Transport Models and PS Products.- 4. Mechanisms of Transport to and through the BBB.- 5. Local Differences in Influx.- 6. Drug Permeability and Distribution.- 7. Summary.- References.- 7. Ontogeny and Phytogeny of the Blood-Brain Barrier.- 1. Introduction.- 2. Ontogenetic and Phylogenetic Animal Models of Barriers.- 3. Structural Configurations of Barrier Systems in Infant Mammals.- 3.1. Blood-Brain Barrier.- 3.2. Blood-CSF Barrier: Choroid Plexus.- 4. Quantitation of Solute Permeation into CNS.- 5. Physiologic Factors Affecting Solute Permeation into CNS.- 5.1. Cerebrovascular Variables.- 5.2. Extracellular Fluid Volume.- 5.3. Cerebrospinal Fluid Sink Action.- 5.4. Brain Cell Metabolism.- 5.5. Macromolecular Composition of CSF, Cells, and Plasma.- 5.6. Acid-Base Effects.- 6. Perinatal Development of Barriers Regulating Solute Movement.- 6.1. Anions.- 6.2. Cations.- 6.3. Nonelectrolytes.- 6.4. Sugars.- 6.5. Amino Acids.- 6.6. Monocarboxylic Acids.- 6.7. Monoamine Neurotransmitters.- 7. Discussion of Ontogeny of Barrier Function in Mammals.- 7.1. Ontogeny of the BBB: Models and Questions.- 7.2. Permeability of the BBB in Infant Rats in in Vivo Experiments.- 7.3. Regional Differences in Barrier Permeability in the Developing CNS.- 7.4. Cation versus Anion and Nonelectrolyte Permeation.- 7.5. Anatomic Substrates for More Permeable Interfaces.- 7.6. Developmental Permeability: Neural versus Peripheral Tissues.- 7.7. Kinetic Constants for Carrier Transport in Immature Brain.- 7.8. Interpretation of BUI Constants for Infants.- 7.9. CNS Hemodynamic and Hydrodynamic Development.- 7.10. Ontogeny of Acid-Base Modulation of Transport.- 7.11. Pharmacologic and Toxicologic Considerations.- 7.12. Pathophysiology of the Developing Barriers.- 7.13. The Rat as an Ontogenetic BBB Model.- 7.14. Future Research Directions.- 8. Recapitulation and Perspective.- References.- 8. The Blood-Nerve Barrier and the Pathologic Significance of Nerve Edema.- 1. Introduction.- 1.2. The Blood-Nerve Barrier and the Endoneurial Compartment.- 2. Endoneurial Fluid Pressure.- 2.1. Mechanisms of Increased Endoneurial Fluid Pressure.- 3. Significance of Endoneurial Edema.- 3.1. Topography of Endoneurial Edema.- 3.2. Impact of Endoneurial Edema.- 4. Nerve Fiber Lesions Associated with Increased EFP.- 4.1. Wallerian Degeneration Secondary to Nerve Crush.- 4.2. Cryoprobe Injury.- 4.3. Chemical Injury.- 4.4. Laser Injury.- 4.5. Entrapment Neuropathy.- 4.6. Secondary Axonal Injury.- 5. Summary.- References.- 9. Potential for Pharmacologic Manipulation of the Blood-Cerebrospinal Fluid Barrier.- 1. Introduction.- 2. Consideration of Gross Structure.- 3. Barrier Cells: Plexus Epithelium versus Cerebral Endothelium.- 4. Polarity of Membranes in CNS Transport Interfaces.- 5. Experimental Preparations of Choroid Plexus.- 5.1. In Vitro.- 5.2. In Situ.- 6. In Vivo Analyses of Choroid Plexus-CSF Systems.- 7. Rate-Limiting Step in Transchoroidal Transport.- 8. Permeability of Tight Junctions and Membrane Poles.- 8.1. Tight Junctions.- 8.2. Basolateral Membrane.- 8.3. Apical Membrane.- 9. Carrier Transport Systems in Choroid Plexus.- 10. Exploitation of Barrier Transport Mechanisms in the Blood-CSF Barrier.- 10.1. Ascorbic Acid.- 10.2. Nucleosides and Vitamins.- 10.3. Purines.- 10.4. Amino Acids.- 11. Transcellular and Paracellular Transport of Proteins.- 11.1. Endothelial Vesicular Transport: Blood-Brain Barrier versus CP.- 11.2. Transcellular Pathway (into or through Epithelium).- 11.3. Paracellular Pathway (between Epithelia).- 11.4. Factors Affecting CSF Protein Concentration.- 11.5. Therapeutic Strategies.- 12. Polypeptide Receptors and Transport.- 12.1. Oligopeptides.- 12.2. Enkephalins.- 12.3. Polypeptide Hormones.- 13. Prostaglandins and Leukotrienes.- 14. Neurotransmitters.- 15. Altered Fluxes of Inorganic Ions across Choroid Plexus.- 15.1. Sodium and Chloride.- 15.2. Bicarbonate.- 15.3. Potassium.- 15.4. Lithium.- 15.5. Calcium and Magnesium.- 16. Hypertensive and Osmotic Opening of the Choroid Plexus.- 17. Future Outlook and Practical Considerations.- References.- 10. The Blood-Brain Barrier and the Immune System.- 1. Basic Concepts of Immunology.- 2. Is the Central Nervous System an Immunologically Privileged Site?.- 3. Cerebrospinal Fluid Composition.- 4. Circulating Antibodies in Neurologic Disease.- 5. Demyelinating Diseases of the Central Nervous System.- 6. Neoplastic Disease of the Central Nervous System.- 7. Is There a Separate Immune System in the Central Nervous System?.- 8. Therapeutic Implications of the Blood-Brain Barrier.- 9. Summary and Conclusions.- References.- 11. Cerebral Edema and the Blood-Brain Barrier.- 1. Introduction.- 1.1. Definition of Edema.- 1.2. Types of Cerebral Edema.- 2. Development and Resolution of Vasogenic Edema.- 2.1. Formation and Spread of Vasogenic Edema.- 2.2. Equilibrium Phase.- 2.3. Resolution of Vasogenic Edema.- 2.4. Chemical Characteristics.- 3. Characteristics and Reversibility of Ischemic Edema.- 3.1. Ischemic Changes.- 3.2. Postischemic Edema.- 3.3. Delayed Breakdown of the Blood-Brain Barrier.- 4. Functional Disturbances in Injured Brain May Not Be Related to Cerebral Edema.- 5. Conclusion.- 6. Summary.- References.- 12. Drug Delivery to the Brain by Blood-Brain Barrier Circumvention and Drug Modification.- 1. Introduction.- 2. Factors Influencing Drug Concentrations in Brain.- 2.1. Influence of Physicochemical Properties on Drug Organ Uptake.- 2.2. Drug Interactions with Plasma Proteins.- 3. Optimization of Drug Uptake by Brain.- 3.1. Frequency of Drug Administration.- 3.2. Route of Drug Administration.- 4. Reversible Blood-Brain Barrier Modification.- 4.1. Osmotic Opening.- 4.2. Metrazol Opening.- 4.3. Miscellaneous Techniques.- 5. Chemical Modification of Drugs.- 5.1. Analogues.- 5.2. Prodrugs.- 5.3. Carrier-Mediated Transport at the Blood-Brain Barrier.- 6. Cerebral Blood Flow.- 7. Conclusions.- References.- 13. The Blood-Ocular Barrier.- 1. Blood-Aqueous Barrier.- 2. Blood-Retinal Barrier.- References.