ABSTRACT

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 II. The Physical Basis of Blood-Brain Barrier Properties. . . . . . . . . . . . . . . . . . 122

A. Endothelial Cells in Brain Vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 B. Adherens and Tight Junctions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 C. Potential Involvement of Acetylcholinesterase . . . . . . . . . . . . . . . . . . . . . 124 D. Signal-Transducing Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 E. Astrocyte Contributions to Blood-Brain Barrier Properties . . . . . . . . . . . 128

III. Functional Characteristics of the Blood-Brain Barrier. . . . . . . . . . . . . . . . . . 128 A. Inward and Outward Movement across the Blood-Brain Barrier:

Physiological Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 B. Cholinergic Involvement in Blood-Brain Barrier Functioning . . . . . . . . . 129 C. Pericellular Passage across Blood-Brain Barrier Structures . . . . . . . . . . . 129 D. Cell Culture, Organ Systems, and Imaging Approaches in

Blood-Brain Barrier Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 E. Transgenic Engineering Models for Blood-Brain

Barrier Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 IV. Modulators of Blood-Brain Barrier Functions and

Their Interrelationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 A. Nitric Oxide and Vasoactive Agents Involvement. . . . . . . . . . . . . . . . . . . 133 B. Immunomodulators and Multi-Drug Transporters . . . . . . . . . . . . . . . . . . 133

V. Conditions Inducing Blood-Brain Barrier Distruption. . . . . . . . . . . . . . . . . . 134 A. Pathophysiological Induction of Blood-Brain Barrier Penetrance . . . . . . 134 B. Blood-Brain Barrier Disruption Following Acute Insults. . . . . . . . . . . . . 135 C. Psychological and Physical Stressors Impair Blood-Brain

Barrier Functioning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

D. Blood-Brain Barrier as a Complex Trait with Genetic and Physiological Components: Prospects . . . . . . . . . . . . . . . . . . . . . . . . 136

VI. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Separation of the brain from the peripheral blood is crucial for protecting this most delicate and important organ from various insidious agents that circulate in the blood. Conversely, the separation must allow for the nutrition of the brain and the removal from it of waste products. The existence of a physical barrier that separates the brain tissue from the general circulation was first proposed 100 years ago, by Ehrlich, who discovered that injection of a series of dyes into laboratory animals resulted in uncolored brains, as opposed to highly stained visceral organs.1 The blood-brain barrier (BBB) is formed during the late embryonic and early postnatal period. It is an endothelial barrier present in the capillaries throughout the brain, contact-influenced by neighboring astrocytes.2 Electron microscopic studies reveal two major factors that distinguish brain endothelial cells from their peripheral relatives: first, they contain lower amounts of endocytic vesicles, and second, the space between adjacent cells is sealed by tight junctions; both factors restrict intercellular flux. These features enable the formation of a barrier that hinders the entry of most xenobiotics into the brain, and is actively involved in exporting such substances from the brain when they do enter it. Small lipophilic molecules enter the brain fairly freely, but hydrophilic molecules enter via active transport, and specific transporters exist for required nutrients such as glucose, L-DOPA, and certain amino acids.3