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Department of Medical Pharmacology, the University of Arizona College of Medicine, Tucson, Arizona
Abstract
Abstract I. The Concept of the Blood-Brain Barrier A. Initial Observations of the Blood-Brain Barrier B. Experimental Controversies C. Anatomical Description II. The Neurovascular Unit: Interactions of the Microvascular Endothelium with Neural Tissue A. Astrocytes B. Pericytes C. Neurons D. The Extracellular Matrix III. Molecular Physiology and Pathophysiology of the Blood-Brain Barrier Junctional Complex A. Junctions of the Blood-Brain Barrier B. Proteins of the Tight Junction 1. Junctional Adhesion Molecules. 2. Occludin. 3. Claudins. 4. Membrane-Associated Guanylate Kinase-Like Proteins. 5. Other Accessory Proteins. C. Intracellular Signaling Pathways Involved in Tight Junction Organization and Function 1. Calcium. 2. Phosphorylation. 3. G-Proteins. D. Alteration of Blood-Brain Barrier Tight Junction in Disease 1. Hypoxia/Ischemia. 2. Inflammation. 3. Other Insults. IV. Conclusions
The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS). Although originally observed by Paul Ehrlich in 1885, the nature of the BBB was debated well into the 20th century. The anatomical substrate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for the health and function of the CNS. Tight junctions (TJ) between endothelial cells of the BBB restrict paracellular diffusion of water-soluble substances from blood to brain. The TJ is an intricate complex of transmembrane (junctional adhesion molecule-1, occludin, and claudins) and cytoplasmic (zonula occludens-1 and -2, cingulin, AF-6, and 7H6) proteins linked to the actin cytoskeleton. The expression and subcellular localization of TJ proteins are modulated by several intrinsic signaling pathways, including those involving calcium, phosphorylation, and G-proteins. Disruption of BBB TJ by disease or drugs can lead to impaired BBB function and thus compromise the CNS. Therefore, understanding how BBB TJ might be affected by various factors holds significant promise for the prevention and treatment of neurological diseases.
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