The blood-brain barrier (BBB) is the interface between blood and brain and, therefore, plays an important role in many disciplines, including psychology, psychiatry, nutrition, general metabolism, as well as pharmacology, neurology, and neurosurgery (Pardridge, 2001). The BBB evolved in parallel with myelination of the brain, is present in the brain of all vertebrates, and is formed within the first trimester of human fetal life. The anatomical localization of the BBB is the capillary endothelium of brain. unlike capillary endothelial cells in peripheral tissues, the en-dothelial cells of capillaries perfusing the brain and spinal cord are joined together by epithelial-like, high-resistance tight junctions that eliminate the normal paracellular pathway of solute flux from blood to the organ interstitium (Brightman, Reese, & Feder, 1970). There is also a 99% reduction in the pinocytosis in endothelia of the central nervous system (CNs), and this eliminates the normal trans-cellular pathway of free solute exchange between blood and the organ interstitial space.
The paracellular and transcellular pathways for free solute exchange across the capillary wall that are present in the microcirculation of peripheral organs are absent in the capillaries perfusing the brain and spinal cord. Therefore, circulating molecules gain access to brain or spinal cord by only one of two processes: (1) free diffusion based on the lipid solubility and molecular weight of the molecule, and (2) catalyzed transport (Oldendorf, 1974). The latter involves either carrier-mediated transport (CMT) for small molecular weight nutrients such as glucose or amino acids, or receptor-mediated transcytosis (RMT) for certain circulating peptides such as insulin, leptin, or transferrin (Pardridge, 2001). The CMT and RMT systems are individual proteins expressed by specific genes within the capillary endothelium. The CMT and RMT systems mediate the transport of nutrients or some endogenous peptides across both the luminal plasma membrane of the capillary endothelium, at the blood surface, and the abluminal membrane of the capillary endothelium, at the side of the brain interstitial fluid. The luminal and abluminal membranes are separated by approximately 300 nm of endothelial cytoplasm. Therefore, transport across the BBB is a process of molecular transfer through two membranes in series: the capillary endothelial luminal and abluminal plasma membranes. If a molecule does not have access to one of the specialized CMT or RMT systems within the BBB membranes, then there is no significant uptake of the molecule by brain.
The capillaries within the brain are approximately 40 microns apart, and it takes a small molecule such as glucose to diffuse 40 microns around 1 second. The capillary transit time in brain is approximately 1 second. Therefore, the angioarchitecture of brain has evolved to allow for instantaneous solute equilibration throughout the brain in-terstitium once the molecule crosses the limiting membrane, which is the BBB. The endothelial cell shares a capillary basement membrane with the pericyte, which sits on the abluminal side of the endothelium. The pericyte has an antigen presentation role in the CNs (Pardridge, 2001). More than 99% of the brain surface of the capillary basement membrane is invested by astrocyte foot processes, and the distance between the astrocyte foot process and the capillary endothelium is only 20 nm or 200 angstroms, and this distance is equal to the thickness of the capillary basement membrane. There are no tight junctions between astrocyte foot processes, and the astrocyte foot process constitutes no permeability barrier in brain. While the permeability of the
BBB is strictly regulated by the endothelial cell, the total function of the brain microvasculature is determined by the paracrine interactions between the endothelial cell, the pericyte, the astrocyte foot process, and the occasional nerve ending that terminates directly on the brain side of the capillary.
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