Summary:The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain ϳ100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.

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The blood-brain barrier (BBB) is formed by epithelial-like high resistance tight junctions within the endothelium of capillaries perfusing the vertebrate brain. Because of the presence of the BBB, circulating molecules gain access to brain cells only via one of two processes: (i) lipid-mediated transport of small molecules through the BBB by free diffusion, or (ii) catalyzed transport. The latter includes carrier-mediated transport processes for low molecular weight nutrients and water soluble vitamins or receptor-mediated transport for circulating peptides (e.g., insulin), plasma proteins (e.g., transferrin), or viruses. While BBB permeability, per se, is controlled by the biochemical properties of the plasma membranes of the capillary endothelial cells, overall brain microvascular biology is a function of the paracrine interactions between the capillary endothelium and the other two major cells comprising the microcirculation of brain, i.e., the capillary pericyte, which shares the basement membrane with the endothelial cell, and the astrocyte foot process, which invests 99% of the abluminal surface of the capillary basement membrane in brain. Microvascular functions frequently ascribed to the capillary endothelium are actually executed by either the capillary pericyte or the capillary astrocyte foot process. With respect to BBB methodology, there are a variety of in vivo methods for studying biological transport across this important membrane. The classical physiologic techniques may now be correlated with modern biochemical and molecular biological approaches using freshly isolated animal or human brain capillaries. Isolated brain capillary endothelial cells can also be grown in tissue culture to form an`in vitro BBB' model. However, BBB research cannot be performed using only the in vitro BBB model, but rather it is necessary to correlate observations made with the in vitro BBB model with in vivo studies.

Lipid‐soluble small molecules with a molecular mass under a 400–600‐Da threshold are transported readily through the blood‐brain barrier in vivo owing to lipid‐mediated transport. However, other small molecules lacking these particular molecular properties, antisense drugs, and peptide‐based pharmaceuticals generally undergo negligible transport through the blood‐brain barrier in pharmacologically significant amounts. Therefore, if present day CNS drug discovery programs are to avoid termination caused by negligible blood‐brain barrier transport, it is important to merge CNS drug discovery and CNS drug delivery as early as possible in the overall CNS drug development process. Strategies for special formulation that enable drug transport through the blood‐brain barrier arise from knowledge of the molecular and cellular biology of blood‐brain barrier transport processes.

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