The concept of a barrier between the blood and the brain arose in the late l9th century when the German bacteriologist Paul Ehrlich observed that certain dyes, e.g., a series of aniline derivates, administered intravenously to small animals stained all the organs except the brain.

Ehrlich's interpretation of his result was that the brain had a lower affinity for the dye than the other tissues. In subsequent experiments, Edwin E. Goldmann, a student of Ehrlich, injected the dye trypan blue directly into the cerebrospinal fluid of rabbits and dogs. Administrered by this route, the dye readily stained the entire brain but did not enter the bloodstream to stain the other internal organs (Goldmann, 1913). This experiment showed that the central nervous system is separated from the blood by a barrier of some kind.

In the late 1960's the hypothesis that brain capillaries provide the anatomical basis of the blood-brain barrier (BBB) could be confirmed using electron microscopy.

The blood-brain barrier (BBB) is present in all vertebrate brains and is laid down within the first trimester of human fetal life. The cellular locus of the BBB is the endothelial cell of the brain capillary.

This figure shows a scanning electron micrograph of a vascular cast of the human cerebellar cortex. The microvessels are formed by the endothelial cells. In the human brain, there are approximately 400 miles of brain capillaries and the surface area of these tubular structures is approximately 100 square feet. Insert: Red blood cells visible in a cross section through a brain capillary.



The endothelial cells comprising the tubular capillaries in brain are cemented together by intercellular tight junctions. These junctions are as tight as any in biology and the electrical resistance across intraparenchymal endothelial cells may be as high as 8000 ohm cm2 . The tight junctions eliminate a paracellular pathway of solute movement through the BBB and the virtual absence of pinocytosis across brain capillary endothelium eliminates transcellular bulk flow of circulating solute through the BBB. Under these conditions, solute may gain access to brain interstitium via only one of two pathways: lipid mediation or catalyzed transport.

Lipid-mediated transport is restricted to small molecules (with a molecular weight less than a threshold of approximately 700 Da) and is generally, but not always, proportional to the lipid solubility of the molecule.

Catalyzed transport includes carrier-mediated or receptor-mediated processes.

The endothelial cell comprises the permeability barrier per se; however, the cell biology of the BBB phenomenon may be viewed within the context of cell-cell interactions between at least four different cell types.

The BBB is actually composed of two membranes in series: the lumenal and the ablumenal membranes of the brain capillary endothelial cell, which are separated by approximately 300 nm of endothelial cytoplasm. Therefore, transport systems must exist on both lumenal and ablumenal membranes of the endothelial cell if solute transcytosis from blood to brain is to occur. There are a number of specialized carrier transport systems within the BBB that mediate brain uptake of circulating nutrients, such as glucose, amino acids, choline, purine bases, or nucleosides.

Nutrient carrier systems mediate BBB transport of the solute within milliseconds. In contrast, BBB receptor-mediated transport occurs within several minutes. Receptor-mediated peptide transport through the BBB occurs owing to the presence of a number of different peptide-receptor systems. Insulin for example gains access to brain via the BBB insulin receptor.