ABSTRACT

The vertebrate central nervous system (CNS) is considered to be the most complex organ in the animal kingdom. Nerve cells communicate with each other through electrical signals, which are generated through ion-based concentration gradients. The brain is endowed with brain fluids, i.e., cerebrospinal fluid (CSF), bathing neurons, and glia and provides a unique milieu, essential for normal CNS functioning. The CSF and extracellular fluids of the brain are in a steady state. For example, the concentrations of Kþ, Ca2þ, bicarbonate, and glucose in the CSF are lower than in blood plasma, whereas the pH is more acidic (1). Unlike in all other organs of the vertebrate body, the brain needs to be protected from the free diffusion between blood plasma and the interstitium in order to maintain the homeostasis necessary for its proper function. The discovery of a vascular barrier between the blood circulation and the CNS dates back to more than 100 years, when in the 1880s Paul Ehrlich discovered that cationic vital dyes, which bind to serum albumin, were rapidly taken up by all organs after injection into the vascular system with the exception of the brain and spinal cord (2). Ehrlich himself interpreted these findings as a lack of affinity of the nervous system for these dyes and could not believe that the cerebral vascular endothelium might selectively exclude them. However, shortly

afterwards Edwin E. Goldman, an apprentice of Ehrlich, could show that the very same dyes, when injected into the CSF exclusively, stained the nervous tissue whereas all other tissues remained unstained. This suggests that these dyes were prevented from getting access to the blood circulation (3). The concept of a vascular blood-brain barrier (BBB), which also functions as a brain-blood barrier, was born (4). The term ‘‘blood-brain barrier’’ was coined, however, by Lewandowsky (5) after he, and later Briedl and Kraus (6), had performed experiments demonstrating that neurotoxic agents affected brain function only when directly injected into the brain but not when injected intravenously. The exact location of the BBB, however, remained unknown at this point and it took another 70 years until Reese and Karnovsky (7) and Brightman and Reese (8) identified the barrier to be located in brain capillary endothelial cells, using electron microscopy studies. By injecting the small electron dense tracers horseradish peroxidase (40 kDa) or lanthanum nitrate (433 Da) either into the blood or into the CSF, they could demonstrate the diffusion of these molecules into the intercellular clefts between brain capillary endothelial cells up to the tight junctions (TJs) and identify the interendothelial TJs as the morphological correlate of the BBB. The localization of the BBB at the level of endothelial cell TJs applies to all vertebrates with the exception of elasmobranch fishes, which have a BBB formed by TJs located in between glial cells (9) as do many invertebrates (10).