Development of the Blood-Brain Barrier

Abstract

The experiments leading to the concept of a vascular blood-brain barrier date back more than 100 years, when Paul Ehrlich and his collaborators discovered in a series of experiments that certain dyes, when injected into the vascular system, were rapidly taken up by all organs with the exception of the brain (Ehrlich, 1904). Ehrlich himself interpreted these findings as a lack of affinity of nervous tissue for these dyes and found it hard to believe that the cerebral vascular endothelium might be selective. However, shortly afterwards, Goldmann (1913), an associate of Ehrlich, could show that the very same dyes, when injected into the cerebrospinal fluid, readily stained neural tissue but were incapable of staining all the other organs. Thus it became clear that these dyes were indeed prevented from getting access to the blood circulation. The concept of a vascular blood-brain barrier, which also functions as a brain-blood barrier was born (Bradbury, 1984; Bradbury, 1979). It remained controversial until 70 years later Reese and Karnovsky (1967) and Brightman and Reese (1969) were able to ultrastructurally locate the barrier. They showed that in mammals horseradish peroxidase, a small molecule of 40 kDa was prevented from passing between endothelial cells by tight junctions connecting most brain endothelial cells.