The brain functions within a well-controlled environment separate from the milieu of the periphery. The mechanisms that control the unique environment of the brain are collectively referred to as the "blood-brain barrier." Paul Ehrlich (1885, 1906) and Edwin Goldman (1909, 1913) observed that water soluble dyes injected into the peripheral circulation did not stain the brain or color the cerebrospinal fluid (CSF); however the choroid plexus showed heavy staining. Additional experiments showed that these same dyes injected into the subarachnoid space colored the brain and CSF, but not peripheral tissues. Lewandowsky, while studying potassium ferrocyannide penetration into the brain (1900), was the first to coin the term blood-brain barrier and called it "bluthirnschranke." The observations drawn from these dye studies brought about the concept of a barrier between blood and brain, as well as between blood and CSF.
Later investigators employed basic dyes that were highly lipid soluble and able to traverse the BBB (Friedemann, 1942), showing that the brain was stained by direct transport of the dyes across the cerebral microvasculature. Broman (1941) observed that there were two barrier systems in the brain, the blood-CSF barrier at the choroid plexus and the blood-brain barrier (BBB) at the cerebral microvasculature. Broman (1941) also argued that barrier function of the BBB was via the capillary endothelial cells and not via the astrocytic end feet. The debate as to whether astrocytic end feet or capillary endothelium comprise the BBB was laid to rest by electron microscopic cytochemical studies performed in the late 1960s by Reese and Karnovsky (1967), and later by Brightman and colleagues (1970). Horseradish peroxidase (MW 39,800) was used to visualize the BBB (Reese and Karnovsky, 1967). Systemic injections of horseradish peroxidase failed to reach brain extracellular fluid, whereas intracerebroventricular injection into the CSF stained the brain extracellular fluid. Horseradish peroxidase diffused past the astrocytic end feet and basement membrane, and stopped at the tight junctions of the cerebral endothelial cells. These experiments substantiated the argument that tight junctions between cerebral endothelial cells comprise the BBB, restricting the free movement of substances from blood and interstitial fluid.
Later, dialogue concerning the uniqueness of BBB tight junctions and physiology, relating to capillary networks of peripheral organs were addressed by and elegant study performed by Stewart and Wiley (1981). In these experiments, embryonic quail brain was transplanted to embryonic chick gut. Although the quail brain was vascularized by chick gut vessels, the transplanted microvessels maintained physiological characteristics of the BBB and excluded dyes, such as trypan blue. Conversely, embryonic quail gut transplanted to embryonic chick brain was vascularized by vessels of chick brain origin, yet these microvessels were leaky to trypan blue and did not maintain BBB characteristics. These experiments support the belief that the physiological characteristics of the BBB arise from the expression of a distinctive set of genes within the capillary endothelium or possibly cofactors from the surrounding tissue.