The dam breaks: disruption of the blood-brain barrier in diabetes mellitus

Abstract

AT THE END OF THE CENTURY before the last, a young graduate student performed an experiment that would forever change the way we look at the microvasculature of the brain. He injected basic dyes into the blood and noted that nearly every tissue of the body was colored by the dye except for the central nervous system (CNS). This experiment and the observation that bile salts could cause seizures when injected into the brain but not intravenously were the seminal 19th century observations giving rise to the concept of a blood-brain barrier (BBB). The young graduate student, Paul Ehrlich, would get many things right in his career, winning a Nobel prize in 1908 for his work on antibiotics. But the BBB he got wrong. Ehrlich thought the brain did not stain because the dye was not taken up by brain tissue, not because a barrier prevented the dye from reaching the brain. Indeed, that a BBB really existed and that it resided at the level of the capillary bed and the choroid plexus were not finally established until the late 1960s. Elegant physiological experiments by Davson and Segal (10) and electron microscopy studies by Reese and Karnovsky (24) demonstrated the basis of the BBB: the capillary bed of adult mammals is modified to exclude the production of a plasma ultrafiltrate. The major modifications include a greatly decreased rate of pinocytosis, a lack of intracellular pores and fenestrae, and obliteration of the intercellular space between brain endothelial cells by tight junctions that essentially “cement” apposing endothelial cells together. The lack of production of an ultrafiltrate means that circulating proteins such as albumin do not exude from blood into brain. This is the basis for Ehrlich’s 120-year-old observation: basic dyes bind to albumin so tightly that they are a visible proxy for plasma