Blood-Brain Barrier

Abstract

While Edwin Goldmann is recognized as the first to provide substantial evidence of a blood-brain barrier (BBB) in 1909 and 1913, the actual term was coined in 1900 by Max Lewandowsky after observing that central injection of sodium ferrocyanide produced seizures in dogs, while larger doses administered peripherally did not. In fact, the earliest clue to the existence of a separation between central nervous system (CNS) and peripheral tissue arose in 1885 from the studies of Paul Ehrlich, including those demonstrating that peripheral dye injection in rats failed to stain nervous tissue. However, these early observations by Ehrlich were attributed to differences in the capacity of dye uptake in CNS tissue. Later, Goldmann intravenously injected a dye, trypan blue, and similarly observed significant staining of all tissues, with the exception of the brain, spinal cord, eyes, peripheral nerves, and gonads. By subsequently showing trypan blue–stained CNS tissue after delivering the dye directly to cerebral spinal fluid (CSF), Goldmann negated theories that different tissue affinities for the dye accounted for lack of CNS staining after peripheral injection. Despite these important observations, the existence of a BBB remained a topic of debate for decades, until ensuing technological advances allowed progress. For example, the ability to visualize tissue ultrastructure using electron microscopy (EM) spurred studies into the cellular basis of the BBB. Notably, in 1967, Reese and Karnovsky analyzed electron micrographs of intravenous tracer-injected mouse brains, demonstrating that endothelial cells of cerebral capillaries act as a barrier between the blood and the brain and further defining characteristics of CNS versus peripheral capillary endothelial cells. Numerous advances have subsequently been made in our understanding of BBB structure, mechanisms, and development. Oldendorf et al. evidenced in 1977 that endothelial cells in the BBB region bear a higher amount of mitochondria (10%) that provides adenosine triphosphate (ATP) driving the ion gradients. In 1985, Combert and Stewart quantified the ultrastructure of the BBB and compared the CNS endothelial cells features to nonbarrier capillaries (e.g., somatic capillaries and area postrema). The wall thickness of the CNS endothelial cells is reduced around 40% in comparison with the area postrema offering exclusive properties to regulate molecules passage within the brain. More information about these developments can be found in Ribatti D, Nico B, Crivellato E, and Artico M (Anat Rec – Part B New Anat 289:3–8, 2006).