Introduction

The advent of electron microscopy and the availability of horseradish peroxidase (HRP) as a marker to study vascular permeability to proteins (Graham and Karnovsky, 1966), opened a new era in the study of the blood–brain barrier (BBB). Over the next two decades there was a plethora of studies of BBB permeability to HRP in steady states and in diverse pathological conditions. Horseradish peroxidase, a glycoprotein with a molecular weight of 40 000, can be localized in tissues by both light and electron microscopy. Both the tracer and the HRP reaction product which forms in tissues following a histochemical reaction will be referred to as HRP.

Blood–brain barrier permeability to HRP in steady states

The morphological features unique to cerebral vessels, in contrast to other body vessels, that account for their relative impermeability to plasma proteins and protein tracers such as HRP in steady states, are limited endothelial pinocytosis and the presence of tight junctions along the interendothelial spaces. Other factors affecting BBB permeability to HRP are endothelial surface charge and endothelial cytoskeletal elements.

Pinocytosis

Fluid-phase transcytosis of HRP across endothelium occurs by pinocytotic vesicles, which are membrane-bound spheres, 50–90 nm in diameter. The classic study of Reese and Karnovsky (1967) drew attention to the finding that during steady states, cerebral endothelium contains few pinocytotic vesicles.