Anatomy and Physiology of the Blood-Brain Barriers*

Abstract

This chapter covers the three main barrier layers separating blood and the CNS: the endothelium of the brain vasculature, the epithelium of the choroid plexus secreting cerebrospinal fluid (CSF) into the ventricles and the arachnoid epithelium forming the middle layer of the meninges on the brain surface. There are three key barrier features at each site that control the composition of brain fluids and regulate CNS drug permeation: (i) physical barriers result from features of the cell membranes and of the tight junctions restricting the paracellular pathway through intercellular clefts; (ii) transport barriers result from membrane transporters mediating solute uptake and efflux, together with vesicular mechanisms mediating transcytosis of larger molecules such as peptides and proteins; and (iii) enzymatic barriers result from cell surface and intracellular enzymes that can modify molecules in transit. Brain fluids (CSF and brain interstitial fluid) are secreted, flow through particular routes and then drain back into the venous system; this fluid turnover aids central homeostasis and also affects CNS drug concentration. Several CNS pathologies involve changes in the barrier layers and the fluid systems. Many of these aspects of physiology and pathology have implications for drug delivery.