Anatomy and Physiology of the Blood–Brain Barriers

Abstract

This chapter covers the three main barrier layers separating blood and the central nervous system (CNS): the endothelium of the brain vasculature, the epithelium of the choroid plexus secreting cerebrospinal fl uid (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 fl uids and regulate CNS drug permeation: (1) physical barriers result from features of the cell membranes and of the tight junctions restricting the paracellular pathway through intercellular clefts; (2) transport barriers result from membrane transporters mediating solute uptake and effl ux, together with vesicular mechanisms mediating transcytosis of larger molecules such as peptides and proteins and (3) enzymatic barriers result from cell surface and intracellular enzymes that can modify molecules in transit. Brain fl uids (CSF and brain interstitial fl uid) are secreted, fl ow through particular routes and then drain back into the venous system; this fl uid turnover aids central homeostasis and also affects CNS drug concentration. Several CNS pathologies involve changes in the barrier layers and the fl uid systems. Many of these aspects of physiology and pathology have implications for drug delivery.

In vitro models of the blood–brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use

“…Efflux transporters of the ABC family and SLCs play essential roles in the BBB permeability of small molecules, both endogenous compounds and xenobiotics. 2 This makes their expression, correct localisation, and functionality important validation characteristics for a BBB model, at least if the model is to be used for BBB permeability screening, CNS-toxicity studies, pro-drug formulation studies, or studies of nutritional status of the BBB. Validation can be performed via protein or mRNA expression studies, but functional validation with accumulation or bi-directional transport of model substrates and inhibitors should be performed if the model is to be applied in studies where transporters may have a direct influence on the outcome.…”

“…1 Both pericytes and astrocytes regulate the phenotype of the endothelium, through mechanisms not yet fully understood but involving cell-cell communication via soluble factors and possibly also direct contact interactions. 2,3 The brain capillary endothelial cells (BCEC) and the surrounding accompanying cell types thus constitute the ''neurovascular unit'' (NVU), a term reflecting the specialized and unique cellular structure of the brain microvasculature.…”

In vitro porcine blood–brain barrier model for permeability studies: pCEL-X software pKaFLUX method for aqueous boundary layer correction and detailed data analysis

“…The blood-brain barrier (BBB) is formed by brain endothelial cells that line the cerebral microvessels and is the major site for regulation of molecular traffic between the blood and the central nervous system (Abbott et al, 2010;Abbott, 2014). Methods available to study the physiology of the BBB include several in vitro BBB models .…”

Anatomy and physiology of the blood–brain barrier

“…The intimate contact between neurons, astrocytes, microglia, pericytes and blood vessels, and the functional interactions and signaling between them form a dynamic functional unit, known as the neurovascular unit . Understanding the function of the neurovascular unit is an important key to the understanding of brain functions in health and disease, including neuronal firing, synaptic plasticity, regulation of blood flow and response to injury (thoroughly reviewed by: [5])…”