17 - Molecular biology of brain capillaries

Summary

Introduction

The brain microvascular endothelium represents the Blood–brain barrier (BBB) in vivo (Brightman, 1977), and the expression of BBB-specific genes provides the anatomical and biochemical properties of this barrier (i.e. tight junctions, nutrient transporters, etc.). Because only lipophilic molecules of less than 600 Da diffuse through the BBB (Pardridge, 1995), the brain is protected against peripheral neurotransmitters (i.e. nor adrenaline), cytotoxins, and microorganisms. From the pharmacological point of view, the protective properties of the BBB represent a disadvantage for brain drug delivery of hydrophilic therapeutics (for example, AZT, antisense oligodeoxynucleotides, nerve growth factor) for the treatment of cerebral HIV-AIDS, brain tumors, Alzheimer's disease and other brain disorders (Boado, 1995a; Pardridge, 1995). On the contrary, polar nutrients, as in the case of glucose and amino acids, and peptides like insulin, gain access to the brain through specific transporters located on both lumenal and ablumenal membranes of the BBB (see Chapter 6). Although the mechanism of gene expression of BBB-specific proteins appears to be directed by factors released by brain cells (i.e. astrocytes) and sequestered by the endothelium (Stewart and Wiley, 1981), little is known in regards to either the identification or isolation of these putative brain trophic factors. This intellectually stimulating field has captivated the attention of several groups of investigators over the last couple of decades, and the progress has been limited to the development of reproducible cell culture models and to the initial characterization of brainderived complex fractions possessing trophic properties.