Transporters in the Blood-Brain Barrier

The mammalian brain restricts the entrance of ions and solutes circulating in the bloodstream by two cellular barriers, namely, the blood-brain barrier (BBB) and bloodcerebrospinal fluid (CSF) barrier (Brightman et al., 1970; Ballabh, 2004). The BBB is built up by a monolayer of endothelial cells (ECs) lining the brain capillaries that restricts the movement of small polar molecules and macromolecules between the blood and the brain interstitial fluid (Reese & Karnovsky, 1967; Brightman & Reese, 1969; Vorbrodt, 1988). The endothelial barrier is supplemented with capillary pericytes that share the basement membrane with the ECs. Moreover, perivascular end-feet of the astrocyte almost totally cover the abluminal surface of the microvascular basement membrane. The blood-CSF barrier is built up by a monolayer of epithelial cells of the choroid plexus separating the blood from the CSF. This blood-CSF epithelial barrier is of great functional importance because the fenestrated endothelium of the choroid plexus capillaries is leaky and permeable to blood-borne solutes. Although the choroid plexus is traditionally considered the major component of the blood-CSF barrier, a similar barrier is formed by the functional complexes between the arachnoid cells. This barrier is also important because substances passing into the stroma of the choroid plexus after intravenous presentation may find their way into the CSF by crossing the ependyma adjacent to the root of the choroid plexus; this is as described as a “functional leak” by Brightman et al. (1970), while van Deurs (1978) denies the existence of this functional leak. These barriers maintain a constant chemical environment within the central nervous system (CNS), which is optimal for the function of neurons. The brain capillaries were characterized morphologically as the site of the BBB by Reese and Karnovsky (1967) after introduction of electron microscopy and the use of horseradish peroxidase as a macromolecular tracer. Further ultrastructural studies (van Deurs, 1980; Brightman, 1989) revealed that the continuous endothelium of brain capillaries possesses several unique structural and functional features (Vorbrodt & Dobrogowska, 2003). First, the paracellular cleft between adjacent ECs is sealed by continuous strands of tight junctions (TJs). Second, the endocytic (pinocytic) and transcytotic activities are very low, and therefore, the transendothelial traffic of solutes (via plasmalemmal vesicles) is low. Third, the uptake of essential nutrients from the bloodstream into the brain interstitial fluid is selectively mediated through specific transport-related molecules such as receptors and carriers. Fourth, the presence of numerous mitochondria in the EC cytoplasm suggests a high metabolic activity and an energy-requiring function of these cells (Oldendorf et al.,