DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 413

Examples of cell surface receptors involved in these processes include the endothelial
barrier antigen OX-47 (an integral plasma membrane glycoprotein that is involved in
cell-to-cell recognition), and endothelial glyocalyx (possible role in vascular perme-
ability and surface charge). 11 , 12 Transferrin, a plasma protein involved in systemic
iron transport, may also be taken up into the brain parenchyma by receptor-mediated
endocytosis and transcytosis. 13 In brain microvessel and capillary endothelial cells,
specialized plasma membrane microdomains known as caveolae are believed to be
involved in endocytosis of various macromolecules, including plasma proteins, im-
munoglobulins, and metaloproteins. 14 Caveolae are involved in other biological pro-
cesses, including signal transduction and cholesterol transport. 15 , 16

14.2.2. Blood-Cerebrospinal Fluid Barrier

The blood-cerebrospinal fluid (BCSF) barrier is formed by the choroid plexus, which
is the major interface between the systemic circulation and the CSF. The BCSF barrier
is located at the outer epithelial surface of the choroid plexus, a leaflike highly vascular
organ that protrudes into all four cerebral ventricles. It is comprised of fenestrated
capillaries that are surrounded by a monolayer of epithelial cells joined together
by tight junctions. 17 These tight junctions form the structural basis of the BCSF
barrier and seal together adjacent polarized epithelial cells (also known as ependymal
cells). Thus, once a solute has crossed the capillary wall, it must also permeate these
ependymal cells before entering the CSF.
The primary function of the choroid plexus is to produce the CSF continuously and
to maintain its composition. The total volume of CSF (140 mL) is replaced approxi-
mately four to five times daily. 18 The continuous flow of CSF through the ventricular
system into the subarachnoid space and exiting into the venous system provides a
“sink” that reduces the steady-state concentration of a molecule penetrating into the
brain and CSF. 19 The sink effect is greater for large-molecular-weight and hydrophilic
molecules. The CSF also contains approximately 0.3% of plasma proteins, totaling
15 to 40 mg/mL, depending on sampling site. 20 This is in contrast to the extracellular
space of the normal adult brain, which contains no detectable plasma proteins. 21
Similar to the BBB, the choroid plexus displays polarized expression of various
receptors, ion channels, and transport systems that regulate the CSF composition via
secretion and reabsorption. 22 The apical membrane expresses the Na + /K + -ATPase
pump and several channels for monovalent anions and cations. 7 Studies have also
demonstrated the expression of facilitated and sodium-dependent carriers for the
transport of nonelectrolytes. 18 , 23 , 24

The basolateral side is lined with Na + /H +

an-

tiporters, Cl − /HCO 3

antiporters, facilitated carriers for nonelectrolytes, and carbonic

anhydrase. 18 , 23

14.2.3. Cellular Compartments of the Brain Parenchyma

The brain parenchyma consists of neurons and the surrounding glial cells. Neurons
form the basic structural and functional component of the CNS. The primary function
of neurons is to respond to stimuli by conducting electrical signals along conductive