ABSTRACT
The brain is probably one of the least accessible organs for the delivery of drugs due to the presence of the blood-brain barrier (BBB) that controls the transport of endogenous and exogenous compounds, thus providing the neuroprotective function. The structural BBB is formed by the cerebral capillary endothelial cells that, in contrast to endothelial cells in capillary blood vessels in most other tissues, are closely joined to each other by tight junctions produced by the interaction of several transmembrane proteins (Fig. 1). Moreover, these endothelial cells demonstrate very little fenestration and display only low pinocytic activity. This physical barrier effectively abolishes any aqueous paracellular diffusional pathways
between the extracellular fluid in the blood and brain. The endothelial cells forming the BBB also exhibit a number of bidirectional and unidirectional transporters. Essential compounds such as amino acids, hexoses, neuropeptides, and proteins employ these transporters or specific carriers to permeate the brain (1,2). Lipophilic solutes are able to diffuse across the BBB by direct permeation through the cell membrane if their molecular weight is not more than 500 Da (3). However, many of these lipophilic molecules will be actively removed from the cerebral compartment by the adenosine triphosphate binding cassette (ABC) efflux transporters, such as P-glycoprotein (P-gp) or multidrug resistance proteins (MRP) (4). Thus, many potential drugs with activity at a particular site or receptor in the brain have failed in the treatment of central nervous system (CNS) disorders. These drugs simply do not enter the CNS in sufficient quantities to be effective, which, consequently, diminishes their therapeutic value.
