Procedures for Penetrating the Blood-Brain-Barrier: Studies of γ-Aminobutyric Acid (GABA)

Abstract

Small molecules including neurotransmitters and peptides are prevented from entry to the CNS by the endothelial cells which line the cerebral microcapillaries. These cells are linked together by tight junctions (Rees and Karnovsky 1976) to form the “so-called” blood-brain-barrier (BBB), To gain entry into the brain, compounds must pass through the BBB traversing the luminal and the abluminal membranes of endothelial cells, by a process that is considered to be receptor mediated and requiring an active transport mechanism (Goldstein and Betz, 1986). Previous studies indicate that one of the desirable features for entry through the BBB is a high lipophilicity (Oldendorph, 1970). Using γ-aminobutyric acid (GABA) as model system, we developed methods for enhancing its brain uptake by as much as 100-fold (Shashoua et al 1984). Cholesteryl, mono and dilinolenoyl glyceride esters of GABA were found to act as prodrugs which, after entry into the CNS and hydrolysis by esterases, released GABA into the central nervous system. In more recent studies we have demonstrated that these methods can also be applied to promote the uptake of dopamine, serotonin and small peptides such as enkephalin.