One of the defects in human
epilepsy appears to be the suboptimal functioning of at least certain central
gamma-aminobutyric acid (
GABA)-mediated synapses. Of the several approaches for the manipulation of the functional state of such synapses that have been investigated, the possibility of interference with
GABA metabolism and
GABA transport processes is reviewed. It is concluded that the efficiency of inhibitors of the
GABA-metabolizing
enzyme,
GABA transaminase, as
antiepileptic drugs is related to the ability of the inhibitors to increase selectively the synaptic or transmitter-related
GABA levels. Whether or not this reflects different modes of action of these inhibitors on neuronal and glial
GABA transaminase remains to be established. Inhibition of the
GABA transport mechanisms seems to represent an alternative approach to increase synaptic
GABA levels. Evidence is presented that inhibitors of glial
GABA uptake possess
anticonvulsant activity. A comparison of drugs that inhibit both neuronal and glial
GABA uptake with selective glial
GABA uptake inhibitors indicates that the latter type of inhibitor most effectively blocks seizure activity. Such a
drug is 4,5,6,7-tetrahydroisoxazolo[4,5c]pyridin-3-ol (
THPO), which unfortunately lacks the important property of easy penetration of the blood-brain barrier.
Prodrugs of this glial-selective
GABA uptake inhibitor may have pharmacological and therapeutic interest.