From studies using pharmacological models of convulsive disorders and also from the neurochemical analysis of epileptogenic tissue removed during neurosurgical resection (cortectomy), there is strong evidence that at least a subgroup of epileptic disorders may be linked (among other things) to a deficit in GABAergic neurotransmissions. This deficit may be found at the level of
GABA synthesis or at the
GABA-recognition site; whether these GABA neurons are lost or are dysfunctional is not yet answered. This suggests that
GABA-agonists will be of potential use in
epilepsy.
GABA-agonists (
progabide,
SL 75102,
muscimol,
THIP) for the classical
GABA-recognition sites as well as other compounds active at sites in the
GABA-receptor macromolecular complex (eg,
diazepam and
phenobarbital) exhibit a wide range of
anticonvulsant effects in different animal models and species. However, for some of these compounds (eg,
muscimol) secondary central effects occur at the same dose level as the
anticonvulsant actions, and for others (eg,
THIP) such secondary effects may limit the use to certain types of
seizures. This problem may be related to the high affinity of such compounds for the
GABA recognition site as compounds with a more moderate affinity (eg,
progabide,
SL 75102) have a wider margin between
anticonvulsant and secondary central effects in rodents. Clinical results using
progabide suggests that the
GABA hypothesis of convulsive disorders has indeed a rational foundation as a significant percent of refractory or unresponsive epileptic patients with different types of
seizures (eg, complex partial or primary generalized) have a significant clinical improvement with this
GABA-agonist.