ANTICONVULSANT ACTION OF TIAGABINE, A NEW GABA-UPTAKE INHIBITOR

This review describes the biochemical and anticonvulsive pharmacology of tiagabine {(R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride}, a new lipophilic gamma-aminobutyric-acid (GABA) u ptake inhibitor. Tiagabine is a potent and selective inhibitor of the GABA uptake into brain-derived glial and neuronal cells in vitro and h as been shown by in vivo microdialysis to increase extracellular GABA overflow in rat brain after parenteral administration. It is a potent blocker of DMCM- (methyl ,7-dimethoxy-4-ethyl-beta-carboline-3-carboxy late) induced seizures in mice and of pentylenetetrazol-induced seizur es in mice and rats. Tiagabine blocks sound-induced seizures in geneti cally epilepsy-prone rats, an animal model of inherited epilepsy in wh ich abnormalities in GABAergic neurotransmission are implicated in sei zure generation. The results of these and other in vitro and in vivo s tudies are consistent with the hypothesis that tiagabine is exerting i ts anticonvulsive pharmacology via an enhancement of GABA-mediated neu rotransmission. In clinical pharmacology studies, tiagabine decreases seizure frequency in simple partial, complex partial, and secondarily generalized tonic-clonic seizures when used as add-on therapy and is w ell-tolerated by patients.