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) uptake inhibitor. Tiagabine is a potent and selective inhibitor of the GABA uptake into brain-derived glial and neuronal cells in vitro and has 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 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) induced seizures in mice and of pentylenetetrazol-induced seizures in mice and rats. Tiagabine blocks sound-induced seizures in genetically epilepsy-prone rats, an animal model of inherited epilepsy in which abnormalities in GABAergic neurotransmission are implicated in seizure generation. The results of these and other in vitro and in vivo studies are consistent with the hypothesis that tiagabine is exerting its anticonvulsive pharmacology via an enhancement of GABA-mediated neurotransmission. 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 well-tolerated by patients.