Abstract
GABA uptake inhibitors are newly developed antiepileptic drugs. In this study, we analyzed the antiepileptic profile of GABA uptake inhibitors, Tiagabine, SKF-89976A and NNC-711, in the rat kindling model, which is a chronic experimental model of human complex partial seizures with secondary generalization. We examined the dosedependent anticonvulsant effects of the GABA uptake inhibitors in amygdala (AM) -and hippocampal (HIPP) -kindled seizures, and compared their anticonvulsant and behavioral side effects with those of Valproate (VPA) and Carbamazepine (CBZ). In AM-and HIPP-kindled rats, intraperitoneal administration of the GABA uptake inhibitors (2.5-20 mg/kg) significantly reduced the seizure stage and afterdischarge (AD) duration in dose-dependent manners, compared with vehicle treatment. The anticonvulsant potencies of the 3 GABA uptake inhibitors were in the order: NNC-711 > Tiagabine >> SKF89976A, which was related to the in vitro GABA uptake efficacy, and they were similar between AM-and HIPP-kindled seizures. High doses of GABA uptake inhibitors (20-40mg/kg) caused sedation, motor impairment and EEG paroxysms with myoclonus. When the correlation between the anticonvulsant and behavioral side effects was examined, GABA uptake inhibitors showed more potent anticonvulsant and less side effects, compared with VPA and CBZ. These results indicate the clinical usefulness of GABA uptake inhibitors in temporal lobe epilepsy.
