Abstracts

RATIONALE:_The aim of the present study was to investigate the anticonvulsant activity of AWD 131-138, a new substance with potent anticonvulsive and anxiolytic activity in a model for partial epilepsy and to characterize its preventive potential in this model. METHODS: AWD 131-138 was investigated in the amygdala kindling model in rats. The anticonvulsant activity was tested in fully kindled rats and the effect on the kindling development of rats was determined. RESULTS: AWD 131-138 increased the seizure threshold of fully kindled rats. Significant effects were seen already at 1 mg/kg i.p. At 20 mg/kg i.p., the seizure threshold was elevated by 161%. The substance also inhibited the motor seizure reaction of kindled rats starting at 10 mg/kg i.p. At 20 mg/kg i.p., all rats showed only limbic seizures (stage 1 and 2). In addition, the duration of epileptiform discharges recorded in the amygdala and the total duration of behavioral impairments were reduced by 50% and 80%, respectively. No motor impairment (as being observed on the rotarod) was evident up to the highest dose tested (30 mg/kg i.p.). Repeated treatment with 20 and 30 mg/kg i.p. before the kindling stimulus during kindling acquisition significantly retarded the kindling development; 10 mg/kg i.p. was less effective. The plasma concentration of AWD 131-138 was determined with a selective HPLC-assay on the 1st, 9th, 15th and 22nd day of repeated administration. During a period of 22 days with daily i.p. administration no accumulation of the substance was observed at the time of anticonvulsant testing. CONCLUSIONS: Unlike other anticonvulsants, AWD 131-138 is more potent in the amygdala kindling model of complex partial seizures than in other seizure models like MES test, suggesting that AWD 131-138 is particularly effective against partial seizures. In addition AWD 131-138 delayed the development of the amygdala kindling in rats indicating a preventive potential of the drug.