AWD 140-190: A potent anticonvulsant in the amygdala-kindling model of partial epilepsy

Purpose: Evaluation of the effect of the new anticonvulsant drug, AWD 140-1 90 [4-(p-bromophenyl)-3morpholino-1 H-pyrrole-2-carboxylic acid methyl este r] on focally induced seizures and on epileptogenesis in the kindling model . Methods: Effects of AWD 140-190 were studied in amygdala kindled rats after oral and intraperitoneal administration. In addition, the effect on kindli ng development was evaluated. In all experiments, behavioral changes in the rats in response to AWD 140-190 were monitored closely. Results: AWD 140-190 exerted potent anticonvulsant activity against focal s eizures. After intraperitoneal and oral administration in fully kindled rat s, the substance dose-dependently increased the threshold for induction of afterdischarges starting at 15 mg/kg. AWD 140-190 only weakly influenced th e seizure severity of the animals after stimulation at the elevated afterdi scharge threshold current. No adverse effects were observed up to 30 mg/kg after intraperitoneal and oral administration in the open field and in the rotarod test. No differences were found between kindled and nonkindled rats when comparing neurotoxicity of AWD 140-190. Prolonged treatment with AWD 140-190 during kindling acquisition did not prevent kindling, but significa ntly retarded the development of fully kindled seizures during the treatmen t. Conclusions: This study demonstrates that AWD 140-190 has anticonvulsant ef fects in the amygdala kindling model in rats, suggesting that the substance is particularly effective against partial seizures. AWD 140-190 is orally active and devoid of neurotoxic effects in anticonvulsant doses, thus indic ating that this compound has potential for antiepileptic therapy. AWD 140-1 90 retards the kindling development during the treatment. This effect could be explained by the acute anticonvulsant effect of the substance.