Abstracts

The models of genetically determined generalized epilepsy have been extensively used to determine the anticonvulsant properties of drugs. In the present work, we report the effects of a new drug in development, RWJ 333369 in the genetic model of non-convulsive absence epilepsy, the GAERS (Genetic Absence Epilepsy Rat from Strasbourg) and in the genetic model of sound-induced convulsive seizures, the audiogenic Wistar AS rat. In GAERS, absence seizures are accompanied by the occurrence of spike-and-wave discharges (SWDs) on the EEG. In Wistar AS, the exposure to an intense sound stimulus induces one or two wild running and bouncing episodes followed by a tonic seizure and a prolonged catatonic state GAERS were equipped with four cortical electrodes over the fronto-parietal cortex and the duration of SWDs on the EEG was recorded in groups of eight rats for periods of 20 to 120 min after the injection of 10, 30 and 60 mg/kg RWJ 333369 i.p. In Wistar AS, the occurrence of, latency to and duration of one or two wild running episodes and the tonic seizure were recorded in groups of eight rats at 60 min after the injection of 10 or 30 mg/kg RWJ 333369. In GAERS, RWJ 333369 dose-dependently reduced the expression of SWDs. The lower 10 mg/kg dose had no significant effect. At 30 mg/kg, SWDs were completely attenuated between 40 and 60 min and the duration of SWDs was reduced by 72% at 80 min, but returned to control levels by 100 min. At 60 mg/kg, SWDs were completely attenuated from 40 to 120 min. In Wistar AS, RWJ 333369 at 10 mg/kg increased the latency to the first running episode by 266% and its duration by 160% in 7 out of 8 rats, and induced the occurrence of a second running episode in 3 out of 8 rats. This second running episode, which was not present in control rats, is indicative of a decrease in sensitivity of the rats to the auditory stimulus. The 10 mg/kg dose of RWJ 333369 also increased the latency to the tonic seizure by 327% in 6 of the 8 studied rats that experienced these seizures, and one out of 8 rats exhibited no wild running and no seizure. At 30 mg/kg, RWJ 333369 suppressed the expression of all seizure-related behaviors in all rats. The present results demonstrate that this novel drug, RWJ 333369, has potent and broad efficacy on primary generalized seizures of both the tonic reflex and the absence type in genetic models of epilepsy (Supported by Johnson [amp] Johnson Pharmaceutical Research [amp] Development, LLC.)