Abstracts

Topiramate has been established as an anticonvulsant in human clinical trials and several animal models of epilepsy. Topiramate is a GABA[sub]A[/sub] modulator, voltage gated sodium channel antagonist, and an AMPA/KA antagonist, L-type Ca channel antagonist that also provides neuroprotection in several animal models of epilepsy, cerebral ischemia, and facial nerve lesions. In epilepsy, Topiramate delays amygdala kindling and protects from excitotoxic neuronal injury in CA1 and CA3 of the hippocampus. The present study examines the anticonvulsant and antiepileptogenic properties of Topiramate in the kainic acid model of partial-onset epilepsy. Adult male Sprague-Dawley rats (200-300g) were administered three doses of kainic acid (5 mg/kg s.c.) in hourly intervals. Topiramate (20 mg/kg s.c.) (n=16) or vehicle (n=11) was administered 75 minutes, 5 hours, and 9 hours (q4 x 3) after the onset of KA-SE. Rat behavior was observed and documented for 4 hours following the first KA treatment using a previously validated behavioral seizure scale (0-5). To dissociate the anticonvulsant properties from the antiepileptogenic effect, we only analyzed rats that experienced sustained kainic acid induced status epilepticus (KA-SE). Status epilepticus was operationally defined as at least one 15 minute epoch of convulsive motor seizures. To assess the long term consequences of KA-SE, after one year rats were monitored for eight hours with intracranial and extracranial electrodes to determine the frequency of late onset spontaneous seizures. Topiramate (20 mg/kg) decreased the probability of convulsive status epilepticus and decreased the mortality associated with KA-SE, indicating an anticonvulsant effect. One year after KA-SE, vehicle treated control rats had a hourly seizure frequency of 0.87 [plusmn] 0.28 (mean [plusmn] sem), where as Topiramate treated rats had a seizure frequency of 0.25 [plusmn] 0.09. This indicates that Topiramate treatment significantly decreased the frequency of late onset spontaneous seizures. This study confirms that Topiramate has anticonvulsant efficacy demonstrated after the onset of KA-SE and a decrease in late onset seizure frequency that indicates an antiepileptogenic effect (Supported by an investigator initiated grant from Johnson and Johnson Pharmaceutical Research and Development, LLC. (Raritan, NJ).)