Abstracts

Rationale: Status epilepticus (SE) is a neurological emergency with significant morbidity and mortality. Generally SE is defined as > 10 min of seizure activity with continuous or intermittent convulsive or nonconvulsive seizures. Treatment for SE consists of intravenous benzodiazepines (lorazepam) or other agents such as phenytoin, fosphenytoin, valproate and levetiracetam. However, little is known about the potential efficacy of neuroactive steroids in the treatment of seizure emergency situations including SE. Neuroactive steroids such as ganaxolone are potent positive allosteric modulators of GABA-A receptors with powerful antiseizure properties. This study aimed to investigate the effectiveness of ganaxolone in treatment of acute SE in epilepsy rats. Methods: SE was induced by pilocarpine in healthy (non-epileptic) and epilepsy rats. Chronic epilepsy was induced in rats by treatment with lithium-pilocarpine. Rats were monitored for spontaneous seizures during 2-6 months post pilocarpine. EEG was recorded from hippocampus and cortex. At 5 months post pilocarpine, majority of rats exhibited spontaneous seizures with average seizure frequency of 2 seizures daily. Rats were challenged with an acute dose of pilocarpine and monitored continuously for behavioral and EEG seizures activity. Ganaxolone was administered by s.c. injection 1 h after onset of SE. This protocol was designed to directly assess ganaxolone’s ability to abort SE. Results: Pilocarpine administration was associated with acute, intense behavioral seizures and EEG discharges lasting for over 3 hours in rats. Cortical and hippocampus EEG monitoring showed persistent, high frequency epileptiform discharges after pilocarpine challenge. Treatment with ganaxolone (5 mg/kg, sc) one hour after onset of SE completely aborted the motor seizure activity as well as electrographic epileptic discharges. The effect of ganaxolone to diminish bilateral forelimb clonic (stage 4/5) seizure activity was rapid with an onset of ~10 min for significant reduction, while complete termination of seizure activity was achieved within 1 h. Ganaxolone has similar and comparable success rates in terminating SE in non-epileptic and epileptic rats. Conclusions: These results suggest that the neuroactive steroid ganaxolone appears to be efficacious in SE in epilepsy rats. Ganaxolone has been shown previously to be a safe and effective antiepileptic drug. Neuroactive steroids may have advantages over benzodiazepines in the treatment of SE because of their robust efficacy and lack of tolerance with repeated administration.