Abstracts

Status-epilepticus (SE) is characterized by prolonged, self-sustaining seizures lasting [ge] 30 minutes, during which patients do not gain consciousness. Clinical and animal studies suggest loss of sensitivity to diazepam (DZ) as the SE duration increases, however, the mechanism remains unclear. While studying the effect of RU486, a glucocorticoid receptor antagonist, on expression of GABA(A) receptor subunits in hippocampus after SE, we found that rats pretreated with RU486 were more sensitive to the therapeutic effects of diazepam in treating SE. In the present study, we explore the possibility of using RU486 as an adjunctive treatment for SE. Adult male Sprague-Dawley rats were implanted with electrodes in CA1 and frontal cortex. After one week of recovery rats were put in recording cages and connected to EEG monitoring system for continuous video-EEG recording. Rats were then treated with RU486 (25 mg/kg body weight) 1 hour before the pilocarpine injection. Thirty minutes later rats were treated with scopalamine (1 mg/kg body weight) to reduce peripheral side effects of pilocarpine. Rats were injected with pilocarpine (385 mg/kg body weight) 30 minutes after scopalamine injection to induce SE. One hour after declared SE, rats were treated with DZ (6 mg/kg) to stop the seizures. Every two hours rats were monitored for signs of behavioral seizures and if required they were injected with 3 mg/kg DZ till they completely stop seizing. Rats that were pretreated with RU486 before SE induction required a significantly lower mean cumulative dose of DZ (n=9; 7[plusmn]0.5 mg/kg body weight) to terminate seizures as compared to those without RU486 pre-treatment (n=18; dose = 9.83[plusmn]0.47 mg/kg body weight; p = 0.001). There was no difference in SE severity between RU486 treated and untreated rats prior to first dose of DZ, suggesting that RU486 treatment did not effect SE directly. Preliminary results from video-EEG monitoring suggest rats that received RU486 had lower frequency of spike-wave discharge and seizure recurrence over 24h hours after SE. The present study suggests that pretreatment with RU486 before SE induction increases the efficacy of diazepam in stopping prolonged seizures and also improves the outcome of SE over the first 24 hours. Further studies are required to determine the possible mechanisms of this effect. (Supported by Epilepsy Foundation of America to YHR and NIH NS38595 to ABK.)