Abstracts

Rationale: Status Epilepticus (SE) is a neurological emergency with a mortality rate estimated at 22% (DeLorenzo et al, 1995). Benzodiazepines are standard first-line treatments for SE (Brophy et al, 2012), but are ineffective in approximately 30% of patients (Silbergleit et al, 2012). Changes in GABA_A receptor subunit surface expression patterns may contribute to the development of acute tolerance to pharmacotherapies in SE (Goodkin et al, 2008; Rajasekaran et al, 2010). Neuroactive steroids (NASs) act as positive allosteric modulators (PAMs) across a broad spectrum of GABA_A receptor isoforms and thus may be less susceptible to acute pharmaco-resistance during SE. Supporting this hypothesis, allopregnanolone, but not diazepam, effectively halts kainic acid-induced SE when administered 75 minutes after onset (Rogawski et al, 2013). Methods: Here, we examined the efficacy of allopregnanolone and SGE-797, a synthetic neuroactive steroid optimized for oral administration, in reducing electrographic seizures in the lithium-pilocarpine rat model of pharmaco-resistant SE. Male SD rats (~300g) implanted with screw electrodes over the frontal cortex for EEG recording and IV jugular vein catheters for IV drug administration were administered lithium (127 mg/kg, IP) and pilocarpine (50 mg/kg, IP, 18 hours after lithium) to elicit SE (Pouliot et al, 2013). Scopolamine (1 mg/kg, IP) was administered 30 min prior to pilocarpine to mitigate its peripheral effects. Test articles were administered immediately, 15 or 60 min after onset of SE, as defined by electrographic and behavioral endpoints (Racine stage ≥ 3, Racine et al, 1972). Results: Administration of diazepam (10 mg/kg, IV, n=6-8/group) halted seizure activity in 100% of rats when administered immediately after onset, partially (50%) at 15 min, and was ineffective (0%) at 60 minutes. In contrast, allopregnanolone (10 or 15 mg/kg, IV, n=4-5/group) completely terminated SE when administered either 15 or 60 minutes after onset of SE. Similarly, SGE-797 (4 mg/kg, IV, n=8), also halted seizure activity in 75% of rats when administered at 60 min after onset of SE. Conclusions: These data are consistent with other studies reporting acute pharmaco-resistance in rodent models of SE, as diazepam was ineffective in halting seizure activity when administered at 60 min following onset of SE. This study demonstrates that both the natural NAS, allopregnanolone and the synthetic NAS, SGE-797 are able to arrest seizure activity in this rodent model of pharmaco-resistant SE. Together, these results suggest that GABA_A receptor PAM NASs may provide an effective treatment for pharmaco-resistant SE in humans.