Abstracts

Rationale: Exposure to organophosphate (OP) nerve-agents produces seizures in both humans and animals. Unless treated, these seizures may rapidly advance to status epilepticus (SE), a life threatening condition associated with neuronal damage and long-term neurological complications. The benzodiazepines (BZs) diazepam or midazolam are the current standard-of-care initial treatment for OP-induced SE; however, these agents are ineffective in stopping SE when administered at a delayed time after seizure onset. BZs act on synaptic GABA-A receptors but are inactive on extrasynaptic GABA-A receptors. With prolonged seizure activity, synaptic GABA-A receptors are internalized and are functionally unavailable to BZs. Neuroactive steroids such as allopregnanolone target both synaptic and extrasynaptic GABA-A receptors and could provide a treatment approach for BZ-refractory SE. The present study was designed to assess whether high dose intramuscular (IM) allopregnanolone is able to terminate DFP-induced refractory SE in rats. Methods: Male SD rats were implanted with 6-cortical screw electrodes for video-EEG recording and monitoring of seizures. The rats were treated with DFP (4 mg/kg, SC) followed 1 min later with atropine sulfate (2 mg/kg, IM) and pralidoxime chloride (25 mg/kg, IM) to avoid peripheral side effects. Forty minutes after DFP, animals were injected with allopregnanolone at 12 or 24 mg/kg, IM. Animals were observed for behavioral and electrographic seizures for 5 h. Results: DFP induced high frequency and high amplitude epileptiform activity within minutes of its administration. Midazolam (1.8 mg/kg, IM) when administered 40 min after DFP, did not stop SE in these animals, confirming that the seizures are BZ refractory. At the lower dose, allopregnanolone (12 mg/kg) terminated SE in 75% (6 of of 8) rats but the effect was slow (mean time to termination, 133 ± 52 min). At the higher dose, allopregnanolone (24 mg/kg) rapidly terminated SE in all (7 of 7) animals tested (mean time to termination, 10.4 ± 2.9 min). In one rat in the latter group, SE resumed after about 4h. Conclusions: High dose allopregnanolone effectively terminates DFP-induced, BZ-refractory SE. Allopregnanolone at appropriate doses may represent a superior initial treatment for OP-induced seizures than BZs. Funding: NINDS Grant 1U54NS079202