Abstracts

Rationale: Diisopropylfluorophosphate (DFP) is a potent organophosphate (OP) insecticide that causes lethal convulsions. Like nerve agents, DFP is an irreversible cholinesterase inhibitor and OP intoxication following exposure to DFP result in persistent seizures, status epilepticus (SE) and brain injury. Benzodiazepines are the first-line drugs for the treatment of SE, but there is evidence for partial or complete resistance, a condition known as refractory SE. In this study, we investigated the time-course of diazepam efficacy in the DFP model of refractory SE in rats. Methods: Rats were implanted with a pair of EEG recording electrodes in the cortex and hippocampus. SE was induced chemically by exposure to DFP (1-4 mg/kg, sc). One minute after DFP exposure, they were given atropine and PAM regimen. Diazepam was administered at 60 or 120 min after exposure to DPF. The onset and termination of SE was determined by video-EEG recordings for up to 24 h. Animals were perfused at 72 h for neuronal damage assessment. Results: DFP exposed animals exhibited electrographic and behavioral seizures within ~10 min. Seizures progressed into SE and persisted for several hours. There was massive neuronal loss in the hippocampus, amygdala and other regions in DFP-treated rats. In this model of SE, diazepam (5-10 mg/kg, ip) became less effective with the passage of time. Diazepam, which is generally effective when dosed within 10 min after seizure onset, was ineffective when given 60 min or 120 min after onset of SE a profile indicative of refractoriness to diazepam. Moreover, such therapy was associated with a marginal neuroprotection, especially at the later time points. Conclusions: DFP model of OP intoxication in rats replicates several features of refractory SE. The DFP-induced SE becomes progressively resistant to delayed treatment with diazepam, suggesting the benzodiazepine insensitivity of DFP intoxication seizures.