Abstracts

Rationale: While current medical countermeasures for acute organophosphate (OP) poisoning are effective in protecting against lethality and peripheral parasympathomimetic symptoms, they do not sufficiently protect against persistent neuropsychological deficits or prevent spontaneous recurrent seizures. The development of more effective neuroprotective strategies has proven challenging, in part because the progression of epileptogenesis following acute OP intoxication has not been well characterized. To address this data gap, we used a rat model to characterize the development of chronic epilepsy following acute intoxication with the OP pesticide, DFP. Methods: Approximately 2 weeks prior to DFP exposure, adult male Sprague-Dawley rats were implanted with telemetry transmitters (F20-EET, Data Science International) in order to measure electrocorticographic recordings (EEG) from the brain. Animals were then treated with either a single dose of DFP (4 mg/kg, sc) or equivalent volume of vehicle (VEH, saline), followed by a combined injection of atropine sulfate (2 mg/kg, im) and pralidoxime (2-PAM, 25 mg/kg, im) to rescue animals from peripheral cholinergic symptoms. This dosing paradigm is sufficient to induce status epilepticus (SE) within approximately 8 min that on average lasts for 4 hours. At 40 min following the DFP injection, a subset of animals were given a single dose of the benzodiazepine midazolam (1.8 mg/kg, im), in order to attenuate SE. Video-EEG recordings were collected 24/7 for up to 30 d following DFP in order to characterize the progression of chronic epilepsy in these animals. Results: Following DFP-induced SE, all animals who were not treated with midazolam developed chronic seizure activity within hours after SE, averaging 1-3 seizures per day during the 30-day recording period. In contrast, DFP animals that were administered midazolam showed no signs of seizure activity during the month following acute DFP intoxication. A subset of DFP-treated animals who did not exhibit electrographic evidence of SE following DFP injection also did not develop chronic seizure activity during the month following intoxication. Conclusions: These preliminary findings suggest that SE is required for developing chronic epilepsy and early intervention with an effective anti-seizure medication to terminate SE is necessary to adequately protect the brain from developing chronic epilepsy following acute OP intoxication.  Funding: NIH CounterACT program (NS079202); David and Dana Loury Foundation predoctoral fellowship to MG