Abstracts

Rationale: Organophosphate (OP) compounds include pesticides and nerve agents. Commercially available OP's are considered chemical threat agents and there is a growing concern that they could be weaponized to cause mass civilian causalities. In addition, accidental OP exposure to pesticides is a major problem in developing nations. OPs act by irreversibly inhibiting the enzyme acetylcholinesterase, causing a cholinergic crises that can ultimately evolve into status epilepticus (SE). There is a need to develop models to evaluate the morbidities associated with OP toxicity. To address this need, we have developed a rodent survival model of OP toxicity using paraoxon (POX, an active metabolite of the pesticide, parathion) that mimics the mortality and behavioral morbidities associated with OP intoxication. A number of animal models have demonstrated that induction of SE can result in prolonged changes in synaptic plasticity and the acquisition of epileptic seizures. It is important to determine if POX-induced SE can also cause changes in synaptic plasticity and the development of spontaneous recurrent seizures (SRSs) or acquired epilepsy (AE) in this model. Methods: Male Sprague-Dawley rats (250-300g) were injected with POX (2 mg/kg, s.c). One minute later, rats were injected with atropine sulfate (0.5 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m). Rats quickly developed SE, which was then stopped with midazolam (2 mg/kg, i.m.) at 1-h post SE onset. Approximately 6-months following POX-SE, rats were fitted with surface electrodes and screened for SRSs using continuous video-EEG monitoring for ten days. Recordings were analyzed to determine frequency and duration of SRSs as well as Racine scores for the degree of convulsing activity. Results: POX exposure produced rapid onset of SE that was treated effectively with midazolam. Video-EEG monitoring revealed the presence of SRS in 64% of rats (n= 16 out of 25) at 6-months post POX SE. Electrographic seizures consisted of poly-spikes or sharp-wave trains with an amplitude that was at least twice that of the background. The average seizure duration was 57.7 6.5 s. POX rats exhibited seizures at a frequency of 22.3 2.7 seizures/day. The behavioral correlates of these seizures consisted of a sudden cessation of activity, associated with vacuous chewing, facial twitching, head-jerks, and forelimb clonus. Most of the observed seizures were generalized convulsive (stage 4) seizures and this behavioral seizure severity as noted using the Racine scale was 4.09 0.36. Conclusions: SE is a leading cause of mortality and is associated with the development of chronic morbidities. In this study, we demonstrate that POX-induced SE leads to the development of SRS, a hallmark of chronic epilepsy. The ability to develop a model of POX SE induced AE offers a unique resource to evaluate effects of lethal OP intoxication on the development of chronic epilepsy and behavioral co-morbidities. This model is also being used to identify molecular mechanisms underlying the development of co-morbid disorders and investigate novel counteract agents for their effective treatment. Funding: U01NS058213-10 to RJD W81XWH-14-1-0478 to LSD