Abstracts

Rationale: A major CNS effect of exposure to organophosphates, such as diisopropylfluorophosphate (DFP), is to induce prolonged repetitive seizures and status epilepticus (SE). To determine the efficacy of current anticonvulsants in an understudied pediatric population, we have developed immature rat models for DFP-induced seizures. As we had previously determined that rats at postnatal days 7 (P7) and 14 (P14) only display a short period of seizure activity and may not develop SE in response to DFP, we began our anticonvulsant studies with P21 rats. Methods: Immature rat pups (P21 and 28) and adult rats (P70) were instrumented for EEG recording using miniature wireless telemetry units. On the day of treatment, rats received pyridostigmine bromide (0.026 mg/kg) as a pretreatment. Thirty minutes after pretreatment, rats were administered DFP. Rats received an admixture of atropine sulfate (0.1 mg/kg) and 2-PAM (25 mg/kg) 1 min later. Sixty min after electrographic seizures began, rats were given vehicle or an anticonvulsant drug treatment of phenobarbital (75 mg/kg) or propofol (100 mg/kg). Status epilepticus was monitored for 24 h with continuous video-EEG recordings to observe both behavioral and electrographic seizure activity. After 24 h, brain tissue was examined with Fluoro-Jade B, a marker for degenerating neurons. Results: Phenobarbital showed modest efficacy in halting electrographic SE in P21 and P28, but not P70, rats. However, there were significant reductions in neurodegeneration as measured by Fluoro-Jade B in all three ages. In contrast, in rats treated with propofol, there were greater effects on halting SE in adult rats, but these effects were lessened in P28 and nonexistent in P21 rats. Conclusions: There is a distinct age-dependent effect of phenobarbital vs. propofol in ameliorating electrographic SE, being enhanced at younger ages but ineffective in older rats with phenobarbital, and enhanced in adults but ineffective in P21 pups with propofol. Furthermore, we found that although phenobarbital has relatively weak anticonvulsant effects on SE, the neuroprotective effects were more pronounced. Funding: Supported by K08-NS-070957, NIH NO1-NS-4-2359, and CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders (NINDS), Grant W81XWH-12-2-0122 as a subcontract from the Military Research Institute of Chemical Defense (MRICD).