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Pediatric Susceptibility to Nerve Agent-Induced Seizures and Effectiveness of Anticonvulsant Treatments

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Final rept. 26 Sep 2012-25 Sep 2014

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Organophosphate OP poisoning can result in status epilepticus SE, which can become pharmacoresistant if treatment is delayed. Virtually no data exist on OP-induced SE in immature animals, even though the immature brain is likely to respond differently to OPs, and the optimal therapies are also likely to differ from adults. Our aim is to identify novel drugs that block pharmacoresistant OP-induced SE, as well as pharmacoresistant LiPilo-induced SE, in immature rats, which would thus be candidate therapies in children. As a collaborative program over the past 2 years, we have provided USAMRICD investigators with our novel miniature telemetry devices and recording apparatus for recording from postnatal day 7 P7 and P14 rats. We have developed rat models for both diisopropylfluorophosphate DFP and LiPilo exposure for ages P7, P14, P21, and P28. Surprisingly, so far, P7 and P14 rat pups have only generated brief i.e., minutes periods of seizure behavior in response to DFP and LiPilo, while P21 and P28 animals develop robust SE that lasts for several hours. We have observed extensive neuronal injury in P28 and P21 rats using Fluoro-Jade B as a marker. We have characterized the effects of midazolam and diazepam on DFP-induced SE in P21 rat pups, and we found that midazolam ameliorates the SE and the neuronal damage triggered by the OP. Diazepam had similar properties, but at the dose tested, was not as effective as midazolam. We have developed and characterized a model for acute DFP and LiPilo inducedt SE that is now ready for testing reference and investigational anti-seizure drugs in P21 and P28 rats. Further experiments are needed to characterize models of P7 and P14 DFP-induced SE.

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  • Medicine and Medical Research

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