Abstracts

Rationale: Across multiple mammalian models, exposure to organophosphorus nerve agents like soman (GD) leads to rapid development of benzodiazepine-resistant status epilepticus (SE). Substantial brain damage is rapidly incurred, followed by development of spontaneous recurrent seizures (SRS). Here, we describe the optimization of a particularly severe mouse model of SRS following GD-induced SE. We also evaluated the ability of several FDA-approved antiepileptic drugs (AEDs) to mitigate seizure activity. Methods: Male C57Bl/6J (n= 35) mice were implanted with DSI ETA-F10 telemetry units for continuous EEG monitoring. Following exposure to 172 µg/kg GD, mice either received 5 mg/kg DZP 120 minutes after onset of SE (n = 20) or got no anticonvulsant (n = 15). Survival, weight, nesting behavior, and onset and frequency of SRS were monitored for at least 28 days in order to establish an optimal exposure model. The optimal model was then used to test three AEDs (VPA, PB, & LEV). Starting 24 hours after SE, mice were repeatedly dosed with an AED or vehicle for 14 days, followed by a 14 day washout period. Dosing regimens were based on published rodent pharmacokinetic data and therapeutic plasma concentrations in humans. Results: Survival was poor in animals that did not receive DZP, with only 40% survival at Day 14 and 13% survival at Day 28. Alternately, animals that received DZP 120 minutes after SE onset had a Day 14 survival rate of 65% and a Day 28 rate of 55%. All animals in both groups that survived to the end of the study demonstrated SRS, and the incidence of pathology among survivors was 100% for no DZP and 72% for 120 minute DZP. Further studies included the 120 minute DZP treatment. VPA (n = 11) had no effect on time to SRS onset, total number of SRS, SRS frequency, SRS duration, or severity of histopathology compared to controls (n = 9). PB (n = 10) significantly delayed time to onset of SRS compared to controls (p = 0.0397), but did not improve any other measures. For all animals except those treated with LEV (n = 10), the length of SRS increased over time. LEV also reduced the severity of damage in the amygdala (p < 0.0001), CA1 (p = 0.0077), and CA4 (p = 0.0260), suggesting that it may have disease-modifying effects in this model. Conclusions: This model consistently produced SRS with a minimal latent period. SRS in these animals were relatively resistant to treatment, but the AEDs tested led to improvements that were consistent with published observations. In the future, this model can be used to screen novel compounds. Funding: This research was supported in part by appointments to the Postgraduate Research Participation Program at the U.S. Army Medical Research Institute of Chemical Defense administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and U.S. Army Medical Research and Materiel Command.  This research was supported by a CounterACT inter-agency agreement between NIH/NINDS (Y1-O6-9613-01) and USAMRICD (A120-B.P2009-2).Disclaimers: The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government.  The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act of 1966 (P.L. 89-544), as amended.