Abstracts

Rationale: Soman is a toxic chemical warfare agent that covalently binds to and inhibits the activity of acetylcholinesterase. The resultant increase in acetylcholine at neuromuscular junctions and within the central nervous system causes dramatic systemic and neurological effects in exposed individuals, including loss of muscle control, respiratory distress, status epilepticus (SE), and often death. Benzodiazepines are the primary line of treatment for soman-induced SE, but such self-sustained SE cases often become refractory to these therapies (Mazarati et al., Brain Res [1998]814: 179-85). Dexmedetomidine (DEX) is a unique sedative/hypnotic compound that produces arousable unconsciousness without respiratory side effects via its highly specific actions at α2 adrenoceptors. It has previously been shown to effectively protect against kainic acid-evoked and kindling-evoked seizures when used as a pretreatment (Kan et al., Neurosci Lett [2013]543: 17-21; Halonen et al., Brain Res [1995]693: 217-24). Here we investigate the utility of DEX as a co-treatment with standard medical countermeasures in a rat model of soman-induced SE.Methods: Adult male rats were exposed to a seizure-inducing dose of soman, entered SE as confirmed by electroencephalograph (EEG), and were then administered standard medical countermeasures (atropine sulfate, pralidoxime [2-PAM], and midazolam) in combination with intraperitoneal saline or different doses of DEX twenty minutes after seizure onset. Outcomes were measured by comparing the spike rate and EEG power in the gamma (20-70 Hz) range.Results: At both the 0.4 mg/kg (n=4)and 0.2 mg/kg (n=5) DEX doses, all animals tested stopped seizing for at least two hours post-treatment, with a subset of animals remaining seizure-free 24 hours later. The latency to seizure termination was 10.6 ± 2.1 min and 32.5 ± 10.4 min respectively. As shown in Figure 1, the spike rate and gamma power for each group was dramatically decreased during the four hours post-treatment compared to saline controls (n=10). Of the two animals treated with 0.1 mg/kg DEX, one remained seizure free at 24 hours post-treatment, while the other never stopped seizing. This suggests that 0.1 mg/kg marks the lower end of the effective dosing range.Conclusions: DEX quickly terminates soman-induced SE at clinically relevant doses, keeping seizures off for hours despite its short duration of action. Its unique status as a reversible anesthetic drug makes it an ideal co-therapy for SE, especially in a battlefield scenario. Further studies will examine the brains of these animals with FluoroJade B as a marker of dying neurons to determine if DEX is neuroprotective as well as anticonvulsant.