Abstract

Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the presently FDA-approved drug for the cessation of nerve agent-induced SE. Here, we compared the efficacy of DZP with that of UBP302‒an antagonist of the kainate receptors that contain the GluK1 subunit‒against seizures, neuropathology, and behavioral deficits induced by soman, in rats. DZP, administered 1 h or 2 h post-exposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 h after soman exposure was similar to (DZP at 1 h) or longer than (DZP at 2 h) that in the soman-exposed rats that did not receive anticonvulsant. Compared to DZP, UBP302 stopped SE with a slower time-course, but reduced dramatically the total duration of SE within 24 h. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 h after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior, assessed in the open field and by the acoustic startle response, 30 days after soman exposure, was increased in the group that did not receive anticonvulsant treatment and in the DZP-treated group, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent-induced seizures and brain damage, and suggest that targeting GluK1-containing receptors is a more effective approach.