Preventing Long-Term Brain Damage by Nerve Agent-induced Status Epilepticus in Rat Models Applicable to Infants: Significant Neuroprotection by Tezampanel Combined with Caramiphen but not by Midazolam Treatment.

Acute exposure to nerve agents induces a peripheral cholinergic crisis and prolonged status epilepticus (SE), causing death or long-term brain damage. To provide preclinical data pertinent to the protection of infants and newborns, we compared the antiseizure and neuroprotective effects of treating soman-induced SE with midazolam (MDZ) versus tezampanel (LY293558) in combination with caramiphen (CRM), in 12- and 7-day-old rats. The anticonvulsants were administered 1 h after soman exposure; neuropathology data were collected up to 6 months post-exposure. In both ages, the total duration of SE within 24 h after soman exposure was significantly shorter in the LY293558+CRM groups compared with the MDZ groups. Neuronal degeneration was substantial in the MDZ-treated groups but absent or minimal in the groups treated with LY293558+CRM. Loss of neurons and interneurons in the basolateral amygdala and CA1 hippocampal area was significant in the MDZ-treated groups but virtually absent in the LY293558+CRM groups. Atrophy of the amygdala and hippocampus occurred only in MDZ-treated groups. Neuronal/interneuronal loss and atrophy of the amygdala and hippocampus deteriorated over time. Reduction of inhibitory activity in the basolateral amygdala and increased anxiety were found only in MDZ groups. Spontaneous recurrent seizures developed in the MDZ groups, deteriorating over time; a small percentage of rats from the LY293558+CRM groups also developed seizures. These results suggest that brain damage can be long-lasting or permanent if nerve agent-induced SE in infant victims is treated with midazolam at a delayed timepoint after SE onset, while antiglutamatergic treatment with tezampanel and caramiphen provide significant neuroprotection. Significance Statement To protect the brain and the lives of infants in the event of mass exposure to nerve agents, an anticonvulsant treatment must be administered that will effectively stop seizures and prevent neuropathology, even if it is offered with a relative delay after seizure onset. The present study shows that midazolam, which was recently approved by the FDA for the treatment of nerve agent-induced status epilepticus, is not an effective neuroprotectant, while brain damage can be prevented by targeting glutamate receptors.