Sex-dependent differences in the antiseizure and neuroprotective effects of midazolam after soman exposure: Superior, sex-independent efficacy of tezampanel and caramiphen

Abstract

Nerve agents are lethal chemical weapons and highly potent chemoconvulsants. For the treatment of nerve agent-induced status epilepticus (SE), the FDA has approved the use of benzodiazepines-initially diazepam and recently midazolam (MDZ); however, benzodiazepines are not neuroprotective, particularly if not administered promptly. Here, we compared the antiseizure and neuroprotective efficacy of MDZ with that of tezampanel (LY293558; an AMPA/GluK1 receptor antagonist) administered with caramiphen (CRM; an antagonist of muscarinic and NMDA receptors), 30 min after the onset of SE induced by exposure of young-adult male and female rats to the nerve agent soman; neuropathology assessments were conducted from 7 days to 6 months post-exposure. Latency to suppression of the initial SE was comparable after MDZ or LY293558 + CRM treatment. However, seizures reoccurred, and MDZ-treated rats had longer SE, followed by significant neurodegeneration, neuronal and interneuronal loss in the CA1 hippocampal area and the basolateral amygdala, hippocampal and amygdalar atrophy, reduced spontaneous IPSCs in the basolateral amygdala, increased anxiety, and spontaneous recurrent seizures (SRS). MDZ-treated males had longer SE than MDZ-treated females and lower 24-h and long-term survival. MDZ-treated females displayed delayed hippocampal neurodegeneration and atrophy, as well as delayed SRS. Males and females treated with LY293558 + CRM presented minimal neurodegeneration and only delayed appearance of brain damage, without significant sex differences. The results suggest that MDZ treatment may carry higher risks for males. Replacing benzodiazepines with antiglutamatergic first-line treatments to prevent long-term brain damage and associated morbidities is overdue; LY293558 + CRM has produced remarkably promising results.

Keywords: Caramiphen; Midazolam; Nerve agents; Organophosphorus compounds; SUDEP; Status epilepticus; Tezampanel.