Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats

Abstract

Acute exposure to nerve agents induces status epilepticus (SE), which causes brain damage or death. LY293558, an antagonist of AMPA and GluK1 kainate receptors is a very effective anticonvulsant and neuroprotectant against soman; however, some neuronal damage is still present after treatment of soman-exposed rats with LY293558. Here, we have tested whether combining LY293558 with an NMDA receptor antagonist can eliminate the residual damage. For this purpose, we chose caramiphen (CRM), an antimuscarinic compound with NMDA receptor antagonistic properties. Adult male rats were exposed to 1.2 × LD₅₀ soman, and at 20 min after soman exposure, were injected with atropine + HI-6, or atropine + HI-6 + LY293558 (15 mg/kg), or atropine + HI-6 + LY293558 + CRM (50 mg/kg). We found that (1) the LY293558 + CRM treatment terminated SE significantly faster than LY293558 alone; (2) after cessation of the initial SE, seizures did not return in the LY293558 + CRM-treated group, during 72 h of monitoring; (3) power spectrum analysis of continuous EEG recordings for 7 days post-exposure showed increased delta and decreased gamma power that lasted beyond 24 h post-exposure only in the rats who did not receive anticonvulsant treatment; (4) spontaneous recurrent seizures appeared on day 7 only in the group that did not receive anticonvulsant treatment; (5) significant neuroprotection was achieved by LY293558 administration, while the rats who received LY293558 + CRM displayed no neurodegeneration; (6) body weight loss and recovery in the LY293558 + CRM-treated rats did not differ from those in control rats who were not exposed to soman. The data show that treatment with LY293558 + CRM provides full antiseizure and neuroprotective efficacy against soman.

Keywords: AMPA receptors; Caramiphen; GluK1-kainate receptors; NMDA receptors; Nerve agents; Status epilepticus.