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.