Abstracts

Rationale: Status Epilepticus (SE) remains a therapeutic challenge, and better treatments are urgently needed. The potent AMPA receptor antagonist perampanel may negate the physiological consequences of SE-induced increase in synaptic AMPA receptors. We previously found that perampanel was more potent in stopping midazolam-refractory SE than drugs used most often as second-line agents in the treatment of SE (levetiracetam, valproate, fosphenytoin and lacosamide). In the current study, we compared their effects on the neuropathological consequences of SE.

Methods: SE was induced in adult male Sprague-Dawley rats by high-dose lithium (5 mEq/kg)/pilocarpine (320 mg/kg), and EEG/video was recorded for 18 hrs. Midazolam (1 mg/kg) was injected i.p. 40 min after SE onset. Perampanel (4 mg/kg), valproate (270 mg/kg), levetiracetam (240 mg/kg), fosphenytoin (120 mg/kg PE) or lacosamide (24 mg/kg) were injected i.p. 60 min after seizure onset (20 min after midazolam) if SE continued. Neuropathology was studied 48 hours after SE onset.

Results: Neuronal injury: Perampanel (4 mg/kg) reduced neuronal injury as revealed by Fluoro-Jade B staining in CA1 from 4+ in rats treated with midazolam alone (median, interquartile range 4-4, n=10) to 0 (0-0, p< 0.0001) when midazolam was followed by perampanel. It also reduced neuronal injury in CA3, thalamus, parietal cortex, piriform and entorhinal cortex, and amygdala. Valproate, levetiracetam and lacosamide (24 mg/kg) failed to reduce neuronal injury. Fosphenytoin also reduced neuronal injury in 6 regions, but perampanel reached a higher degree of significance in 4 of them.