The neuroprotective effect of perampanel in lithium-pilocarpine rat seizure model

Abstract Purpose Status epilepticus (SE) causes irreversible neurodegeneration if not terminated quickly. Perampanel (PER), a potent AMPA receptor antagonist, has previously been shown to terminate seizures in the lithium-pilocarpine SE model. In the present study, we assessed whether PER would also prevent neuronal damage in this model. Methods SE was induced in rats using lithium chloride and pilocarpine. Initiation of SE was defined as continuous seizures that exhibited as rearing accompanied by bilateral forelimb clonus (Racine score 4). Either PER (0.6, 2, or 6mg/kg) or diazepam (DZP, 10mg/kg) was administered intravenously 30min after SE initiation. Histopathological samples from treated and seizure-naive rats were taken one week after treatment and then stained with an anti–neuronal nuclei (NeuN) antibody. The sections were analyzed by using a pixel-counting algorithm to quantify the amount of staining in the CA1 subregion of the hippocampus, piriform cortex (Pir), and mediodorsal thalamic nucleus (MD). Results DZP administration did not suppress seizures or the degeneration of neurons in the examined areas. Seizures were terminated in 100% of rats treated with 6mg/kg PER (n=8) and in 47% (7/15) of rats treated with 2mg/kg PER, and neurons in the analyzed areas of these animals were preserved to the level seen in naive rats. In the eight animals in which 2mg/kg PER did not terminate the seizures, neuronal loss was partially attenuated in CA1 and Pir, and neurons were fully preserved in MD. Treatment with 0.6mg/kg PER did not terminate the seizures or significantly preserve neurons. The anti-seizure effect of PER correlated well with the degree of neuroprotection in each analyzed area. Conclusions PER exhibited a strong neuroprotective effect in a drug-refractory SE model, and this effect was correlated with its attenuation of seizure.