Efficacy of perampanel in a rat model of hypoxic neonatal serizures

Abstract

Neonatal seizures often lead to the later development of epilepsy and other cognitive disabilities, which may in part be due to calcium (Ca2+)-permeable AMPA receptor (CP-AMPAR)-mediated increases in synaptic plasticity and neuronal excitability. AMPAR subunit trafficking and the mTORC1 pathway are thought to be regulated by CP-AMPAR activity, and both have been implicated in the epileptogenic changes that follow neonatal seizures. The most common cause of neonatal seizures is hypoxic-ischemic encephalopathy. Using an established rat model of neonatal hypoxia- induced seizures, we demonstrate efficacy of the novel AMPAR-antagonist, perampanel, in suppressing seizures. We also attempt to demonstrate the efficacy of perampanel in reversing seizure-induced post-translational changes to GluR1 and two downstream targets of mTORC1, p70S6 kinase and ribosomal protein S6. However, due to limited time and insufficient sample numbers (n) we were unable to show any significant effect of perampanel on these protein targets. We could not replicate the seizure-induced increases in GluR1 subunit (Ser831/845), p70S6 kinase, and S6 phosphorylation that have previously been shown. We were also unable to replicate the efficacy of a different AMPAR antagonist, NBQX, in reversing these seizure-induced increases. These two facts, when taken together with the low n, suggest that our lack of results are likely do to insufficient sample number, and do not necessarily indicate a lack of efficacy for perampanel. Considering perampanel’s favorable anticonvulsant effect in our model, and the previously demonstrated success of other AMPARs as antiepileptogenics, we are hopeful that a further and more in depth study of perampanel will yield more favorable results.