Perampanel, an Antagonist of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors, for the Treatment of Epilepsy: Studies in Human Epileptic Brain and Nonepileptic Brain and in Rodent Models

Abstract

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC 50 values ranging from 2.6 to 7.0 mM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 mM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and sideeffect profile in rodents and epileptic patients.

A Comment on "Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8"

“…We also point out that an article published in JPET in 2014 predicted the data presented by Maher et al (Zwart et al, 2014). In the abstract, we stated that "These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side effect profile in rodents and epileptic patients."…”

“…Given the unique localizations of these AMPA receptors in the brain, the molecule was anticonvulsant and had fewer motor-impacting effects than non-TARP-dependent AMPA receptor antagonists. For example, the antiepileptic perampanel (Fycompa; Eisai Inc., Woodcliff Lake, NJ) produces motor-impairing effects in rodents and humans (see data and discussion in Zwart et al, 2014). We believe the clinical implications of these new data are therefore important.…”

Use of Perampanel in the Treatment of Epilepsy: A Review of Literature and a Case Report

“…Перампа-нел -мощный высокоселективный неконкурентный ингибитор ионотропных AMPA-рецепторов постсинап-тических мембран нейронов на уровне неокортекса и гиппокампа [6,9,26,41]. По мнению многих авторов, перампанел -первый АЭП со специфическим дейст-вием на обмен глутамата (опосредованное глутаматом возбуждение в ЦНС), эффективность и переносимость которого при резистентных фокальных приступах были доказаны в клинических исследованиях III фазы [13, 17-21, 27, 28, 31].…”

Reply to "A Comment on 'Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8"

“…Within a couple of weeks of the publication of our JPET article online, the anticipated manuscript appeared in the Journal of Medicinal Chemistry . We regret that we did not reference the article by members of the Lilly group (Zwart et al, 2014) in our discussion section, as those authors had speculated on the likely benefit of designing an a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulator selective for transmembrane AMPA receptor regulatory protein g8.…”