Perampanel, an antagonist of a-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

R. Zwart, E. Sher, X. Ping, X. Jin, J. R. Sims, A. S. Chappell, S. D. Gleason, P. J. Hahn, K. Gardinier, D. L. Gernert, J. Hobbs, J. L. Smith, S. N. Valli, J. M. Witkin

Research output: Contribution to journalArticle

37 Scopus citations

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 (α-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 (IC50values ranging from 2.6 to 7.0 μM). 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 μM 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. Copyright

Original languageEnglish (US)
Pages (from-to)124-133
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume351
Issue number1
DOIs
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Zwart, R., Sher, E., Ping, X., Jin, X., Sims, J. R., Chappell, A. S., Gleason, S. D., Hahn, P. J., Gardinier, K., Gernert, D. L., Hobbs, J., Smith, J. L., Valli, S. N., & Witkin, J. M. (2014). Perampanel, an antagonist of a-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. Journal of Pharmacology and Experimental Therapeutics, 351(1), 124-133. https://doi.org/10.1124/jpet.114.212779