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Research ArticleNeuropharmacology

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

R. Zwart, E. Sher, X. Ping, X. Jin, J. R. Sims Jr., A. S. Chappell, S. D. Gleason, P. J. Hahn, K. Gardinier, D. L. Gernert, J. Hobbs, J. L. Smith, S. N. Valli and J. M. Witkin
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 124-133; DOI: https://doi.org/10.1124/jpet.114.212779
R. Zwart
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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E. Sher
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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X. Ping
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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X. Jin
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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J. R. Sims Jr.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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A. S. Chappell
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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S. D. Gleason
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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P. J. Hahn
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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K. Gardinier
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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D. L. Gernert
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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J. Hobbs
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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J. L. Smith
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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S. N. Valli
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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J. M. Witkin
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.R.S., A.S.C., S.D.G., P.J.H., K.G., D.L.G., S.N.V., J.M.W.); Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (R.Z., E.S.); and Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana (X.P., X.J., J.H., J.L.S.)
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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 (IC50 values 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 side-effect profile in rodents and epileptic patients.

Footnotes

    • Received January 3, 2014.
    • Accepted July 14, 2014.
  • This work was supported by a Pence Foundation grant (to J.L.S.).

  • dx.doi.org/10.1124/jpet.114.212779.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 2014
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Research ArticleNeuropharmacology

Perampanel and AMPA Receptor Antagonism

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 and J. M. Witkin
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 124-133; DOI: https://doi.org/10.1124/jpet.114.212779

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Research ArticleNeuropharmacology

Perampanel and AMPA Receptor Antagonism

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 and J. M. Witkin
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 124-133; DOI: https://doi.org/10.1124/jpet.114.212779
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