title: 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 (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.
authors.affiliation: 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.).
authors.forename: R
authors.initials: R
authors.lastname: Zwart
authors.affiliation: 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.).
authors.forename: E
authors.initials: E
authors.lastname: Sher
authors.affiliation: 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.).
authors.forename: X
authors.initials: X
authors.lastname: Ping
authors.affiliation: 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.).
authors.forename: X
authors.initials: X
authors.lastname: Jin
authors.affiliation: 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.).
authors.forename: J R
authors.initials: JR
authors.lastname: Sims
authors.affiliation: 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.).
authors.forename: A S
authors.initials: AS
authors.lastname: Chappell
authors.affiliation: 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.).
authors.forename: S D
authors.initials: SD
authors.lastname: Gleason
authors.affiliation: 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.).
authors.forename: P J
authors.initials: PJ
authors.lastname: Hahn
authors.affiliation: 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.).
authors.forename: K
authors.initials: K
authors.lastname: Gardinier
authors.affiliation: 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.).
authors.forename: D L
authors.initials: DL
authors.lastname: Gernert
authors.affiliation: 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.).
authors.forename: J
authors.initials: J
authors.lastname: Hobbs
authors.affiliation: 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.).
authors.forename: J L
authors.initials: JL
authors.lastname: Smith
authors.affiliation: 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.).
authors.forename: S N
authors.initials: SN
authors.lastname: Valli
authors.affiliation: 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.) jwitkin@lilly.com.
authors.forename: J M
authors.initials: JM
authors.lastname: Witkin
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D016022:Case-Control Studies; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D008297:Male; D009570:Nitriles; D009928:Organ Specificity; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D018091:Receptors, AMPA; C551441:perampanel