PT  - JOURNAL ARTICLE
AU  - Zwart, R
AU  - Sher, E
AU  - Ping, X
AU  - Jin, X
AU  - Sims, J R
AU  - Chappell, A S
AU  - Gleason, S D
AU  - Hahn, P J
AU  - Gardinier, K
AU  - Gernert, D
AU  - Hobbs, J
AU  - Smith, J L
AU  - Valli, S N
AU  - Witkin, J M
TI  - Perampanel, an Antagonist of α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) Receptors for the Treatment of Epilepsy: Studies in Human Epileptic Brain, Non-Epileptic Brain, and in Rodent Models
AID  - 10.1124/jpet.114.212779
DP  - 2014 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.114.212779
4099  - http://jpet.aspetjournals.org/content/early/2014/07/15/jpet.114.212779.short
4100  - http://jpet.aspetjournals.org/content/early/2014/07/15/jpet.114.212779.full
AB  - Perampanel (Fycompa®) is and AMPA receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both cerebral cortex and hippocampus, associated with antiepileptic efficacy, and also in cerebellum, associated with motor side-effects, in rodent and human brain. We also asked if epileptic and non-epileptic 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, perampanel inhibited AMPA receptors from hippocampal tissue that was removed from a patient undergoing 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 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.