title: A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus.
abstract: Perampanel is a non-competitive AMPA receptor antagonist that is under development as an anti-epileptic therapy. Although it is known to reduce calcium flux mediated by AMPA receptors in cultured cortical neurons, there are no studies of its selectivity in synaptic transmission in more intact systems. In the present study using hippocampal slices, perampanel (0.01-10 μM) has been tested on pharmacologically isolated synaptic responses mediated by AMPA, NMDA or kainate receptors. Perampanel reduced AMPA receptor-mediated excitatory postsynaptic field potentials (f-EPSPs) with an IC(50) of 0.23 μM and a full block at 3 μM. This compares with an IC(50) of 7.8 μM for GYKI52466 on these responses. By contrast, perampanel at 10 μM had no effect on responses mediated by NMDA or kainate receptors, which were completely blocked by 30 μM D-AP5 and 10 μM NBQX respectively. The concentrations of perampanel required to reduce AMPA receptor-mediated responses are not dissimilar to those in plasma following anti-convulsant doses and are consistent with AMPA receptor antagonism being its primary mode of action.
authors.affiliation: MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Ceolin
authors.forename: Zuner A
authors.initials: ZA
authors.lastname: Bortolotto
authors.forename: Neil
authors.initials: N
authors.lastname: Bannister
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: David
authors.initials: D
authors.lastname: Lodge
authors.forename: Arturas
authors.initials: A
authors.lastname: Volianskis
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009570:Nitriles; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D018091:Receptors, AMPA; C551441:perampanel