A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus Laura Ceolin, Zuner A. Bortolotto, Neil Bannister, Graham L. Collingridge, David Lodge, Arturas Volianskis ⇑ MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom article info Article history: Available online 10 March 2012 Keywords: Perampanel GYKI52466 D-AP5 AMPA receptors NMDA receptors Kainate receptors abstract Perampanel is a non-competitive AMPA receptor antagonist that is under development as an anti-epilep- tic 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 lM) 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 lM and a full block at 3 lM. This compares with an IC 50 of 7.8 lM for GYKI52466 on these responses. By contrast, per- ampanel at 10 lM had no effect on responses mediated by NMDA or kainate receptors, which were com- pletely blocked by 30 lM D-AP5 and 10 lM 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. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction The ability to convey an anti-epileptic profile in humans can be seen with a wide variety of pharmacological agents (Lason et al., 2011; Rogawski, 2006) including sodium (see White et al. (2007)) and calcium (Weiergraber et al., 2010) channel blockers, potassium channel enhancers (Rogawski and Bazil, 2008), potenti- ators of GABA function (Czuczwar and Patsalos, 2001; Schousboe et al., 2011) and modulators of glutamate release (Moldrich et al., 2003; Sebastiao and Ribeiro, 2009). This list now extends into antagonists of glutamate receptors including convincing preclinical evidence for inhibition of N-methyl-D-aspartic acid (NMDA), a- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors delivering anti-convulsant activity. Thus, agonists for NMDA (Chapman, 1998; Loscher, 1998), AMPA (Scharfman, 2007) and kainate (Lerma, 2006) receptors all induce seizure activity and their antagonists are effective in many seizure models (Meldrum and Rogawski, 2007; Rogawski, 2011). For example, the competitive, channel-blocking and glycine-site antagonists of NMDA receptors are anti-convulsant but have unto- ward side-effects, which limit their use (Kalia et al., 2008; Meldrum and Rogawski, 2007; Wasterlain and Chen, 2008). NMDA antagonism may, however, contribute to the anti-convulsant pro- file of felbamate (Kleckner et al., 1999) and possibly that of lacosamide (Beyreuther et al., 2007). AMPA receptor antagonists do not have such marked side effects and yet are very effective in animal models of epilepsy (Bleakman and Lodge, 1998; De Sarro et al., 2005; Hanada et al., 2011; Loscher and Honack, 1994; Rogawski, 2011; Yamaguchi et al., 1993). AMPA receptor antago- nists may be particularly beneficial in combination with other treatments (Jonker et al., 2007) and have been shown to be effec- tive in add-on studies in man with a limited side effect profile (Chappell et al., 2002; Langan et al., 2003). AMPA receptor antago- nism contributes to the anti-convulsant effects of lamotrigine (Lee et al., 2008). Kainic acid is the prototypical amino acid convulsant (Jane et al., 2009; Nadler et al., 1981; Vincent and Mulle, 2009) and kainate antagonists particularly of the GluK1 subtype have anti- epileptic potential (Jane et al., 2009; Matute, 2010; Smolders et al., 2002). It seems likely that GluK1 antagonism underlies some of the anticonvulsant effects of topiramate (Braga et al., 2009). De- spite the rationale and the preclinical evidence, no compound developed as a glutamate receptor antagonist has yet become a clinically accepted therapy for the treatment of epilepsy. It is therefore of considerable interest that perampanel, a com- pound thought to be a non-competitive antagonist of AMPA recep- tors, is under development for epilepsy treatment (Hanada et al., 2011). Perampanel has been shown to reduce AMPA-, but not NMDA-evoked calcium signals in rat cortical neurones in culture (Hanada et al., 2011). However, no studies on excitatory synaptic transmission in mammalian brain have been reported for this com- pound. We therefore investigated the actions of perampanel on 0197-0186/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuint.2012.02.035 ⇑ Corresponding author. Tel.: +44 1173311968. E-mail address: A.Volianskis@bristol.ac.uk (A. Volianskis). Neurochemistry International 61 (2012) 517–522 Contents lists available at SciVerse ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci