The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia

Anderson Brito Da Silva, Jane Pennifold, Ben Henley, Koustav Chatterjee, David Bateman, Roger W. Whittaker, Abhijit Joshi, Hrishikesh Kumar, Claire Nicholson, Mark R. Baker, Stuart D. Greenhill, Richard Walsh, Stefano Seri, Roland S.g. Jones, Gavin L. Woodhall*, Mark O. Cunningham*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.
Original languageEnglish
JournalEpilepsia Open
Early online date15 Oct 2021
DOIs
Publication statusE-pub ahead of print - 15 Oct 2021

Bibliographical note

This article is protected by copyright. All rights reserved. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Funding: This work has been supported by investigator-initiated grants from Eisai (MOC and GLW), Birmingham Children’s Hospital Charities grant BCHRF349 (SS, GLW) and Aston Brain Centre (GLW), the Wellcome Trust/EPSRC (102037; RGW and MOC), and a CAPES-funded (Brazil) PhD studentship (BEX-0437-14-0; ABDS, RGW, and MOC).

Keywords

  • Epilepsy
  • focal cortical dysplasia
  • glutamate
  • perampanel
  • AMPA

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