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

doi:10.1002/epi4.12549

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 journal › Article › peer-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 language	English
Journal	Epilepsia Open
Early online date	15 Oct 2021
DOIs	https://doi.org/10.1002/epi4.12549
Publication status	E-pub ahead of print - 15 Oct 2021

Bibliographical note

© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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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10.1002/epi4.12549Licence: CC BY 4.0

The AMPA receptor antagonist perampanel suppresses epileptic activity in human
© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Final published version, 892 KBLicence: CC BY 4.0

Cite this

Brito Da Silva, A., Pennifold, J., Henley, B., Chatterjee, K., Bateman, D., Whittaker, R. W., Joshi, A., Kumar, H., Nicholson, C., Baker, M. R., Greenhill, S. D., Walsh, R., Seri, S., Jones, R. S. G., Woodhall, G. L., & Cunningham, M. O. (2021). The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia. Epilepsia Open. Advance online publication. https://doi.org/10.1002/epi4.12549

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title = "The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia",

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.",

keywords = "Epilepsy, focal cortical dysplasia, glutamate, perampanel, AMPA",

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

note = "{\textcopyright} 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Funding: This work has been supported by investigator-initiated grants from Eisai (MOC and GLW), Birmingham Children{\textquoteright}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).",

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Brito Da Silva, A, Pennifold, J, Henley, B, Chatterjee, K, Bateman, D, Whittaker, RW, Joshi, A, Kumar, H, Nicholson, C, Baker, MR, Greenhill, SD, Walsh, R, Seri, S, Jones, RSG, Woodhall, GL & Cunningham, MO 2021, 'The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia', Epilepsia Open. https://doi.org/10.1002/epi4.12549

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AU - Brito Da Silva, Anderson

AU - Pennifold, Jane

AU - Henley, Ben

AU - Chatterjee, Koustav

AU - Bateman, David

AU - Whittaker, Roger W.

AU - Joshi, Abhijit

AU - Kumar, Hrishikesh

AU - Nicholson, Claire

AU - Baker, Mark R.

AU - Greenhill, Stuart D.

AU - Walsh, Richard

AU - Seri, Stefano

AU - Jones, Roland S.g.

AU - Woodhall, Gavin L.

AU - Cunningham, Mark O.

N1 - © 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 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).

PY - 2021/10/15

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N2 - 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.

AB - 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.

KW - Epilepsy

KW - focal cortical dysplasia

KW - glutamate

KW - perampanel

KW - AMPA

UR - https://onlinelibrary.wiley.com/doi/10.1002/epi4.12549

U2 - 10.1002/epi4.12549

DO - 10.1002/epi4.12549

M3 - Article

SN - 2470-9239

JO - Epilepsia Open

JF - Epilepsia Open

ER -

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

Abstract

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Keywords

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