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

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

5 Citations (SciVal)

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, noncompetitive 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
Pages (from-to)	488-495
Number of pages	8
Journal	Epilepsia Open
Volume	7
Issue number	3
Early online date	11 May 2022
DOIs	https://doi.org/10.1002/epi4.12549
Publication status	Published - 30 Sept 2022

Bibliographical note

Funding Information:
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). Editorial support, under the direction of the authors, was provided by Stephanie Agbu, PhD, of CMC AFFINITY, a division of Complete Medical Communications Inc, Hackensack, NJ, USA, funded by Eisai Inc, in accordance with Good Publication Practice (GPP3) guidelines.

Funding Information:
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). Editorial support, under the direction of the authors, was provided by Stephanie Agbu, PhD, of CMC AFFINITY, a division of Complete Medical Communications Inc, Hackensack, NJ, USA, funded by Eisai Inc, in accordance with Good Publication Practice (GPP3) guidelines.

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

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). Editorial support, under the direction of the authors, was provided by Stephanie Agbu, PhD, of CMC AFFINITY, a division of Complete Medical Communications Inc, Hackensack, NJ, USA, funded by Eisai Inc, in accordance with Good Publication Practice (GPP3) guidelines.

Keywords

AMPA
epilepsy
focal cortical dysplasia
glutamate
perampanel

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/epi4.12549Licence: CC BY

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, MO. (2022). The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia. Epilepsia Open, 7(3), 488-495. https://doi.org/10.1002/epi4.12549

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 2022, 'The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia', Epilepsia Open, vol. 7, no. 3, pp. 488-495. 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, noncompetitive 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.",

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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 Mark O Cunningham",

note = "Funding Information: 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). Editorial support, under the direction of the authors, was provided by Stephanie Agbu, PhD, of CMC AFFINITY, a division of Complete Medical Communications Inc, Hackensack, NJ, USA, funded by Eisai Inc, in accordance with Good Publication Practice (GPP3) guidelines. Funding Information: 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). Editorial support, under the direction of the authors, was provided by Stephanie Agbu, PhD, of CMC AFFINITY, a division of Complete Medical Communications Inc, Hackensack, NJ, USA, funded by Eisai Inc, in accordance with Good Publication Practice (GPP3) guidelines. Publisher Copyright: {\textcopyright} 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",

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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

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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, noncompetitive 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.

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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