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The ATP-gated P2X7 receptor contributes to the development of drug-resistant status epilepticus in mice
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  • Edward Beamer,
  • James Morgan,
  • Mariana Alves,
  • Aida Menendez Mendez,
  • Gareth Morris,
  • Bela Zimmer,
  • Giorgia Conte,
  • Laura de Diego-Garcia,
  • Nico Ka Yiu Ng,
  • Stephen Madden,
  • Francesco Calzaferri,
  • Cristobal de los Rios,
  • Antonio Garcia,
  • Michael Hamacher,
  • Klaus Dinkel,
  • Pablo Pelegrin,
  • David Henshall,
  • Annette Nicke,
  • Tobias Engel
Edward Beamer
Nottingham Trent University

Corresponding Author:[email protected]

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James Morgan
University of Manchester Institute of Science and Technology Department of Biomolecular Science
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Mariana Alves
Royal College of Surgeons in Ireland
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Aida Menendez Mendez
Royal College of Surgeons in Ireland
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Gareth Morris
Royal College of Surgeons in Ireland
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Bela Zimmer
Ludwig-Maximilians-Universit√§t M√ľnchen
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Giorgia Conte
Royal College of Surgeons in Ireland
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Laura de Diego-Garcia
Royal College of Surgeons in Ireland
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Nico Ka Yiu Ng
Royal College of Surgeons in Ireland
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Stephen Madden
RCSI
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Francesco Calzaferri
Universidad Autonoma de Madrid
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Cristobal de los Rios
Universidad Autonoma de Madrid
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Antonio Garcia
Universidad Autonoma de Madrid
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Michael Hamacher
Affectis Pharmaceuticals AG
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Klaus Dinkel
Lead Discovery Center GmbH
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Pablo Pelegrin
Hospital Virgen Arrixaca-FFIS
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David Henshall
Royal College of Surgeons in Ireland
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Annette Nicke
LMU Munich, Faculty of Medicine
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Tobias Engel
Royal College of Surgeons in Ireland
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Abstract

Background and Purpose Refractory status epilepticus is a clinical emergency associated with high mortality and morbidity. Increasing evidence suggests neuroinflammatory pathways contribute to the development of drug-refractoriness during status epilepticus. The ATP-gated P2X7 receptor (P2X7R) has been described as potential link between inflammation and increased hyperexcitability. The aim of the present study was to determine the contribution of the P2X7R to drug-refractory status epilepticus and its therapeutic potential. Experimental Approach Status epilepticus was induced via a unilateral microinjection of kainic acid into the amygdala in adult mice. Severity of status epilepticus was compared in animals overexpressing or knock-out in the P2X7R, after inflammatory priming by the pre-injection of bacterial lipopolysaccharide (LPS) and in mice treated with P2X7R-targeting and anti-inflammatory drugs. Key Results P2X7R overexpressing mice were unresponsive to several anticonvulsants (lorazepam, midazolam, phenytoin and carbamazepine) during status epilepticus. P2X7R expression was increased in microglia during drug-refractory status epilepticus, P2X7R overexpression led to a pro-inflammatory phenotype in microglia during status epilepticus and the anti-inflammatory drug minocycline restored normal responsiveness to anticonvulsants in P2X7R overexpressing mice. Pre-treatment of wildtype mice with LPS increased P2X7R levels in the brain and promoted the development of pharmaco-resistant status epilepticus, which was overcome by either a genetic deletion of the P2X7R or the administration of the P2X7R antagonists AFC-5128 or ITH15004. Conclusion and Implications Our results demonstrate that P2X7R-induced pro-inflammatory effects contribute to resistance to pharmacotherapy during status epilepticus and suggest therapies targeting the P2X7R as novel adjunctive treatments for drug-refractory status epilepticus.
28 Aug 2021Submitted to British Journal of Pharmacology
30 Aug 2021Submission Checks Completed
30 Aug 2021Assigned to Editor
09 Sep 2021Reviewer(s) Assigned
21 Sep 2021Review(s) Completed, Editorial Evaluation Pending
29 Sep 2021Editorial Decision: Revise Minor
29 Nov 20211st Revision Received
01 Dec 2021Submission Checks Completed
01 Dec 2021Assigned to Editor
02 Dec 2021Reviewer(s) Assigned
06 Dec 2021Review(s) Completed, Editorial Evaluation Pending
14 Dec 2021Editorial Decision: Accept