Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models

The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treat...

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Autores principales: Fischer, Wolfgang, Franke, Heike, Krügel, Ute, Müller, Heiko, Dinkel, Klaus, Lord, Brian, Letavic, Michael A., Henshall, David C., Engel, Tobias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900628/
https://www.ncbi.nlm.nih.gov/pubmed/27281030
http://dx.doi.org/10.1371/journal.pone.0156468
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author Fischer, Wolfgang
Franke, Heike
Krügel, Ute
Müller, Heiko
Dinkel, Klaus
Lord, Brian
Letavic, Michael A.
Henshall, David C.
Engel, Tobias
author_facet Fischer, Wolfgang
Franke, Heike
Krügel, Ute
Müller, Heiko
Dinkel, Klaus
Lord, Brian
Letavic, Michael A.
Henshall, David C.
Engel, Tobias
author_sort Fischer, Wolfgang
collection PubMed
description The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.
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spelling pubmed-49006282016-06-24 Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models Fischer, Wolfgang Franke, Heike Krügel, Ute Müller, Heiko Dinkel, Klaus Lord, Brian Letavic, Michael A. Henshall, David C. Engel, Tobias PLoS One Research Article The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders. Public Library of Science 2016-06-09 /pmc/articles/PMC4900628/ /pubmed/27281030 http://dx.doi.org/10.1371/journal.pone.0156468 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Fischer, Wolfgang
Franke, Heike
Krügel, Ute
Müller, Heiko
Dinkel, Klaus
Lord, Brian
Letavic, Michael A.
Henshall, David C.
Engel, Tobias
Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models
title Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models
title_full Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models
title_fullStr Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models
title_full_unstemmed Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models
title_short Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models
title_sort critical evaluation of p2x7 receptor antagonists in selected seizure models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900628/
https://www.ncbi.nlm.nih.gov/pubmed/27281030
http://dx.doi.org/10.1371/journal.pone.0156468
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