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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2016
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Materias: | |
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. |
format | Online Article Text |
id | pubmed-4900628 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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