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 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.
Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany.
Wolfgang
W
Fischer
Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany.
Heike
H
Franke
Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany.
Ute
U
Krügel
Lead Discovery Center GmbH, Dortmund, Germany.
Heiko
H
Müller
Lead Discovery Center GmbH, Dortmund, Germany.|Affectis Pharmaceutical AG, Dortmund, Germany.
Klaus
K
Dinkel
Neuroscience Therapeutic Area, Janssen Research & Development, LLC, San Diego, California, United States of America.
Brian
B
Lord
Neuroscience Therapeutic Area, Janssen Research & Development, LLC, San Diego, California, United States of America.
Michael A
MA
Letavic
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
David C
DC
Henshall
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Tobias
T
Engel
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D058920:Purinergic P2X Receptor Antagonists / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*
D000927:Anticonvulsants; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7