title: Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage.
abstract: The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to ~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise.
authors.affiliation: Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa, Spain.
authors.forename: Abraham
authors.initials: A
authors.lastname: Cisneros-Mejorado
authors.affiliation: 1] Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa, Spain [2] Institute of Neurobiology, Slovak Academy of Sciences, Kosice, Slovak Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Gottlieb
authors.affiliation: 1] Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa, Spain [2] Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, Zamudio, Spain.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cavaliere
authors.affiliation: Department of Neurology, University Hospital Hamburg, Hamburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.affiliation: Department of Immunology, University Hospital, Hamburg, Hamburg, Germany.
authors.forename: Friederich
authors.initials: F
authors.lastname: Koch-Nolte
authors.affiliation: Dominick P. Purpura Department of Neurosciences, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Eliana
authors.initials: E
authors.lastname: Scemes
authors.affiliation: 1] Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa, Spain [2] Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, Zamudio, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Samartín
authors.affiliation: 1] Achucarro Basque Center for Neuroscience, Departamento de Neurociencias and CIBERNED, Universidad del País Vasco (UPV/EHU), Leioa, Spain [2] Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, Zamudio, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D017630:Connexins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C479936:pannexin 1, rat