Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage
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Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage. / Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Cavaliere, Fabio; Magnus, Tim; Nolte, Friedrich; Scemes, Eliana; Pérez-Samartín, Alberto; Matute, Carlos.
in: J CEREBR BLOOD F MET, Jahrgang 35, Nr. 5, 05.2015, S. 843-50.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage
AU - Cisneros-Mejorado, Abraham
AU - Gottlieb, Miroslav
AU - Cavaliere, Fabio
AU - Magnus, Tim
AU - Nolte, Friedrich
AU - Scemes, Eliana
AU - Pérez-Samartín, Alberto
AU - Matute, Carlos
PY - 2015/5
Y1 - 2015/5
N2 - 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.
AB - 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.
KW - Animals
KW - Brain
KW - Brain Ischemia
KW - Cell Death
KW - Cell Hypoxia
KW - Cells, Cultured
KW - Connexins
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - Nerve Tissue Proteins
KW - Neurons
KW - Purinergic P2X Receptor Antagonists
KW - Rats
KW - Receptors, Purinergic P2X7
KW - Signal Transduction
U2 - 10.1038/jcbfm.2014.262
DO - 10.1038/jcbfm.2014.262
M3 - SCORING: Journal article
C2 - 25605289
VL - 35
SP - 843
EP - 850
JO - J CEREBR BLOOD F MET
JF - J CEREBR BLOOD F MET
SN - 0271-678X
IS - 5
ER -