title: P2X7 receptors mediate ischemic damage to oligodendrocytes.
abstract: Brain ischemia leading to stroke is a major cause of disability in developed countries. Therapeutic strategies have most commonly focused on protecting neurons from ischemic damage. However, ischemic damage to white matter causes oligodendrocyte death, myelin disruption, and axon dysfunction, and it is partially mediated by glutamate excitotoxicity. We have previously demonstrated that oligodendrocytes express ionotropic purinergic receptors. The objective of this study was to investigate the role of purinergic signaling in white matter ischemia. We show that, in addition to glutamate, enhanced ATP signaling during ischemia is also deleterious to oligodendrocytes and myelin, and impairs white matter function. Thus, ischemic oligodendrocytes in culture display an inward current and cytosolic Ca(2+) overload, which is partially mediated by P2X7 receptors. Indeed, oligodendrocytes release ATP after oxygen and glucose deprivation through the opening of pannexin hemichannels. Consistently, ischemia-induced mitochondrial depolarization as well as oxidative stress culminating in cell death are partially reversed by P2X7 receptor antagonists, by the ATP degrading enzyme apyrase and by blockers of pannexin hemichannels. In turn, ischemic damage in isolated optic nerves, which share the properties of brain white matter, is greatly attenuated by all these drugs. Ultrastructural analysis and electrophysiological recordings demonstrated that P2X7 antagonists prevent ischemic damage to oligodendrocytes and myelin, and improved action potential recovery after ischemia. These data indicate that ATP released during ischemia and the subsequent activation of P2X7 receptor is critical to white matter demise during stroke and point to this receptor type as a therapeutic target to limit tissue damage in cerebrovascular diseases.
authors.affiliation: Centro de Investigaciones Biomédicas en Red Enfermedades Neurodegenerativas (CIBERNED) and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Domercq
authors.forename: Alberto
authors.initials: A
authors.lastname: Perez-Samartin
authors.forename: David
authors.initials: D
authors.lastname: Aparicio
authors.forename: Elena
authors.initials: E
authors.lastname: Alberdi
authors.forename: Olatz
authors.initials: O
authors.lastname: Pampliega
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009900:Optic Nerve / Q000166:cytology; D018917:Optic Neuropathy, Ischemic / Q000378:metabolism* / Q000473:pathology*; D018408:Patch-Clamp Techniques / Q000379:methods; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7
chemical_list: C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D017630:Connexins; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; C546470:P2rx7 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D017382:Reactive Oxygen Species; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C479936:pannexin 1, rat; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C017199:2',3'-dialdehyde ATP; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D002118:Calcium