Centro de Investigaciones Biomédicas en Red Enfermedades Neurodegenerativas (CIBERNED) and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain.
Glia. 2010 Apr 15;58(6):730-40. doi: 10.1002/glia.20958.
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.
脑缺血导致中风是发达国家残疾的主要原因。治疗策略通常集中在保护神经元免受缺血损伤上。然而，缺血对白质的损伤导致少突胶质细胞死亡、髓鞘破坏和轴突功能障碍，部分由谷氨酸兴奋性毒性介导。我们之前已经证明，少突胶质细胞表达离子型嘌呤能受体。本研究的目的是研究嘌呤能信号在白质缺血中的作用。我们表明，除了谷氨酸外，缺血期间增强的 ATP 信号也对少突胶质细胞和髓鞘有害，并损害白质功能。因此，培养中的缺血性少突胶质细胞显示出内向电流和细胞溶质 Ca(2+)超载，这部分是由 P2X7 受体介导的。事实上，少突胶质细胞在缺氧和葡萄糖剥夺后通过打开连接蛋白半通道释放 ATP。一致地，缺血诱导的线粒体去极化以及导致细胞死亡的氧化应激部分被 P2X7 受体拮抗剂、ATP 降解酶 apyrase 和连接蛋白半通道阻断剂逆转。反过来，这些药物大大减轻了在孤立的视神经中诱导的缺血性损伤，视神经具有与脑白质相同的特性。超微结构分析和电生理记录表明，P2X7 拮抗剂可防止缺血性少突胶质细胞和髓鞘损伤，并改善缺血后动作电位的恢复。这些数据表明，缺血期间释放的 ATP 和随后激活的 P2X7 受体对中风期间白质死亡至关重要，并将该受体类型作为限制脑血管疾病组织损伤的治疗靶点。
