P2X7 Receptors Mediate Ischemic Damage to Oligodendrocytes
P2X7 Receptors Mediate Ischemic Damage to Oligodendrocytes
复制标题
DOI：
10.1002/glia.20958
复制
发表时间：
2010-04-15
期刊：
影响因子：
6.2
通讯作者：
Matute, Carlos
中科院分区：
文献类型：
--
作者：
Domercq, Maria;Perez-Samartin, Alberto;Matute, Carlos
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性损伤。然而，白色物质的缺血性损伤引起少突胶质细胞死亡、髓鞘破坏和轴突功能障碍，并且其部分由谷氨酸兴奋性毒性介导。我们以前已经证明，少突胶质细胞表达离子型嘌呤受体。本研究的目的是探讨嘌呤能信号在白色物质缺血中的作用。我们发现，除了谷氨酸，缺血期间增强的ATP信号也对少突胶质细胞和髓鞘有害，并损害白色物质功能。因此，缺血性少突胶质细胞在培养中显示内向电流和胞质Ca 2+超载，这部分是由P2 X7受体介导的。事实上，少突胶质细胞通过开放泛连接蛋白半通道在氧和葡萄糖剥夺后释放ATP。一致的是，缺血诱导的线粒体去极化以及氧化应激最终导致细胞死亡部分逆转P2 X7受体拮抗剂，ATP降解酶腺苷三磷酸双磷酸酶和泛连接蛋白半通道阻滞剂。反过来，所有这些药物都大大减弱了具有脑白色物质特性的孤立视神经的缺血性损伤。超微结构分析和电生理记录表明，P2 X7拮抗剂防止缺血性损伤少突胶质细胞和髓鞘，并改善缺血后的动作电位恢复。这些数据表明，在缺血期间释放的ATP和随后的P2 X7受体的激活对于中风期间的白色物质死亡是至关重要的，并且指出这种受体类型作为限制脑血管疾病中的组织损伤的治疗靶点。(C)2009威利-利斯公司
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 Ca2+ 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. (C) 2009 Wiley-Liss, Inc.