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.

Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion

“…Inflammation and tissue trauma may entail high extracellular ATP concentrations [2] and trigger the activation of P2X7 [3]. Subsequent Ca 2+ entry may cause neuronal and oligodendrocyte cell death [4,5], but activation of P2X7 has also been shown to induce microglia proliferation [6]. Consistently, the receptor is involved in pathophysiological events following ischemic brain damage, but studies to clarify its exact role yielded inconsistent results.…”

Intertwining extracellular nucleotides and their receptors with Ca2+in determining adult neural stem cell survival, proliferation and final fate

“…P2X7R overactivation opens the non-selective channel pannexin1 (Panx1), which becomes permeable to ATP, allowing massive calcium entry into cells, thus contributing to cell death [100]. OPC cultures exhibit high sensitivity to oxygen-glucose deprivation (OGD) toxicity, which can be attenuated by Brilliant Blue G (BBG), a P2X7R-preferring antagonist [101]. In SCI, high levels of extracellular ATP in spinal cord resulted in massive cell death, whereas the P2X7R antagonist oxidized ATP (oATP) significantly diminished death of OPCs in both grey and white matter [102].…”

Oligodendrocyte Fate after Spinal Cord Injury

“…ATP is elevated within 2 h after SCI and is likely released by multiple cell types, including OLs [17,19]. Both glutamate and ATP lead to calcium overload, which can trigger multiple intracellular pathways leading to cell demise [19,20].…”

“…ATP is elevated within 2 h after SCI and is likely released by multiple cell types, including OLs [17,19]. Both glutamate and ATP lead to calcium overload, which can trigger multiple intracellular pathways leading to cell demise [19,20]. In addition, cytokines such as tumor necrosis factor-α and interleukin (IL)-1β, which are up-regulated within minutes after SCI [21,22], can exacerbate excitotoxicity by impairing glutamate uptake [23].…”