P2X7 receptors mediate ischemic damage to oligodendrocytes
Maria Domercq1, Alberto Perez-Samartin, David Aparicio
1Centro de Investigaciones Biomédicas en Red Enfermedades Neurodegenerativas (CIBERNED) and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain.
Glia
|December 24, 2009
Summary
Enhanced ATP signaling damages oligodendrocytes and white matter during stroke. Blocking P2X7 receptors and pannexin hemichannels protects against this ischemic damage, offering new therapeutic targets for cerebrovascular diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Stroke-induced brain ischemia causes significant disability, with current therapies focusing on neuronal protection.
- White matter damage, including oligodendrocyte death and myelin disruption, contributes to ischemic injury and is partly mediated by glutamate excitotoxicity.
- Oligodendrocytes express ionotropic purinergic receptors, suggesting a role for purinergic signaling in white matter ischemia.
Purpose of the Study:
- To investigate the role of purinergic signaling in white matter ischemia.
- To determine if adenosine triphosphate (ATP) signaling contributes to oligodendrocyte and myelin damage during ischemia.
- To explore P2X7 receptors as potential therapeutic targets for white matter protection in stroke.
Main Methods:
- Cultured oligodendrocytes were subjected to oxygen and glucose deprivation to mimic ischemic conditions.
- ATP release was measured, and its effects on oligodendrocyte function (inward currents, Ca(2+) overload) were assessed.
- P2X7 receptor antagonists, apyrase (ATP-degrading enzyme), and pannexin hemichannel blockers were used to evaluate their protective effects.
- Experiments were conducted on isolated optic nerves to assess white matter function and damage in vivo.
- Ultrastructural analysis and electrophysiological recordings were used to evaluate myelin integrity and nerve function.
Main Results:
- Ischemia induced ATP release from oligodendrocytes via pannexin hemichannels, leading to P2X7 receptor activation.
- Enhanced ATP signaling and P2X7 receptor activation caused inward currents, cytosolic Ca(2+) overload, mitochondrial depolarization, and oxidative stress in oligodendrocytes.
- P2X7 receptor antagonists, apyrase, and pannexin hemichannel blockers significantly reversed ischemia-induced damage in cultured oligodendrocytes and isolated optic nerves.
- These interventions preserved oligodendrocyte and myelin integrity and improved action potential recovery after ischemia.
- Ultrastructural and electrophysiological data confirmed the protective effects of blocking P2X7 receptors.
Conclusions:
- Enhanced ATP signaling, mediated by P2X7 receptor activation, plays a critical role in white matter damage during brain ischemia.
- Oligodendrocytes release ATP during ischemia, contributing to their own demise and myelin disruption.
- Targeting P2X7 receptors and pannexin hemichannels represents a promising therapeutic strategy to mitigate white matter injury in stroke and other cerebrovascular diseases.
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