P2X7 receptors on microglial cells mediate injury to cortical neurons in vitro
✍ Scribed by Stephen D. Skaper; Laura Facci; Ainsley A. Culbert; Nicholas A. Evans; Iain Chessell; John B. Davis; Jill C. Richardson
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 462 KB
- Volume
- 54
- Category
- Article
- ISSN
- 0894-1491
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✦ Synopsis
Abstract
The P2X~7~ receptor has been implicated in the release of cytokines and in the induction of cell death, and is up‐regulated in a transgenic mouse model of Alzheimer's disease. Using cocultures of rat cortical neurons and microglia, we show that ATP and the more potent P2X~7~ agonist benzoylbenzoyl‐ATP (BzATP) cause neuronal cell injury. The deleterious effects of BzATP‐treated microglia were prevented by nonselective P2X antagonists (PPADS and oxidized ATP) and by the more selective P2X~7~ antagonist Brilliant Blue G. Similar concentrations of BzATP caused release of superoxide and nitric oxide from isolated microglia, and neuronal cell injury was attenuated by a superoxide dismutase mimetic and by a peroxynitrite decomposition catalyst, suggesting a role for reactive oxide species. Cocultures composed of wild‐type cortical neurons, and microglia from P2X~7~ receptor‐deficient mice failed to exhibit neuronal cell injury in the presence of BzATP, but retained sensitivity to injury when microglia were derived from genotypically matched normal (P2X~7~^+/+^ mice), thereby establishing P2X~7~ involvement in the injury process. P2X~7~ receptor activation on microglia thus appears necessary for microglial‐mediated injury of neurons, and proposes that targeting P2X~7~ receptors may constitute a novel approach for the treatment of acute and chronic neurodegenerative disorders where a microglial component is evident. © 2006 Wiley‐Liss, Inc.