P2X 7 receptors on microglial cells mediate injury to cortical neurons in vitro

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.