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.
Skaper
Stephen D
SD
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, Essex, United Kingdom. Stephen_D_Skaper@gsk.com
Facci
Laura
L
Culbert
Ainsley A
AA
Evans
Nicholas A
NA
Chessell
Iain
I
Davis
John B
JB
Richardson
Jill C
JC
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000196:embryology / Q000293:injuries*; D018920:Coculture Techniques; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D013481:Superoxides / Q000378:metabolism
C546469:P2rx7 protein, mouse; C546470:P2rx7 protein, rat; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013481:Superoxides; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase