Abstract
Primary rat microglia stimulated with either ATP or 2'- and 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) release copious amounts of superoxide (O(2)(-)*). ATP and BzATP stimulate O(2)(-)* production through purinergic receptors, primarily the P2X(7) receptor. O(2)(-)* is produced through the activation of the NADPH oxidase. Although both p42/44 MAPK and p38 MAPK were activated rapidly in cells stimulated with BzATP, only pharmacological inhibition of p38 MAPK attenuated O(2)(-)* production. Furthermore, an inhibitor of phosphatidylinositol 3-kinase attenuated O(2)(-)* production to a greater extent than an inhibitor of p38 MAPK. Both ATP and BzATP stimulated microglia-induced cortical cell death indicating this pathway may contribute to neurodegeneration. Consistent with this hypothesis, P2X(7) receptor was specifically up-regulated around beta-amyloid plaques in a mouse model of Alzheimer's disease (Tg2576).
MeSH terms
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Adenosine Triphosphate / analogs & derivatives*
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Adenosine Triphosphate / pharmacology
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Alzheimer Disease / genetics*
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Animals
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Animals, Newborn
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Calcium / physiology
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Cerebral Cortex / physiology
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Chromones / pharmacology
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Disease Models, Animal
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Embryo, Mammalian
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Kinetics
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MAP Kinase Signaling System / physiology
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Mice
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Mice, Transgenic
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Microglia / drug effects
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Microglia / physiology*
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Morpholines / pharmacology
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NADPH Oxidases / metabolism
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Neutrophils / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Pregnancy
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Rats
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Rats, Sprague-Dawley
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Receptors, Purinergic P2 / physiology*
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Receptors, Purinergic P2X7
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Superoxides / metabolism*
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Up-Regulation
Substances
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Chromones
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Enzyme Inhibitors
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Morpholines
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P2RX7 protein, human
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P2rx7 protein, mouse
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P2rx7 protein, rat
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Purinergic P2
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Receptors, Purinergic P2X7
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Superoxides
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
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Adenosine Triphosphate
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NADPH Oxidases
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Calcium