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1.
J Med Chem ; 46(15): 3197-200, 2003 Jul 17.
Article in English | MEDLINE | ID: mdl-12852750
2.
J Biol Chem ; 278(15): 13309-17, 2003 Apr 11.
Article in English | MEDLINE | ID: mdl-12551918

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).


Subject(s)
Adenosine Triphosphate/analogs & derivatives , Alzheimer Disease/genetics , Microglia/physiology , Receptors, Purinergic P2/physiology , Superoxides/metabolism , Adenosine Triphosphate/pharmacology , Animals , Animals, Newborn , Calcium/physiology , Cerebral Cortex/physiology , Chromones/pharmacology , Disease Models, Animal , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Female , Humans , Kinetics , MAP Kinase Signaling System/physiology , Mice , Mice, Transgenic , Microglia/drug effects , Morpholines/pharmacology , NADPH Oxidases/metabolism , Neutrophils/physiology , Phosphoinositide-3 Kinase Inhibitors , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2X7 , Up-Regulation
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