Neuronal damage by secretory phospholipase A2: modulation by cytosolic phospholipase A2, platelet-activating factor, and cyclooxygenase-2 in neuronal cells in culture.
Activation of cytosolic phospholipase A(2) (cPLA(2)) is an early event in brain injury, which leads to the formation and accumulation of bioactive lipids: platelet-activating factor (PAF), free arachidonic acid, and eicosanoids. A cross-talk between secretory PLA(2) (sPLA(2)) and cPLA(2) in neural signal transduction has previously been suggested (J Biol Chem 271:32722; 1996). Here we show, using neuronal cell cultures, an up-regulation of cPLA(2) expression and an inhibition by the selective cPLA(2) inhibitor AACOCF3 after exposure to neurotoxic concentrations of sPLA(2)-OS2. Pretreatment of neuronal cultures with recombinant PAF acetylhydrolase (rPAF-AH) or the presynaptic PAF receptor antagonist, BN52021, partially blocked neuronal cell death induced by sPLA(2)-OS2. Furthermore, selective COX-2 inhibitors ameliorated sPLA(2)-OS2-induced neurotoxicity. We conclude that sPLA(2)-OS2 activates a neuronal signaling cascade that includes activation of cPLA(2), arachidonic acid release, PAF production, and induction of COX-2.
Kolko
Miriam
M
Louisiana State University Health Sciences Center Neuroscience Center of Excellence, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA.
Rodriguez de Turco
Elena B
EB
Diemer
Nils H
NH
Bazan
Nicolas G
NG
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004224:Diterpenes; D004622:Embryo, Mammalian / Q000166:cytology; D004790:Enzyme Induction; D046934:Ginkgolides; D007527:Isoenzymes / Q000096:biosynthesis*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins / Q000494:pharmacology; D030162:Reptilian Proteins; D015854:Up-Regulation
D001095:Arachidonic Acids; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004224:Diterpenes; D046934:Ginkgolides; D007527:Isoenzymes; D007783:Lactones; D009498:Neurotoxins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D030162:Reptilian Proteins; C039351:platelet activating factor receptor; C081565:arachidonyltrifluoromethane; C045856:ginkgolide B; D007770:L-Lactate Dehydrogenase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; C073206:Oxyuranus scutellatus toxin 2; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase