Arachidonic acid: a key molecule for astrocyte survival to peroxynitrite.
Nontoxic concentrations of peroxynitrite (ONOO(-)) nevertheless commit rat astrocytes to mitochondrial permeability transition-dependent toxicity, however prevented by a signaling response driven by arachidonic acid (ARA). The lipid messenger was released upon ONOO(-)-dependent activation of cytosolic phospholipase A(2) and its pharmacological inhibition, or knock-down, was invariably associated with a prompt apoptotic response sensitive to exogenous ARA, but insensitive to other polyunsaturated fatty acids, as eicosapentaenoic or linoleic acid. Interestingly, while microglia also used ARA to cope with ONOO(-), cerebellar granule cells were killed by the same concentrations of ONOO(-) employed in astrocyte/microglia experiments via a mechanism sensitive to inhibition of ARA release. These results collectively support the notion that resistance of glial cells to ONOO(-), a species extensively produced under neuroinflammatory conditions, is largely based on a critical survival signaling triggered by the inflammatory product ARA. In remarkable contrast with these results, the lipid messenger appears to mediate toxicity in neuronal cells.
Palomba
Letizia
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Istituto di Farmacologia e Farmacognosia, Università di Urbino Carlo Bo, Urbino (PU), Italy.
Cerioni
Liana
L
Cantoni
Orazio
O
D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014162:Transfection / Q000379:methods
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D020319:Oligodeoxyribonucleotides, Antisense; C081565:arachidonyltrifluoromethane; D030421:Peroxynitrous Acid; D016718:Arachidonic Acid; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D054467:Phospholipases A2; D053148:Caspase 3; C007740:fluorexon