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. © 2009 Wiley‐Liss, Inc.