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Early release of arachidonic acid prevents an otherwise immediate formation of toxic levels of peroxynitrite in astrocytes stimulated with lipopolysaccharide/interferon‐γ
Author(s) -
Palomba Letizia,
Amadori Alessandra,
Cantoni Orazio
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04793.x
Subject(s) - peroxynitrite , nitric oxide synthase , nitric oxide , superoxide , chemistry , arachidonic acid , nadph oxidase , lipopolysaccharide , biochemistry , microbiology and biotechnology , biology , oxidative stress , immunology , enzyme , organic chemistry
Addition of bacterial lipopolysaccharides (LPS) and interferon‐γ (IFN‐γ) to rat astrocytes in primary culture promotes an early release of arachidonic acid (ARA) associated with an immediate inhibition of neuronal nitric oxide synthase (nNOS). Preventing the release of constitutive nitric oxide (NO) is indeed critical for activation of the nuclear factor kappa B, and for the expression of inducible nitric oxide synthase responsible for the formation of large amounts of NO. LPS/IFN‐γ also promotes an early release of superoxide, via activation of NADPH oxidase, but the generation of peroxynitrite (ONOO − ) is prevented by the different timing of superoxide (minutes) and NO (hours) formation. Upstream inhibition of the ARA‐dependent nNOS inhibitory signaling, however, caused the parallel release of superoxide and constitutive NO, thereby leading to formation of ONOO − levels triggering loss of ATP and mitochondrial membrane potential followed by the mitochondrial release of cytochrome c , activation of caspase 3 and morphological evidence of apoptosis. Nanomolar levels of exogenous ARA prevented all these events via inhibition of early ONOO − formation. Thus, the ARA‐dependent nNOS inhibition observed in astrocytes exposed to pro‐inflammatory stimuli, as LPS/IFN‐γ, is critical for both the expression of nuclear factor kappa B‐dependent genes and for survival.