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Neuronal oxidative damage from activated innate immunity is EP 2 receptor‐dependent
Author(s) -
Montine Thomas J.,
Milatovic Dejan,
Gupta Ramesh C.,
ValyiNagy Tibor,
Morrow Jason D.,
Breyer Richard M.
Publication year - 2002
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 - 10.1046/j.1471-4159.2002.01157.x
Subject(s) - innate immune system , lipopolysaccharide , receptor , oxidative phosphorylation , arachidonic acid , nitric oxide , chemistry , pharmacology , docosahexaenoic acid , oxidative stress , medicine , endocrinology , biology , biochemistry , fatty acid , polyunsaturated fatty acid , enzyme
Increase in prostaglandin (PG) E 2 levels and oxidative damage are associated with diseases of brain that involve activation of innate immunity. We tested the hypothesis that cerebral oxidative damage resulting from activation of innate immunity with intracerebroventricular (icv) lipopolysaccharide (LPS) is dependent on PGE 2 ‐mediated signaling. We measured two quantitative in vivo biomarkers of lipid peroxidation: F 2 ‐isoprostanes (IsoPs) that derive from arachidonic acid (AA) that is uniformly distributed in all cell types in brain, and F 4 ‐neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is highly concentrated in neuronal membranes. LPS stimulated delayed elevations in cerebral F 2 ‐IsoPs and F 4 ‐NeuroPs that were completely suppressed by indomethacin or ibuprofen pre‐treatment. LPS‐induced cerebral oxidative damage was abolished by disruption of subtype 2 receptor for PGE 2 (EP 2 ). In contrast, initial oxidative damage from icv kainic acid (KA) was more rapid than with LPS also was completely suppressed by indomethacin or ibuprofen pre‐treatment but was independent of EP 2 receptor activation. The protective effect of deleting the EP 2 receptor was not associated with changes in cerebral eicosaniod production, but was partially related to reduced induction of nitric oxide synthase (NOS) activity. These results suggest the EP 2 receptor as a therapeutic target to limit oxidative damage from activation of innate immunity in cerebrum.