Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent.

Montine TJ, Milatovic D, Gupta RC, Valyi-Nagy T, Morrow JD, Breyer RM
J Neurochem. 2002 83 (2): 463-70

PMID: 12423256 · DOI:10.1046/j.1471-4159.2002.01157.x

Increase in prostaglandin (PG) E2 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 PGE2-mediated signaling. We measured two quantitative in vivo biomarkers of lipid peroxidation: F2-isoprostanes (IsoPs) that derive from arachidonic acid (AA) that is uniformly distributed in all cell types in brain, and F4-neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is highly concentrated in neuronal membranes. LPS stimulated delayed elevations in cerebral F2-IsoPs and F4-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 PGE2 (EP2). 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 EP2 receptor activation. The protective effect of deleting the EP2 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 EP2 receptor as a therapeutic target to limit oxidative damage from activation of innate immunity in cerebrum.

MeSH Terms (24)

Animals Anti-Inflammatory Agents, Non-Steroidal Autoimmune Diseases of the Nervous System Biomarkers Brain Chemistry Citrulline Disease Models, Animal Docosahexaenoic Acids F2-Isoprostanes Immunity, Innate Isoprostanes Kainic Acid Lipid Peroxidation Lipopolysaccharides Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Neurons Oxidation-Reduction Oxidative Stress Receptors, Prostaglandin E Receptors, Prostaglandin E, EP2 Subtype

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