Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-mediated Leukocyte Infiltration and Pro-inflammatory Gene Expression

• Published in: The Journal of biological chemistry Vol. 278; no. 44; pp. 43807 - 43817
• Main Authors: Marcheselli, Victor L., Hong, Song, Lukiw, Walter J., Tian, Xiao Hua, Gronert, Karsten, Musto, Alberto, Hardy, Mattie, Gimenez, Juan M., Chiang, Nan, Serhan, Charles N., Bazan, Nicolas G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.10.2003; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aspirin - pharmacology; Brain - pathology; Cells, Cultured; Cerebral Arteries - pathology; Cyclooxygenase 2; Docosahexaenoic Acids - chemistry; Docosahexaenoic Acids - pharmacology; docosanoids; Hippocampus - metabolism; Humans; Immunohistochemistry; Interleukin-1 - metabolism; Isoenzymes - metabolism; Leukocytes - metabolism; Leukocytes - pathology; Lipid Peroxidation; Medicin och hälsovetenskap; Membrane Proteins; Mice; Microscopy, Fluorescence; Models, Chemical; Neurons - metabolism; NF-kappa B - metabolism; Prostaglandin-Endoperoxide Synthases - metabolism; Reperfusion Injury; Signal Transduction; Stem Cells - metabolism; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M305841200

Ischemic stroke triggers lipid peroxidation and neuronal injury. Docosahexaenoic acid released from membrane phospholipids during brain ischemia is a major source of lipid peroxides. Leukocyte infiltration and pro-inflammatory gene expression also contribute to stroke damage. In this study using lipidomic analysis, we have identified stereospecific messengers from docosahexaenoate-oxygenation pathways in a mouse stroke model. Aspirin, widely used to prevent cerebrovascular disease, activates an additional pathway, which includes the 17R-resolvins. The newly discovered brain messenger 10,17S-docosatriene potently inhibited leukocyte infiltration, NFκB, and cyclooxygenase-2 induction in experimental stroke and elicited neuroprotection. In addition, in neural cells in culture, this lipid messenger also inhibited both interleukin 1-β-induced NFκB activation and cyclooxygenase-2 expression. Thus, the specific novel bioactive docosanoids generated in vivo counteract leukocyte-mediated injury as well as pro-inflammatory gene induction. These results challenge the view that docosahexaenoate only participates in brain damage and demonstrate that this fatty acid is also the endogenous precursor to a neuroprotective signaling response to ischemia-reperfusion.