Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.

Abstract

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, NFkappaB, 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-beta-induced NFkappaB 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.

• Authors: Victor L Marcheselli, Song Hong, Walter J Lukiw, Xiao Hua Tian, Karsten Gronert, Alberto Musto, Mattie Hardy, Juan M Gimenez, Nan Chiang, Charles N Serhan, Nicolas G Bazan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 44 Pg. 43807-17 (Oct 31 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12923200 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Interleukin-1
• Isoenzymes
• Membrane Proteins
• NF-kappa B
• Docosahexaenoic Acids
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Aspirin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Aspirin (pharmacology)
• Brain (pathology)
• Cells, Cultured
• Cerebral Arteries (pathology)
• Cyclooxygenase 2
• Docosahexaenoic Acids (chemistry, pharmacology)
• Hippocampus (metabolism)
• Humans
• Immunohistochemistry
• Interleukin-1 (metabolism)
• Isoenzymes (metabolism)
• Leukocytes (metabolism, pathology)
• Lipid Peroxidation
• Membrane Proteins
• Mice
• Microscopy, Fluorescence
• Models, Chemical
• NF-kappa B (metabolism)
• Neurons (metabolism)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Reperfusion Injury
• Signal Transduction
• Stem Cells (metabolism)
• Time Factors