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
|