Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression.
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.
Marcheselli
Victor L
VL
Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Hong
Song
S
Lukiw
Walter J
WJ
Tian
Xiao Hua
XH
Gronert
Karsten
K
Musto
Alberto
A
Hardy
Mattie
M
Gimenez
Juan M
JM
Chiang
Nan
N
Serhan
Charles N
CN
Bazan
Nicolas G
NG
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000473:pathology; D051546:Cyclooxygenase 2; D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation; D008565:Membrane Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D015427:Reperfusion Injury; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D004281:Docosahexaenoic Acids; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin