Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 44, Pages 43807-43817Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M305841200
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Funding
- NCRR NIH HHS [P20 RR016816] Funding Source: Medline
- NIA NIH HHS [AG18031] Funding Source: Medline
- NIDCR NIH HHS [P01 DE13499] Funding Source: Medline
- NIDDK NIH HHS [K01 DK060583-03] Funding Source: Medline
- NIGMS NIH HHS [GM38765] Funding Source: Medline
- NINDS NIH HHS [NS23002] Funding Source: Medline
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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.
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