Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 32, Issue 5, Pages 835-843Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2011.189
Keywords
fisetin; flavonoids; macrophages; microglia; stroke
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Funding
- AHA [075514Y]
- Landesexzellenzinitiative (LEXI) Hamburg
- DFG HO [3312/1-1]
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The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor alpha (TNF alpha) production. Fisetin also inhibited LPS-induced TNF alpha production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor kappa B activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 835-843; doi:10.1038/jcbfm.2011.189; published online 11 January 2012
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