title: The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice.
abstract: 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 α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB 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.
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.forename: Frank
authors.initials: F
authors.lastname: Leypoldt
authors.forename: Jan
authors.initials: J
authors.lastname: Lewerenz
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkenmayer
authors.forename: Denise
authors.initials: D
authors.lastname: Orozco
authors.forename: Peter
authors.initials: P
authors.lastname: Ludewig
authors.forename: John
authors.initials: J
authors.lastname: Thundyil
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Christian
authors.initials: C
authors.lastname: Gerloff
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
authors.forename: Pamela
authors.initials: P
authors.lastname: Maher
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D020520:Brain Infarction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005419:Flavonoids; D044948:Flavonols; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C017875:fisetin