title: Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke.
abstract: Targeting newly identified damage pathways in the ischemic brain can help to circumvent the currently severe limitations of acute stroke therapy. Here we show that the activity of 12/15-lipoxygenase was increased in the ischemic mouse brain, and 12/15-lipoxygenase colocalized with a marker for oxidized lipids, MDA2. This colocalization was also detected in the brain of 2 human stroke patients, where it also coincided with increased apoptosis-inducing factor. A novel inhibitor of 12/15-lipoxygenase, LOXBlock-1, protected neuronal HT22 cells against oxidative stress. In a mouse model of transient focal ischemia, the inhibitor reduced infarct sizes both 24 hours and 14 days poststroke, with improved behavioral parameters. Even when treatment was delayed until at least 4 hours after onset of ischemia, LOXBlock-1 was protective. Furthermore, it reduced tissue plasminogen activator-associated hemorrhage in a clot model of ischemia/reperfusion. This study establishes inhibition of 12/15-lipoxygenase as a viable strategy for first-line stroke treatment.
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
authors.forename: Kazim
authors.initials: K
authors.lastname: Yigitkanli
authors.forename: Anton
authors.initials: A
authors.lastname: Pekcec
authors.forename: Hulya
authors.initials: H
authors.lastname: Karatas
authors.forename: Stefanie
authors.initials: S
authors.lastname: Pallast
authors.forename: Emiri
authors.initials: E
authors.lastname: Mandeville
authors.forename: Netra
authors.initials: N
authors.lastname: Joshi
authors.forename: Natalya
authors.initials: N
authors.lastname: Smirnova
authors.forename: Irina
authors.initials: I
authors.lastname: Gazaryan
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
mesh_terms: D000368:Aged; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D005260:Female; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology*; D016896:Treatment Outcome
chemical_list: C475064:12-15-lipoxygenase; D016859:Lipoxygenase Inhibitors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase