Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke.
Kazim Yigitkanli,Anton Pekcec,Hulya Karatas,Stefanie Pallast,Emiri T. Mandeville,Netra Joshi,N. A. Smirnova,Irina G. Gazaryan,Rajiv R. Ratan,Joseph L. Witztum,Joan Montaner,Theodore R. Holman,Eng H. Lo,Klaus van Leyen +13 more
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In a mouse model of transient focal ischemia, the inhibitor reduces infarct sizes both 24 hours and 14 days poststroke, with improved behavioral parameters, and establishes inhibition of 12/15‐lipoxygenase as a viable strategy for first‐line stroke treatment.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.read more
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Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke.
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