Inhibition of 12/15‐lipoxygenase as therapeutic strategy to treat stroke. Issue 1 (28th November 2012)

• Record Type: Journal Article
• Authors: Yigitkanli, Kazim; Pekcec, Anton; Karatas, Hulya; Pallast, Stefanie; Mandeville, Emiri; Joshi, Netra; Smirnova, Natalya; Gazaryan, Irina; Ratan, Rajiv R.; Witztum, Joseph L.; Montaner, Joan; Holman, Theodore R.; Lo, Eng H.; van Leyen, Klaus
• Is Part Of: Annals of neurology. Volume 73:Issue 1(2013:Jan.)
• Page Start: 129
• Page End: 135
• Publication Date: 2012-11-28
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.23734
• Languages: English
• ISSNs: 0364-5134

Abstract

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. Ann Neurol 2013