Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke
| Autor: | Klaus van Leyen, Eng H. Lo, Anton Pekcec, Joseph L. Witztum, Hulya Karatas, Theodore R. Holman, Rajiv R. Ratan, Stefanie Pallast, N. A. Smirnova, Netra Joshi, Kazim Yigitkanli, Irina G. Gazaryan, Emiri T. Mandeville, Joan Montaner |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
Pathology medicine.medical_specialty Stroke patient Ischemia Pharmacology Arachidonate 12-Lipoxygenase medicine.disease_cause Article Mice Lipoxygenase Text mining Animals Arachidonate 15-Lipoxygenase Humans Medicine cardiovascular diseases Lipoxygenase Inhibitors Stroke Aged Therapeutic strategy biology business.industry Colocalization Middle Aged medicine.disease Treatment Outcome Neurology biology.protein Female Neurology (clinical) business Oxidative stress |
| Zdroj: | Annals of Neurology. 73:129-135 |
| ISSN: | 0364-5134 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text