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Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke

  1. Kazim Yigitkanli MD1,
  2. Anton Pekcec DVM1,
  3. Hulya Karatas MD, PhD1,
  4. Stefanie Pallast PhD1,
  5. Emiri Mandeville MD1,
  6. Netra Joshi MSc2,
  7. Natalya Smirnova PhD3,
  8. Irina Gazaryan PhD3,
  9. Rajiv R. Ratan MD, PhD3,
  10. Joseph L. Witztum MD4,
  11. Joan Montaner MD, PhD5,
  12. Theodore R. Holman PhD2,
  13. Eng H. Lo PhD1,
  14. Klaus van Leyen PhD1,*

Article first published online: 28 NOV 2012

DOI: 10.1002/ana.23734

Issue

Annals of Neurology

Annals of Neurology

Volume 73, Issue 1, pages 129–135, January 2013

Additional Information

How to Cite

Yigitkanli, K., Pekcec, A., Karatas, H., Pallast, S., Mandeville, E., Joshi, N., Smirnova, N., Gazaryan, I., Ratan, R. R., Witztum, J. L., Montaner, J., Holman, T. R., Lo, E. H. and van Leyen, K. (2013), Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke. Ann Neurol., 73: 129–135. doi: 10.1002/ana.23734

Author Information

  1. 1

    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA

  2. 2

    Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, CA

  3. 3

    The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY

  4. 4

    Department of Medicine, University of California at San Diego, La Jolla, CA

  5. 5

    Neurovascular Research Laboratory, Vall d'Hebron University Hospital Research Institute, Barcelona, Spain

*Massachusetts General Hospital, Neuroprotection Research Laboratory, 149 13th St., R. 2401, Charlestown, MA 02129

Publication History

  1. Issue published online: 1 FEB 2013
  2. Article first published online: 28 NOV 2012
  3. Accepted manuscript online: 18 AUG 2012 04:19AM EST
  4. Manuscript Accepted: 10 AUG 2012
  5. Manuscript Revised: 30 JUL 2012
  6. Manuscript Received: 31 DEC 2011

Funded by

  • NIH NINDS. Grant Number: R01NS049430
  • NIGMS. Grant Number: R01GM56062

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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

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