Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage

Dominic A. Siler, Ross P. Martini, Jonathan P. Ward, Jonathan W. Nelson, Rohan N. Borkar, Kristen L. Zuloaga, Jesse J. Liu, Stacy L. Fairbanks, Jeffrey S. Raskin, Valerie Anderson, Aclan Dogan, Ruikang K. Wang, Nabil J. Alkayed, Justin Cetas

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Background: Patients recovering from aneurysmal subarachnoid hemorrhage (SAH) are at risk for developing delayed cerebral ischemia (DCI). Experimental and human studies implicate the vasoconstrictor P450 eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) in the pathogenesis of DCI. To date, no studies have evaluated the role of vasodilator epoxyeicosatrienoic acids (EETs) in DCI. Methods: Using mass spectrometry, we measured P450 eicosanoids in cerebrospinal fluid (CSF) from 34 SAH patients from 1 to 14 days after admission. CSF eicosanoid levels were compared in patients who experienced DCI versus those who did not. We then studied the effect of EETs in a model of SAH using mice lacking the enzyme soluble epoxide hydrolase (sEH), which catabolizes EETs into their inactive diol. To assess changes in vessel morphology and cortical perfusion in the mouse brain, we used optical microangiography, a non-invasive coherence-based imaging technique. Results: Along with increases in 20-HETE, we found that CSF levels of 14,15-EET were elevated in SAH patients compared to control CSF, and levels were significantly higher in patients who experienced DCI compared to those who did not. Mice lacking sEH had elevated 14,15-EET and were protected from the delayed decrease in microvascular cortical perfusion after SAH, compared to wild type mice. Conclusions: Our findings suggest that P450 eicosanoids play an important role in the pathogenesis of DCI. While 20-HETE may contribute to the development of DCI, 14,15-EET may afford protection against DCI. Strategies to enhance 14,15-EET, including sEH inhibition, should be considered as part of a comprehensive approach to prevent DCI.

Original languageEnglish (US)
Pages (from-to)306-319
Number of pages14
JournalNeurocritical Care
Issue number2
StatePublished - Apr 2015


  • 20-HETE
  • Delayed cerebral ischemia
  • Epoxyeicosatrienoic acid
  • Soluble epoxide hydrolase
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Clinical Neurology


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