Skip to main content
SpringerLink
Log in

Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage

  • Translational Research
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. le Roux AA, Wallace MC. Outcome and cost of aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am. 2010;21:235–46.

    Article  PubMed  Google Scholar 

  2. Dorhout Mees SM, Kerr RS, Rinkel GJ, Algra A, Molyneux AJ. Occurrence and impact of delayed cerebral ischemia after coiling and after clipping in the International Subarachnoid Aneurysm Trial (ISAT). J Neurol. 2012;259:679–83.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Dorsch N. A clinical review of cerebral vasospasm and delayed ischaemia following aneurysm rupture. Acta Neurochir Suppl. 2011;110:5–6.

    PubMed  Google Scholar 

  4. Brathwaite S, Macdonald RL. Current management of delayed cerebral ischemia: update from results of recent clinical trials. Transl Stroke Res. 2013;5:207–26.

    Article  PubMed  Google Scholar 

  5. Dankbaar JW, de Rooij NK, Velthuis BK, Frijns CJ, Rinkel GJ, van der Schaaf IC. Diagnosing delayed cerebral ischemia with different CT modalities in patients with subarachnoid hemorrhage with clinical deterioration. Stroke. 2009;40:3493–8.

    Article  PubMed  Google Scholar 

  6. You J, Johnson TD, Marrelli SP, Bryan RM Jr. Functional heterogeneity of endothelial P2 purinoceptors in the cerebrovascular tree of the rat. Am J Physiol. 1999;277:H893–900.

    CAS  PubMed  Google Scholar 

  7. Pluta RM, Hansen-Schwartz J, Dreier J, et al. Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res. 2009;31:151–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10:44–58.

    Article  CAS  PubMed  Google Scholar 

  9. Iliff JJ, Jia J, Nelson J, Goyagi T, Klaus J, Alkayed NJ. Epoxyeicosanoid signaling in CNS function and disease. Prostaglandins Other Lipid Mediat. 2010;91:68–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Poloyac SM, Reynolds RB, Yonas H, Kerr ME. Identification and quantification of the hydroxyeicosatetraenoic acids, 20-HETE and 12-HETE, in the cerebrospinal fluid after subarachnoid hemorrhage. J Neurosci Methods. 2005;144:257–63.

    Article  CAS  PubMed  Google Scholar 

  11. Cambj-Sapunar L, Yu M, Harder DR, Roman RJ. Contribution of 5-hydroxytryptamine1B receptors and 20-hydroxyeiscosatetraenoic acid to fall in cerebral blood flow after subarachnoid hemorrhage. Stroke. 2003;34:1269–75.

    Article  PubMed  Google Scholar 

  12. Dietrich HH, Horiuchi T, Xiang C, Hongo K, Falck JR, Dacey RG Jr. Mechanism of ATP-induced local and conducted vasomotor responses in isolated rat cerebral penetrating arterioles. J Vasc Res. 2009;46:253–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Zhang W, Koerner IP, Noppens R, et al. Soluble epoxide hydrolase: a novel therapeutic target in stroke. J Cereb Blood Flow Metab. 2007;27:1931–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Node K, Huo Y, Ruan X, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science. 1999;285:1276–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Nation DA, Edland SD, Bondi MW, et al. Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults. Neurology. 2013;81:2024–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Iliff JJ, Fairbanks SL, Balkowiec A, Alkayed NJ. Epoxyeicosatrienoic acids are endogenous regulators of vasoactive neuropeptide release from trigeminal ganglion neurons. J Neurochem. 2010;115:1530–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Zhang W, Otsuka T, Sugo N, et al. Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia. Stroke. 2008;39:2073–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. McGirt MJ, Lynch JR, Parra A, et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002;33:2950–6.

    Article  CAS  PubMed  Google Scholar 

  19. Sozen T, Tsuchiyama R, Hasegawa Y, et al. Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice. Stroke. 2009;40:2519–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Sugawara T, Ayer R, Jadhav V, Zhang JH. A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods. 2008;167:327–34.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Wang RK, Jacques SL, Ma Z, Hurst S, Hanson SR, Gruber A. Three dimensional optical angiography. Opt Express. 2007;15:4083–97.

    Article  PubMed  Google Scholar 

  22. Zhang W, Iliff JJ, Campbell CJ, Wang RK, Hurn PD, Alkayed NJ. Role of soluble epoxide hydrolase in the sex-specific vascular response to cerebral ischemia. J Cereb Blood Flow Metab. 2009;29:1475–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. An L, Qin J, Wang RK. Ultrahigh sensitive optical microangiography for in vivo imaging of microcirculations within human skin tissue beds. Opt Express. 2010;18:8220–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Abramoff MD, Magalhaes PJ, Ram SJ. Image processing with ImageJ. Biophotonics Int. 2004;11:36–42.

    Google Scholar 

  25. Jouihan SA, Zuloaga KL, Zhang W, et al. Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus. J Cereb Blood Flow Metab. 2013;33(10):1650–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2004;101:255–61.

    Article  PubMed  Google Scholar 

  27. Crago EA, Thampatty BP, Sherwood PR, et al. Cerebrospinal fluid 20-HETE is associated with delayed cerebral ischemia and poor outcomes after aneurysmal subarachnoid hemorrhage. Stroke. 2011;42:1872–7.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Barden AE, Croft KD, Beilin LJ, Phillips M, Ledowski T, Puddey IB. Acute effects of red wine on cytochrome P450 eicosanoids and blood pressure in men. J Hypertens. 2013;31:2195–202 discussion 202.

    Article  CAS  PubMed  Google Scholar 

  29. Pradilla G, Chaichana KL, Hoang S, Huang J, Tamargo RJ. Inflammation and cerebral vasospasm after subarachnoid hemorrhage. Neurosurg Clin N Am. 2010;21:365–79.

    Article  PubMed  Google Scholar 

  30. Alkayed NJ, Goyagi T, Joh HD, et al. Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack. Stroke. 2002;33:1677–84.

    Article  CAS  PubMed  Google Scholar 

  31. Kawasaki T, Marumo T, Shirakami K, et al. Increase of 20-HETE synthase after brain ischemia in rats revealed by PET study with 11C-labeled 20-HETE synthase-specific inhibitor. J Cereb Blood Flow Metab. 2012;32:1737–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Martini R, Ward J, Siler D, et al. Genetic variation in soluble epoxide hydrolase is associated with outcome after aneurysmal subarachnoid hemorrhage. J Neurosurg 2014 (in press).

  33. Sehba FA, Hou J, Pluta RM, Zhang JH. The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol. 2012;97:14–37.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Fu C, Yu W, Sun L, Li D, Zhao C. Early cerebral infarction following aneurysmal subarachnoid hemorrhage: frequency, risk factors, patterns, and prognosis. Curr Neurovasc Res. 2013;10:316–24.

    Article  PubMed  Google Scholar 

  35. de Rooij NK, Greving JP, Rinkel GJE, Frijns CJM. Early prediction of delayed cerebral ischemia after subarachnoid hemorrhage: development and validation of a practical risk chart. Stroke. 2013;44:1288–94.

    Article  PubMed  Google Scholar 

  36. Rabinstein AA, Weigand S, Atkinson JL, Wijdicks EF. Patterns of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke. 2005;36:992–7.

    Article  PubMed  Google Scholar 

  37. Shimoda M, Takeuchi M, Tominaga J, Oda S, Kumasaka A, Tsugane R. Asymptomatic versus symptomatic infarcts from vasospasm in patients with subarachnoid hemorrhage: serial magnetic resonance imaging. Neurosurgery. 2001;49:1341–8 discussion 8-50.

    Article  CAS  PubMed  Google Scholar 

  38. Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011;31:1443–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Sabri M, Ai J, Lakovic K, D’Abbondanza J, Ilodigwe D, Macdonald RL. Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage. Neuroscience. 2012;224:26–37.

    Article  CAS  PubMed  Google Scholar 

  40. Deng Y, Edin ML, Theken KN, et al. Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J. 2011;25:703–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Iliff JJ, Alkayed NJ. Soluble epoxide hydrolase inhibition: targeting multiple mechanisms of ischemic brain injury with a single agent. Future Neurol. 2009;4:179–99.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Ostergaard L, Aamand R, Karabegovic S, et al. The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2013;33:1825–37.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Koerner IP, Jacks R, DeBarber AE, et al. Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. J Neurosci. 2007;27:4642–9.

    Article  CAS  PubMed  Google Scholar 

  44. Liu M, Alkayed NJ. Hypoxic preconditioning and tolerance via hypoxia inducible factor (HIF) 1alpha-linked induction of P450 2C11 epoxygenase in astrocytes. J Cereb Blood Flow Metab. 2005;25:939–48.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Joseph Quinn for generously supplying cerebrospinal fluid samples from the Oregon Alzheimer Center, NIA—AG0801, UL1TR000128. We thank Dennis Koop, Lisa Bleyle, and the Bioanalytical Shared Resource/Pharmacokinetics Core facility for their expertise in eicosanoid analysis. We thank Mary Heinricher for help with statistical analysis and manuscript composition. Dominic A. Siler—NHLBI F30 HL108624, Oregon Brain Institute; Nabil J. Alkayed—NINDS R01 NS044313 and NS070837; Ruikang K. Wang—NHLBI R01 HL093140. NIBIB R01 EB009682; Justin S. Cetas—Brain Aneurysm Foundation; Valerie C. Anderson—NIA K25 AG033638.

Conflict of interest

Dominic A. Siler, Ross Martini, Jonathan Ward, Jonathan Nelson, Rohan Borkar, Kristen Zuloaga, Jesse Liu Jeffrey Raskin, Stacy Fairbanks, Valerie Anderson, Aclan Dogan, Ruikang K. Wang, Nabil J. Alkayed, Justin S. Cetas declare that they have no conflict of interest

Author information

Authors and Affiliations

  1. Department of Anesthesiology & Perioperative Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA

    Dominic A. Siler, Ross P. Martini, Jonathan P. Ward, Jonathan W. Nelson, Rohan N. Borkar, Kristen L. Zuloaga, Stacy L. Fairbanks & Nabil J. Alkayed

  2. Department of Neurological Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239-3098, USA

    Dominic A. Siler, Jesse J. Liu, Jeffrey S. Raskin, Valerie C. Anderson, Aclan Dogan, Nabil J. Alkayed & Justin S. Cetas

  3. Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA

    Ruikang K. Wang

  4. Portland Veterans Affairs Medical Center (PVAMC), Portland, OR, USA

    Justin S. Cetas

Authors
  1. Dominic A. Siler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ross P. Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan P. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan W. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rohan N. Borkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kristen L. Zuloaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jesse J. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stacy L. Fairbanks
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeffrey S. Raskin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Valerie C. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aclan Dogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ruikang K. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nabil J. Alkayed
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Justin S. Cetas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Justin S. Cetas.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12028_2014_11_MOESM1_ESM.eps

Supplementary material 1 (EPS 1470 kb). Supplemental Fig. 1: Eicosanoid levels following SAH. Concentration of A) 15-HETE, B) 12-HETE, C) 11-HETE, D) 11,12-EET and E.) 8,9-EET in picograms per milliliter of CSF in an age-/sex-matched control group (Ctrl n = 10) and in SAH patients (n = 34) up to fourteen days following SAH. nd = not detected (EPS 875 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Siler, D.A., Martini, R.P., Ward, J.P. et al. Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage. Neurocrit Care 22, 306–319 (2015). https://doi.org/10.1007/s12028-014-0011-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-014-0011-y

Keywords

Search

Navigation