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Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6034-E6043. doi: 10.1073/pnas.1610325114. Epub 2017 Jul 7.

Anti-inflammatory ω-3 endocannabinoid epoxides.

Author information

1
Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801.
2
Medical Scholars Program, University of Illinois at Urbana-Champaign, Champaign, IL 61801.
3
Department of Biochemistry, University of Illinois at Urbana-Champaign, Champaign, IL 61801.
4
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Champaign, IL 61801.
5
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
6
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801.
7
College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Champaign, IL 61801.
8
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801.
9
Department of Bioengineering, University of Illinois at Urbana-Champaign, Champaign IL 61801.
10
Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109.
11
Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801; aditidas@illinois.edu.
12
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Champaign, IL 61801.

Abstract

Clinical studies suggest that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of ω-3 PUFA-derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ-EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the ω-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides' physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.

KEYWORDS:

cytochrome P450; endocannabinoid; epoxyeicosatrienoic acids; epoxygenase; neuroinflammation

PMID:
28687674
PMCID:
PMC5544256
DOI:
10.1073/pnas.1610325114
[Indexed for MEDLINE]
Free PMC Article

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