Anti-inflammatory ω-3 endocannabinoid epoxides

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / metabolism
  • Animals
  • Anti-Inflammatory Agents / blood*
  • Brain / metabolism
  • Cattle
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Evaluation, Preclinical
  • Endocannabinoids / metabolism*
  • Epoxide Hydrolases / metabolism
  • Epoxy Compounds / blood*
  • Epoxy Compounds / pharmacology
  • Epoxy Compounds / therapeutic use
  • Ethanolamines / blood*
  • Ethanolamines / pharmacology
  • Ethanolamines / therapeutic use
  • Fatty Acids, Omega-3 / metabolism*
  • Humans
  • Lipid Metabolism
  • Mice
  • Microglia / metabolism
  • Neovascularization, Pathologic / prevention & control
  • Platelet Aggregation / drug effects
  • Rats
  • Vasodilation / drug effects

Substances

  • Anti-Inflammatory Agents
  • Endocannabinoids
  • Epoxy Compounds
  • Ethanolamines
  • Fatty Acids, Omega-3
  • Cytochrome P-450 Enzyme System
  • arachidonate epoxygenase
  • Epoxide Hydrolases
  • Amidohydrolases
  • fatty-acid amide hydrolase