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Anti-inflammatory ω-3 endocannabinoid epoxides.
Proc Natl Acad Sci U S A. 2017 07 25; 114(30):E6034-E6043.PN

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.

Authors+Show Affiliations

Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801. Medical Scholars Program, University of Illinois at Urbana-Champaign, Champaign, IL 61801.Department of Biochemistry, University of Illinois at Urbana-Champaign, Champaign, IL 61801.Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Champaign, IL 61801.Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801. College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Champaign, IL 61801.Department of Biochemistry, University of Illinois at Urbana-Champaign, Champaign, IL 61801.Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801. Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801.Department of Bioengineering, University of Illinois at Urbana-Champaign, Champaign IL 61801.Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109. Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109.Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801; aditidas@illinois.edu. Department of Biochemistry, University of Illinois at Urbana-Champaign, Champaign, IL 61801. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Champaign IL 61801. Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Champaign, IL 61801.

Pub Type(s)

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

Language

eng

PubMed ID

28687674

Citation

McDougle, Daniel R., et al. "Anti-inflammatory Ω-3 Endocannabinoid Epoxides." Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 30, 2017, pp. E6034-E6043.
McDougle DR, Watson JE, Abdeen AA, et al. Anti-inflammatory ω-3 endocannabinoid epoxides. Proc Natl Acad Sci USA. 2017;114(30):E6034-E6043.
McDougle, D. R., Watson, J. E., Abdeen, A. A., Adili, R., Caputo, M. P., Krapf, J. E., Johnson, R. W., Kilian, K. A., Holinstat, M., & Das, A. (2017). Anti-inflammatory ω-3 endocannabinoid epoxides. Proceedings of the National Academy of Sciences of the United States of America, 114(30), E6034-E6043. https://doi.org/10.1073/pnas.1610325114
McDougle DR, et al. Anti-inflammatory Ω-3 Endocannabinoid Epoxides. Proc Natl Acad Sci USA. 2017 07 25;114(30):E6034-E6043. PubMed PMID: 28687674.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-inflammatory ω-3 endocannabinoid epoxides. AU - McDougle,Daniel R, AU - Watson,Josephine E, AU - Abdeen,Amr A, AU - Adili,Reheman, AU - Caputo,Megan P, AU - Krapf,John E, AU - Johnson,Rodney W, AU - Kilian,Kristopher A, AU - Holinstat,Michael, AU - Das,Aditi, Y1 - 2017/07/07/ PY - 2017/7/9/pubmed PY - 2018/6/7/medline PY - 2017/7/9/entrez KW - cytochrome P450 KW - endocannabinoid KW - epoxyeicosatrienoic acids KW - epoxygenase KW - neuroinflammation SP - E6034 EP - E6043 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 114 IS - 30 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/28687674/Anti_inflammatory_ω_3_endocannabinoid_epoxides_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=28687674 DB - PRIME DP - Unbound Medicine ER -