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Novel Anti-inflammatory and Vasodilatory ω-3 Endocannabinoid Epoxide Regioisomers

Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 1161)

Abstract

Accumulating evidence suggests that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) offer protection against vascular inflammation, neuroinflammation, hypertension, and thrombosis. Recently, biochemical studies have demonstrated that these benefits are partially mediated by their conversion to ω-3 endocannabinoid epoxide metabolites. These lipid metabolites originate from the epoxidation of ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by cytochrome P450 (CYP) epoxygenases to form epoxydocosapentaenoic acid-ethanolamides (EDP-EAs) and epoxyeicosatetraenoic acid-ethanolamides (EEQ-EAs), respectively. The EDP-EAs and EEQ-EAs are endogenously produced in rat brain and peripheral organs. Additionally, EDP-EAs and EEQ-EAs dose-dependently decrease pro-inflammatory IL-6 cytokine and increased anti-inflammatory IL-10 cytokine. Furthermore, the EEQ-EAs and EDP-EAs attenuate angiogenesis and cell migration in cancer cells, induce vasodilation in bovine coronary arteries, and reciprocally regulate platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides represent a new class of dual acting molecules that display unique pharmacological properties.

Keywords

  • Cytochrome p450
  • Epoxygenase
  • Neuroinflammation
  • Endocannabinoid
  • Epoxyeicosatrienoic acids
  • Cannabinoid receptors 1 and 2
  • Omega-3 fatty acids

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Fig. 17.1
Fig. 17.2

Abbreviations

2-AG:

2-arachidonoyl-glycerol

2-DHG:

2-docosahexaenoyl-glycerol

2-EPG:

2-eicosapentaenoyl-glycerol

AA:

arachidonic acid

AEA:

anandamide

cAMP:

cyclic adenosine monophosphate

CB1:

cannabinoid receptor 1

CB2:

cannabinoid receptor 2

CYP:

cytochrome P450

DHA:

docosahexaenoic acid

DHEA:

docosahexaenoyl ethanolamide

eCB:

endocannabinoid

EDP-EA:

docosapentaenoic acid ethanolamide

EEQ-EA:

epoxyeicosatetraenoic acid ethanolamide

EPA:

eicosapentaenoic acid

EPEA:

eicosapentaenoyl ethanolamide

FAAH:

fatty amide hydrolase

GPCR:

G-Protein coupled receptor

MAGL:

monoacylglycerol lipase

sEH:

soluble epoxide hydrolase

Δ9-THC:

Δ9-tetrahydrocannabinol

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Acknowledgements

This work was partly supported by American Heart Association Scientist Development Grant 15SDG25760064 (A.D.), National Institutes of Health (NIH) Grant R01 GM1155884 (A.D.), and R03 DA042365 (A.D). We would like to acknowledge Daniel R. McDougle, William R. Arnold, Jahnabi Roy, and Josephine E. Watson for doing the research related to omega-3 endocannabinoid epoxides.

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Carnevale, L.N., Das, A. (2019). Novel Anti-inflammatory and Vasodilatory ω-3 Endocannabinoid Epoxide Regioisomers. In: Honn, K., Zeldin, D. (eds) The Role of Bioactive Lipids in Cancer, Inflammation and Related Diseases. Advances in Experimental Medicine and Biology, vol 1161. Springer, Cham. https://doi.org/10.1007/978-3-030-21735-8_17

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