The human body contains endocannabinoids that elicit similar psychoactive and anti-nociceptive effects to phytocannabinoids in cannabis. We recently reported the endogenous production of a previously unknown class of ω-3 PUFA–derived endocannabinoid epoxides 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 epoxygenase. Neuroinflammation studies revealed that the endocannabinoid epoxides dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 and PPAR gamma activation. Furthermore, the ω-3 endocannabinoid epoxides exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries (BCA) and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides’ are formed via the cross-talk of two important pathways in the body and the physiological effects are also mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In future, the identification of these metabolites may aid in the development of therapeutics for neuro-inflammatory and cerebrovascular diseases.
American Heart Association Scientist Development grant 15SDG25760064, National Institute of Health (NIH) R01 grant 1R01GM115584-01A1 and NIH R03 grant 1R03DA042365-01A1