Anti-inflammatory ω-3 endocannabinoid epoxides

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.

Metabolomics revealed decreased level of omega‐3 PUFA‐derived protective eicosanoids in pregnant women with pre‐eclampsia

“…EEQs are analogs of EETs derived from EPA . They have more potent anti‐inflammatory and vasodilation effects than EETs . Although levels of EETs were not changed in this work, the level of 8,9‐EEQ was significantly decreased, which suggests that EEQs are a protective factor.…”

Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation

“…In addition to its function as a unique building block of cell membranes, DHA is also a precursor for docosanoids and other bioactive endogenous derivatives in the neural tissue [37]. The number of recently identified DHA derivatives in neural tissue is increasingly growing and includes neuroprotectin D1 (NPD1), synaptamide, endocannabinoid epoxides, and elovanoids [38][39][40]. Collectively, the potent bioactive properties of these DHA derivatives contribute to preservation of normal neuronal function, tissue homeostasis, and neuronal survival [37][38][39][40][41].…”

“…The number of recently identified DHA derivatives in neural tissue is increasingly growing and includes neuroprotectin D1 (NPD1), synaptamide, endocannabinoid epoxides, and elovanoids [38][39][40]. Collectively, the potent bioactive properties of these DHA derivatives contribute to preservation of normal neuronal function, tissue homeostasis, and neuronal survival [37][38][39][40][41]. In addition, the DHA derivatives exert a range of potent neuroprotective properties that include inhibition of proinflammatory gene expression and leukocyte infiltration.…”

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

“…15–19 These metabolites are collectively called the epoxyeicosanoids and consist of a variety of classes (e.g., epoxyeicosatrienoic acid, EET; epoxyeicosatrienoic acid ethanolamine, EET-EA; etc.). 20–23 Previously, these molecules have been shown to act as cardioprotective agents against atherosclerosis, ischemia reperfusion, and regulate blood pressure. 9,17,20 Specifically, AEA and 2-AG interact with CYPs and undergo epoxidation to their more bioactive products, EET-EA and EET-G with varied biological activities.…”

“…20–23 Previously, these molecules have been shown to act as cardioprotective agents against atherosclerosis, ischemia reperfusion, and regulate blood pressure. 9,17,20 Specifically, AEA and 2-AG interact with CYPs and undergo epoxidation to their more bioactive products, EET-EA and EET-G with varied biological activities. 16,20,24–26 These metabolites are targets of both FAAH and soluble epoxide hydrolase (sEH) which degrades CYP epoxygenase-derived eCB metabolites to yield the corresponding diol product, which is a current target for the development of anti-inflammatory drugs.…”