N‐acyl amines of docosahexaenoic acid and other n–3 polyunsatured fatty acids – from fishy endocannabinoids to potential leads

Abstract

N–3 long‐chain polyunsaturated fatty acids (n–3 LC‐PUFAs), in particular α‐linolenic acid (18:3n‐3), eicosapentaenoic acid (EPA; 20:5n‐3) and docosahexaenoic acid (DHA; 22:6n‐3) are receiving much attention because of their presumed beneficial health effects. To explain these, a variety of mechanisms have been proposed, but their interactions with the endocannabinoid system have received relatively little attention so far. However, it has already been shown some time ago that consumption of n–3 LC‐PUFAs not only affects the synthesis of prototypic endocannabinoids like anandamide but also stimulates the formation of specific n–3 LC‐PUFA‐derived conjugates with ethanolamine, dopamine, serotonin or other amines. Some of these fatty amides show overlapping biological activities with those of typical endocannabinoids, whereas others possess distinct and sometimes largely unknown receptor affinities and other properties. The ethanolamine and dopamine conjugates of DHA have been the most investigated thus far. These mediators may provide promising new leads to the field of inflammatory and neurological disorders and for other pharmacological applications, including their use as carrier molecules for neurotransmitters to target the brain. Furthermore, combinations of n–3 LC‐PUFA‐derived fatty acid amides, their precursors and FAAH inhibitors offer possibilities to optimise their effects in health and disease. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit &

Anti-inflammatory ω-3 endocannabinoid epoxides

“…Conversely, relatively low levels of the EPEA parent compound were detected, with levels significantly lower than those of 17,18-EEQ-EA. Importantly, the relatively higher DHEA levels and lower EPEA levels are consistent with reports in the literature (10), lending credibility to the quantitative values. Some of the metabolites also were detected at lower levels in porcine brains and in pooled human plasma (SI Appendix, Table ST1).…”

“…4 C and D, we determined that the antiinflammatory action of the ω-3 endocannabinoid epoxides is mediated partly by CB2. In the literature, EPEA and DHEA are reported to be weak agonists of the cannabinoid receptors (10). To explore if oxygenation of EPEA or DHEA by CYPs led to the formation of metabolites with altered cannabinoid receptor activity, we performed receptor functional assays using a β-arrestin recruitment PRESTO-Tango assay (42).…”

“…DHEA exhibits anticancer (4,5), anti-inflammatory (10), and synaptogenic (11) properties and has been detected in both the brain and retina at concentrations comparable to those of AEA (12)(13)(14). EPEA also has been shown to activate anti-inflammatory pathways ( Fig.…”

“…EPEA also has been shown to activate anti-inflammatory pathways ( Fig. 1) (10). Interestingly, dietary supplementation with EPA and DHA resulted in increased levels of EPEA and DHEA at the expense of AEA, thereby providing a means for increasing the levels of ω-3 endocannabinoids through dietary consumption (15,16).…”

Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS

“…In blood, higher concentrations of DHA, the fatty acid of DHEA, were reported in the elderly (65 years, gender not reported) (38). Intake of DHA can alter DHEA concentrations in blood and brain (39). Additionally, age-related changes in DHA metabolism could play important roles as well (40).…”