Emerging class of omega-3 fatty acid endocannabinoids & their derivatives

Abstract

Cannabinoid receptor activation is involved in homeostatic regulation of the body. These receptors are activated by cannabinoids, that include the active constituents of Cannabis sativa as well as endocannabinoids (eCBs). The eCBs are endogenously synthesized from the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). The consumption of omega-3 fatty acids shifts the balance towards a higher proportion of omega-3 eCBs, whose physiological functions warrants further investigation. Herein, we review the discovery of omega-3 fatty acid derived eCBs that are generated from long chain omega-3 PUFAs - docosahexaenoyl ethanolamide (DHA-EA or synaptamide), docosahexanoyl-glycerol (DHG), eicosapentaenoyl ethanolamide (EPA-EA), eicosapentanoylglycerol (EPG). Furthermore, we outline the lesser known omega-3 eCB-like molecules that arise from the conjugation of the omega-3 fatty acids with neurotransmitters serotonin and dopamine - DHA-serotonin (DHA-5HT), EPA-serotonin (EPA-5HT), DHA-dopamine (DHA-DA) and EPA-dopamine (EPA-DA). Additionally, we describe the role of these omega-3 eCBs and their derivatives in different disease states such as pain, inflammation and cancer. Moreover, we detail the formation and potential physiological roles of the oxidative metabolites that arise from the metabolism of omega-3 eCBs by eicosanoid synthesizing enzymes - cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 epoxygenase (CYP450). In summary, we outline the novel findings regarding a growing class of signaling molecules, omega-3 eCBs, that can control the physiological and pathophysiological processes in the body.

n–3 Polyunsaturated Fatty Acid Amides: New Avenues in the Prevention and Treatment of Breast Cancer

“…Along with the anti-inflammatory and antineoplastic properties found for conjugates of the n−3 PUFAs [53], the effects of two DHA metabolites, DHEA and DHA-5HT on the polarization of human macrophages co-cultured with different breast cancer cells, that mimic the features of tumor associated macrophages within the tumor microenvironment have also been reported [100]. Interestingly, DHEA as well as DHA-5HT attenuated cytokine secretion by macrophages associated to breast cancer in a PPARγ dependent-manner [100].…”

“…Increasing evidence suggests that many n-3 PUFA amides are important signaling molecules in animals and humans, mediating a wide range of biological effects [53]. Based on the ubiquitous presence of the enzyme systems that are able to synthesize amides, the hypothesis has been raised that any available long-chain fatty acid can be amidated with any amino acid or related compounds.…”

“…However, in vivo fatty acid amides are known to occur in fluctuating mixtures of structurally related molecules with pleiotropic and tissue specific activities. Indeed, the number of amides detected in tissues is rapidly increasing and several n−3 PUFA conjugates with amino acids and neurotransmitters have been found in mammal tissues, in plasma, and recently also in human milk [37,53]. For many of these molecules, relatively little is known about their biological significance and in many cases, only in vitro data are available, often obtained from testing single compounds.…”

The identification of a cannabinoid-like compound (adrenoyl-EA), in the flowers of a South African medicinal plant (Leonotis leonurus)

“…Adrenoyl-EA is structurally similar to the major endocannabinoid anandamide and functions as an agonist of the CB 1 and TRPV 1 receptor proteins, two major receptors of the human ECS [21,24]. Agonists of these receptors are ideal candidates in a range of therapeutic targets, speci cally exhibiting antiin ammatory, neuroprotective, and anticancer activities, among others [23,25,26].…”

“…It is estimated that the domestic South Africa Cannabis market will reach USD $1.8 billion by 2023 however, this projection is based on export value only, excluding Cannabis-derived pCB products. The value proposition lies within the latter, given the therapeutic potential of pCBs in chronic disease treatment [23][24][25][26]. South African agriculture is typi ed by both large scale mechanized, and smallholder practices and Cannabis cultivation is considered viable.…”