Endogenous cannabinoids revisited: A biochemistry perspective

Fonseca, Bruno M.; Costa, María Arminda Mendes; Almada, Marta; Correia-da-Silva, Georgina; Teixeira, Natércia

doi:10.1016/j.prostaglandins.2013.02.002

Cited by 126 publications

(103 citation statements)

References 238 publications

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“…The endocannabinoids AEA, DHEA, and EPEA exert effects similar to those of Δ9-tetrahydrocannabinol (THC), the active ingredient of Cannabis sativa. Endocannabinoids play important physiological roles that are exerted primarily through the activation of cannabinoid receptor-1 (CB1) and -2 (CB2) (6,7). CB1 is found predominantly in the CNS, and CB2 is found in both peripheral and CNS immune cells (8).…”

mentioning

confidence: 99%

Anti-inflammatory ω-3 endocannabinoid epoxides

McDougle

Watson

Abdeen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

138

152

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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.

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mentioning

confidence: 99%

Anti-inflammatory ω-3 endocannabinoid epoxides

McDougle

Watson

Abdeen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

138

152

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“…It is comprised of endogenous ligands N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), two types of G protein-coupled cannabinoid receptors (CBs; CB1 and CB2), and the corresponding biosynthetic enzymes (N-acylphosphatidyl-ethanolamine selective phospholipase D [NAPE-PLD] for AEA, diacylglycerol lipase [DAGL] for 2-AG) and degradative enzymes (fatty acid amidohydrolase [FAAH] for AEA, monoacylglycerol lipase [MAGL] for 2-AG) (1). CB1 is highly expressed in the CNS, and lower yet functionally relevant in the periphery under physiological conditions (1), whereas CB2 is predominantly expressed in immune cells and participates in modulating the immune system (2).…”

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confidence: 99%

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

Mai

Yang

Tian

et al. 2015

The Journal of Immunology

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Hepatic injury undergoes significant increases in endocannabinoidsand infiltrations of macrophages, yet the concrete mechanisms of changes in endocannabinoids and the functions of macrophage-expressed cannabinoid receptors (CBs) are unclear. Biosynthetic and degradative enzymes of endocannabinoids revealed a significant change in human fibrotic liver. Meanwhile, we showed dynamic changes of these enzymes and CBs (CB1 and CB2) from 1 to 56 d in carbon tetrachloride–induced murine liver injury. Biosynthetic enzymes (N-acylphosphatidyl-ethanolamine selective phospholipase D and diacylglycerol lipase-α) and CBs were markedly increased, whereas degradative enzymes (fatty acid amidohydrolase and monoacylglycerol lipase) were downregulated. Moreover, these enzymes intimately correlated with the fibrosis parameter [procollagen α1(III)]. Bone marrow–derived monocytes/macrophages (BMM) expressed CBs. Interestingly, CB1 but not CB2 mediated BMM migration through a Boyden chambers assay, and the effect depended on the G(α)i/o/RhoA/ROCK signaling pathway. ICR mice were lethally irradiated and received BM transplants from enhanced GFP transgenic mice. Four weeks later, mice of BM reconstruction were subjected to carbon tetrachloride–induced liver injury. In the chimeric murine model, we found that blockade of CB1 by administration of a CB1 antagonist inhibited the recruitment of BMM into injured liver using immunofluorescence staining and FACS, but it did not have effects on migration of T cells and dendritic cells without CB1 expression. Furthermore, activation of CB1 enhanced cytokine expression of BMM. In vivo, inhibition of CB1 attenuated the inflammatory cytokine level through real-time RT-PCR and cytometric bead array, ameliorating hepatic inflammation and fibrosis. In this study, we identify inactivation of BMM-expressed CB1 as a therapeutic strategy for reducing hepatic inflammation and fibrosis.

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“…The endocannabinoid system is an important regulatory lipid signaling system found in all vertebrates and throughout the human body [1]. It consists of cannabinoid receptors, their endogenous ligands, collectively known as endocannabinoids, and the enzymes that synthesize and degrade the ligands.…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

Cannabis for Inflammatory Bowel Disease

Naftali

Mechulam

Lev³

et al. 2014

Dig Dis

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The marijuana plant Cannabis sativa has been used for centuries as a treatment for a variety of ailments. It contains over 60 different cannabinoid compounds. Studies have revealed that the endocannabinoid system is involved in almost all major immune events. Cannabinoids may, therefore, be beneficial in inflammatory disorders. In murine colitis, cannabinoids decrease histologic and microscopic inflammation. In humans, cannabis has been used to treat a plethora of gastrointestinal problems, including anorexia, emesis, abdominal pain, diarrhea, and diabetic gastroparesis. Despite anecdotal reports on medical cannabis in inflammatory bowel disease (IBD), there are few controlled studies. In an observational study in 30 patients with Crohn's disease (CD), we found that medical cannabis was associated with improvement in disease activity and reduction in the use of other medications. In a more recent placebo-controlled study in 21 chronic CD patients, we showed a decrease in the CD activity index >100 in 10 of 11 subjects on cannabis compared to 4 of 10 on placebo. Complete remission was achieved in 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group. Yet, in an additional study, low-dose cannabidiol did not have an effect on CD activity. In summary, evidence is gathering that manipulating the endocannabinoid system can have beneficial effects in IBD, but further research is required to declare cannabinoids a medicine. We need to establish the specific cannabinoids, as well as appropriate medical conditions, optimal dose, and mode of administration, to maximize the beneficial effects while avoiding any potential harmful effects of cannabinoid use.

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Endogenous cannabinoids revisited: A biochemistry perspective

Cited by 126 publications

References 238 publications

Anti-inflammatory ω-3 endocannabinoid epoxides

Anti-inflammatory ω-3 endocannabinoid epoxides

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

Cannabis for Inflammatory Bowel Disease

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