Pharmacological Characterization of the Anandamide Cyclooxygenase Metabolite: Prostaglandin E<sub>2</sub> Ethanolamide

Ross, Ruth A.; Craib, Susan J; Stevenson, Lesley; Pertwee, Roger G.; Henderson, Andrea; Toole, John J.; Ellington, H. C.

doi:10.1124/jpet.301.3.900

Cited by 101 publications

(75 citation statements)

References 19 publications

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“…Experiments using endocannabinoids in human neutrophil suspensions in which adenosine is present might therefore result in COX-II expression and the biosynthesis of PG-ethanolamides and/or glyceryl-PGs. These endocannabinoid-derived lipids could modulate human neutrophil functions, possibly through the prostanoid receptor EP 2 (58,59), which inhibits LT biosynthesis in neutrophils (60). This would not be observed in freshly-isolated, adenosine-depleted neutrophils because they do not express significant levels of COX-II (57).…”

Section: Discussionmentioning

confidence: 99%

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

Chouinard

Lefebvre

Navarro

et al. 2011

The Journal of Immunology

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Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro- and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B4 biosynthesis, or LTB4 receptor 1 activation prevented all the effects of 2-AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB4 biosynthesis, and an autocrine activation loop involving LTB4 receptor 1.

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Section: Discussionmentioning

confidence: 99%

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

Chouinard

Lefebvre

Navarro

et al. 2011

The Journal of Immunology

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“…Cyclooxygenase-2, and subsequent action of the various prostaglandin synthases, transforms AEA and 2-AG into the corresponding prostaglandin ethanolamides (or prostamides) and prostaglandin glyceryl esters, which, in some assays, exhibit high potency even though they have no activity on either cannabinoid or prostanoid receptors (Woodward et al, 2001;Ross et al, 2002). These metabolites are rather stable to further metabolism, except for prostamide E 2 that undergoes slow dehydration/isomerization to prostamide B 2 (Kozak et al, 2001).…”

Section: De Petrocellis Et Almentioning

confidence: 99%

The endocannabinoid system: a general view and latest additions

Petrocellis

Cascio

Marzo

2004

British J Pharmacology

430

356

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After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana's psychoactive principle D 9 -tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest 'additions' to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids.

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“…Although their physiological actions have not been fully investigated, a synthetic prostamide analog (Bimatoprost) has been shown to be very potent in reducing IOP by increasing both uveosceral and trabecular outflow of aqueous humor (Woodward et al, 2001). The activities of prostamides as endogenous ligands at prostaglandin receptor(s) have been investigated, but have been shown to exert no meaningful activity (Berglund et al, 1999;Woodward et al, 2001;Ross et al, 2002;Matias et al, 2004). Studies on their metabolic rate clearly demonstrate that prostamides and their synthetic analog Bimatoprost exert their in vitro pharmacological effects (Matias et al, 2004) and the ocular hypotensive effects as the intact molecule .…”

Section: Introductionmentioning

confidence: 99%

“…Studies on their metabolic rate clearly demonstrate that prostamides and their synthetic analog Bimatoprost exert their in vitro pharmacological effects (Matias et al, 2004) and the ocular hypotensive effects as the intact molecule . Experimental evidence suggests that prostamides may act as endogenous ligands at their own receptors (Woodward et al, 2001;Ross et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of orphan nuclear receptor Nur77 following PGF_2α, Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP₂ receptor activated Nur77 gene transcription

Liang

Guzmán

et al. 2004

British J Pharmacology

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Using gene chip technology, we first identified that PGF2α (FP agonist) and Butaprost (EP2 agonist) induced about a five‐fold upregulation of Nur77 mRNA expression in hFP‐HEK 293/EBNA and hEP2‐HEK293/EBNA cells. Northern Blot analysis revealed that PGF2α‐ and Butaprost‐induced upregulation of Nur77 expression are dose‐ and time‐dependent. Both PGF2α and Butaprost upregulated Nur77 gene expression through the protein kinase C (PKC) pathway. These data are the first showing a link between EP2 receptor stimulation and protein kinase C activation. Calcineurin was found to be involved downstream of the PKC pathway in PGF2α‐induced Nur77 expression, but not in Butaprost‐induced Nur77 expression. We also used Nur77 as a marker gene to compare the effects of PGF2α, Butaprost, and Bimatoprost (a prostamide) on Nur77 expression in human primary trabecular meshwork and ciliary smooth muscle (SM) cells, which are target cells for antiglaucoma drugs. The results showed that PGF2α and Butaprost, but not Bimatoprost, induced upregulation of Nur77 expression in human TM cells. PGF2α, but not Bimatoprost, dramatically induced upregulation of Nur77 mRNA expression in human ciliary SM cells, whereas Butaprost slightly upregulated Nur77 mRNA expression in SM cells. Nur77 promoter deletion analysis indicated that PGF2α, but not Bimatoprost, activated Nur77 promoter‐luciferase reporter in hFP‐HEK 293/EBNA cells. Butaprost was less efficacious in inducing Nur77 promoter‐luciferase reporter activity in hEP2‐HEK293/EBNA cells relative to PGF2α in the comparable assay. The data for Nur77 promoter functional analysis were matched to the Northern blot analysis. It appears that PGF2α and Butaprost activate Nur77 transcription mechanisms through the activation of FP and EP2 receptor‐coupled signaling pathways, whereas Bimatoprost stimulates neither FP nor EP2 receptors. British Journal of Pharmacology (2004) 142, 737–748. doi:10.1038/sj.bjp.0705829

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Pharmacological Characterization of the Anandamide Cyclooxygenase Metabolite: Prostaglandin E₂ Ethanolamide

Cited by 101 publications

References 19 publications

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

The endocannabinoid system: a general view and latest additions

Upregulation of orphan nuclear receptor Nur77 following PGF_2α, Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP₂ receptor activated Nur77 gene transcription

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Pharmacological Characterization of the Anandamide Cyclooxygenase Metabolite: Prostaglandin E2 Ethanolamide

Cited by 101 publications

References 19 publications

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

The endocannabinoid system: a general view and latest additions

Upregulation of orphan nuclear receptor Nur77 following PGF2α, Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP2 receptor activated Nur77 gene transcription

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Pharmacological Characterization of the Anandamide Cyclooxygenase Metabolite: Prostaglandin E₂ Ethanolamide

Upregulation of orphan nuclear receptor Nur77 following PGF_2α, Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP₂ receptor activated Nur77 gene transcription