Activation of platelets by the endocannabinoids 2-arachidonoylglycerol and virodhamine is mediated by their conversion to arachidonic acid and thromboxane A2, not by activation of cannabinoid receptors

Brantl, S. Annette; Khandoga, Anna L.; Siess, Wolfgang

doi:10.3109/09537104.2013.835040

Cited by 8 publications

(9 citation statements)

References 13 publications

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“…Previous data suggest that 2‐AG induced aggregation is cannabinoid receptor dependent and metabolic breakdown independent [Maccarrone et al, ], in agreement with more recent data indicating that 2‐AG does not activate human platelets through the release of arachidonic acid [Signorello et al, ]. In contrast data presented by Keown et al [] and Brantl et al [] have shown that 2‐AG stimulates platelets by a MAGL (monoacylglycerol lipase) triggered mechanism leading to free arachidonic acid and its metabolism. CB1, CB2 or non CB1/CB2 seems to be not involved, as suggested by Baldassarri et al [].…”

Section: Discussionsupporting

confidence: 75%

Regulation of cAMP Intracellular Levels in Human Platelets Stimulated by 2‐Arachidonoylglycerol

Signorello

Leoncini

2015

J of Cellular Biochemistry

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We demonstrated that in human platelets the endocannabinoid 2-arachidonoylglycerol (2-AG) decreased dose- and time-dependently cAMP intracellular levels. No effect on cAMP decrease induced by 2-AG was observed in the presence of the adenylate cyclase inhibitor SQ22536 as well in platelets pretreated with the thromboxane A2 receptor antagonist, SQ29548 or with aspirin, inhibitor of arachidonic acid metabolism through the cyclooxygenase pathway. An almost complete recovering of cAMP level was measured in platelets pretreated with the specific inhibitor of phosphodiesterase (PDE) 3A, milrinone. In platelets pretreated with LY294002 or MK2206, inhibitors of PI3K/AKT pathway, and with U73122, inhibitor of phospholipase C pathway, only a partial prevention was shown. cAMP intracellular level depends on synthesis by adenylate cyclase and hydrolysis by PDEs. In 2-AG-stimulated platelets adenylate cyclase activity seems to be unchanged. In contrast PDEs appear to be involved. In particular PDE3A was specifically activated, as milrinone reversed cAMP reduction by 2-AG. 2-AG enhanced PDE3A activity through its phosphorylation. The PI3K/AKT pathway and PKC participate to this PDE3A phosphorylation/activation mechanism as it was greatly inhibited by platelet pretreatment with LY294002, MK2206, U73122, or the PKC specific inhibitor GF109203X. Taken together these data suggest that 2-AG potentiates its power of platelet agonist reducing cAMP intracellular level.

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Section: Discussionsupporting

confidence: 75%

Regulation of cAMP Intracellular Levels in Human Platelets Stimulated by 2‐Arachidonoylglycerol

Signorello

Leoncini

2015

J of Cellular Biochemistry

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“…Inhibition of monoacylglyerol lipase abolished platelet aggregation induced by 2‐AG and virodhamin. Therefore both Brantl et al as well as Braud et al suggest a pivotal role of the endocannabinoid metabolite AA and cyclooxygenase‐dependently synthesized products in conferring the platelet aggregatory action of endocannabinoids. Finally, Baldassari et al provided evidence for a CB1‐ and CB2‐dependent activation of human platelets by 2‐AG.…”

Section: Discussionmentioning

confidence: 99%

“…The loss of the proaggregatory effect at high concentrations of AA and AEA observed in this study was explained by the production of inhibitory prostaglandins such as PGE 2 . Recently, Brantl et al revealed a proaggregatory effect of 2‐AG and virodhamin at concentrations of 100–800 µM but not of AEA on human PRP and whole blood. Inhibition of monoacylglyerol lipase abolished platelet aggregation induced by 2‐AG and virodhamin.…”

Section: Discussionmentioning

confidence: 99%

“…However, despite some knowledge regarding the effects of AEA on the cardiovascular system, it remains unclear how this lipid modulates thrombosis. Accordingly, the only available in vitro data published in this context are controversial [4,[12][13][14][15][16][17][18]. Noteworthy, platelets have been suggested as potential target cells for cannabinoids, as both CB1 and CB2 are present in platelet membranes [14,19].…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of endogenous, phyto and synthetic cannabinoids on thrombogenesis and platelet activity

et al. 2016

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This study analysed the impact of anandamide, cannabidiol (CBD), and WIN55,212-2 on platelet activity and thrombogenesis for the first time. The effects of the cannabinoids on venular thrombosis were studied in the ear of hairless mice. Cannabinoid treatment was performed either once or repetitive by a once-daily administration for three days. To assess the role of cyclooxygenase metabolites in the putative action of anandamide, in vivo studies likewise included a combined administration of anandamide with indomethacin. In vitro, the effect of the cannabinoids on human platelet activation was studied by means of P-selectin expression using flow cytometry. Platelets were analysed under resting or thrombin receptor activating peptide (TRAP)-stimulated conditions, both after cannabinoid treatment alone and after TRAP stimulation and subsequent cannabinoid exposure. Finally, platelet count was assessed after treatment with high concentrations of anandamide. Anandamide, but not CBD and WIN55,212-2, significantly accelerated thrombus growth after one-time treatment as compared to vehicle control. Co-administration with indomethacin neutralized this effect. However, thrombogenesis was not altered by repeated treatment with the cannabinoids. In vitro, anandamide was shown to elicit a concentration-dependent activation of resting human platelets. However, at higher concentrations anandamide reduced the response to TRAP activation associated with a decrease of platelet count. CBD and WIN55,212-2 neither increased nor reduced activation of platelets. Acute exposure to anandamide elicits a cyclooxygenase-dependent prothrombotic effect in vivo. Anandamide seems to affect human platelet activation by a concentration-dependent toxic effect. By contrast, CBD and WIN55,212-2 were not associated with induction of thrombosis or activation of platelets. © 2016 BioFactors, 42(6):581-590, 2016.

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“…Interestingly, CB 1 and CB 2 have been detected in human platelets, within the cell membrane (Catani et al 2010a). More recently, virodhamine and 2-AG, but not AEA, were shown to share the ability of arachidonic acid to induce human platelet aggregation (Brantl et al 2014). This could be blocked by inhibitors of their metabolism by MAGL or COX, and was not mimicked by CB 1 or CB 2 agonists, suggesting it is metabolites of virodhamine and 2-AG that mediate their effects.…”

Section: Endocannabinoids and Bloodmentioning

confidence: 99%

Endocannabinoids

2015

Handbook of Experimental Pharmacology

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Activation of platelets by the endocannabinoids 2-arachidonoylglycerol and virodhamine is mediated by their conversion to arachidonic acid and thromboxane A2, not by activation of cannabinoid receptors

Cited by 8 publications

References 13 publications

Regulation of cAMP Intracellular Levels in Human Platelets Stimulated by 2‐Arachidonoylglycerol

Regulation of cAMP Intracellular Levels in Human Platelets Stimulated by 2‐Arachidonoylglycerol

Differential effects of endogenous, phyto and synthetic cannabinoids on thrombogenesis and platelet activity

Endocannabinoids

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