Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level Functional and modelling studies

Abstract

While resveratrol and quercetin possess antiplatelet activity, little is known on the effect of gallic acid on platelets. We studied the interactions of these three different polyphenols among themselves and with aspirin, at the level of platelet cyclooxygenase-1 (COX-1). Both functional (in vitro and in vivo) and molecular modelling approaches were used. All three polyphenols showed comparable antioxidant activity (arachidonic acid [AA]-induced intraplatelet ROS production); however, resveratrol and quercetin, but not gallic acid, inhibited AA-induced platelet aggregation. Gallic acid, similarly to salicylic acid, the major aspirin metabolite, prevented inhibition of AA-induced platelet function by aspirin but, at variance with salicylic acid, also prevented inhibition by the other two polyphenols. Molecular modelling studies, performed by in silico docking the polyphenols into the crystal structure of COX-1, suggested that all compounds form stable complexes into the COX-1 channel, with slightly different but functionally relevant interaction geometries. Experiments in mice showed that gallic acid administered before aspirin, resveratrol or quercetin fully prevented their inhibitory effect on serum TxB(2). Finally, a mixture of resveratrol, quercetin and gallic acid, at relative concentrations similar to those contained in most red wines, did not inhibit platelet aggregation, but potentiated sub-inhibitory concentrations of aspirin. Gallic acid interactions with other polyphenols or aspirin at the level of platelet COX-1 might partly explain the complex, and possibly contrasting, effects of wine and other components of the Mediterranean diet on platelets and on the pharmacologic effect of low-dose aspirin.

Cardiovascular and Overall Mortality Risk in Relation to Alcohol Consumption in Patients With Cardiovascular Disease

“…58 Aspirin and other nonsteroidal antiinflammatory drugs, when combined with alcohol, can raise the risk of gastrointestinal bleeding by injuring the gastric mucosa and increasing the bleeding tendency 58 ; however, aspirin and alcohol appeared to act as independent risk factors, with additive effects on gastrointestinal bleeding but no interaction. 60 Experimental data 61 suggest that wine polyphenols might interact with aspirin, because they form stable complexes in the platelet cyclooxygenase-1 enzyme channel. Mixtures of resveratrol, quercetin, and gallic acid did potentiate the platelet inhibitory effect of subinhibitory concentrations of aspirin.…”

The structure, occurrence and biological activity of ellagitannins: a general review

“…Ellagitannins exhibit a wide range of biological activity, refl ected in their anti-atherogenic [Kaplan et al 2001, Khateeb et al 2010, antithrombotic [Teng et al 1997, Umar et al 2003, Crescente et al 2009, De Lange et al 2007, Mattiello et al 2009], anti-infl ammatory , Ngoumfo et al 2008 and anti-angiogenic [Jeon et al 2005, Lee and Lee 2005, Oak et al 2006 properties. Studies have confi rmed a correlation between the consumption of foods rich in ellagitannins (walnuts, pomegranates) and improved cardiovascular health [Beretta et al 2009, Larossa et al 2010.…”

Pharmacogenomics of Antiplatelet Drugs

“…Residual platelet activation in aspirin-treated patients was associated in other studies with an eightfold excess in the occurrence of future cardiovascular events (Frelinger et al 2006). In a systematic review of eight studies comprising 847 subjects, aspirin nonresponders, as identified by PFA-100, were more likely to have vascular events than aspirin responders (relative risk (RR) 1.63; 95 % CI 1.16-2.28) ), a finding confirmed in a large meta-analysis of 19 studies comprising 3003 patients (Crescente et al 2009). …”

“…The possibility that salicylate, rapidly accumulating in blood during chronic administration of aspirin, could interfere with the antiplatelet effect of the parent compound and induce a variable response to the latter was also proposed and demonstrated by different techniques (Dejana et al 1981Cerletti et al 1982a, b). Functional and modelling studies recently extended to different plant-derived polyphenols (such as gallic acid, resveratrol, quercetin) that have the capacity to bind to platelet COX-1 and to influence the effect of aspirin on platelet function (Crescente et al 2009). Nutritional compounds of different chemical nature may thus interfere with antiplatelet drugs and partially explain interindividual variability of inhibition of platelet response; but this interesting approach is at the moment of theoretical interest only.…”