Protocatechualdehyde Synergizes with Aspirin at the Platelet Cyclooxygenase-1 Level

Abstract

Polyphenol-aspirin interactions were recently identified; however, the interaction mode and underlying mechanisms remained elusive. Here, we quantitatively assessed the potential interactions among two important polyphenolic compounds, caffeic acid (CA) and protocatechualdehyde (Pro), and aspirin in the AA-induced platelet aggregation model by applying the isobologram and universal response surface approach (URSA) methods. A molecular docking approach and an originally developed platelet-associated aspirin clearance approach (PAACA) were then applied to explore the potential interaction mechanisms. Although Pro and CA themselves exhibited weak inhibitory effect on arachidonic acid (AA)-induced platelet aggregation and the production of thromboxane B₂ (TXB₂), both Pro and CA potentiated aspirin action in a synergistic manner. The most prominent synergism was found between Pro and aspirin. Pro formed a stable complex into the cyclooxygenase-1 (COX-1) channel by in silico docking and significantly promoted the platelet-associated aspirin clearance, suggesting that the Pro interaction with COX-1 was favorable to the binding of aspirin with COX-1. Taken together, our findings suggest that the capacity of Pro and potentially other structurally similar polyphenolic compounds on promoting the binding of aspirin on platelet COX-1 might be the main mechanism of their synergism with aspirin.

Key words

polyphenols - aspirin - cyclooxygenase-1 - platelet-associated aspirin clearance - synergism

References

• 1 Patrono C, Garcia Rodriguez L A, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis.  N Engl J Med. 2005;  353 2373-2383
• 2 Miners J O. Drug interactions involving aspirin (acetylsalicylic acid) and salicylic acid.  Clin Pharmacokinet. 1989;  17 327-344
• 3 Crescente M, Jessen G, Momi S, Holtje H D, Gresele P, Cerletti C, de Gaetano G. Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level. Functional and modelling studies.  Thromb Haemost. 2009;  102 336-346
• 4 Scalbert A, Manach C, Morand C, Remesy C, Jimenez L. Dietary polyphenols and the prevention of diseases.  Crit Rev Food Sci Nutr. 2005;  45 287-306
• 5 Navarro-Nunez L, Rivera J, Guerrero J A, Martinez C, Vicente V, Lozano M L. Differential effects of quercetin, apigenin and genistein on signalling pathways of protease-activated receptors PAR(1) and PAR(4) in platelets.  Br J Pharmacol. 2009;  158 1548-1556
• 6 Gresele P, Cerletti C, Guglielmini G, Pignatelli P, de Gaetano G, Violi F. Effects of resveratrol and other wine polyphenols on vascular function: an update.  J Nutr Biochem. 2011;  22 201-211
• 7 Kostyuk V, Potapovich A, Suhan T, De Luca C, Pressi G, Dal Toso R, Korkina L. Plant polyphenols against UV-C-induced cellular death.  Planta Med. 2008;  74 509-514
• 8 Schini-Kerth V B, Etienne-Selloum N, Chataigneau T, Auger C. Vascular protection by natural product-derived polyphenols: in vitro and in vivo evidence.  Planta Med. advance online publication 2011;  DOI: 10.1055/s-0030-1250737
• 9 Murase T, Misawa K, Minegishi Y, Aoki M, Ominami H, Suzuki Y, Shibuya Y, Hase T. Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice.  Am J Physiol Endocrinol Metab. 2010;  , in press
• 10 Uto-Kondo H, Ayaori M, Ogura M, Nakaya K, Ito M, Suzuki A, Takiguchi S, Yakushiji E, Terao Y, Ozasa H, Hisada T, Sasaki M, Ohsuzu F, Ikewaki K. Coffee consumption enhances high-density lipoprotein-mediated cholesterol efflux in macrophages.  Circ Res. 2010;  106 779-787
• 11 Nardini M, Leonardi F, Scaccini C, Virgili F. Modulation of ceramide-induced NF-kappaB binding activity and apoptotic response by caffeic acid in U937 cells: comparison with other antioxidants.  Free Radic Biol Med. 2001;  30 722-733
• 12 Park J B. 5-Caffeoylquinic acid and caffeic acid orally administered suppress P-selectin expression on mouse platelets.  J Nutr Biochem. 2009;  20 800-805
• 13 Singh N, Rajini P S. Antioxidant-mediated protective effect of potato peel extract in erythrocytes against oxidative damage.  Chem Biol Interact. 2008;  173 97-104
• 14 Pari L, Prasath A. Efficacy of caffeic acid in preventing nickel induced oxidative damage in liver of rats.  Chem Biol Interact. 2008;  173 77-83
• 15 Czompa A, Dinya Z, Antus S, Varga Z. Synthesis and antioxidant activity of flavanoid derivatives containing a 1,4-benzodioxane moiety.  Arch Pharm (Weinheim). 2000;  333 175-180
• 16 Kim Y S, Kim N H, Lee S W, Lee Y M, Jang D S, Kim J S. Effect of protocatechualdehyde on receptor for advanced glycation end products and TGF-beta1 expression in human lens epithelial cells cultured under diabetic conditions and on lens opacity in streptozotocin-diabetic rats.  Eur J Pharmacol. 2007;  569 171-179
• 17 Prachayasittikul S, Buraparuangsang P, Worachartcheewan A, Isarankura-Na-Ayudhya C, Ruchirawat S, Prachayasittikul V. Antimicrobial and antioxidative activities of bioactive constituents from Hydnophytum formicarum Jack.  Molecules. 2008;  13 904-921
• 18 Born G V, Cross M J. The aggregation of blood platelets.  J Physiol. 1963;  168 178-195
• 19 Loll P J, Picot D, Ekabo O, Garavito R M. Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site.  Biochemistry. 1996;  35 7330-7340
• 20 Greco W R, Park H S, Rustum Y M. Application of a new approach for the quantitation of drug synergism to the combination of cis-diamminedichloroplatinum and 1-beta-D-arabinofuranosylcytosine.  Cancer Res. 1990;  50 5318-5327
• 21 Ferron G M, Jusko W J. Species- and gender-related differences in cyclosporine/prednisolone/sirolimus interactions in whole blood lymphocyte proliferation assays.  J Pharmacol Exp Ther. 1998;  286 191-200
• 22 Cerletti C, Livio M, De Gaetano G. Non-steroidal anti-inflammatory drugs react with two sites on platelet cyclo-oxygenase. Evidence from “in vivo” drug interaction studies in rats.  Biochim Biophys Acta. 1982;  714 122-128
• 23 Loll P J, Picot D, Garavito R M. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.  Nat Struct Biol. 1995;  2 637-643
• 24 Roth G J, Stanford N, Majerus P W. Acetylation of prostaglandin synthase by aspirin.  Proc Natl Acad Sci USA. 1975;  72 3073-3076
• 25 Olthof M R, Hollman P C, Zock P L, Katan M B. Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans.  Am J Clin Nutr. 2001;  73 532-538
• 26 Azuma K, Ippoushi K, Nakayama M, Ito H, Higashio H, Terao J. Absorption of chlorogenic acid and caffeic acid in rats after oral administration.  J Agric Food Chem. 2000;  48 5496-5500
• 27 Olthof M R, Hollman P C, Katan M B. Chlorogenic acid and caffeic acid are absorbed in humans.  J Nutr. 2001;  131 66-71
• 28 Nardini M, Cirillo E, Natella F, Scaccini C. Absorption of phenolic acids in humans after coffee consumption.  J Agric Food Chem. 2002;  50 5735-5741