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Plant extracts inhibit ADP-induced platelet activation in humans: their potential therapeutic role as ADP antagonists

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Abstract

Adenosine diphosphate (ADP) plays a pivotal role in platelet activation. Platelet hyperactivity is associated with vascular disease and also has a key role in haemostasis and thrombosis. ADP activates platelets through three purinoceptor subtypes, the Gq-coupled P2Y1 receptor, Gi-coupled P2Y12 receptor and P2X1 ligand-gated cation channel. Platelet ADP purinergic receptors are therefore suitable targets for antiplatelet drugs. Thienopyridines such as clopidogrel and ticlopidine, as well as other ADP receptor antagonists like prasugrel, ticagrelor, cangrelor and elinogrel have demonstrated clinical benefits via the inhibition of the selective purinergic ADP receptor, P2Y12. However, they still have limitations in their mode of action and efficacy, like increased risk of bleeding. Thus, the ongoing pursuit to develop newer and more effective antiplatelet agents continues. There is a growing interest in the purinergic antiplatelet properties exhibited by plant extracts. This article considers the following: pomolic acid isolated from Licania pittieri, brazilin isolated from the heartwood of Caesalpinia sappan L, phylligenin isolated from the twigs of Muraltia vulpina, bark oil of Gonystylus velutinus, seed and bark extracts from Aesculus hippocastanum L. and red wine phenolics and catechins isolated from green tea. Moreover, the method used to investigate platelet purinergic receptors should be considered, since using a more sensitive, high-resolution platelet sizer can sometimes detect platelet variations when the light transmission method was not able to do so. The exact mechanisms by which these plant extracts work need further investigation. They all however inhibit ADP-induced activation in human platelets. This could explain, at least in part, the protective effect of plant extracts as antiplatelet agents.

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References

  1. Gachet C (2005) The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol Ther 10:180–192

    Article  Google Scholar 

  2. Burnstock G (2011) Introductory overview of purinergic signalling. Front Biosci (Elite Ed) 3:896–900

    Google Scholar 

  3. Jagroop IA, Kakafika AI, Mikhailidis DP (2007) Platelets and vascular risk: an option for treatment. Curr Pharm Des 13:1669–1683

    Article  CAS  PubMed  Google Scholar 

  4. Pang L, Weiss MJ, Poncz M (2005) Megakaryocyte biology and related disorders. J Clin Invest 115:3332–3338

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Hechler B, Cattaneo M, Gachet C (2005) The P2 receptors in platelet function. Semin Thromb Hemost 31:150–161

    Article  CAS  PubMed  Google Scholar 

  6. Cattaneo M (2005) The P2 receptors and congenital platelet function defects. Semin Thromb Hemost 31:168–173

    Article  CAS  PubMed  Google Scholar 

  7. Kunapuli SP (2002) P2 receptors and platelet activation. Sci World J 13:424–433

    Article  Google Scholar 

  8. Jagroop IA, Burnstock G, Mikhailidis DP (2003) Both the ADP receptors P2Y1 and P2Y12, play a role in controlling shape change in human platelets. Platelets 14:15–20

    Article  PubMed  Google Scholar 

  9. Mahaut-Smith MP, Jones S, Evans RJ (2011) The P2X1 receptor and platelet function. Purinergic Signal 7:341–356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Jennings LK (2009) Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 102:248–257

    CAS  PubMed  Google Scholar 

  11. Xiang YZ, Kang LY, Gao XM, Shang HC, Zhang JH, Zhang BL (2008) Strategies for antiplatelet targets and agents. Thromb Res 123:35–49

    Article  CAS  PubMed  Google Scholar 

  12. Barn K, Steinhubl SR (2012) A brief review of the past and future of platelet P2Y12 antagonist. Coron Artery Dis 23:368–374

    Article  PubMed  Google Scholar 

  13. Cattaneo M, Lecchi A (2007) Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. J Thromb Haemost 5:577–582

    Article  CAS  PubMed  Google Scholar 

  14. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM (2000) Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 84:891–896

    CAS  PubMed  Google Scholar 

  15. Bernlochner I, Sibbing D (2012) Thienopyridines and other ADP-receptor antagonists. Handb Exp Pharmacol 210:165–198

    Article  CAS  PubMed  Google Scholar 

  16. Kim L, Charitakis K, Swaminathan RV, Feldman DN (2012) Novel antiplatelet therapies. Curr Atheroscler Rep 14:78–84

    Article  CAS  PubMed  Google Scholar 

  17. Panak E, Maffrand JP, Picard-Fraire C, Vallée E, Blanchard J, Roncucci R (1983) Ticlopidine: a promise for the prevention and treatment of thrombosis and its complications. Haemostasis 13:1–54

    PubMed  Google Scholar 

  18. Packham MA, Mustard JF (2005) Platelet aggregation and adenosine diphosphate/adenosine triphosphate receptors: a historical perspective. Semin Thromb Hemost 31:129–138

    Article  CAS  PubMed  Google Scholar 

  19. Cattaneo M, Podda GM (2010) State of the art of new P2Y12 antagonists. Intern Emerg Med 5:385–391

    Article  PubMed  Google Scholar 

  20. Gresele P, Agnelli G (2002) Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci 23:25–32

    Article  CAS  PubMed  Google Scholar 

  21. Wiviott SD, Trenk D, Frelinger AL, O'Donoghue M, Neumann FJ, Michelson AD, Angiolillo DJ, Hod H, Montalescot G, Miller DL, Jakubowski JA, Cairns R, Murphy SA, McCabe CH, Antman EM, Braunwald E, PRINCIPLE-TIMI 44 Investigators (2007) Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 116:2923–2932

    Article  CAS  PubMed  Google Scholar 

  22. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015

    Article  CAS  PubMed  Google Scholar 

  23. Gurbel PA, Bliden KP, Butler K, Antonino MJ, Wei C, Teng R, Rasmussen L, Storey RF, Nielsen T, Eikelboom JW, Sabe-Affaki G, Husted S, Kereiakes DJ, Henderson D, Patel DV, Tantry US (2010) Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 121:1188–1199

    Article  CAS  PubMed  Google Scholar 

  24. Storey RF, Angiolillo DJ, Patil SB, Desai B, Ecob R, Husted S, Emanuelsson H, Cannon CP, Becker RC, Wallentin L (2010) Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 56:1456–1462

    Article  CAS  PubMed  Google Scholar 

  25. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G (2006) Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 27:1038–1047

    Article  CAS  PubMed  Google Scholar 

  26. Norgard NB (2009) Cangrelor: a novel P2Y12 receptor antagonist. Expert Opin Investig Drugs 18:1219–1230

    Article  CAS  PubMed  Google Scholar 

  27. Oestreich JH (2010) Elinogrel, a reversible P2Y12 receptor antagonist for the treatment of acute coronary syndrome and prevention of secondary thrombotic events. Curr Opin Investig Drugs 11:340–348

    CAS  PubMed  Google Scholar 

  28. Patel PA, Lane B, Augoustides JG (2013) Progress in platelet blockers: the target is the P2Y12 receptor. J Cardiothorac Vasc Anesth 27:620–624

    Article  CAS  PubMed  Google Scholar 

  29. Collet JP, O'Connor S (2012) Clinical effects and outcomes with new P2Y12 inhibitors in ACS. Fundam Clin Pharmacol 26:16–18

    Article  CAS  PubMed  Google Scholar 

  30. Estrada O, Alvarado-Castillo C, Fernandez A, Lopez M, Romero-Vecchione E, Vasquez J et al (2009) Pomolic acid isolated from the leaves of Licania pittieri inhibits ADP- and epinephrine-induced platelet aggregation and has hypotensive effect on rats. Current Bioactive Compounds 5:219–225

    Article  CAS  Google Scholar 

  31. Alvarado-Castillo C, Estrada O, Carvajal E (2012) Pomolic acid (PA), triterpenoid isolated from Licania pittieri, as a competitive antagonist of ADP-induced aggregation of human platelets. Phytomedicine 19:484–487

    Article  CAS  PubMed  Google Scholar 

  32. Barradas MA, Jagroop IA, O'Donoghue S, Jeremy JY, Mikhailidis DP (1993) Effect of milrinone on human platelet shape change, aggregation and thromboxane A2 synthesis: an in vitro study. Thromb Res 71:227–236

    Article  CAS  PubMed  Google Scholar 

  33. Barradas MA, O'Donoghue S, Mikhailidis DP (1992) Measurement of platelet volume using a channelyzer: assessment of the effect of agonists and antagonists. In Vivo 6:629–634

    CAS  PubMed  Google Scholar 

  34. Jagroop IA, Clathworthy I, Lewin J, Mikhailidis DP (2000) Shape change in human platelet: measurements with a channelyzer and visualisation by electron microscopy. Platelets 11:28–32

    Article  CAS  PubMed  Google Scholar 

  35. Jagroop IA, Mikhailidis DP (2001) Doxazosin, an alpha1-adrenoceptor antagonist, inhibits serotonin-induced shape change in human platelets. J Human Hypertens 15:203–207

    Article  CAS  Google Scholar 

  36. Jagroop IA, Mikhailidis DP (2008) The effect of tirofiban on fibrinogen/agonist-induced platelet shape change and aggregation. Clin Appl Thromb Hemost 14:295–302

    Article  CAS  PubMed  Google Scholar 

  37. Estrada O, González-Guzmán JM, Salazar-Bookaman M, Fernández AZ, Cardozo A, Alvarado-Castillo C (2011) Pomolic acid of Licania pittieri elicits endothelium-dependent relaxation in rat aortic rings. Phytomedicine 18:464–469

    Article  CAS  PubMed  Google Scholar 

  38. Barradas MA (1993) Serotonin and platelet studies in vascular disease. Doctor of Philosophy Thesis, p 74, University of London

  39. Chang Y, Huang SK, Lu WJ, Chung CL, Chen WL, Lu SH, Lin KH, Sheu JR (2013) Brazilin isolated from Caesalpinia sappan L. acts as a novel collagen receptor agonist in human platelets. J Biomed Sci 20:4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Hwang GS, Kim JY, Chang TS, Jeon SD, So DS, Moon CK (1998) Effects of brazilin on the phospholipase A2 activity and changes of intracellular free calcium concentration in rat platelets. Arch Pharm Res 21:774–778

    Article  CAS  PubMed  Google Scholar 

  41. Moharam BA, Jantan I, Jalil J, Shaari K (2010) Inhibitory effects of phylligenin and quebrachitol isolated from Mitrephora vulpina on platelet activating factor receptor binding and platelet aggregation. Molecules 15:7840–7848

    Article  CAS  PubMed  Google Scholar 

  42. Moharam BA, Jantan I, Fb A, Jalil J (2010) Antiplatelet aggregation and platelet activating factor (PAF) receptor antagonistic activities of the essential oils of five Goniothalamus species. Molecules 15:5124–5138

    Article  CAS  PubMed  Google Scholar 

  43. Ballabeni V, Tognolini M, Chiavarini M, Impicciatore M, Bruni R, Bianchi A, Barocelli E (2004) Novel antiplatelet and antithrombotic activities of essential oil from Lavandula hybrida Reverchon "grosso". Phytomedicine 11:596–601

    Article  CAS  PubMed  Google Scholar 

  44. Felixsson E, Persson IA, Eriksson AC, Persson K (2010) Horse chestnut extract contracts bovine vessels and affects human platelet aggregation through 5-HT(2A) receptors: an in vitro study. Phytother Res 24:1297–1301

    Article  CAS  PubMed  Google Scholar 

  45. Tiffany N, Boon H, Ulbricht C, Basch E, Bent S, Barrette EP, Smith M, Sollars D, Dennehy CE, Szapary P (2002) Horse chestnut: a multidisciplinary clinical review. J Herb Pharmacother 2:71–85

    PubMed  Google Scholar 

  46. Siebert U, Brach M, Sroczynski G, Berla K (2002) Efficacy, routine effectiveness, and safety of horse chestnut seed extract in the treatment of chronic venous insufficiency. A meta-analysis of randomized controlled trials and large observational studies. Int Angiol 21:305–315

    CAS  PubMed  Google Scholar 

  47. Kronberger L, Gölles J (1969) On the prevention of thrombosis with Aesculus extract. Med Klin 64:1207–1209

    CAS  PubMed  Google Scholar 

  48. Marmot M (2001) Aetiology of coronary heart disease. BMJ 323:1261–1262

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. de Lange DW, Verhoef S, Gorter G, Kraaijenhagen RJ, van de Wiel A, Akkerman JW (2007) Polyphenolic grape extract inhibits platelet activation through PECAM-1: an explanation for the French paradox. Alcohol Clin Exp Res 31:1308–1314

    Article  PubMed  Google Scholar 

  50. Ruf JC (1999) Wine and polyphenols related to platelet aggregation and atherothrombosis. Drugs Exp Clin Res 25:125–131

    CAS  PubMed  Google Scholar 

  51. Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM (1995) The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta 235:207–219

    Article  CAS  PubMed  Google Scholar 

  52. Soleas GJ, Diamandis EP, Goldberg DM (1997) Wine as a biological fluid: history, production, and role in disease prevention. J Clin Lab Anal 11:287–313

    Article  CAS  PubMed  Google Scholar 

  53. Freedman JE, Parker C 3rd, Li L, Perlman JA, Frei B, Ivanov V, Deak LR, Iafrati MD, Folts JD (2001) Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation 103:2792–2798

    Article  CAS  PubMed  Google Scholar 

  54. Pignatelli P, Lenti L, Pulcinelli FM, Catasca R, Saccani G, Germanò G, Marcoccia A, Silvestri MA, Ghiselli A, Violi F (2002) Red and white wine differently affect collagen-induced platelet aggregation. Pathophysiol Haemost Thromb 32:356–358

    Article  CAS  PubMed  Google Scholar 

  55. Clutton P, Folts JD, Freedman JE (2001) Pharmacological control of platelet function. Pharmacol Res 44:255–264

    Article  CAS  PubMed  Google Scholar 

  56. Ralevic V, Burnstock G (2003) Involvement of purinergic signaling in cardiovascular diseases. Drug News Perspect 16:133–140

    Article  CAS  PubMed  Google Scholar 

  57. Jagroop IA, Matsagas MI, Geroulakos G, Mikhailidis DP (2004) The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease. Platelets 15:117–125

    Article  CAS  PubMed  Google Scholar 

  58. Erlinge D, Burnstock G (2008) P2 receptors in cardiovascular physiology and disease. Purinergic Signalling 4:1–20

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Yun AJ, Bazar KA, Lee PY, Gerber A, Daniel SM (2005) The smoking gun: many conditions associated with tobacco exposure may be attributable to paradoxical compensatory autonomic responses to nicotine. Med Hypotheses 64:1073–1079

    Article  CAS  PubMed  Google Scholar 

  60. Sumpio BE, Cordova AC, Berke-Schlessel DW, Qin F, Chen QH (2006) Green tea, the "Asian paradox," and cardiovascular disease. J Am Coll Surg 202:813–825

    Article  PubMed  Google Scholar 

  61. Imai K, Nakachi K (1995) Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. BMJ 310:693–696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Kang WS, Lim IH, Yuk DY, Chung KH, Park JB, Yoo HS, Yun YP (1999) Antithrombotic activities of green tea catechins and (−)-epigallocatechin gallate. Thromb Res 96:229–337

    Article  CAS  PubMed  Google Scholar 

  63. Islam MA (2012) Cardiovascular effects of green tea catechins: progress and promise. Recent Pat Cardiovasc Drug Discov 7:88–99

    Article  CAS  PubMed  Google Scholar 

  64. Cattaneo M (2007) Platelet P2 receptors: old and new targets for antithrombotic drugs. Expert Rev Cardiovasc Ther 5:45–55

    Article  CAS  PubMed  Google Scholar 

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  1. Academic Department of Surgery, Division of Surgical and Interventional Science, Royal Free Campus, University College London Medical School, University College London (UCL), Pond Street, London, NW3 2QG, UK

    Indera Anita Jagroop

  2. Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), Pond Street, London, NW3 2QG, UK

    Indera Anita Jagroop

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Jagroop, I.A. Plant extracts inhibit ADP-induced platelet activation in humans: their potential therapeutic role as ADP antagonists. Purinergic Signalling 10, 233–239 (2014). https://doi.org/10.1007/s11302-013-9393-0

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