Journal of Natural Medicines

, Volume 71, Issue 1, pp 249–256 | Cite as

Aged garlic extract suppresses platelet aggregation by changing the functional property of platelets

Original Paper

Abstract

Aged garlic extract (AGE), a garlic preparation rich in water-soluble cysteinyl moieties, has been reported to have multiple beneficial effects on cardiovascular disease including inhibition of platelet aggregation. However, the mode of AGE action on platelets has not been clear. In this study, we examined the effect of AGE on the functional property of platelet by administering AGE to rats and evaluating the platelet aggregation in response to collagen in vitro. We found that AGE treatment significantly reduced the ability of platelet to aggregate and this effect of AGE was manifested on the 14 day, but not 7 day of treatment. In addition, AGE treatment produced platelets that responded to collagen by significantly increasing the amount of both the extracellular ATP and the extra- and intracellular TXB2. AGE treatment also dose-dependently suppressed the phosphorylation of collagen-induced ERK, p38 and JNK. However, AGE administration did not affect the bleeding time. These findings suggest that AGE treatment results in suppression of platelet aggregation by changing the functional property of platelets to respond to collagen.

Keywords

Aged garlic extract Collagen MAP kinase P2X1 receptor Platelet aggregation Rat Thromboxane receptor 

Notes

Acknowledgments

The authors thank Dr. Takami Oka, Dr. Koichi Tamura and Mr. Hirotaka Amano of Wakunaga Pharmaceutical Co. Ltd. for their helpful advise, encouragement and critical reading of the manuscript, and Dr. Kazuhiko Imamura and Dr. Yukihiro Kodera, Wakunaga Pharmaceutical Co. Ltd., for preparation of AGE.

References

  1. 1.
    Patel SR, Hartwig JH, Italiano JE (2005) The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest 115:3348–3354CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Coller BS, Shattil SJ (2008) The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood 112:3011–3025CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Smyth SS, Woulfe DS, Weitz JI, Gachet C, Conley PB, Goodman SG, Roe MT, Kuliopulos A, Moliterno DJ, French PA, Steinhubl SR, Becker RC (2009) G-protein-coupled receptors as signaling targets for antiplatelet therapy. Arterioscler Thromb Vasc Biol 29:449–457CrossRefPubMedGoogle Scholar
  4. 4.
    Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, Massarotti EM, Remold-O’Donnell E, Farndale RW, Ware J, Lee DM (2010) Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327:580–583CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Leslie M (2010) Cell biology. Beyond clotting: the powers of platelets. Science 328:562–564CrossRefPubMedGoogle Scholar
  6. 6.
    Barrett NE, Holbrook L, Jones S, Kaiser WJ, Moraes LA, Rana R, Sage T, Stanley RG, Tucker KL, Wright B, Gibbins JM (2008) Future innovations in anti-platelet therapies. Br J Pharmacol 154:918–939CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Watson SP, Auger JM, McCarty OJ, Pearce AC (2005) GPVI and integrin alphaIIb beta3 signaling in platelets. J Thromb Haemost 3:1752–1762CrossRefPubMedGoogle Scholar
  8. 8.
    Davì G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494CrossRefPubMedGoogle Scholar
  9. 9.
    Jennings LK (2009) Role of platelets in atherothrombosis. Am J Cardiol 103:4A–10ACrossRefPubMedGoogle Scholar
  10. 10.
    Ruggeri ZM (2002) Platelets in atherothrombosis. Nat Med 8:1227–1234CrossRefPubMedGoogle Scholar
  11. 11.
    Banerjee SK, Maulik SK (2002) Effect of garlic on cardiovascular disorders: a review. Nutr J 1:4CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Dillon SA, Burmi RS, Lowe GM, Billington D, Rahman K (2003) Antioxidant properties of aged garlic extract: an in vitro study incorporating human low density lipoprotein. Life Sci 72:1583–1594CrossRefPubMedGoogle Scholar
  13. 13.
    Rahman K, Lowe GM (2006) Garlic and cardiovascular disease: a critical review. J Nutr 136:736S–740SCrossRefPubMedGoogle Scholar
  14. 14.
    Tattelman E (2005) Health effects of garlic. Am Fam Physician 72:103–106PubMedGoogle Scholar
  15. 15.
    Amagase H, Petesch BL, Matsuura H, Kasuga S, Itakura Y (2001) Intake of garlic and its bioactive components. J Nutr 131:955S–962SCrossRefPubMedGoogle Scholar
  16. 16.
    Matsutomo T, Kodera Y (2016) Development of an analytic method for sulfur compounds in aged garlic extract with the use of a postcolumn high performance liquid chromatography method with sulfur-specific detection. J Nutr 146:450S–455SCrossRefPubMedGoogle Scholar
  17. 17.
    Ahmadi N, Nabavi V, Hajsadeghi F, Zeb I, Flores F, Ebrahimi R, Budoff M (2013) Aged garlic extract with supplement is associated with increase in brown adipose, decrease in white adipose tissue and predict lack of progression in coronary atherosclerosis. Int J Cardiol 168:2310–2314CrossRefPubMedGoogle Scholar
  18. 18.
    Budoff MJ, Ahmadi N, Gul KM, Liu ST, Flores FR, Tiano J, Takasu J, Miller E, Tsimikas S (2009) Aged garlic extract supplemented with B vitamins, folic acid and l-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial. Prev Med 49:101–107CrossRefPubMedGoogle Scholar
  19. 19.
    Matsumoto S, Nakanishi R, Li D, Alani A, Rezaeian P, Prabhu S, Abraham J, Fahmy MA, Dailing C, Flores F, Hamal S, Broersen A, Kitslaar PH, Budoff MJ (2016) Aged garlic extract reduces low attenuation plaque in coronary arteries of patients with metabolic syndrome in a prospective randomized double-blind study. J Nutr 146:427S–432SCrossRefPubMedGoogle Scholar
  20. 20.
    Weiss N, Papatheodorou L, Morihara N, Hilge R, Ide N (2013) Aged garlic extract restores nitric oxide bioavailability in cultured human endothelial cells even under conditions of homocysteine elevation. J Ethnopharmacol 145:162–167CrossRefPubMedGoogle Scholar
  21. 21.
    Ried K, Frank OR, Stocks NP (2013) Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial. Eur J Clin Nutr 67:64–70CrossRefPubMedGoogle Scholar
  22. 22.
    Morihara N, Ide N, Sumioka I, Kyo E (2005) Aged garlic extract inhibits peroxynitrite-induced hemolysis. Redox Rep 10:159–165CrossRefPubMedGoogle Scholar
  23. 23.
    Morihara N, Ide N, Weiss N (2011) Aged garlic extract inhibits homocysteine-induced scavenger receptor CD36 expression and oxidized low-density lipoprotein cholesterol uptake in human macrophages in vitro. J Ethnopharmacol 134:711–716CrossRefPubMedGoogle Scholar
  24. 24.
    Morihara N, Hino A, Yamaguchi T, Suzuki J (2016) Aged garlic extract suppresses the development of atherosclerosis in apolipoprotein E-Knockout mice. J Nutr 146:460S–463SCrossRefPubMedGoogle Scholar
  25. 25.
    Allison GL, Lowe GM, Rahman K (2012) Aged garlic extract inhibits platelet activation by increasing intracellular cAMP and reducing the interaction of GPIIb/IIIa receptor with fibrinogen. Life Sci 91:1275–1280CrossRefPubMedGoogle Scholar
  26. 26.
    Steiner M, Lin RS (1998) Changes in platelet function and susceptibility of lipoproteins to oxidation associated with administration of aged garlic extract. J Cardiovasc Pharmacol 31:904–908CrossRefPubMedGoogle Scholar
  27. 27.
    Rahman K, Billington D (2000) Dietary supplementation with aged garlic extract inhibits ADP-induced platelet aggregation in humans. J Nutr 130:2662–2665CrossRefPubMedGoogle Scholar
  28. 28.
    United States Pharmacopeial Convention I (2015) United States Pharmacopoeia 38 Garlic Fluidextract USP 38-NF 33. United States Pharmacopeial Convention, Rockville, pp 6052–6055Google Scholar
  29. 29.
    Lau AJ, Toh DF, Chua TK, Pang YK, Woo SO, Koh HL (2009) Antiplatelet and anticoagulant effects of Panax notoginseng: comparison of raw and steamed Panax notoginseng with Panax ginseng and Panax quinquefolium. J Ethnopharmacol 125:380–386CrossRefPubMedGoogle Scholar
  30. 30.
    Dejana E, Callioni A, Quintana A, de Gaetano G (1979) Bleeding time in laboratory animals. II—a comparison of different assay conditions in rats. Thromb Res 15:191–197CrossRefPubMedGoogle Scholar
  31. 31.
    Kodera Y, Matsuura H, Sumiyoshi H, Sumi S (2003) Garlic chemistry: chemical and biological properties of sulfur-containing compounds derived from garlic. In: Shahidi F (ed) Food factors in health promotion and disease prevention. American Chemical Society, Washington DC, pp 346–357CrossRefGoogle Scholar
  32. 32.
    Hechler B, Cattaneo M, Gachet C (2005) The P2 receptors in platelet function. Semin Thromb Hemost 31:150–161CrossRefPubMedGoogle Scholar
  33. 33.
    Rosenfeld L, Grover GJ, Stier CT (2001) Ifetroban sodium: an effective TxA2/PGH2 receptor antagonist. Cardiovasc Drug Rev 19:97–115CrossRefPubMedGoogle Scholar
  34. 34.
    Toth-Zsamboki E, Oury C, Cornelissen H, De Vos R, Vermylen J, Hoylaerts MF (2003) P2X1-mediated ERK2 activation amplifies the collagen-induced platelet secretion by enhancing myosin light chain kinase activation. J Biol Chem 278:46661–46667CrossRefPubMedGoogle Scholar
  35. 35.
    Mazharian A, Roger S, Maurice P, Berrou E, Popoff MR, Hoylaerts MF, Fauvel-Lafeve F, Bonnefoy A, Bryckaert M (2005) Differential Involvement of ERK2 and p38 in platelet adhesion to collagen. J Biol Chem 280:26002–26010CrossRefPubMedGoogle Scholar
  36. 36.
    Adam F, Kauskot A, Nurden P, Sulpice E, Hoylaerts MF, Davis RJ, Rosa JP, Bryckaert M (2010) Platelet JNK1 is involved in secretion and thrombus formation. Blood 115:4083–4092CrossRefPubMedGoogle Scholar
  37. 37.
    Okuma M, Yamori Y (1976) Platelet survival studies in stroke-prone spontaneously hypertensive rats (SHRSP). Stroke 7:60–64CrossRefPubMedGoogle Scholar
  38. 38.
    Jackson SP, Nesbitt WS, Kulkarni S (2003) Signaling events underlying thrombus formation. J Thromb Haemost 1:1602–1612CrossRefPubMedGoogle Scholar
  39. 39.
    Zarbock A, Polanowska-Grabowska RK, Ley K (2007) Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 21:99–111CrossRefPubMedGoogle Scholar
  40. 40.
    Mangin P, Yuan Y, Goncalves I, Eckly A, Freund M, Cazenave JP, Gachet C, Jackson SP, Lanza F (2003) Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA. J Biol Chem 278:32880–32891CrossRefPubMedGoogle Scholar
  41. 41.
    Oury C, Sticker E, Cornelissen H, De Vos R, Vermylen J, Hoylaerts MF (2004) ATP augments von Willebrand factor-dependent shear-induced platelet aggregation through Ca2+-calmodulin and myosin light chain kinase activation. J Biol Chem 279:26266–26273CrossRefPubMedGoogle Scholar
  42. 42.
    Chamorro A (2009) TP receptor antagonism: a new concept in atherothrombosis and stroke prevention. Cerebrovasc dis 27:20–27CrossRefPubMedGoogle Scholar
  43. 43.
    Adam F, Kauskot A, Rosa JP, Bryckaert M (2008) Mitogen-activated protein kinases in hemostasis and thrombosis. J Thromb Haemost 6:2007–2016CrossRefPubMedGoogle Scholar
  44. 44.
    Chan KC, Hsu CC, Yin MC (2002) Protective effect of three diallyl sulphides against glucose-induced erythrocyte and platelet oxidation, and ADP-induced platelet aggregation. Thromb Res 108:317–322CrossRefPubMedGoogle Scholar
  45. 45.
    Srivastava KC, Tyagi OD (1993) Effects of a garlic-derived principle (ajoene) on aggregation and arachidonic acid metabolism in human blood platelets. Prostaglandins Leukot Essent Fat Acids 49:587–595CrossRefGoogle Scholar
  46. 46.
    Louson LD, Wang ZJ (1993) Pre-hepatic fate of the organosulfur compounds derived from garlic (Allium sativum). Planta Med 59:A688–A689CrossRefGoogle Scholar
  47. 47.
    Amano H, Kazamori D, Itoh K (2016) Pharmacokinetics of S-allyl-l-cysteine in rats is characterized by high oral absorption and extensive renal reabsorption. J Nutr 146:456S–459SCrossRefPubMedGoogle Scholar
  48. 48.
    Suzuki J, Yamaguchi T, Matsutomo T, Amano H, Morihara N, Kodera Y (2016) S-1-Propenylcysteine promotes the differentiation of B cells into IgA-producing cells by the induction of Erk1/2-dependent Xbp1 expression in Peyer’s patches. Nutrition 32:884–889CrossRefPubMedGoogle Scholar
  49. 49.
    Ogawa T, Kodera Y, Hirata D, Blackwell TK, Mizunuma M (2016) Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf. Sci Rep 6:21611CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Akiyama H, Kudo S, Shimizu T (1985) The absorption, distribution and excretion of a new antithrombotic and vasodilating agent, cilostazol, in rat, rabbit, dog and man. Arzneimittelforschung 35:1124–1132PubMedGoogle Scholar
  51. 51.
    Vaes LP, Chyka PA (2000) Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence. Ann Pharmacother 34:1478–1482CrossRefPubMedGoogle Scholar
  52. 52.
    Macan H, Uykimpang R, Alconcel M, Takasu J, Razon R, Amagase H, Niihara Y (2006) Aged garlic extract may be safe for patients on warfarin therapy. J Nut 136:793S–795SCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan 2016

Authors and Affiliations

  1. 1.Drug Discovery LaboratoryWakunaga Pharmaceutical Co. Ltd.AkitakataJapan
  2. 2.Healthcare Research and Development DivisionWakunaga Pharmaceutical Co. Ltd.AkitakataJapan

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