Platelet-Activating Factor and Its Antagonists: Scientific Background and Clinical Applications of Ginkgolides

  • Pierre G. Braquet


Platelet-activating factor (PAF), a potent phospholipid inflammatory mediator, has been implicated in several pathophysiological disorders. The discovery of selective PAF receptor antagonists has greatly facilitated the accumulation of knowledge on the role of PAF in animal models of these disorders (see, for reviews, [1–3]). The use of selective, potent, orally active PAF receptor antagonists may, at least in part, allow us to successfully explore the problematic points of PAF research.


Septic Shock Systemic Inflammatory Response Syndrome Endotoxic Shock Inflammatory Mediator Release Eicosanoid Release 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Braquet P, Touqui L, Shen TS, Vargaftig BB (1987) Perspectives in platelet-activating factor research. Pharmacol Rev 39: 97–145PubMedGoogle Scholar
  2. 2.
    Koltai M, Hosford D, Guinot P, Esanu A, Braquet P (1991) Platelet-activating factor (PAF): a review of its effects, antagonists and possible future clinical applications. Drugs 42 (part I): 9–29PubMedCrossRefGoogle Scholar
  3. 3.
    Koltai M, Hosford D, Guinot P, Esanu A, Braquet P (1991) Platelet-activating factor (PAF): a review of its effects, antagonists and possible future clinical applications. Drugs 42 (part II): 174–204PubMedCrossRefGoogle Scholar
  4. 4.
    Braquet P, Hosford D (1991) Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents. J Ethnopharmacol 32: 135–139PubMedCrossRefGoogle Scholar
  5. 5.
    Braquet P, Esanu A, Busine E, Hosford D, Broquet C, Koltai M (1991) Recent progress in ginkgolide research. Med Res Rev 11: 295–355PubMedCrossRefGoogle Scholar
  6. 6.
    Braquet P, Spinnewyn B, Braquet M, Bourgain RH, Taylor JE, Etienne A, Drieu K (1985) BN 52021 and related compounds: a new series of highly specific PAF-acether antagonists isolated from Ginkgo biloba. Blood Vessels 16: 559–572Google Scholar
  7. 7.
    Huxtable JR (1992) The pharmacology of extinction. J Ethnopharmacol 37: 1–11PubMedCrossRefGoogle Scholar
  8. 8.
    Etienne A, Hecquet F, Guilmard C, Soulard C, Braquet P (1987) A potential link between platelet-activating factor and plasma protease activity. Int J Tissue React 9: 19 - 26PubMedGoogle Scholar
  9. 9.
    Etienne A, Hecquet F, Soulard C, Spinnewyn B, Clostre F, Braquet P (1987) In vivo inhibition of plasma protein leakage and Salmonella enteritidis-induced mortality in the rat by specific PAF acether antagonist BN 52021. Agents Actions 17: 368–370CrossRefGoogle Scholar
  10. 10.
    Corey EJ, Gavai AV (1988) Enantioselective route to a key intermediate in the total synthesis of ginkgolide B. Tetrahedron Lett 29: 3201–3204CrossRefGoogle Scholar
  11. 11.
    Corey EJ, Kang MC, Desai MC, Ghosh AK, Houpis IN (1988) Total synthesis of (±)ginkgolide B. J Amer Chem Soc 110: 649–651CrossRefGoogle Scholar
  12. 12.
    Corey EJ, Rao KS (1991) Enantioselective total synthesis of ginkgolide derivatives lacking the tert-butyl group, an essential structural subunit for antagonism of platelet- activating factor. Tetrahedron Lett 32: 4623–1626CrossRefGoogle Scholar
  13. 13.
    Domingo MT, Piro F, Broquet C, Auclair E, Chabrier PE, Braquet P (1992) Reversible or irreversible modification of [3H]PAF binding on rabbit platelet membranes differentiates various PAF receptor antagonists. Lipids 27: 582–686PubMedCrossRefGoogle Scholar
  14. 14.
    Godfroid JJ, Dive G, Lamotte-Brasseur J, Heymans (1991) PAF-receptor structure: a hypothesis. Lipids 26: 1162–1166Google Scholar
  15. 15.
    Lamotte-Brasseur J, Heymans F, Dive G, Lamouri A, Batt JP, Reduilh C, Hosford D, Braquet P, Godfroid JJ (1991) PAF-receptor and “Cacheoreilles” effect: 2. Simple PAF-antagonists. Lipids 26: 1167–1171PubMedCrossRefGoogle Scholar
  16. 16.
    Ye RD, Prossnitz ER, Zou AH, Cochrane CG (1991) Characterization of a human cDNA that encodes a functional receptor for platelet activating factor. Biochem Biophys Res Commun 180: 105–111PubMedCrossRefGoogle Scholar
  17. 17.
    Nakamura M, Honda Z, Izumi T, Sakanaka C, Mutoh H, Minami M, Bito H, Seyama Y, Matsumoto T, Noma M, Shimizu T (1991) Molecular cloning and expression of platlet-activating factor receptor from human leukocytes J Biol Chem 266: 20400–20405Google Scholar
  18. 18.
    Honda Z, Nakamura M, Seyama Y, Shimizu T (1992) Properties of the guinea-pig lung platelet-activating factor receptor encoded by the cloned cDNA. J Lipid Mediators 5: 105–107Google Scholar
  19. 19.
    Braquet P, Paubert-Braquet M, Bourgain R, Bussolino F, Hosford D (1989) PAF/cytokine autogenerated feedback networks in microvascular immune injury: consequences in shock, ischemia and graft rejection. J Lipid Mediators 1: 75–112Google Scholar
  20. 20.
    Braquet P, Paubert-Braquet M, Koltai M, Bourgain R, Bussolino F, Hosford D (1989) Is there a case for PAF antagonists in the treatment of ischemic states? Trends Pharmacol Sci 10: 23–30PubMedCrossRefGoogle Scholar
  21. 21.
    McColl SR, Krump E, Naccache PH, Poubelle PE, Braquet P, Braquet M, Boergeat P (1991) Granulocyte-macrophage colony-stimulating factor increases the synthesis of leukotriene B4 by human neutrophils in response to platelet-activating factor. Enhancement of both arachidonic acid availability and 5-lipoxygenase activation. J Immunol 146: 1204–1211PubMedGoogle Scholar
  22. 22.
    Paubert-Braquet M, Hosford D, Koltz P, Guilbaud J, Braquet P (1990) Tumor necrosis factor primes PAF-induced superoxide production by human neutrophils: possible involvement of G proteins. J Lipid Mediators 2: S1–S14Google Scholar
  23. 23.
    Gatti S, Faggioni R, Echtenacher B, Ghezzi P (1993) Role of tumour necrosis factor and reactive oxygen intermediates in lipopolysaccharide-induced pulmonary oedema and lethality. Clin Exp Immunol 91: 456–461PubMedCrossRefGoogle Scholar
  24. 24.
    Pignol B, Henane S, Sorlin B, Rola-Pleszczynski M, Mencia-Huerta JM, Braquet P (1990) Effect of long-term treatment with platelet-activating factor on IL-1 and IL-2 production by rat spleen cells. J Immunol 145: 980–984PubMedGoogle Scholar
  25. 25.
    Merlos M, Gomez M, Giral M, Vericat ML, Garcia-Rafanell J, Forn J (1991) Effects of PAF-antagonists in mouse ear oedema induced by several inflammatory agents. Br J Pharmacol 104: 990–994PubMedGoogle Scholar
  26. 26.
    Zarco P, Maestre C, Herrero-Beaumont G, Gonzales E, Garcia-Hoyo R, Navarro FJ, Braquet P, Egido J (1992) Involvement of platelet-activating factor and tumour necrosis factor in the pathogenesis of joint inflammation in rabbits. Clin Exp Immunol 88: 318–323PubMedCrossRefGoogle Scholar
  27. 27.
    Bone RC (1992) Towards an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 268: 3452–3456PubMedCrossRefGoogle Scholar
  28. 28.
    Bone RC (1991) The pathogenesis of sepsis. Ann Intern Med 115: 457–469PubMedGoogle Scholar
  29. 29.
    Koltai M, Hosford D, Braquet P (1992) The role of PAF and cytokines in microvascular tissue injury. J Lab Clin Med 19: 461–465Google Scholar
  30. 30.
    Zimmerman GA, Ringer TV (1992) Inflammatory host responses in sepsis. Prog Pediatr Crit Care 8: 163–189Google Scholar
  31. 31.
    Koltai M, Hosford D, Braquet P (1993) PAF-induced amplification of mediator release in septic shock: prevention of downregulation by PAF antagonists. J Lipid Mediators 6: 183–198Google Scholar
  32. 32.
    Koltai M, Hosford D, Braquet PG (1993) Platelet-activating factor in septic shock. New Horizons 1: 87–95PubMedGoogle Scholar
  33. 33.
    Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ III, Zentella A, Albert DJ, Shires GT, Cerami A (1986) Shock and tissue injury induced by recombinant human cachectin. Science (Wash DC) 234: 470–474CrossRefGoogle Scholar
  34. 34.
    Mozes T, Heiligers JPC, Tak CJAM, Zijlstra FJ, Ben-Efraim S, Saxena PR, Bonta IL (1991) Platelet activating factor is one of the mediators involved in endotoxic shock in pigs. J Lipid Mediators 4: 309–325Google Scholar
  35. 35.
    Mozes T, Zijlstra FJ, Heiligers JPC (1992) Interactions between platelet activating factor and eicosanoids during endotoxic shock in anaesthetized pigs. Mediat Inflamm 1: 183–190CrossRefGoogle Scholar
  36. 36.
    Klosterhalfen B, Horstmann-Jungemann K, Vogel P, Flohe S, Offner F, Kirkpatrick CJ, Heinrich PC (1992) The time course of various inflammatory mediators during recurrent endotoxemia. Biochem Pharmacol 43: 2103–2109PubMedCrossRefGoogle Scholar
  37. 37.
    Yue T-L, Rabinovici R, Farhat M, Feuerstein G (1990) Pharmacological profile of BN 50739, a new PAF antagonist in vitro and in vivo. Prostaglandins 39: 469–480PubMedCrossRefGoogle Scholar
  38. 38.
    Moore JM, Ernest MA, DiSimone AG, Abumrad NN, Fletcher JR (1991) A PAF receptor antagonist, BN 52021, attenuates thromboxane release and improves survival in lethal canine endotoxemia. Circ Shock 36: 53–59Google Scholar
  39. 39.
    Fletcher JR, DiSimone AG, Earnest M (1990) Platelet activating factor antagonist improves survival and attenuates eicosanoid release in severe endotoxemia. Ann Surg 211: 312–316PubMedGoogle Scholar
  40. 40.
    Rabinovici R, Yue TL, Farhat M, Smith EF III, Esser KM, Slivjak M, Feuerstein GPlatelet activating factor (PAF) and tumor necrosis factor-a (TNF-a) interactions in endotoxemic shock: Studies with BN 50739, a novel PAF antagonist. J Pharmacol Exp Ther 255: 256–263Google Scholar
  41. 41.
    Mozes T, Zijlstra FJ, Heiligers JPC, Tak CJAM, Ben-Efraim S, Bonta IL, Saxena PR (1991) Sequential release of tumour necrosis factor, platelet activating factor and eicosanoids during endotoxic shock in anaesthetized pigs: protective effect of indomethacin. Br J Pharmacol 104:691–699Google Scholar
  42. 42.
    Nakamura T, Kasai K, Sekiguchi Y, Banba N, Takahashi K, Emoto T, Hattori Y, Shimoda SI (1991) Elevation of plasma endothelin concentrations during endotoxic shock in dogs. Eur J Pharmacol 205: 277–282PubMedCrossRefGoogle Scholar
  43. 43.
    Pons L, Droy-Lefaix MT, Braquet P, Bueno P (1991) Role of free radicals and platelet-activating factor in the genesis of intestinal motor disturbances induced by Escherichia coli endotoxins in rats. Gastroenterology 100: 946–953PubMedGoogle Scholar
  44. 44.
    Pons L, Droy-Lefaix MT, Braquet P, Bueno P (1991) Myoelectric intestinal disturbances in Escherichia coli endotoxic shock in rats. Involvement of platelet-activating factor. Lipids 26: 1359–1361PubMedCrossRefGoogle Scholar
  45. 45.
    Redl H, Vogl C, Schiesser A, Paul E, Thurnher M, Bahrami S, Schlag G (1990) Effect of PAF antagonist BN 52021 in an ovine endotoxin shock. J Lipid Mediators 2 (suppl): S195–S201Google Scholar
  46. 46.
    Anderson BO, Poggetti RS, Shanley PF, Bensard DD, Pitman JM, Nelson DW, Whitman GJ, Harken AH (1991) Primed neutrophils injure rat lung through a platelet-activating factor-dependent mechanism. J Surg Res 50: 510–514PubMedCrossRefGoogle Scholar
  47. 47.
    Inoue Y, Kohno S, Miyazaki T, Yamaguchi K (1991) Effect of a platelet activating factor antagonist and antithrombin III on septicemia and endotoxemia in rats. Tohoku J Exp Med 163: 175–185PubMedCrossRefGoogle Scholar
  48. 48.
    Kucey DS, Kubicki EI, Rotstein DD (1991) Platelet-activating factor primes endotoxin-stimulated macrophage procoagulant activity. J Surg Res 50: 436–441PubMedCrossRefGoogle Scholar
  49. 49.
    Hsieh KM (1991) Effects of PAF antagonist, BN 52021, on the PAF-, methacholine-, and allergen-induced bronchoconstriction in asthmatic children. Chest 99: 877–882PubMedCrossRefGoogle Scholar
  50. 50.
    Desquand S, Lefort J, Dumarey C, Vargaftig BB (1990) The booster injection of antigen during active sensitization modifies the antianaphylactic activity of the PAF antagonist WEB 2086. Br J Pharamacol 100: 217–222Google Scholar
  51. 51.
    Desquand S, Lefort J, Dumarey C, Vargaftig BB (1991) Interference of BN 52021, an antagonist of PAF, with different forms of active anaphylaxis in the guinea-pig: importance of the booster injection. Br J Pharmacol 102: 687–695PubMedGoogle Scholar
  52. 52.
    Kuitert LM, Hui KP, Uthayarkumar S, Burke W, Newland AC, Uden S, Barnes NC (1993) Effect of the platelet-activating factor antagonist UK-74,505 on the early and late response to allergen. Am Rev Respir Dis 147: 82–86PubMedCrossRefGoogle Scholar
  53. 53.
    Giers G, Janzarik H, Kempe ER, Müller-Eckhardt C (1990) Failure of the platelet- activating factor antagonist WEB 2086 BS for treatment of chronic autoimmune thrombocytopenia. Blut 61: 21–24Google Scholar
  54. 54.
    Guinot P, Braquet P, Duchier J, Cournot A (1986) Inhibition of PAF-acether induced weal and flare reaction in man by a specific PAF antagonist. Prostaglandins 32: 160–163PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1997

Authors and Affiliations

  • Pierre G. Braquet
    • 1
  1. 1.Bio-InovaPlaisirFrance

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