Protective effect of SR 27417, a novel PAF antagonist, on lethal anaphylactic and endotoxin-induced shock in mice

doi:10.1016/0014-2999(91)90909-A

European Journal of Pharmacology

Volume 205, Issue 3, 3 December 1991, Pages 271-276

https://doi.org/10.1016/0014-2999(91)90909-A Get rights and content

Abstract

In anaphylactic shock, SR 27417, the first member of a newly developed series of PAF (platelet-activating factor) antagonists, inhibited in a dose-dependent manner the lethal effect of antigen (ovalbumin) rechallenge in actively sensitized mice. It protected mice when given i.v. 5 min before ovalbumin challenge (ED⁵⁰ = 50 μg/kg) or when given p.o. 1 h before ovalbumin administration (ED₅₀ = 1.25 mg/kg). After i.v. or oral administration, SR 27417 (2.5 and 10 mg/kg, respectively) greatly improved the survival rate of mice after antigen challenge and had an extremely long duration of action (48 and 30 h, respectively). Similarly, i.v. or oral doses of SR 27417 afforded in mice complete protection against endotoxin-induced lethality (ED50 values were 100 and 150 μg/kg, respectively). SR 27417 (1 mg/kg) inhibited endotoxin-induced death in mice with impressive oral or i.v. durations of action of 66 and 110 h, respectively. These results confirm that PAF plays a major role in anaphylactic and endotoxin-induced shock and that SR 27417 may be an effective preventative drug.

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The effect of human recombinant plasma-type platelet-activating factor (PAF) acetylhydrolase was examined in two murine models, PAF-induced death and active anaphylactic models. In the PAF-induced death model where mice were injected intravenously with 40 μg/kg of PAF, the administration of PAF acetylhydrolase reduced mortality in a dose-dependent manner, showing complete prevention of mortality at 1.0 mg/kg. Myeloperoxidase activity, the marker for neutrophils, was increased in the lung by PAF injection, and the PAF acetylhydrolase treatment significantly reversed the increase in myeloperoxidase activity. As in the PAF-induced model, PAF acetylhydrolase also decreased mortality in the active anaphylactic shock model where bovine serum albumin was injected intravenously to mice previously immunized with bovine serum albumin. The protective effect of PAF acetylhydrolase on mortality in this model was significant at 1.0 mg/kg. These results suggest that PAF is an important mediator in the lethality of systemic anaphylaxis, and that PAF acetylhydrolase may be beneficial for treatment of anaphylactic shock.
Platelet-activating factor (PAF) receptor and genetically engineered PAF receptor mutant mice
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Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a biologically active phospholipid mediator. Although PAF was initially recognized for its potential to induce platelet aggregation and secretion, intense investigations have elucidated potent biological actions of PAF in a broad range of cell types and tissues, many of which also produce the molecule. PAF acts by binding to a unique G-protein-coupled seven transmembrane receptor. PAF receptor is linked to intracellular signal transduction pathways, including turnover of phosphatidylinositol, elevation in intracellular calcium concentration, and activation of kinases, resulting in versatile bioactions. On the basis of numerous pharmacological reports, PAF is thought to have many pathophysiological and physiological functions. Recently advanced molecular technics enable us not only to clone PAF receptor cDNAs and genes, but also generate PAF receptor mutant animals, i.e., PAF receptor-overexpressing mouse and PAF receptor-deficient mouse. These mutant mice gave us a novel and specific approach for identifying the pathophysiological and physiological functions of PAF. This review also describes the phenotypes of these mutant mice and discusses them by referring to previously reported pharmacological and genetical data.
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Yangambin, a new naturally-occuring platelet activating receptor (PAF) receptor antagonist competitively displaced [³H]-PAF from its high affinity binding sites on washed human platelets with a Ki value of 1.1 ± 0.3 μM (n = 3). Studies carried out in parallel demonstrated that SR 27417, a newly-developed PAF receptor antagonist also antagonized [³H]-PAF binding to these cells with a Ki value of 51 ± 2 pM. SR 27 417 (N-(2-dimethylamino ethyl)-N-(3-pyridinyl methyl) [4-(2,4,6-triisopropyl phenyl) thiazol-2-yl] amine) selectively and competitively inhibited the specific binding of [³H]-PAF on human polymorphonuclear leukocytes (Ki = 65 ± 5.2 pM) whereas high doses of yangambin remained ineffective. Yangambin inhibited PAF-induced aggregation of human platelets in vitro (IC₅₀ = 1.0 ± 0.2 μM) but had no effect PAF-induced oxidative burst in human polymorphonuclear leukocytes. In guinea pigs, yangambin inhibited PAF-induced thrombocytopenia but did not affect leukocytopenia whereas SR 27 417 afforded complete protection against both PAF-induced thrombocytopenia and leukocytopenia. In conclusion, yangambin discriminates between two different types of PAF receptors on platelets and polymorphonuclear leukocytes and can be considered as the first PAF receptor antagonist described to date exhibiting such an effect.
Effect of SR 27417, a novel PAF antagonist on antigen-induced hypotension in the rat
1997, Journal of Lipid Mediators and Cell Signalling
SR 27417, a potent PAF receptor antagonist, inhibited in a dose-dependent manner the hypotensive effect of PAF in rats. It protected rats with an ED₅₀ value of 6 ± 2 μg/kg (n = 6), when given i.v., 1 min before PAF administration. After i.v. administration, SR 27417 exhibited extended duration of action, a significant protective effect was observed up to 48 h after the administration. After i.v. injection, SR 27417 (0.3, 1 and 3 mg/kg) afforded dose-dependent protection of actively sensitized rats against ovalbumin-induced hypotension but also totally reversed established antigen-induced hypotension. These results therefore confirm that PAF plays a major role in anaphylactic shock and suggest that SR 27417 may be an effective prophylactic as well as a potent curative drug in this pathology.
Protective effects of Yangambin - A naturally occurring platelet-activating factor (PAF) receptor antagonist - On anaphylactic shock in rats
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The purpose of this study was to investigate the ability of yangambin to inhibit cardiovascular collapse and to reduce the mortality due to systemic anaphylaxis induced by antigen challenge in actively sensitized rats. The i.v. injection of the antigen (ovalbumin, 250 or 500 μg/kg), induced a systemic anaphylactic reaction mainly characterized by sudden and marked arterial hypotension and high mortality rates. Yangambin, a PAF receptor antagonist isolated from the Brazilian plant Ocotea duckei Vattimo (Lauraceae), as well as the reference PAF receptor antagonist SR 27417, significantly prevented and partially reversed the circulatory collapse elicited by antigen challenge. Moreover, yangambin and SR 27417, when administered 5 min before re-exposure of the animals to the antigen, markedly improved the survival rate at 120 min. These results confirm that PAF plays an important role in the pathophysiology of anaphylactic shock and show that yangambin presents good therapeutic potential in the treatment of the cardiovascular alterations observed during immediate hypersensitivity reactions.
Importance of platelet activating factor in anaphylaxis-induced t-PA and PAI-1 increase in the rabbit
1995, Fibrinolysis and Proteolysis
Single injections of ovalbumin to presensitized rabbits dramatically increased the circulating activities of plasma tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) and induced a severe thrombocytopenia. These effects occurred in a time- and dose-dependent manner, the maximum circulating levels of t-PA and PAI-1 being observed 30 min after administration of the antigen. In order to determine the importance of platelet activating factor (PAF) in this phenomenon, SR 27417, a potent and selective PAF receptor antagonist, was administered prior to antigen challenge. The intravenous administration of SR 27417 strongly inhibited the effects of ovalbumin, showing that t-PA and PAI-1 increase resulting from the anaphylaxis reaction depend on PAF release. SR 27417 also strongly inhibited ovalbumin-induced thrombocytopenia. The mechanism of action of PAF leading to t-PA and PAI-1 increase during anaphylaxis is still unclear, but might be considered as a contributing mechanism during the allergic reaction.

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Regular paperProtective effect of SR 27417, a novel PAF antagonist, on lethal anaphylactic and endotoxin-induced shock in mice

Abstract

Trends Pharmacol. Sci.

Prostaglandins

Immunopharmacology

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Immunopharmacology

Prostaglandins

Eur. J. Pharmacol.

Biochem. Pharmacol.

Leukocyte-dependent histamine release from rabbit platelets: the role for IgE, basophils and PAF

J. Exp. Med.

The promise of platelet activating factor

ISI Atlas Sci.

Perspectives in platelet-activating factor research

Pharmacol. Rev.

PAF/cytokine auto-generated feedback networks in microvascular immune injury: consequences in shock, ischemia and graft rejection

J. Lipid Med.

The release of histomine and the formation of a show reacting substance (SRS-A) during anaphylactic shock

J. Physiol.

Protective effect of WEB 2086, a novel platelet-activating factor antagonist, in endotoxin shock

Eur. J. Pharmacy

Pharmacological actions of WEB-2086, a new specific antagonist of platelet activating factor

J. Pharmacol. Exp. Ther.

Regular paper
Protective effect of SR 27417, a novel PAF antagonist, on lethal anaphylactic and endotoxin-induced shock in mice