Inhibition of platelet-activating factor (PAF)-induced chemotaxis and PAF binding to human eosinophils and neutrophils by the specific ginkgolide-derived PAF antagonist, BN 52021.
We have investigated the effects of BN 52021 (a specific PAF antagonist derived from Ginkgo biloba) on PAF-induced human eosinophil and neutrophil chemotaxis. In response to an optimal concentration of PAF (10(-6) mol/L), the drug was significantly more potent (p less than 0.001) in inhibiting eosinophil as compared to neutrophil locomotion. These inhibitory effects were observed in a dose-dependent manner with a concentration of drug required to produce 50% inhibition of 7.0 (+/- 2.2) X 10(-6) mol/L and 2.3 (+/- 0.2) X 10(-5) mol/L for eosinophils and neutrophils, respectively. Sodium cromoglycate, nedocromil sodium, salbutamol, and dexamethasone (preincubated with cells up to 6 hours) had no effect over a wide dose range (10(-3) to 10(-9) mol/L). BN 52021 was significantly more effective in inhibiting chemotaxis when the cells were preincubated with the compound for up to 1 hour before commencement of the locomotion assay, whereas washing the cells completely abolished this effect. Inhibition by BN 52021 was specific for PAF in that it had no effect on chemotaxis induced by either leukotriene B4, N-formyl-methionyl-leucyl-phenylalanine, or a purified human mononuclear cell-derived neutrophil chemotactic factor. BN 52021 also inhibited the specific binding of [3H]-PAF (10(-8) mol/L) to eosinophils and neutrophils in a concentration-dependent fashion with a concentration of drug required to produce 50% inhibition of 1.5 (+/- 0.3) X 10(-6) mol/L and 9.1 (+/- 2.5) X 10(-7) mol/L, respectively. These results suggest that BN 52021 has potential as an anti-inflammatory agent in conditions associated with PAF-induced accumulation of neutrophils and eosinophils.
Kurihara
K
K
Department of Allergy and Clinical Immunology, National Heart & Lung Institute, London, England.
Wardlaw
A J
AJ
Moqbel
R
R
Kay
A B
AB
D000420:Albuterol / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D004224:Diterpenes; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism*; D046934:Ginkgolides; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D017835:Nedocromil; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins; D015363:Quinolones / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled
D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D015363:Quinolones; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D017835:Nedocromil; D003907:Dexamethasone; C045856:ginkgolide B; D000420:Albuterol