lignans and Thrombocytopenia

In this study we examined the ability of the furofuran lignan yangambin to influence the local and systemic responses induced by antigen or PAF in actively sensitized or normal rats. Given intraperitoneally 1 h before stimulation, yangambin inhibited the pleural neutrophil and eosinophil infiltration evoked by the i.pl. injection of PAF or antigen into normal or 14 daysensitized rats whereas plasma exudation evoked by both stimuli was unaffected. The pleural neutrophil influx (6 h) after LTB4 stimulation was also significantly inhibited by yangambin. We also evidenced that the hemoconcentration, thrombocytopenia, and leucocytosis noted after i.v. PAF were all attenuated by yangambin. In actively sensitized rats, pretreatment with yangambin failed to modify the antigen-induced hemoconcentration and leucocytosis, but dose-dependently abrogated the thrombocytopenia noted 1 h post-stimulation. In vitro, the anaphylactic contraction of longitudinal jejunal segments to antigen challenge was significantly inhibited by yangambin (10(-5)-10(-4) M). Likewise, the contraction of jejunal segments from normal rats to PAF was markedly blocked by yangambin under conditions where the response to 5-hydroxytryptamine (5-HT) was not altered. In conclusion, our results show that antigen- and PAF-induced pleural neutrophil and eosinophil accumulation, but not exudation, is sensitive to treatment with yangambin. In addition, yangambin also suppressed the pleural neutrophil infiltration triggered by LTB4 as well as the blood thrombocytopenia and intestinal anaphylaxis elicited by antigen in rats. Thus, our findings indicate that yangambin shows an antagonistic action on receptors other than those of PAF, i.e., LTB4, and strongly suggest that it may be a useful drug in the treatment of some allergic inflammatory responses.

Topics: Animals; Anti-Allergic Agents; Eosinophils; Female; Furans; Leukocytosis; Lignans; Male; Neutrophils; Plant Extracts; Platelet Activating Factor; Pleurisy; Rats; Rats, Wistar; Thrombocytopenia

Yangambin, a new naturally-occurring 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 microM (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 27417 (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 microM) 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 27417 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.

Topics: Animals; Blood Platelets; Furans; Guinea Pigs; Humans; Interleukin-1; Interleukin-6; Kinetics; Leukocytes; Leukopenia; Lignans; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Respiratory Burst; Thiazoles; Thrombocytopenia; Tumor Necrosis Factor-alpha

The ability of a furofuran lignan, epiyangambin, to inhibit PAF-induced rabbit platelet aggregation in vitro and thrombocytopenia in rats was investigated. Epiyangambin dose-dependently inhibited PAF-induced platelet aggregation without modifying the amplitude of the maximal response, indicating a competitive antagonism. The IC50 value of epiyangambin for 10(-9) M PAF-induced aggregation was 6.1 x 10(-7) M and the Schild analysis provided a pA2 of 6.91 +/- 0.2 with a slope of 0.98 +/- 0.25 (n = 4) and a pKb of 6.94 +/- 0.19. Epiyangambin had no effect upon the platelet aggregation induced by collagen, thrombin or ADP. The in vivo administration of the lignan at 20 mg/kg significantly inhibited PAF-induced thrombocytopenia in rats. These data indicate that epiyangambin is a potent and selective antagonist of PAF both in vitro and in vivo.

Topics: Animals; Furans; Lignans; Lignin; Male; Molecular Structure; Platelet Activating Factor; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Wistar; Thrombocytopenia