Counteracting effect of glycyrrhizin on the hemostatic abnormalities induced by Bothrops jararaca snake venom

1 Envenomation by the snake Bothrops jararaca is typically associated with hemostatic abnormalities including pro- and anticoagulant disturbances. Glycyrrhizin (GL) is a plant-derived thrombin inhibitor that also exhibits in vivo antithrombotic properties. Here, we evaluated the ability of GL to counteract the hemostatic abnormalities promoted by B. jararaca venom. 2 GL inhibited the human fibrinogen clotting (IC50 = similar to 1.0 mg ml(-1); 1.2 mM), H-D-phenylalanyl-L-pipecolyl-L-arginine-p-nitroanilide dihydrochloride hydrolysis (IC50 = similar to 0.4 mg ml(-1); 0.47 mM) and platelet aggregation (IC50 = similar to 0.28 mg ml(-1); 0.33 mM) induced by B. jararaca venom, in vitro. 3 The in vivo effect of GL was tested in rats using a model of venous thrombosis in which intravenous (i.v.) administration of B. jararaca venom (100 mu g kg(-1)) produced in all animals a thrombus with a mean weight of 10.6 +/- 1.7 mg. 4 Prior administration of GL (180 mg kg(-1)) or antibothropic serum (27 mu l kg(-1)) inhibited thrombus formation by 86 and 67%, respectively. Remarkably, co-administration of ineffective doses of GL and antibothropic serum markedly decreased thrombus weight, suggesting a synergistic effect. 5 Co-administration of GL with antibothropic serum abolished venom-induced bleeding. Ex vivo clotting times showed that rat plasma was non-clotting after i.v. administration of B. jararaca venom. Treatment with GL, antibothropic serum or both before venom administration efficiently prevented this abnormality. 6 Altogether, we demonstrate here that GL prevents both in vitro and in vivo venom-induced changes in hemostasis, suggesting a potential antiophidic activity.