Effects of Preoperative Glycyrrhizin Infusion for the Prevention of Venous Thrombosis on the Tissue Expression of Antithrombin in a Rat Model

Abstract

Objective: Using a thrombus model prepared by ligation of the inferior vena cava (IVC), the influences of the glycoside, glycyrrhizin, on plasma antithrombin levels and antithrombin mRNA expression levels in the liver and IVC with the inhibition of venous thrombosis were investigated. Materials and Methods: The rat IVC was exposed and ligated for 24 h immediately after the intravenous administration of 300 mg/kg glycyrrhizin. Among antithrombotic drugs, the Xa inhibitor, fondaparinux sodium, was used as a control drug. Results: The mean thrombus weight was significantly smaller in the glycyrrhizin-treated group (18.3 mg) than in the salinetreated group (34.3 mg). In contrast, the inhibition of thrombosis was not observed in the fondaparinux-treated group. Antithrombin mRNA expression levels in the liver were significantly higher in the ligated groups than in the baseline control group. The mean plasma antithrombin level was significantly lower in the glycyrrhizin group (96.6%) than in the saline group (114.4%), but was not significantly different from that in the baseline control group (102.4%). Conclusion:The pretreatment with glycyrrhizin inhibited venous thrombosis, and antithrombin mRNA expression levels in the liver and IVC as well as plasma antithrombin levels were significantly lower than those in the saline group.Keywords: glycyrrhizin, antithrombin, DVT targets being thrombin, factor Xa, and factor IXa. A sequence-specific pentasaccharide present in only a fraction of heparin molecules mediates the high-affinity binding and anticoagulant activation of antithrombin by this polysaccharide. 1) Antithrombin has lysine binding sites to which heparin binds at a molar ratio of 1:1. The half-life of thrombin is reduced to 20 ms in the presence of a high concentration of heparin, which is an approximately 2000-fold acceleration of this reaction. 2) Griffith previously identified thrombin-heparin binding as the most important factor for efficient thrombin inhibition by antithrombin. 3) P-and E-selectins have been known to mediate the linkage of endothelial cells to neutrophils through the binding to sialyl-Lewis X glycoproteins, which are expressed on the surface of neutrophils. 4,5) Neutrophils adherent to the endothelium also undergo transendothelial migration, leading to endothelial cell sloughing and exposure of the underlying basement membrane to the accelerated formation of deep vein thrombosis (DVT). 6) Glycyrrhizin, which is a natural triterpenoid saponin with a molecular mass of 840 Daltons, has been approved for useful drug for the treatment of allergic disorders and chronic hepatitis in Japan. We previously showed that glycyrrhizin was effective on the prevention of the tissue damage caused by ischemia-reperfusion in the rabbit hind limb. 7) were the first to demonstrate that glycyrrhizin exhibits antithrombotic activity in vivo and, it has, thus, been characterized as a potential thrombin inhibitor. Assafim et al. 9) showed that glycyrrhizin was effective in preventing venom-induced thrombus formati...

Analysis of the network pharmacology and the structure-activity relationship of glycyrrhizic acid and glycyrrhetinic acid

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