Antithrombotic Effect of Chikusetsusaponin IVa Isolated fromIlex paraguariensis(Maté)

Abstract

The triterpene chikusetsusaponin IVa was isolated from the fruit of Ilex paraguariensis. Using biochemical and pharmacological methods, we demonstrated that chikusetsusaponin IVa (1) prolongs the recalcification time, prothrombin time, activated partial thromboplastin time, and thrombin time of normal human plasma in a dose-dependent manner, (2) inhibits the amidolytic activity of thrombin and factor Xa upon synthetic substrates S2238 and S2222, (3) inhibits thrombin-induced fibrinogen clotting (50% inhibition concentration, 199.4 ± 9.1 μM), and (4) inhibits thrombin- and collagen-induced platelet aggregation. The results also indicate that chikusetsusaponin IVa preferentially inhibits thrombin in a competitive manner (K(i)=219.6 μM). Furthermore, when administered intravenously to rats, chikusetsusaponin IVa inhibited thrombus formation in a stasis model of venous thrombosis, although it did not induce a significant bleeding effect. Chikusetsusaponin IVa also prolonged the ex vivo activated partial thromboplastin time. Altogether, these data suggest that chikusetsusaponin IVa exerts antithrombotic effects, including minor hemorrhagic events. This appears to be important for the development of new therapeutic agents.

Improving the Thrombin Inhibitory Activity of Glycyrrhizin, a Triterpenic Saponin, Through a Molecular Simplification of the Carbohydrate Moiety

“…Additionally, as the inhibitory effect upon thrombin is expected to modulate the conformation of its catalytic site, each docking complex was further refined through molecular docking (MD) simulations to search for potential allosteric influences of the compounds, in comparison with non‐inhibited thrombin, as reported for the modulation of thrombin by sulphated arabinans . A simulation of uncomplexed thrombin was employed as a negative control, and in addition to the use of glycyrrhizin as the positive control, another anticoagulant saponin, through thrombin inhibition, chikusetsusaponin IVa (β‐ D ‐glucopyranosiduronic acid, (3 β )‐28‐( β ‐ D ‐glucopyranosyloxy)‐28‐oxoolean‐12‐en‐3‐yl) ( 6 ) was also simulated in complex to its target protein. The so‐obtained data from the combination of docking and MD are presented in Figure and Table .…”

Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic

“…Some studies described marine products from seaweeds as feasible anticoagulants to be explored such as those isolated from the brown alga, Canistrocarpus cervicornis (e.g., heterofucans) [9] and fruits of Ilex paraguariensis [10]. Diterpenes also represent a class of secondary metabolites with high biotechnological potential [11].…”

Chikusetsusaponin IVa Methyl Ester Isolated from the Roots of <i>Achyranthes japonica</i> Suppresses LPS-Induced iNOS, TNF-α, IL-6, and IL-1β Expression by NF-κB and AP-1 Inactivation

“…From each sample, 1 µg of RNA was reverse-transcribed by MuLV reverse transcriptase, 1 mM deoxyribonucleotide triphosphate (dNTP) and (dT [12][13][14][15][16][17][18] ) 0.5 µg/ µL. PCR amplification was performed using the incorporation of SYBR green.…”