Combination of Colchicine and Ticagrelor Inhibits Carrageenan-Induced Thrombi in Mice

Abstract

The formation of a thrombus is closely related to oxidative stress and inflammation. Colchicine is one of the most commonly prescribed medication for gout treatment, with anti-inflammation and antioxidative stress properties. Therefore, we speculated that it is possible for colchicine to treat thrombosis. In this study, we used carrageenan to induce thrombosis in BALB/c mice and fed mice with colchicine, ticagrelor, and their combination, respectively. We found colchicine inhibited carrageenan-induced thrombi in mouse tail, and the inhibition was enhanced by ticagrelor. In vitro, colchicine inhibited thrombin-induced retraction of human platelet clots. Mechanically, colchicine inhibited platelet activation by reducing the expression of platelet receptors, protease-activated receptor 4 (PAR4) and CD36, and inactivating of AKT and ERK1/2 pathways. Furthermore, in human umbilical vein endothelial cells (HUVECs), colchicine showed antioxidative stress effects through increasing protein expression of glutathione peroxidase-1 (GPx-1), and mRNA levels of forkhead box O3 (FOXO3a) and superoxide dismutase 2 (SOD2). In RAW264.7 cells, colchicine reduced LPS-enhanced inflammatory response through attenuating toll-like receptor 4 (TLR4) activation. In addition, colchicine reduced LPS or ox-LDL-induced monocyte adhesion to HUVECs by inhibiting intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) levels. Taken together, our study demonstrates that colchicine exerts antithrombotic function by attenuating platelet activation and inhibiting oxidative stress and inflammation. We also provide a potential new strategy for clinical treatment.