Antiplatelet Activity of Tussilagone via Inhibition of the GPVI Downstream Signaling Pathway in Platelets

Abstract

Tussilagone is a sesquiterpenoid extracted from Tussilago farfara and is used as an oriental medicine for asthma and bronchitis. Although previous studies have shown that tussilagone has an inhibitory effect on platelet aggregation, no studies have been performed to investigate its precise effect on platelets, and the underlying mechanism remains unclear. In the present study, we showed that tussilagone inhibited platelet aggregation induced by collagen, thrombin and ADP, as well as platelet release induced by collagen and thrombin, in mice. Tussilagone decreased P-selectin expression and αIIbβ3 activation (JON/A binding) in activated platelets, which indicated that tussilagone inhibited platelet activation. Moreover, tussilagone suppressed platelet spreading on fibrinogen and clot retraction. The levels of phosphorylated Syk, PLCγ2, Akt, GSK3β, and MAPK (ERK1/2 and P38) and molecules associated with GPVI downstream signaling were downregulated in the presence of tussilagone. In addition, tussilagone prolonged the occlusion time in a mouse model of FeCl 3-induced carotid artery thrombosis and had no effect on mouse tail bleeding time. These results indicate that tussilagone inhibits platelet function in vitro and in vivo and that the underlying mechanism involves the Syk/PLCγ2-PKC/MAPK and PI3K-Akt-GSK3β signaling pathways downstream of GPVI. This research suggests that tussilagone is a potential candidate antiplatelet drug for the prevention of thrombosis.

Pimpinellin Inhibits Collagen-induced Platelet Aggregation and Activation Through Inhibiting Granule Secretion and PI3K/Akt Pathway

“…Many compounds or extracts of plant origin inhibited platelet function and mediated the collagen-induced GPVI signalling pathway. Glaucocalyxin A incubation reduced phosphorylation of SYK, LAT and PLCγ2 (Li et al, 2013); Tussilagone decreased the phosphorylation of Syk/PLCγ2-PKC/MAPK signaling pathways (Zhou et al, 2020); Salidroside inhibits platelet function through AKT/GSK3β signaling pathway (Wei et al, 2020). In the present study, we also demonstrated that pimpinellin inhibited multiple key protein phosphorylation related to collagen-induced signaling pathways in platelets.…”

Perspective: Collagen induced platelet activation via the GPVI receptor as a primary target of colchicine in cardiovascular disease

“…Like ACT017 and Revacept, colchicine treatment has not been linked to bleeding complications. Other potential GPVI related targets, undergoing clinical trials and scientific investigation, have shown decreased platelet responses including aggregation, P-selectin expression and GPIIb/IIIa conformational change in response to multiple agonists, some of these targets are in use for treatment of hematological malignancies ( 68 – 70 ).…”