Costunolide, a Sesquiterpene Lactone, Protects Against Platelet Activation and Thrombus Formation

Background/Objectives: Circulating platelets mediate physiological hemostasis and are implicated in pathological thrombosis, which can cause vascular occlusion, leading to heart attacks or strokes. Costunolide is a sesquiterpene lactone extracted from Saussurea lappa. Although this lactone has multiple biological effects, including anti-inflammatory and antioxidant effects, that help slow the progression of atherosclerosis, its influence on platelet activation remains unclear. In this study, we examined the potential antiplatelet and antithrombotic effects of costunolide. Methods: We used platelet aggregation, flow cytometry, and Western blot analysis to examine its in vitro antiplatelet effects. Results: Our results indicated that costunolide inhibited platelet aggregation induced by collagen, but not by thrombin or the thromboxane A2 analog U46619, suggesting that costunolide selectively inhibits collagen-induced platelet activation. Additionally, costunolide blocked collagen-mediated granule release, calcium mobilization, and glycoprotein IIb/IIIa (GPIIb/IIIa) activation. Costunolide also inhibited phospholipase Cγ2 (PLCγ2), pleckstrin (a downstream target of protein kinase C), Akt, and mitogen-activated protein kinase. Moreover, it prevented collagen/epinephrine-induced pulmonary thrombosis and increased the survival rate of mice. Furthermore, costunolide delayed thrombus formation in the mesenteric vessels while it did not significantly affect hemostasis, suggesting it exhibits antithrombotic activity without bleeding tendency. These findings indicate that costunolide can block PLCγ2-PKC, Akt, and MAPK signaling pathways and subsequent granule release, calcium mobilization, and GPIIb/IIIa activation, eventually impeding platelet activation, platelet aggregation, and thrombus formation. Conclusions: In conclusion, besides its multiple biological activities that are beneficial for slowing the progression of atherosclerosis, we also demonstrated the antiplatelet and antithrombotic activities of costunolide. These effects highlight the therapeutic potential of costunolide in the treatment of patients with cardiovascular disease, particularly stroke and heart attack.