Ginsenoside Rg5 inhibits platelet aggregation by regulating GPVI signaling pathways and ferric chloride-induced...

Platelet hyperactivation is a major factor in thrombotic complications such as myocardial infarction and ischemic stroke. Ginsenoside Rg5 is a minor ginsenoside, and among its various beneficial pharmacological effects, its antithrombotic potential has not been extensively studied.

Human platelets were isolated and treated with Rg5 (35-100 μM) before stimulation with agonists such as collagen, thrombin, and U46619. Platelet aggregation, granule secretion, calcium mobilization, thromboxane A₂ production, fibrinogen binding, and clot retraction were evaluated. The effects of Rg5 on signaling pathways were determined via Western blot analysis of key proteins. In vivo, the antithrombotic efficacy was assessed using ferric chloride (FeCl₃)-induced thrombosis in mice.

Rg5 dose-dependently inhibited collagen-induced platelet aggregation (IC₅₀ = 42.5 μM) and selectively inhibited GPVI-mediated signaling compared to thrombin and U46619. Rg5 suppressed intracellular calcium mobilization, granule secretion, and thromboxane A₂ production, with no cytotoxicity observed. Rg5 downregulated key signaling proteins (p-PI3K, p-AKT, p-cPLA2, and p-p38) while upregulating p-VASP (S157 and S239), suggesting its role in elevating cyclic nucleotide signaling. Additionally, Rg5 inhibited CD162 expression that was induced in the presence of collagen and oxidized low-density lipoprotein. It also prevented fibrinogen and fibronectin binding and significantly reduced clot retraction. In vivo, Rg5 (20 mg/kg) significantly prolonged the carotid artery occlusion time and prevented thrombus formation, outperforming aspirin (100 mg/kg).

Ginsenoside Rg5 exhibits potent antiplatelet activity by selectively targeting GPVI-mediated platelet activation and modulating key intracellular signaling pathways. These results suggest that Rg5 could be utilized to develop safer and natural antiplatelet therapies.