Ginsenoside Re: Are we Close to a Safer Antiplatelet Therapy?

A boundary is not that at which something stops, but that from which something begins. Martin Heidegger. Antiplatelet therapy represents the cornerstone for the treatment of atherosclerotic cardiovascular diseases, especially coronary artery disease, given the fundamental pathophysiological role played by platelet activation.1 This does not hold true in the setting of primary prevention, in which poor concrete evidence is provided about benefits of antiplatelet therapy outweighing bleeding risk, whereas in secondary prevention, long-term antiplatelet therapy is lifesaving.1 Currently available antiplatelet drugs target different pathways of platelet activation: thromboxane A2 synthesis, adenosine diphosphate-mediated signaling, integrin αIIbβ3 (GPIIb/IIIa), thrombin-mediated platelet activation via the PAR1 receptor, and phosphodiesterases.2 Although there is no doubt about the efficacy of these drugs, their major drawback is represented by bleeding risk, which is associated with increased mortality and its impact on long-term prognosis is currently being considered more and more.3 Thus, several studies have highlighted the importance of predicting out-of-hospital bleeding risk during antiplatelet therapy, to tailor treatment duration through standardized tools such as the PRECISE-DAPT score.4 Over the last years, efforts have been made to discover new receptors and signaling pathways potentially targetable to develop new antiplatelet agents with lower bleeding risk without any trade-off in antithrombotic efficacy.5 Plenty of novel insights about platelet physiology, in particular regarding complex molecular dynamics and regulatory networks involving even ion homeostasis are being provided.6 A physiological pathway that is currently matter of research involves the glycoprotein V, a platelet transmembrane protein which is proteolytically cleaved by thrombin during thrombus formation: it was recently shown that the soluble glycoprotein V released from platelet surface specifically reduces fibrin formation in vitro and in vivo and thereby may prevent occlusive thrombosis without causing hemostatic impairments.7 Other recent studies found that shear-induced platelet aggregation (SIPA) is primarily involved in platelet activation and aggregation, because local shear stress generated by blood flow in obstructed vessels can be more than 3-fold higher compared with normal vessels.8 In particular, an intense shear stress level induces a specific interaction between von Willebrand factor and glycoprotein Ib (GPIb) by triggering an intracellular signal through the PI3K/Akt pathway, consequently leading to platelet activation and aggregation.9 In their study, Huang et al10 used shear force as a platelet stimulant to explore the antiplatelet action of Ginsenoside Re, a derivative of tetracyclic triterpenoids, demonstrating its significant effectiveness in vitro in inhibiting von Willebrand factor-glycoprotein Ib interaction, thereby affecting the PI3K/Akt signaling pathway. Noteworthy, these effects of Ginsenoside Re were not associated with cytotoxicity and bleeding risk, evaluated by measuring coagulation parameters such as PT, APTT, TT, and thromboelastography, did not increase.10 Moreover, it emerged how Ginsenoside Re also inhibited platelet aggregation mediated by ADP and arachidonic acid, suggesting its potential regulatory role in balancing the activation of ADP-P2Y12 and AA-TXA2 pathways: in vivo this interplay may result in a strong effectiveness on thrombosis prevention.10 Eventually, not only atherosclerotic plaques but also implantable cardiovascular devices such as vascular grafts, stents or prosthetic heart valves significantly increase shear forces: we have no data thus far, but it will be worthy to evaluate benefits of Ginsenoside Re in the prevention and treatment of device-related thrombosis.10 In addition, many other studies have demonstrated that Ginsenoside Re produces various beneficial effects on the cardiovascular system. First, its antiarrhythmic effect, which seems to be because of a regulation of intracellular sites involved in Ca2+ homeostasis, has been described in vitro- and in vivo-studies: it was found that Ginsenoside Re suppresses pacing-induced delayed afterdepolarizations and spontaneous action potentials, especially in ventricular myocytes.11 Other studies pointed out that Ginsenoside Re exerts anti-ischemic effects, in particular Liu et al,12 using rat cardiac cells, demonstrated that Ginsenoside Re significantly inhibits cardiac cell apoptosis induced by ischemia/reperfusion injury: this seems to be because of a decreased expression of proapoptotic Bax gene and an higher ratio of Bcl-2/Bax genes. Other studies documented also that Ginsenoside Re may induce angiogenesis, possibly contributing to cardiovascular tissues regeneration (Fig. 1).13FIGURE 1.: Novel antiplatelet activity of Ginsenoside Re.CONCLUSIONS Tackling ischemic risk is of crucial importance in patients with previous coronary disease deemed to be at high risk of further ischemic events; however, treatment strategy should be customized on every single patient, trying to balance bleeding and ischemic risk.14 A clear example of this, is the management of elderly patients loaded by many comorbidities, with multiple conditions associated with high bleeding risk and the concomitant need for chronic anticoagulant therapy.14 We believe that finding new antiplatelet therapies, capable of decoupling pathologic platelet response from the physiological one, may be of utmost importance in clinical practice, especially in patients with frailty and comorbidity. At this aim, we now know that shear stress, induced by blood flow, is an important factor involved in platelet activation and aggregation: recent studies found that targeting SIPA may play a consistent role in reducing pathologic arterial thrombosis. In this context, the work by Huang et al10 demonstrates that Ginsenoside Re selectively inhibits platelet aggregation mediated by high shear stress, in a concentration-dependent manner, without significant bleeding issues. However, these first data should be viewed with caution and mainly as hypothesis generating, with further evidence, especially clinic trials, needed. Despite the journey from these encouraging preclinical results to randomized clinical trials and finally administration of Ginsenoside Re in daily clinical routine being enough far, we cannot exclude that in the future SIPA-inhibiting agents may become a precious addition to the current state-of-the-art antithrombotic therapy or, maybe, prove to be safer and more effective in the treatment of atherothrombotic diseases. Until that time, we are gladly looking forward to reading new and encouraging molecular and clinical studies on SIPA inhibitors.