Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation

Abstract

Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties.However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85µM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100µM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50>100µM) but inhibited collagen induced platelet aggregation at 50µM and 100µM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion.Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100µM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85µM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor.

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

“…Isorhapontigenin increased adenosine 3’,5’-cyclic monophosphate (cAMP) levels and phosphorylation of vasodilator-stimulated phosphoprotein (VASP). On the other hand, decreased Akt phosphorylation was found, suggesting a potential effect of this drug on cAMP and phosphoinositide 3-kinases (PI3K) signaling pathways that are downstream effectors of P2Y 12 receptor ( 262 ). Although clopidogrel enhanced anti-tumor and/or anti-metastatic activity of chemotherapeutic agents such as 5-fluorouracil, cyclophosphamide and mitoxantrone, on the other hand, it reduces the anti-cancer activity of doxorubicin, cisplatin and tamoxifen ( 263 ).…”

More Than Resveratrol: New Insights into Stilbene-Based Compounds

“…ISO is well-known for its various beneficial effects, including antiplatelet activity [49]. Comparing to RSV, it exhibited a more substantial selective inhibitory effect on ADP-induced platelet aggregation.…”

“…Isorhapontigenin (trans-3,5,4 -trihydroxy-3 -methoxystilbene, ISO) is a resveratrol analogue with methoxy groups at the ring B, found in the Chinese herb Gnetum cleistostachyum and grapes [49]. Dai et al characterized the pharmacokinetic profile of ISO and RSV in Sprague-Dawley rats after a single oral administration (200 µmol/kg b.w.)…”

Polyphenols: Modulators of Platelet Function and Platelet Microparticle Generation?

“…Both polyphenol treatments may inhibit PAR receptor activation by modulating its response to proteolytic (thrombin) and non-proteolytic (TRAP) activation. Furthermore, resveratrol and its analogue isorhapontigenin have been demonstrated to inhibit ADP induced platelet activation [84,85]. However, grape seed extracts contain multiple polyphenols that may interact with several pathways in platelet activation, leading to decreased degranulation and PMP shedding, thus contributing to its higher inhibition than pure resveratrol.…”