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

Eur J Pharmacol. 2019 Nov 5:862:172627. doi: 10.1016/j.ejphar.2019.172627. Epub 2019 Aug 25.

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 1.85 μM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100 μM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50 > 100 μM) but inhibited collagen induced platelet aggregation at 50 μM and 100 μM. 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 100 μM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85 μM). 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.

Keywords: Haemostasis; Isorhapontigenin; Platelets; Polyphenols; Thrombosis.

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Animals
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Drug Evaluation, Preclinical
  • Female
  • Healthy Volunteers
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Models, Animal
  • Molecular Docking Simulation
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Aggregation Inhibitors / therapeutic use
  • Platelet Function Tests
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Receptors, Purinergic P2Y12 / chemistry
  • Receptors, Purinergic P2Y12 / metabolism
  • Resveratrol / analogs & derivatives
  • Resveratrol / pharmacology
  • Signal Transduction / drug effects
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*
  • Stilbenes / therapeutic use
  • Thrombosis / drug therapy

Substances

  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Receptors, Purinergic P2Y12
  • Stilbenes
  • isorhapontigenin
  • Adenosine Diphosphate
  • Resveratrol