Anti-platelet role of Korean ginseng and ginsenosides in cardiovascular diseases

Abstract

Cardiovascular diseases prevail among modern societies and underdeveloped countries, and a high mortality rate has also been reported by the World Health Organization affecting millions of people worldwide. Hyperactive platelets are the major culprits in thrombotic disorders. A group of drugs is available to deal with such platelet-related disorders; however, sometimes, side effects and complications caused by these drugs outweigh their benefits. Ginseng and its nutraceuticals have been reported to reduce the impact of thrombotic conditions and improve cardiovascular health by antiplatelet mechanisms. This review provides (1) a comprehensive insight into the available pharmacological options from ginseng and ginsenosides (saponin and nonsaponin fractions) for platelet-originated cardiovascular disorders; (2) a discussion on the impact of specific functional groups on the modulation of platelet functions and how structural modifications among ginsenosides affect platelet activation, which may further provide a basis for drug design, optimization, and the development of ginsenoside scaffolds as pharmacological antiplatelet agents; (3) an insight into the synergistic effects of ginsenosides on platelet functions; and (4) a perspective on future research and the development of ginseng and ginsenosides as super nutraceuticals.

Keywords: AA, arachidonic acid; AC, adenylyl cyclase; ADP, adenosine diphosphate; ASA, acetylsalicylic acid; ATP, adenosine triphosphate; Akt, protein kinase B; Antiplatelet; COX, cyclooxygenase; CRP, collagen-related peptide; CSF, crude saponin fraction; ERK, extracellular signal–regulated kinase; GPVI, glycoprotein VI; Ginsenosides; IC50, half maximal (50%) inhibitory concentration; IP3, inositol-1,4,5-triphosphate; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MKK4, mitogen-activated protein kinase kinase 4; MLC, myosin light chain; Nutraceutical; PAF, platelet-activating factor; PAR, proteinase-activated receptor; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLA2, phospholipase A2; PLCγ2, phospholipase C gamma-2; PPD, protopanaxadiol; PPT, protopanaxatriol; PT, prothrombin time; ROCK, Rho-associated protein kinase; SFK, Src family kinase; Structural modification; Syk, spleen tyrosine kinase; Synergism; TS, total saponin; TxA2, thromboxane A2; TxAS, thromboxane-A synthase; TxB2, thromboxane B2; TxR, thromboxane receptor; VASP, vasodilator-stimulated phosphoprotein; [Ca2+]i, intracellular calcium ion; aPTT, activated partial thromboplastin time; cAMP, cyclic adenosine monophosphate; cPLA2α, cytosolic phospholipase A2α; vWF, von Willebrand factor.

Fig. 1

Mechanism of platelet activation showing intracellular signaling pathways and effects of different ginsenosides on the modulation of platelet functions that affect various receptors or downstream signaling events. AA, arachidonic acid; AC, adenylyl cyclase; Akt, protein kinase B; COX, cyclooxygenase; CSF, crude saponin fraction; IP3, inositol-1,4,5-triphosphate; MAPK, mitogen-activated protein kinase; MLC, myosin light chain; PAR, proteinase-activated receptor; PKA, protein kinase A; PKC, protein kinase C; PLA₂, phospholipase A2; PLCγ2, phospholipase C gamma-2; ROCK, Rho-associated protein kinase; SFK, Src family kinase; TS, total saponin; TxAS, thromboxane synthase; TxA₂, thromboxane A2; VASP, vasodilator-stimulated phosphoprotein; vWF, von Willebrand factor.

Fig. 2

Chemical structures and schematic conversion of the ginsenosides with respect to the structural modification among specific functional groups. Rb1→Rg5→Rh4, Rg1→Rh1→Rp4, Re→Rg2→Rp3, Rb1→Rg3→Rh2→Rp2, and Rg3→2H-Rg3→Rp1. PPD, protopanaxadiol; PPT, protopanaxatriol.