Glabridin, a Bioactive Flavonoid from Licorice, Effectively Inhibits Platelet Activation in Humans and Mice

Abstract

Platelets are crucial for hemostasis and arterial thrombosis, which may lead to severe cardiovascular diseases (CVDs). Thus, therapeutic agents must be developed to prevent pathological platelet activation. Glabridin, a major bioalkaloid extracted from licorice root, improves metabolic abnormalities (i.e., obesity and diabetes) and protects against CVDs and neuronal disorders. To the best of our knowledge, no studies have focused on glabridin’s effects on platelet activation. Therefore, we investigated these effects in humans and mice. Glabridin exhibited the highest inhibitory effects on collagen-stimulated platelet aggregation and moderate effects on arachidonic-acid-stimulated activation; however, no effects were observed for any other agonists (e.g., thrombin or U46619). Glabridin evidently reduced P-selectin expression, ATP release, and intracellular Ca2+ ([Ca2+]i) mobilization and thromboxane A2 formation; it further reduced the activation of phospholipase C (PLC)γ2/protein kinase C (PKC), phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β), mitogen-activated protein kinase (MAPK), and NF-κB. In mice, glabridin reduced the mortality rate caused by acute pulmonary thromboembolism without altering bleeding time. Thus, glabridin effectively inhibits the PLCγ2/PKC cascade and prevents the activation of the PI3K/Akt/GSK3β and MAPK pathways; this leads to a reduction in [Ca2+]i mobilization, which eventually inhibits platelet aggregation. Therefore, glabridin may be a promising therapeutic agent for thromboembolic disorders.

Mechanisms of glabridin inhibition of integrin αIIbβ3 inside-out signals and NF-κB activation in human platelets

“…In one study [ 12 ], glabridin (Fig. 1 A and 10–40 µM) most strongly inhibited human platelet aggregation by collagen (1 µg/mL) stimulation and moderately inhibited by AA (60 µM) stimulation; it did not affect platelet aggregation stimulated by thrombin (0.01 U/mL) or U46619 (1 µM).…”

“…1 A and 10–40 µM) most strongly inhibited human platelet aggregation by collagen (1 µg/mL) stimulation and moderately inhibited by AA (60 µM) stimulation; it did not affect platelet aggregation stimulated by thrombin (0.01 U/mL) or U46619 (1 µM). In that study [ 12 ], the authors used only three concentrations of glabridin to estimate the approximate IC 50 value for collagen-stimulated platelet aggregation. In this study, we used six concentrations (5–30 µM) of glabridin to obtain a more accurate concentration–response profile for collagen (1 µg/mL) stimulation (Fig.…”

“…Conversely, licochalcone, a bioactive compound in licorice root, was reported to exhibit antiplatelet activity through inhibition of phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation in human platelets [ 11 ]. Chung et al [ 12 ] found that glabridin most strongly inhibits collagen-stimulated human platelet aggregation and moderately inhibits arachidonic acid (AA) stimulation but has no effect on thrombin or U46619 stimulation, whose mechanisms may be mediated by inhibition of PLCγ2/PKC and phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β activation. Concurrently, they found that glabridin clearly reduces pulmonary thromboembolism without prolonging bleeding time as compared with aspirin [ 12 ].…”

“…Chung et al [ 12 ] found that glabridin most strongly inhibits collagen-stimulated human platelet aggregation and moderately inhibits arachidonic acid (AA) stimulation but has no effect on thrombin or U46619 stimulation, whose mechanisms may be mediated by inhibition of PLCγ2/PKC and phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β activation. Concurrently, they found that glabridin clearly reduces pulmonary thromboembolism without prolonging bleeding time as compared with aspirin [ 12 ]. Therefore, glabridin may have therapeutic potential against thromboembolic-related diseases.…”

Tetrahedral framework nucleic acid loaded with glabridin: A transdermal delivery system applicated to anti‐hyperpigmentation

“…[1][2][3] The most common types of hyperpigmentation include melasma, freckles, senile plaques, and postinflammatory hyperpigmentation. [4][5][6][7][8] Although the clinical and pathological manifestations of each type differ, increased melanin production and uneven distribution are the leading causes of hyperpigmentation and are related to hormones, inflammation, and ultraviolet (UV) exposure. [9][10][11][12][13] Melanin, the primary pigment in human hair and skin, is synthesized in the melanosomes of melanocytes and protects the skin from the harmful effects of UV exposure and other environmental factors.…”