Natural Antiplatelet Drugs in Thrombosis Treatment ... · Multifaceted hemostatic mechanisms are associated with the ... is a strong antioxidant and anti-in- ... tial protective effects

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Review Article

45輔仁醫學期刊　第 16卷　第 1期　2018

Natural Antiplatelet Drugs in Thrombosis Treatment: Prospective Molecular Mechanisms

Eng-Thiam Ong1, Shin-Yi Tsao2, Chi-Tong Kuok1, Chao-Chien Chang1,3,*

ABSTRACT

Multifaceted hemostatic mechanisms are associated with the pathophysiology of various diseases, including cardiovascular diseases. Among them, dysregulation of platelet activi-ty is related to the progression of atherosclerosis and mainly involves platelet aggregation and decreased blood flow in the vascular endothelium. The major platelet activation path-ways mediated by agonists are the arachidonic acid, adenosine diphosphate, serotonin, and nitric oxide pathways. Free radicals also affect the molecules involved in platelet aggrega-tion. These mechanisms have been widely studied and discussed because they are inhibited by plant-based compounds that are used in complementary and alternative medicine for re-ducing platelet aggregation. Current antiplatelet therapy is highly effective in preventing atherothrombotic complications. Nevertheless, some patients continue to experience recur-rent complications despite receiving appropriate treatment because of the pharmacokinetics and interactions of consumed drugs, the genetic backgrounds of the patients, and the in-creased frequency of thrombus formation . Hence, considerable research has been directed toward providing new antiplatelet drugs that exhibit superior aggregation-preventing poten-tial but do not increase bleeding risk. In this review, we discuss unique natural antiplatelet drugs and their potential inhibition of platelet aggregation.

Keywords: antiplatelets; natural products; antithrombosis; molecular mechanism

1 Division of Cardiology, Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan2 Division of Endocrinology and Metabolism, Department of Internal Medicine, Sijhih Cathay General Hospital3 Graduate Institute of Medical Sciences and Department of Pharmacology, Taipei Medical University, Taipei, Taiwan* Corresponding author: Dr. Chao-Chien Chang Division of Cardiology, Department of Internal Medicine, Cathay General Hospital, No. 280, Section 4, Ren-Ai Road, 106 Taipei, Taiwan E-mail: [email protected]

DOI 10.3966/181020932018031601006

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Eng-Thiam Ong Shin-Yi Tsao Chi-Tong Kuok Chao-Chien Chang　

46 Fu-Jen Journal of Medicine Vol.16 No.1 2018

INTRODUCTION

In recent years, antithrombotic drugs, which can be divided into three major categories de-pending on whether they possess anticoagulation, antiplatelet aggregation, or fibrinolysis activities, have been intensively studied and developed as po-tential therapies for arterial and venous thrombosis [1]. Among these clinically used drugs, heparin [2], warfarin [3], and their derivatives are mainly used for the inhibition of blood coagulation factors, while antiplatelet drugs such as aspirin, clopi-dogrel, and abciximab have been used to reduce the risk of cardiovascular diseases (CVDs) [4,5]. Over the past 40 years, although intense investi-gation has been directed toward the discovery and development of increasingly effective antithrom-botic drugs, these drugs have been ineffective in reducing thrombosis-related mortality rates [6]; this situation will probably become increasingly challenging in the future because the incidence of obesity, diabetes, and the metabolic syndromes is rapidly rising. The reasons for the low cure rates of these drugs are mainly drug resistance, limited effi-cacy in some patients, and side effects such as high bleeding risk and gastrointestinal dysfunction [7]. Therefore, the development of novel therapeutic approaches to reduce the adverse effects of current-ly available antithrombotic drugs without impairing their efficacy is crucial.

In recent years, considerable effort has been invested in discovering natural products that are effective supplements or substitutes for currently available antithrombotic drugs [8]. These natural products are derived from plants [9, 10] described in traditional Chinese medicine (TCM) [11],

known as functional foods [12]. They have been demonstrated to possess remarkable antithrom-botic properties in both the experimental and clinical stages. Drugs used in TCM have a long history of treating many types of human diseases, including thrombotic diseases and blood stasis syndrome. The main reasons underlying the use of natural products to treat thrombotic diseases is that these products contain multiple constituents, each of which may have multiple targets. The constituents may exert pleiotropic and synergis-tic effects that increase the therapeutic efficacy of the products. In addition, the constituents of nat-ural products usually exhibit fewer side effects on the gastrointestinal system than do synthet-ic drugs [13]. This review provides an overview of the antithrombotic effects exhibited by natural products that result in reduced thrombotic risks (Table 1).

Antiplatelet and antithrombotic effects

of natural products

Studies have demonstrated that natural prod-ucts are increasingly crucial in reducing thrombotic risks and treating various CVDs. As previous-ly mentioned, drugs for treating thrombosis can be divided into the following three categories: (1) an-ticoagulants, which inhibit the coagulation system and interfere with subsequent plaque expansion; (2) antiplatelet agents, which reduce platelet ag-gregation and inhibit thrombus formation; and (3) fibrinolytic drugs, which directly dissolve the formed thrombus [14].

Kinetin

Kinetin (Figure 1A), a cytokine, is an es-sential plant growth hormone that regulates cell

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　Natural Antiplatelet Drugs in Thrombosis Treatment: Prospective Molecular Mechanisms


growth and differentiation. It has also been detect-ed in human cell extracts and urine and has been identified as a naturally occurring base modifica-tion agent of DNA that promotes cell division in plants [15]. Kinetin is used in molecular medicine because of its remarkable properties [16]. A pre-vious study demonstrated that kinetin inhibits the aggregation of washed human platelets [17]. The effectiveness of kinetin in scavenging free radicals formed in platelets was evaluated using electron spin resonance (ESR), and the results revealed that kinetin (70 and 150 µM) reduced the ESR signal intensity of the hydroxyl radicals in collagen (1 µg/mL)-activated platelets in a concentration-de-pendent manner [17]. Intravenously administered kinetin effectively reduced the mortality rates of mice with adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism [17]. More-

over, in this same study, kinetin increased the bleeding time when administered as a bolus to rats. At 2 mg/kg, kinetin showed no significant ef-fects on the bleeding time. At 4 and 6 mg/kg, it significantly increased the bleeding time approxi-mately 1.9- and 2.1-fold, respectively, the bleeding time with normal saline.

Rutin

Rutin (2-(3,4-dihydroxyphenyl)-4,5-dihy-droxy-3-[3,4,5-trihydroxy-6-[(3,4,5-trihydroxy-6 ethyl-oxan-2-yl)oxymethyl] oxan-2-yl]oxy-chro-men-7-one), also known as quercetin-3-rutinoside, is a flavonol glycoside consisting of the flavo-nol quercetin and the disaccharide rutinose. Rutin (Figure 1B), is a strong antioxidant and anti-in-flammatory flavonoid abundantly found in various fruits and vegetables such as buckwheat seeds,

Table 1. Antiplateleteffectsofnaturalbioactivecompoundsthroughactiononmultipletargets

S. No Drugs Inducers of platelet aggregation Mechanisms of action References

1. Kinetin Collagen, ADP (in mice)

　 OH○ levels　 bleeding time

17

2. Rutin PAF

Collagen(in mice)

　 5-HT release ,Ca2+ mobilization　 fibrin clot, 　 aPTT, PT, and CT　 thromboembolism

18

8

3. Lycopene Collagen, ADP, and AA 　 platelet aggregation 214. Resveratrol ADP 　 P-PLCβ3

　 ratio of P-PLCβ3 to T-PLCβ325

5. Sesamol Collagen

Collagen

　　 Ca2+ mobilization; TxA2 formation, and phosphorylation of PLCγ2, PKC, MAPK, and Akt

　 cGMP, eNOS, NO, and p-VASP

30

316. Andrographolide Collagen 　　 TxA2 formation and phosphorylation ofPLCγ2,

PKC, MAPK, and Akt phosphorylation 　 GMP

33

34Abbreviations:OH○: hydroxyl radicals, aPTT: activated partial thromboplastin time, PT: prothrombin time, CT: closure time, AA: arachidonic acid, PAF: platelet activating factor, cGMP: cyclic GMP, eNOS: endothelial nitric oxide synthase, TxA2: thromboxane A2, PLC: phospholipase C, PKC: protein kinase C, VASP: vasodilator-stimulated phosphoprotein, PLCγ2: phospholipase Cγ2, NO: nitric oxide; MAPKs: mitogen-activated protein kinases

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passion flowers, onions, oranges, apples, lem-ons, and grapes as well as in tea and red wine. A previous study demonstrated the inhibition of col-lagen-induced platelet aggregation in super-fused cat blood by rutin through the inhibition of cy-clooxygenase or lipoxygenase. An in vitro study revealed that rutin inhibited platelet activating factor (PAF)-induced platelet aggregation and re-duced intraplatelet free calcium concentration in washed rabbit platelets [18]. An antithrombotic ef-fect of rutin was recently investigated; the results revealed that rutin inhibited fibrin clot formation as well as prolonged activated partial thrombo-plastin time (aPTT), prothrombin time (PT), and closure time (CT) [8].

An in vitro study demonstrated that rutin in-hibits collagen-induced platelet activation through the activation of phospholipase C, followed by the inhibition of protein kinase (PK)C activity and thromboxane A2 (TxA2) formation. Thus, rutin in-hibits the phosphorylation of p47 and intracellular Ca2+ mobilization [9]. The inhibitory effect of ru-tin on platelet aggregation is suggested to be due to the inhibition of PAF activation; prolongation of aPTT, PT, and CT; phospholipase C inhibition; and the inhibition of protein kinase C activation and TxA2 formation, which inhibit the phosphorylation of p47 and intracellular Ca2+ mobilization. These findings suggest that rutin may effectively treat thromboembolic-related disorders.

Lycopene

Lycopene (Figure 1C), a pigment that is pri-marily responsible for the characteristic deep red color of ripe tomatoes and other fruits and veg-etables, has attracted attention because of its biological and physicochemical properties, par-

ticularly its effects as a natural antioxidant. Carotenoids, the yellow, orange, and red pigments present in a number of fruits and vegetables, con-stitute a class of compounds that have long been considered CVD-preventive food ingredients the past two decades [19]. Lycopene is reported to exhibit high antioxidant potential [20]. It ex-erts protective effects in chronic CVDs as well as in respiratory and digestive epithelial cancers [21]. A previous study demonstrated that lyco-pene (2–12 µM) inhibited platelet aggregation and the adenosine triphosphate (ATP)-release re-action stimulated by collagen (1 µg/mL), ADP (20 µM), and arachidonic acid (60 µM) in both washed human platelets and platelet-rich plasma [21]. Moreover, another study demonstrated that lycopene (6 and 12 µM) markedly reduced the ra-dioactivity of inositol phosphate formation in collagen-stimulated human platelets [22]. A re-cent study compared the inhibition of ADP- and collagen-induced platelet activation by lycopene and aspirin; the results suggest that lycopene can be considered a potential target for inhibiting the thrombotic and proinflammatory events associat-ed with platelet activation [23].

Resveratrol

Resveratrol (3, 5, 4’-trihydroxy-trans-stilbene; Figure 1D), a phytoalexin naturally synthesized or induced in plants, is a widely researched anti-oxidant and anti-inflammatory agent that has been shown to reverse age-related pathologies in small mammals. It is a nonflavonoid polyphenolic com-pound belonging to the stilbene group and is found in many plant-based foods and beverages includ-ing red wine, grapes, berries, and peanuts. The effect of resveratrol on platelet aggregation was in-

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vestigated in a model of hyperhomocysteinemia, and the results revealed that resveratrol reduced the toxic effects of homocysteine and homocyste-ine thiolactone on blood platelet aggregation and inhibited superoxide anion radical production in platelets. Hence, the results suggest that its poten-tial protective effects on hemostasis are negatively affected by homocysteine [24]. The effect of resve-ratrol on platelet aggregation induced by a TxA2 receptor agonist, U46619 (9,11-Dideoxy-11α, 9α-epoxymethanoprostaglandin F(2α)), was studied [25]. The results showed that resveratrol blocked U46619-induced platelet aggregation in a concen-tration-dependent manner. The study also showed that resveratrol inhibited ADP-induced platelet ag-gregation in a concentration-dependent manner, and at 25 µM, resveratrol notably reduced the ex-pression of P-phospholipase C (PLC)β3 and the ratio of P-PLCβ3 to T-PLCβ3 in the platelets of healthy human volunteers [26]. Resveratrol sig-nificantly enhanced the inhibitory activities of endogenous antiplatelet substances prostaglad-in (PG)I2 and PGE1 in collagen-induced human platelet suspension at relatively low concentrations (2 or 5 µM) without affecting platelet function [27]. Resveratrol was recently reported to exhibit the du-al ability to reduce unwanted platelet activation during storage while simultaneously preserving critical hemostatic function [28].

Sesamol

Sesamol (5-hydroxy-1,3-benzodioxole or 3,4-methylenedioxyphenol; Figure 1E) is the pre-dominant active component of sesame seed oil obtained from Sesamum indicum L. Sesamol has previously been demonstrated to exhibit potent an-tioxidant activity in ultraviolet and Fe3+/ascorbate-

induced lipid peroxidation in the rat brain [29]. Furthermore, sesamol appears to act as a neuropro-tective agent and exhibits hepatoprotective, anti-inflammatory, anticancer, and antiaging properties [30, 31].

Recent studies have reported that sesamol (2.5–100 μM) inhibits platelet aggregation by increasing the rate of cyclic adenosine monophos-phate (cAMP) formation and attenuating nuclear factor-kappa B (NF-κB) signaling events, thus in-dicating that sesamol is an antithrombotic and cardioprotective compound. In an earlier study, sesamol was reported to inhibit collagen-induced platelet activation through inhibition of Ca2+ mo-bilization, TxA2 formation, and phosphorylation of PLC γ2, PKC and mitogen-activated protein ki-nases (MAPK) [32]. In the same study, sesamol was also found to increase the levels of cAMP and cyclic guanosine monophosphate (cGMP), ex-pression of endothelial nitric oxide synthase, and release of NO in platelets during collagen-induced platelet aggregation. Another study revealed that sesamol (2.5–25 μM) stimulated cAMP-PKA sig-naling, subsequently inhibiting the NF-κB–PLC–PKC cascade. Thus, sesamol attenuated Ca2+ mobilization and inhibited platelet aggregation [33]. Thushara et al. [34] reported that sesamol at con-centrations ≥0.25 mM induced platelet apoptosis through the endogenous generation of reactive ox-ygen species, depletion of the thiol pool, and Ca2+ mobilization. The study demonstrated that although sesamol inhibited platelet aggregation, it tended to elicit platelet apoptosis at high concentrations. The pharmacokinetic data of sesamol were calcu-lated in biological fluids after a dose of 50 mg/kg through gastric gavage (P.O.) or intravenous injec-tion. The authors found that the oral bioavailability

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of sesamol was 35.5% ± 8.5%. Furthermore, ses-amol penetrated the blood–brain barrier and was eliminated through hepatobiliary excretion. Gao et al. reported the neuroprotective effects of sesa-mol on cerebral tissue exposed to middle cerebral artery occlusion-reperfusion and ischemic damage in rats, mainly attributing this effect to the inhibi-tion of neurological deficits and lipid peroxidation, restoration of antioxidants, and mitigation of in-flammation and apoptosis responses [35]. Their study suggested that sesamol may be a suitable candidate for the clinical treatment of various brain ischemic conditions resulting from oxidative stress.

Andrographolide

Andrographolide (Figure 1F), a labdanedi-terpene lactone, is the primary active constituent isolated from the leaves of Andrographis panicu-lata. In Asia and Scandinavia, A. paniculata has long been used for the prevention and treatment of upper respiratory tract infections, diarrhea, rheu-matoid arthritis, and laryngitis. It has also served as a valuable health food, and its extract is used as a nutritional supplement for the prevention of in-flammatory diseases in Taiwan. A previous study revealed that andrographolide significantly inhib-ited thrombin-induced platelet aggregation in a concentration-dependent (1–100 µM) and time-de-pendent manner through inhibition of the ERK1/2 pathway. The study also suggested that the con-sumption of A. paniculata products may facilitate the prevention or treatment of cardiovascular dis-orders such as thrombosis [36]. A study also reported potent inhibition by andrographolide (25–75 μΜ) of collagen-induced platelet aggregation as well as of the inhibition of Ca2+ mobiliza-tion; TxA2 formation; and PLCγ2, PKC, MAPK,

and Akt phosphorylation [37]. Andrographolide was found to increase the levels of cGMP but not those of cAMP. An in vivo study revealed that andrographolide (22 and 55 μg/kg) effectively re-duced the mortality associated with ADP-induced acute pulmonary thromboembolism and signifi-cantly prolonged platelet plug formation in mice [37]. A recent study demonstrated that this natu-ral compound stimulated p38MAPK-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 sig-naling in the primary cerebral endothelial cells in rats, thereby protecting the rats against ischemic stroke [38].

CONCLUSION

Thrombosis is the major underlying cause of some of the most common diseases, such as myocardial infarction and stroke. Despite consid-erable development in understanding the biology of thrombus formation and the pathophysiolo-gy of thrombosis, pharmacological agents have mainly been used for the prevention or treat-ment of thrombosis. Natural products have been reported to exhibit preventive effects against thrombotic diseases in both the experimental and clinical stages; thus, a useful approach to pre-vent thrombotic diseases is available in addition to pharmacological treatments. Advances in the knowledge of the mechanisms underlying throm-bus formation and the biological functions of natural products will provide new insights in-to promoting human health. In the future, with an improved understanding of the complex molecu-lar bases of thrombotic disease, we may be able to develop antiplatelet agents that are suited to indi-vidualized patient treatment.

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Figure 1. Chemical structures of (A) kinetin, (B) rutin, (C) lycopene, (D) resveratrol, (E) sesamol, and (F) andrographolide

A B

C D

E F

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ACKNOWLEDGMENTS

This work was supported by grants from the Cathay General Hospital–Taipei Medical Univer-sity (103CGH-TMU-06; CGH-MR-A10308), and we acknowledge Wallace Academic Editing for ed-iting this manuscript.

AUTHOR DISCLOSURE STATEMENT

The authors declare that they have no conflicts of interest to disclose.

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天然抗血小板化合物應用於血栓的治療：其分子機轉的探討

王榮添 1，曹心怡 2，郭志東 1，張釗監 1,3,*

中文摘要

複雜的凝血機制所牽涉的各種病理生理狀態，包括心血管疾病。其中，血小板活

性的失調關係到動脈粥樣硬化的進展，主要是血小板凝集和血管內皮細胞內的血流量

減少。活化血小板的主要分子途徑包括花生四烯酸途徑、二磷酸腺苷途徑、血清素途

徑、一氧化氮途徑及自由基的作用，它們都參與血小板凝集作用。在替代醫學中，利

用藥用植物來減少血小板聚集抑制作用，這些機制已經被廣泛的研究和討論。目前的

抗血小板治療是非常有效防止動脈粥樣硬化的併發症。然而，有些患者儘管被妥善治

療仍會出現復發性併發症，可能跟藥物的相互作用與個人體質有關。因此大量的研究

者致力於發展新的抗血小板藥物能具有更好的抗血小板效果且不增加出血風險。在這

篇文章中，我們回顧討論多種天然抗血小板化合物，它們獨特的抑制血小板凝集作用，

未來在心血管疾病治療上可提供方向。

關鍵字：抗血小板；天然化合物；抗血栓；分子機轉

1 台北市國泰綜合醫院心臟內科2 新北市汐止國泰綜合醫院內分泌科3 台北市台北醫學大學藥理學科暨醫學科學研究所* 收稿日期：2017年 8月 11日接受日期：2017年 12月 18日* 通訊作者：張釗監　電子信箱：[email protected]

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Natural Antiplatelet Drugs in Thrombosis Treatment ... · Multifaceted hemostatic mechanisms are associated with the ... is a strong antioxidant and anti-in- ... tial protective effects