Medicinal Properties of Eucommia

38 Medicinal Properties of Eucommia

Bark and Leaves

Eu Leong Yong National University of Singapore

Republic of Singapore

I. INTRODUCTION Eucommia ulmoides Oliver (Du-Zhong) (EU), of the family Eucommiacaea, is

a large deciduous tree originating in China. The barkof the tree (commonly referred to as cortex eucommiae) has been used as a natural medicine since ancient times in China (1,2). Currently, the herb is widely used as decoctions or commercially manufactured pills, essences, and extracts in Chinese com- munities worldwide especially in mainland China, Taiwan, Hong Kong, and Singapore. In Japan, dried eucommia leaves are consumed commonly as Tochu tea. The trunkbarkof E. ulcommia ulmoides Oli is produced mainly in the Sichuan, Yunnan, Guizhou, Hubei, and Shanxi provinces of China. The barkis stripped off between April and June. After the coarse outer corky layer is scraped off, the barkpieces are piled up until the inner surface becomes purplish-brown and then dried in the sun. The large barkis cut into segments and stir-baked with salt. This herb is called fried ‘‘eucommia bark’’ or ‘‘eucommia barkcharcoal.’’ The herb appears as flattened pieces that are 3–7 mm thick. The outer surface of the bark is fissured longitudinally. Pieces

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are easily broken from the bark and such pieces are linked by fine, dense silvery and elastic rubber bands. The tree has been cultivated for its rubber.

II. CLASSIC ACTION AND USES In ancient pharmacopoeia, the herb is used to tonify the liver and kidney, to

strengthen bones and tendons, and to prevent miscarriage (1,2). Decoctions of eucommia barkhave been used for, among other things, the relief of back pain, to increase strength, to make bones and muscles strong, to increase recovery from fatigue, to increase ability to remember, and to induce an antiaging effect. It is prepared as Du-Zhong tincture (5 or 100%), 1–5 mL taken orally thrice daily. It is frequently formulated with ginseng, Cordyceps, angelica root, and many other herbs (3). Ingestion of EU barkand leaves and their extracts has not been reported to induce any known side effects.

A. Formulation

A synergistic effect by using the leaves of E. ulmoides Oliver, Eucomiaceae (Du-Zhong leaf) and the roots of Panax ginseng C. A. Meyer (Ginseng) has been reported (4). The formula consists of amounts that exert no effect when used individually. Several formula ratios of ginseng and Du-Zhong leaf, 1:1, 1:2, 1:3, and 1:4, were tested. It was demonstrated that the formula ratio of ginseng to Du-Zhong leaf of 1:3 was the most effective for stimulation of col- lagen synthesis and prevention of decreased protein metabolism in aging (4).

III. CHEMISTRY The herb contains irridoids, phenols (pyrogallol, protocatechuic acid, and p-

trans -coumaric acid), tannins, coumarin, lactones and their glycosides, alkaloids, triterpenes, saponins, (+)-pinoresinol-di-O-h- D -glucopyranoside, catechol, 3-(3-hydroxyphenyl)propionic acid, dihydrocaffeic acid, guiacygly- cerol, trans-4-hydroxycyclohexane-1-carboxylic acid resins, long-chain poly-

trans prenols ( >9 mers), ajugoside, reptoside, harpagide acetate (C 26 H 32 O 12 ), other organic acids, and some alkaloids (5–9). Among the constituents, irri- doids are considered to be bioactive; these include geniposidic acid, genipo- side, asperulosidic acid, deacetyl asperulosidic acid, asperuloside, and their

glycoxylated derivatives such as encommiol (C 9 H 16 O 4 ) and 1-deoxyeucom- miol and aucubin (C 15 H 22 O 9 ). Three percent of the leaf contains cholorogenic acid. The biological actions of many of these compounds have not been investigated.

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A. Effect of Processing Processing affects the chemical composition of the herb. Concentrations of

compounds in eucommia are influenced by the area where it is produced, harvest time, and treatment after harvesting. Thus the content of pinoresinol diglucoside in postprocessed barkis higher than that in preprocessed bark (10). Leaves collected from June to September had an aucubin content that was 2.5% higher than at other times (11). On the other hand, geniposidic acid concentration was 5.5% higher in June and July. Since leaves are usually harvested in October and November, the levels of the suspected bioactives, aucubin and geniposidic acid, are actually lowest in marketed Tochu leaves.

IV. TOXICITY AND DRUG METABOLISM When the dose of geniposide was higher than 50 mg/kg/day, toxicity was

encountered in rat models (12). Eucommia leaf extracts also increased the activities of cytochrome P450 and carboxylesterase and accelerated detoxifi- cation of an organophosphorus insecticide, chlorpyrifos, in the livers of mice pretreated with the herbal extract (13). This increase in liver metabolism may have implications for other ingested drugs that are metabolized in the liver.

V. BIOLOGICAL ACTIONS Modern research on the mode of action of eucommia has been performed in

only limited number of laboratories, most notably from the group at Nihon University, Chiba, Japan (4,5,12,14–18). Efforts have focused on verifying the basis of the herb’s traditional use to strengthen bone and muscles. More modern approaches include studies on its potential applications as an antimutagenic agent, as an antioxidant, antihypertensive, hypocholesterole- mic agent, and also as an antibiotic against bacteria, fungi, and viruses.

A. Muscle Strength, Stamina, Collagen Metabolism It has been noted that the muscles of eels fed Tochu leaf powder were 1.8 times

harder than those of the controls (19). Although the component analysis showed no difference in moisture, lipid, or protein content between the mus- cles of control and Tochu-fed eels, there was a great difference in the amount of muscle protein stroma fraction that consisted of collagen. The perimysium and endomysium of the muscle was observed microscopically to be firm and thickcompared to control. The administration of E. ulmoides Oliver leaf along with light intensity training was reported to enhance the ability of a muscle to resist fatigue in rat studies (16). Mechanical training and the use of EU leaf extracts cooperatively can increase the ability of rats to avoid lactate

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accumulation in skeletal muscle, and the administration of the EU leaf along with light intensity training enhances the ability of a muscle to resist fatigue. EU leaves contain compounds similar to the barkand are reported to have similar pharmacological effects. Since irridoid monoglycosides, such as geniposidic acid and aucubin, in EU can stimulate collagen synthesis in aged model rats (15), it is thought that the active compounds are actually geniposidic acid or aucubin (17).

Granuloma maturation and deposition of collagen in the granuloma of rats were also reported to be improved by the oral administration of E. ulmoides Oliver leaf (12). Granuloma formation, induced by the formalin- soaked filter-paper-pellet method, was significantly increased owing to inges- tion of the dried leaf at a dose of 1.8 g/kg of body weight/day. The collagen content in the granuloma was also significantly increased. In the case of the collagen profile, the pepsin-solubilized collagen content and its relative percentage of the total collagen were significantly higher than in the control. Histochemical examination showed that the granuloma tissues were well developed and displayed many newly synthesized capillary vessels and a greater quantity of fibroblasts and monocytes in the 1.8-g-leaf group. High- density-lipoprotein (HDL) cholesterol and triglyceride content in the blood plasma were significantly higher than in the control. These results suggest that granuloma maturation was accelerated and the energy was supplied from fatty acid metabolism. Eucommiol, a main component in the water fraction of the methanol extract, was found to be the effective compound and geniposidic acid and aucubin were the main effective compounds in the leaf for collagen synthesis. The administration of geniposidic acid or aucubin stimulated collagen synthesis in aged model rats (18) Thus administration of E. ulmoides Oliver leaf may be effective in speeding up the wound-healing process.

B. Antimutagenic Activity Crude extracts of Tochu tea were able to suppress the induction of chromo-

some aberrations in CHO cells and mice (7). When CHO cells were treated with Tochu tea crude extract after MMC treatment, the frequency of chromosome aberrations was reduced. Of 17 Tochu tea components, five irridoids (geniposidic acid, geniposide, asperulosidic acid, deacetyl asperulo- sidic acid, and asperuloside) and three phenols (pyrogallol, protocatechuic acid, and p-trans-coumaric acid) were found to have anticlastogenic activity. Since the anticlastogenic irridoids had an a-unsaturated carbonyl group, this structure was considered to play an important role in the anticlastogenicity (protective effect against chromosomal aberrations). The mutagenic potential of eucommia was studied with the Ames test (20). E. ulmoides Oliver was found to significantly induce His + revertants in Salmonella typhimurium

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TA98 and/or TA100. The mutagenicity of Tochu tea in the urine before and after ingestion of raw fish and cooked beef had been studied using S. typhimurium YG1024 (21). Urine samples were examined from seven healthy, nonsmoking Japanese women before and after ingestion of raw fish and cooked beef. The mutagenicity of urine from the Tochu-tea-drinking group was much lower. Similar results were observed when the women switched groups; the tea-drinking group became the control group, and the control group became the Tochu-tea-drinking group. Again, the mutagenicity of urine collected from the Tochu-tea-drinking group was much lower. These results suggest that the decrease in the mutagenicity of the urine from the Tochu-tea-drinking group was due to the intake of Tochu tea, suggesting that the ingestion of Tochu tea may reduce human exposure to dietary mutagens.

C. Antioxidant Action The molecular mechanism of this antimutagenic activity may be related to its

reported antioxidant properties. Leaf extract of Du-Zhong had an inhibitory effect on oxidative damage in biomolecules such as deoxyribose, DNA, and 2V-deoxyguanosine (2V-dG) as induced by the Fenton reaction (22). All of the Du-Zhong extract inhibited the oxidation of deoxyribose induced by Fe (3+) -

EDTA/H 2 O 2 /ascorbic acid in a concentration-dependent manner. At a concentration of 1.14 mg/mL, the inhibitory effect of the extracts of leaves, roasted cortex, and raw cortex was 85.2%, 68.0%, and 49.3%, respectively. The extract of leaves inhibited the strand breaking of DNA induced by the Fenton reaction at concentrations of 5 and 10 Ag/AL. The leaf extract had a marked inhibitory effect on Fenton-reaction-induced oxidative damage in biomolecules. The extract of roasted cortex exhibited modest inhibition while the extract of raw cortex had the least inhibitory effect on oxidative damage in biomolecules. This is in contrast to gallic acid in the same reaction system, whose higher reducing power and weaker chelating ability may contribute to its pro-oxidant effect. Biologically active compounds from Du-Zhong leaves, raw cortex, and roasted cortex demonstrated free-radical or reactive oxygen species (ROS)-scavenging effect (23). The hot-water extract of Du-Zhong leaves showed marked activity as a ROS scavenger, and the scavenging effect was concentration-dependent. The extract of roasted cortex exhibited a modest scavenging effect on ROS, while the extract of raw cortex had the weakest scavenging effect. The scavenging activity of Du-Zhong extract on ROS was correlated to its protocatechuic acid (PCA) content. The content of PCA in Du-Zhong determined by HPLC followed the order of leaves (17.17 mg/g) > roasted cortex (2.99 mg/g) > raw cortex (1.16 mg/g). The inhibitory activity of leaf extract of Du-Zhong was stronger than that of PCA on the peroxidation of linoleic acid at the same concentration of 0.1 mg/mL. The

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results indicate that extract of Du-Zhong could possibly act as a prophylactic agent to prevent free-radical-related diseases. Therefore, drinking of Du- Zhong tea over a long period of time may have anticancer potential because of this antioxidant activity.

D. Lipid Metabolism Du-Zhong leaf extract can suppress significantly the high-fat-diet-induced

increases in serum cholesterol and serum triacyglyerol in animal models. The herb was able to suppress diet-induced increases in VLDL and LDL lipol- proteins, suggesting the leaf extract may be beneficial for the regulation of hyperlipedimia (14). In another study, administration of 5% Tochu leaf powder was reported to markedly prevent the elevation of serum total cholesterol in a stroke-prone, spontaneously hypertensive rat fed a high-fat- and-high-cholesterol diet (24). High-density lipoprotein (HDL) cholesterol and triglyceride content in the blood plasma were significantly higher than in the control.

E. Antihypertensive Effect The herb has reported antihypertensive effects that are mild but long in

duration (25). It acts centrally and its effects can be reduced by atropine or vagotomy. In low doses it can dilate the peripheral vessels while in high doses it causes vasoconstriction. The herb also has a diuretic effect. The major antihypertensive principle was thought to be pinoresinol diglucoside (26).

F. Antiviral The alkaline extract of Du-Zhong tea leaves was reported to suppress HIV-

induced cytopathicity using HIV (HTLV-III)-infected MT-4 cells, having extremely low cytotoxicity (27). Its 50% effective concentration (EC 50 ) was 12–67 Ag/mL, while 50% cytotoxic concentration (CC 50 ) was higher than 1.0 mg/mL. The authors suggest that HIV infection may be suppressed by daily intake of the alkaline extract of Du-Zhong tea.

G. Antifungal Activity Antifungal peptides have been purified from the barkof E. ulmoides Oliver

(28). Their primary structures consists of 41 residues with a N-terminal blockage by pyroglutamic acid and all contain 10 cysteines, which are cross-linked to form five disulfide bridges with a pairing pattern (C1–C5, C2–C9, C3–C6, C4–C7, C8–C10). They exhibit relatively broad spectra of antifungal activities against eight pathogenic fungi from cotton, wheat,

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potato, tomato, and tobacco. Their inhibition activity can be effective on both chitin-containing and chitin-free fungi. The values of IC 50 range from 35 to 155 Ag/mL for EAFP1 and from 18 to 109 Ag/mL for EAFP2. Their antifungal effects are strongly antagonized by calcium ions. Five active principles against yeast enzyme were isolated and characterized. Among them, quercetin was considered to contribute mostly to the activity of the Tochu leaves (29).

H. Other Effects a-Glucosidase inhibitory activity was found in aqueous methanol extracts of

Tochu-cha, (29) and anticomplementary activities of its constituents have been described (30). Inhibition of adenosine 3V,5V-cyclic monophosphate phos- phodiesterase by lignan glucosides of eucommia barkhad been reported (31).

VI. SUMMARY Although Du-Zhong and Tochu tea have been used for millennia alone, and

as part of complex formulations with other herbs, no clinical studies on their effects have been conducted using modern scientific methods. Some of their chemical constituents have been characterized, and a limited number of cell and animal studies have been performed to establish their physiological effects. These animal models suggest that crude extracts of these herbs may increase muscle bulkand stamina and improve collagen deposition and maturation. Antimutagenic, antioxidant, antihypertensive, antiviral, and antifungal properties have been reported in cell and animal studies. The lack of modern human studies makes it difficult to comment on the safety and efficacy of these herbs when used as medicinal drugs.

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