Journal of Ethnopharmacology 141 (2012) 1–8

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Journal of Ethnopharmacology
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Review

Botany, traditional uses, phytochemistry and pharmacology of Apocynum

venetum L. (Luobuma): A review
Wenyan Xiea, Xiaoying Zhanga,∗ , Tian Wanga, Jianjun Hub
a
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China
b
Key Laboratory of Tarim Animal Husbandry Science and Technology, College of Animal Science and Technology, Tarim University, Alar 843300, Xinjiang Uygur Autonomous Region,
China

artic l e i nf o abstract

Article history: Ethnopharmacological relevance: Apocynum venetum L. (Apocynaceae, Luobuma ) has a long history
Received 20 October 2011 as a Chinese traditional medicine with uses to calm the liver, soothe the nerves, dissipate heat, and pro-
Received in revised form 2 February 2012 mote diuresis. Recently, Luobuma tea has been commercialized as a sedative and anti-aging supplement
Accepted 2 February 2012
that has become increasingly popular in North American and East Asian health food markets.
Available online 6 March 2012
Aims of the review: The aim of this review is to provide an up-to-date and comprehensive overview of the
botany, chemical constituents, traditional uses, pharmacological activities and safety aspects of Apocynum
Keywords:
venetum in order to assess its ethnopharmacological use and to explore its therapeutic potentials and
Apocynum venetum L.
Luobuma
future opportunities for research.
Phytochemistry Background and methods: The accessible literature on Apocynum venetum written in English, Chinese
Pharmacology and Japanese were collected and analyzed. The literatures included ancient Chinese herbal classics,
Traditional medicine pharmacopoeias and articles that included in Pubmed, Web of Science, Google Scholar and Wanfang.
Key findings: Modern pharmacological studies demonstrated that Apocynum venetum possess wide
pharmacological activities that include antihypertensive, cardiotonic, hepatoprotective, antioxidant,
lipid-lowering, antidepressant and anxiolytic effects, which can be explained by the presence of var i-
ous flavonoid compounds in this plant. The traditional (Lop Nor region) use of Apocynum venetum with
tobacco as an agent to detoxify nicotine may receive interest as a possible therapeutic option to detoxify
the body from smoking. Based on animal studies and clinical trials, Apocynum venetum causes no severe
side effects, even in a stable daily dosage (50 mg/person/day) for more than three years.
Conclusions: Apocynum venetum potentially has therapeutic potential in the prevention and treatment
for the cardiovascular and neurological diseases, especially for high blood pressure, high cholesterol,
neurasthenia, depression and anxiety. Further investigations are needed to explore individual bioactive
compounds responsible for these in vitro and in vivo pharmacological effects and the mode of actions. Fur-
ther safety assessments and clinical trials should be performed before it can be integrated into medicinal
practices.
© 2012 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction ............................................................................................................................................................................................................................ 2
2. Botanical aspects .................................................................................................................................................................................................................... 2
3. Traditional uses and modern indications ............................................................................................................................................................................. 2
4. Constituents of Apocynum venetum ........................................................................................................................................................................... 3
5. Pharmacological properties .................................................................................................................................................................................................. 4
5.1. Antihypertensive effect ............................................................................................................................................................................................... 4
5.2. Cardiotonic effect........................................................................................................................................................................................................ 5
5.3. Hepatoprotective effect ............................................................................................................................................................................................. 5

∗ Corresponding author at: Post Box 19, College of Veterinary Medicine, Northwest A&F University (North Campus), Xinong Road 22, Yangling, Shaanxi Province 712100,
China. Tel.: +86 29 8709 1239; fax: +86 29 8709 1239.
E-mail address: zhang.xy@nwsuaf.edu.cn (X. Zhang).

0378-8741/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2012.02.003
2 W. Xie et al. / Journal of Ethnopharmacology 141 (2012) 1–8

5.4. Free radical scavenging effect ....................................................................................................................................................................................6

5.5. Antidepressant effect ................................................................................................................................................................................................ 6
5.6. Anxiolytic effect ..........................................................................................................................................................................................................7
6. Safety and drug interactions ................................................................................................................................................................................................. 7
7. Conclusions .............................................................................................................................................................................................................................7
Acknowledgments ................................................................................................................................................................................................................ 7
References ...............................................................................................................................................................................................................................7

1. Introduction
Apocynum venetum L., commonly known as Luobuma in China,
is a traditional and popular Chinese herb with a long history of use
as a medicine and tea. Apocynum venetum was first scientifically
studied in the 1950s with modern taxonomic and pharmacological
methods in Lop Nor Region and the first bibliography was pub-
lished in 1958 (Dong, 1958). Research on Apocynum venetum with
current technology has been conducted mainly in China and Japan
(Fig. 1). A series of studies (Kim et al., 2000a,b; Xiong et al., 2000;
Cao et al., 2003; Irie et al., 2009) showed that Apocynum venetum
effectively lowers blood pressure and has hepatoprotective, car-
diotonic, and antioxidant activities. Other publications (Butterweck
et al., 2001; Grundmann et al., 2007, 2009) indicated that Apocynum
venetum has an antidepressant potential and can reduce anxiety.
Animal experiments and limited clinical trials suggest that Apoc-
ynum venetum is safe even when used chronically. Luobuma tea
has been billed as an antihypertensive, anti-aging, sedative nutri-
tional supplement and has become increasingly popular in both
North American and East Asian health food markets (Kobayashi
et al., 2004).
To provide further support and evidence for the ethnopharma-
cological use of this herb, we performed a systematic review on the
chemical constituents, pharmacological effects, and safety aspects
of Apocynum venetum.
2. Botanical aspects
Apocynum venetum (Luobuma in Chinese, Apocynaceae)
is a perennial herbaceous or half-shrub plant (Editorial Committee
of the Flora of China of Chinese Academy of Science, 1977; He et al.,
1992). It is 1–2 m tall and exudes a milky juice when wounded. The
slender cylindrical stems are purplish to light red. The leaf arrange-
ment is opposite, with lanceolate to ovate leaves that are 1–5 cm
long and 4–15 mm wide. The purplish red or pink flowers are bell-
shaped and flower from June to July. Fruits are paired fusiform
(spindle-shaped) follicles that reach a length of up to 20 cm and
hang down together in pairs (Fig. 2). The fruits become mature in
the autumn, 7–8 months after flowering (He et al., 1992).
Apocynum venetum is widely distributed in the temperate zones
of Eurasia and North America, especially in saline–alkali land, river-
banks, fluvial plains and sandy soils (Editorial Committee of the
Flora of China of Chinese Academy of Science, 1977). Apocynum
venetum grows widely in northern China, specifically in the Lop
Nor and Dunhuang regions where the plant material is considered
best for commercialized Luobuma tea.
Two easily confusable herbs for Apocynum venetum, P. pictum
(Schrenk) Baill (P. pictum) and P. hendersonii (Hook. f.) Woodson (P.
hendersonii), both belong to the genus of Poacynum Baill of Apoc-
ynaceae. Their geographical distribution is similar to Apocynum
venetum. Generally, P. pictum and P. hendersonii are known as White
Hemp, and Apocynum venetum is known as Red Hemp, probably due
to the different colors and shapes of their flowers and leaves. The
industrial applications of P. pictum and P. hendersonii are limited
to fibers for spinning and papermaking rather than medicinal pur-
poses. Because of excessive exploitation, wild Apocynum venetum
in Xinjiang has dropped from over 5000 km 2 in the 1950s to less
than 2000 km2 in recent years (Wang et al., 2011). Some protec-
tive measures have been enacted, but their effect is still unclear.
Apocynum venetum may be replaced with P. pictum and/or P. hen-
dersonii, which causes confusion in medicine and health product
markets. To better distinguish Apocynum venetum from P. pictum, a
specific identification primer (GenBank ID: ET030150) was recently
designed and synthesized through the combined technologies of
bulked segregate analysis and randomly amplified polymorphic
DNA (Lu et al., 2010).
Considering its hostile growing environment, Apocynum vene-
tum is highly tolerant to salt and drought stress and resists strong
winds and sands. A salt-induced gene that encodes the protein
AvDH1, which is a DEAD-box helicase, has been cloned and charac-
terized, and it plays a key role in various abiotic stresses (Liu et al.,
2008).
3. Traditional uses and modern indications

Apocynum venetum has long been used in traditional Chinese

Fig. 1. Research papers in different aspects of Apocynum venetum with different
languages. (English Papers were collected via Pubmed and Web of Science, and
Chinese Papers were from Wanfang database (www.wanfang.com.cn) with search
terms “A. venetum” or “Luobuma”. Besides, one Japanese paper was available through
Pubmed.)
and Uygur medicine. The first record of Apocynum venetum can
be traced back to the early 15th century, when it was docu-
mented in the ancient Chinese herbal book Jiu-Huang-Ben-Cao
(Ming Dynasty, by ZHU Su), which is translated as “Herbal for Relief
of Famines”. The book stated that the fired leaves and tender stems
of Apocynum venetum could be served as food and tea. The Com-
pendium of Materia Medica (Ming Dynasty, by LI Shizhen) stated
that the herb eliminates dampness through diuresis. According to
the 2010 Chinese Pharmacopoeia, the leaves of Apocynum vene-
tum should be collected and dried in summer for medical uses,
including calming the liver, soothing nerves, clearing heat and
promoting diuresis. Recently, there have been efforts in China to
develop therapeutic applications of oral formulas containing pow-
der from Apocynum venetum leaves and other medical herbs such as
Chrysanthemum indicum L., Stephania tetrandea S. Moore, the com-
bination of which is a promising antihypertensive formula.
 W. Xie et al. / Journal of Ethnopharmacology 141 (2012) 1–8 3

Fig. 2. Apocynum venetum L. (a) Apocynum venetum L.; (b) flower; (c) leaf; and (d) fruit.

Apocynum venetum is much more popular in traditional Uygur isolated from the flower of Apocynum venetum (Chen et al., 2005)
medicine, especially in the Lop Nor region of Xinjiang, China. The (Table 1).
Uygur Materia Medica (Liu, 1999) documented that Apocynum Apocynins A–D (Fig. 4) are four new phenylpropanoid-
venetum has properties of clearing heat, cooling blood, diuresis, substituted flavan-3-ols isolated from Apocynum venetum leaves
relieving dryness, diminishing inflammation, detumescence and (Fan et al., 1999), and apocynosides I and II (Fig. 5) are two new
relieving anxiety. A formula consisting of Apocynum venetum leaves ionone glucosides purified from processed leaves of Apocynum
(9 g), celery seed (6 g), Sea Buckthorn berry (4.5 g), Costus root venetum (Murakami et al., 2001).
(4.5 g), Chamomile (3 g) and adiantum (3 g) has been used to treat Apocynum venetum leaves are rich in ash elements and min-
hypertension, dizziness and neurasthenia. Another recommended erals, including relatively high amounts of sodium (6 mg/g),
formula mainly composed of Apocynum venetum leaves, Suosuo magnesium (5 mg/g), calcium (1 mg/g), iron (0.2 mg/g), manganese
grape and Ci tang (a kind of sugar secreted by Alhagi pseudoalhagi (0.5 mg/g), potassium (0.08 mg/g), copper (0.03 mg/g), and alu-
Desv.) is believed to be useful for treating inflammation, swelling minum (0.0002 mg/g) (Fan et al., 2006). However, the contents of
and hepatitis. However, the relevant pharmacological bases for
these indications are often absent.
Besides its therapeutic applications, Apocynum venetum has
been commonly applied in daily routines and appears to be a popu-
lar daily beverage in China, Japan and the US. The tea products have
different formulations, including tea bags, powder, and crimped
and curled roasted leaves. These roasted leaves differ from green tea
leaves in that they lack the stimulating effects of caffeine. Rather,
they have a calming effect that is attributable to supposed sedative
substances in Apocynum venetum. This unique property has aroused
the interest of many researchers (Yokozawa et al., 2002).
It is noteworthy that the local people of Lop Nor smoke Apoc-
ynum venetum leaves in conjunction with tobacco. The leaves have
low levels of tar and potentially detoxify nicotine, perhaps because
of their milky juices. However, further study is needed to confirm
this hypothesis.

4. Constituents of Apocynum venetum

Multiple classes of phytochemicals including flavonoids, car-

diac glycosides and organic acids, as well as many other medicinal
ingredients and several minerals, have been identified in Apoc-
ynum venetum leaves in different investigations. The predominant
flavonoids include flavonols and flavan-3-ols (Fig. 3). Although the
compounds contained in the plant’s flowers have not been well
studied, several flavonol compounds and organic acids have been Fig. 3. Chemical structures of Apocynum venetum flavonols and their glycosides.
4 W. Xie et al. / Journal of Ethnopharmacology 141 (2012) 1–8

Table 1
Chemical constituents of Apocynum venetum.

Class Chemical constituents Origins Reference

Flavonol Quercetin (1) Leaves, flowers Chen et al. (2005), Murakami et al. (2001), Kamata et al.
(2008) and Zhang et al. (2010a,b)
Kaempferol (2) Leaves, flowers Kamata et al. (2008) and Chen et al. (2005)

Flavonol glycosides Astragalin (3) Leaves Chen et al. (2005) and Zhang et al. (2010a,b)
Avicularin (4) Leaves Zhang et al. (2010b)
Hyperoside (5) Leaves Kim et al. (2000a), Xiong et al. (2000), Murakami et al.
(2001), Kamata et al. (2008) and Zhang et al. (2010a,b)
Isoquercetin (6) Leaves Kim et al. (2000a), Xiong et al. (2000), Chen et al. (2005),
Kamata et al. (2008) and Zhang et al. (2010a,b)
Querciturone (7) Leaves Zhang et al. (2010b)
Rutin (8) Leaves Zhang et al. (2010a,b)
Trifolin (9) Leaves Zhang et al. (2010a,b)
Acetylated hyperoside (10) Leaves Zhang et al. (2010a,b)
Acetylated isoquercetin (11) Leaves Zhang et al. (2010b)
Malonated hyperoside (12) Leaves Kamata et al. (2008)
Malonated isoquercitrin (13) Leaves Kamata et al. (2008)
Kaempferol-6∗ -o-acetate (14) Leaves Xiong et al. (2000)
Isoquercetin-6∗ -o-acetate (15) Leaves Xiong et al. (2000)
Kaempferol-3-o-þ-d-galactopyranoside (16) Roasted leaves Murakami et al. (2001)
Quercetin-3-o-þ-d-glucosyl-þ-d-glucopyranoside Leaves Zhang et al. (2010a,b)
(17)
Flavan-3-ols (−)-Epicatechin (18) Leaves Kim et al. (2000a), Fan et al. (1999), Xiong et al. (2000) and
Yokozawa and Nakagawa (2004)
(−)-Epigallocatechin (19) Leaves Kim et al. (2000a), Fan et al. (1999), Xiong et al. (2000) and
Yokozawa and Nakagawa (2004)
(+)-Catechin (20) Leaves Kim et al. (2000a) and Fan et al. (1999)
(+)-Gallocatechin (21) Leaves Kim et al. (2000a) and Fan et al. (1999)
Apocynin A (22) Leaves Kim et al. (2000a) and Fan et al. (1999)
Apocynin B (23) Leaves Kim et al. (2000a) and Fan et al. (1999)
Apocynin C (24) Leaves Kim et al. (2000a) and Fan et al. (1999)
Apocynin D (25) Leaves Kim et al. (2000a) and Fan et al. (1999)
Cinchonain Ia (26) Leaves Kim et al. (2000a) and Fan et al. (1999)
Procyanidin B-2 (27) Leaves Xiong et al. (2000) and Yokozawa and Nakagawa (2004)
Epicatechin-(4þ-8)-gallocatechin (28) Leaves Yokozawa and Nakagawa (2004)
Epigallocatechin-(4þ-8)-epicatechin (29) Leaves Yokozawa and Nakagawa (2004)
Catechin-[8,7-e]-4a-(3,4-dihydroxyphenyl)- Leaves Kim et al. (2000a) and Fan et al. (1999)
dihydro-2(3H)-pyranone
(30)
Biflavonoids Amentoflavone (31) Leaves Zhang et al. (2010a,b)
Biapigenin (32) Leaves Zhang et al. (2010a,b)

Other glycosides Apocynoside I (33) Roasted leaves Murakami et al. (2001)

Apocynoside II (34) Roasted leaves Murakami et al. (2001)
Cymarin (35) Leaves, stem, root Irie et al. (2009)
Phenethyl alcohol xylopyranosyl (1 → 6) Roasted leaves Murakami et al. (2001)
glucopyranoside (36)
Z-hex-3-en-1-ol xylopyranosyl(1 → 6) Roasted leaves Murakami et al. (2001)
glucopyranoside (37)
Benzyl alcohol xylopyranosyl(1 → 6) Roasted leaves Murakami et al. (2001)
glucopyranoside (38)
Organic acid Chlorogenic acid (39) Leaves Kim et al. (2000a) and Zhang et al. (2010a,b)
Vanillic acid (40) Flowers Chen et al. (2005)

Phoroglucinols Adhyperforin (41) Leaves Zhang et al. (2010a,b)

Hyperforin (42) Leaves Zhang et al. (2010a,b)

Phytosterols Phytol (43) Roasted leaves Murakami et al. (2001)

Lupeol (44) Roasted leaves Murakami et al. (2001)
Daucosterol (45) Flowers Chen et al. (2005)

these microelements may differ depending on the collection season
(Zhang et al., 2009).
5. Pharmacological properties
Various studies have confirmed cholesterol-lowering and anti-
hypertensive effects of Apocynum venetum extracts. Their calming
effects on nerves, including sedative, antidepressant and anxiolytic
effects, have been investigated in animal models. These activities
might be related to general mechanisms of antioxidation, free rad-
ical scavenging and diuresis. Other studies have suggested that
flavonoids, flavonols and glycosides are the major active com-
pounds in Apocynum venetum.
5.1. Antihypertensive effect
A series of studies have confirmed the antihypertensive effect
of Apocynum venetum extracts and clarified possible mecha-
nisms in the past few decades. Reduced blood pressure was
observed after long term treatment (70 mg/rat for at least
40 days) with Apocynum venetum aqueous extract in different
hypertensive rat models, including spontaneously hypertensive
rats, nephrectomized rats and NaCl-induced hypertensive rats.
Decreased blood urea nitrogen levels, increased urine volume and
sodium (Na+) and potassium (K+) ion urine excretion were also
evaluated in rat models, and suggested that increased glomeru-
lar filtration may be explained by the ability of Apocynum
 W. Xie et al. / Journal of Ethnopharmacology 141 (2012) 1–8
Fig. 4. Chemical structures of apocynins A–D from Apocynum venetum.
venetum aqueous extract to enhance kidney function (Kim et al.,
2000b).
The vasodilation properties of Apocynum venetum have been
investigated in vitro. In rat mesenteric vascular beds, perfusion of
Apocynum venetum extract (from 0.1 ng to 100 mg/mL for 15 min)
caused dose-dependent vasodilation, and this effect was abol-
ished by the chemical removal of the endothelial layer, but not
by NG-nitro-l-arginine methyl ester (l-NAME), suggesting that
the effect was mediated by endothelial cells that release the
endothelium-derived relaxation factor nitric oxide (NO) (Tagawa
et al., 2004). Similarly, Apocynum venetum ethanol (EtOH) extract
(0.3–10 µg/mL) caused relaxation in agonist-precontracted rat
aorta and superior mesenteric artery mediated by endothelium-
derived NO. Interestingly, the generation of endothelial NO
persisted even after subsequent washout of Apocynum venetum
EtOH extract. This may be due to the high affinity of Apocynum
venetum active ingredients for the NO-generating system or that
Apocynum venetum protects NO from degradation by superoxide
anions (Kwan et al., 2005).
Apocynum venetum EtOH extract-induced vasorelaxation was
sensitive to K V, KIR and KCa channel inhibitions (Kwan et al., 2005),
further indicating that endothelium-derived NO may act on K+
channels (KV, KIR and KCa), leading to membrane
Fig. 5. Chemical structures of apocynosides I and II from Apocynum venetum.
5
hyperpolarization and the closure of voltage-operated Ca2+ chan-
nels; this prevents extracellular Ca2+ entry into the cytosol
and results in decreased cytosolic Ca2+ and smooth muscle cell
relaxation.
5.2. Cardiotonic effect
The roots of Apocynum cannabium and Apocynum androsaemi-
folium, which also belong to the family of Apocynaceae, were
used in the first half of the 20th century for the treatment
of heart diseases in Europe (Soos and Strum, 1949). Their car-
diotonic activity was thought to be induced by the cardiac glycoside
cymarin, a cardiogenic toxin, which can also cause many side
effects, such as nausea, catharsis, and cardiac arrhythmia when
given in high doses. The root of Apocynum venetum has lower
amounts of cymarin, and may be suggested as an alternative
heart disease treatment (Soos and Strum, 1949). Cymarin con-
tents determined from various parts of Apocynum venetum are
ranked as follows: old stem (1310 µg/g) > stem (367 µg/g) > root
(195 µg/g) > leaf (113 µg/g) > Venetron (2 µg/g, a polyphenol-rich
leaf extract) (Irie et al., 2009).
Recently, an in vitro study showed that Apocynum venetum
EtOH extract increased the contractile force and pulses of isolated
guinea pig atria, although the effect was very weak (action was
observed at concentration of 1 mg/mL). In preliminary phospho-
diesterase 3 (PDE3) inhibition assays, Apocynum venetum EtOH
extract significantly inhibited PDE3 activity at 1 mg/mL, consis-
tent with the effective concentration examined in guinea pig atria,
suggesting Apocynum venetum extract may act as a PDE3 inhibitor
(Irie et al., 2009). Detailed analyses of Apocynum venetum extract
mechanisms for PDE inhibition and the correlation between PDE
inhibition and cardiotonic effects, such as specificity for PDE sub-
types and IC50 values for each of subtype, are anticipated in future
studies.
5.3. Hepatoprotective effect
Aqueous Apocynum venetum extract can protect the liver
against chemically induced injuries in animal models. It has been
6 W. Xie et al. / Journal of Ethnopharmacology 141 (2012) 1–8
shown that administration of water-extracted Apocynum vene-
tum at a dose of 500 mg/kg for one week can significantly inhibit
increased serum alanine aminotransferase (ALT) levels in carbon
tetrachloride- (CCl4-) induced mice (Xiong et al., 2000). In the case
of d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced liver
injury in mice, one week pre-administration of Apocynum vene-
tum aqueous extract (50 mg/kg/day) resulted in a marked decrease
of serum ALT (Xiong et al., 2000). Although Apocynum venetum
showed no apparent inhibition of TNF-a production, it exhib-
ited a potential inhibitory effect against TNF-a-induced cell death
(Xiong et al., 2000). In addition, Apocynum venetum extract (100
and 200 mg/kg/day for 8 weeks) showed protective effects in rats
with fatty liver disease and metabolic syndrome, comparable to
those treated with captopril (30 mg/kg/day for 8 weeks) (Yang et al.,
2009).
As for active constituents that exert hepatoprotective effects, the
flavonol glycoside (isoquercetin, hyperin, kaempferol-6∗ -o-acetate,
isoquercetin-6’-o-acetate) showed the strongest activity against
d-GalN/LPS-induced cell death in primary cultured mouse hep-
atocytes among the four types of flavonoids (flavonol, flavonol
glycoside, flavan-3-ols and phenylpropanoid-substituted flavan-
3-ols), suggesting the structural requirement of a substituted
sugar for flavonoid effectiveness. On the other hand, the activi-
ties of flavan-3-ols were considerably improved when they were
phenylpropanoid-substituted, indicating that this substitution may
improve the hepatoprotective activity of flavonoids (Xiong et al.,
2000).
It is possible that the protection against hepatocyte injury by
Apocynum venetum is due to the radical scavenging activity of these
flavonoids. The available literature suggests that there are likely
multiple potent mechanisms, such as antihypertensive effect and
amelioration of insulin allergy (Yang et al., 2009), that are responsi-
ble for the hepatoprotective effects of Apocynum venetum. Further
investigations are needed to fully elucidate the exact mechanisms.
5.4. Free radical scavenging effect
Seven compounds purified by chromatography from the
EtOH-soluble fractions of the aqueous extract of Apocynum
venetum roasted leaves were found to decrease peroxyni-
trite activity (Yokozawa et al., 2002). Of these compounds,
epigallocatechin-(4þ-8)-epicatechin showed the highest activ-
ity, with an inhibition rate of 16.99% at a concentration of
0.17 µg/mL, followed by epicatechin-(4þ-8)-gallocatechin, pro-
cyanidin B-2, ±( )-gallocatechin, −( )-epigallocatechin, ±( )-catechin
and (− )-epicatechin, which indicated that dimers consisting of
epigallocatechin, epicatechin or gallocatechin possessed higher
activities than those of monomers (Yokozawa et al., 2002).
Dose-dependent hydroxyl radical scavenging activities (scaveng-
ing rate from 48.4% to 80.6% for Apocynum venetum extract
concentrations from 0.1 to 2.0 mg/mL) (Cao et al., 2003) and 1,1-
diphenyl-2-picrylhdrazyl (DPPH) radical scavenging capacity (IC50
of 33.72 µg/mL) (Liang et al., 2010) were also detected.
Kim et al. detected inhibitory activity of Apocynum venetum
leaf and its constituents against Cu2+-induced lipid peroxidation.
Chlorogenic acid (IC50 of 1.9 µM), hyperoside (IC50 of 4.6 µM), iso-
quercitin (IC50 of 9.0 µM) and epigallocatechin (IC50 of 2.3 µM)
purified from the aqueous extract of Apocynum venetum leaves,
showed strong inhibition of the formation of thiobarbituric acid
reactive substances (TBARS), which are products of Cu2+-induced
LDL oxidation. In addition, the time of conjugated-diene forma-
tion in Cu2+-induced oxidation was prolonged in a dose-dependent
manner by addition of aqueous extract and its constituents (Kim
et al., 2000a). In general, it is believed that the LDL oxidation
occur when free radicals attack, depleting protective antioxidants
such as a-tocopherol, retinoid and carotinoid. Based on previous
studies, it can be concluded that Apocynum venetum extract and its
constituents increase LDL resistance to oxidation, thus protecting
the consumption of endogenous antioxidants. However, the exact
molecular mechanism of Apocynum venetum is still unclear. Other
mechanisms such as the modulation of protein function, intracel-
lular cascades and gene expression may also be involved.
It has been shown that Apocynum venetum inhibits the forma-
tion of advanced glycation end products (AGEs) that contribute to
diabetic vascular complications and correlate with atherosclerotic
lesion severity (Yokozawa and Nakagawa, 2004). Because some
radical species, including hydrogen peroxide, superoxide anion
radicals, and singlet oxygen, participate in AGE formation (Chace
et al., 1991; Yim et al., 1995), the inhibitory effect may relate to
Apocynum venetum radical scavenging activity.
Collectively, these data indicate that Apocynum venetum sup-
presses free radical formation, protects exogenous antioxidants
present in LDL, and inhibits AGE formation, which provide protec-
tion against many cardiovascular diseases. However, determining
the exact mechanisms will require further investigation.
5.5. Antidepressant effect
Many reports suggested that Apocynum venetum extracts have
antidepressant and neuroprotective effects. In the forced swim-
ming test, Apocynum venetum EtOH extract clearly shortens
immobility time at a dose range of 30–125 mg/kg for 14 days in
rats, which is comparable to that of the tricyclic antidepressant
imipramine (20 mg/kg) (Butterweck et al., 2001). The long-term
(8 weeks) administration of Apocynum venetum EtOH extract
(15–250 mg/kg) to rats reduced norepinephrine (NE) and dopamine
(DA) concentrations in the rat hypothalamus, striatum and hip-
pocampus, but failed to affect serotonin (5-HT) levels, indicating
that monoamine receptors such as presynaptic a2-receptors that
regulate NE levels, as well as presynaptic dopaminergic receptors
that modulate DA synthesis and release, might contribute to these
changes in the brain (Butterweck et al., 2003). It is noteworthy
that unlike imipramine, Apocynum venetum extract had no effect
on þ-adrenergic receptors (Butterweck et al., 2003).
By decreasing the Ca2+ concentration and up-regulating
expression of brain-derived neurotrophic factor (BDNF) and
microtubule-associated protein 4 (MAP4), Apocynum venetum
extract protects against corticosterone-induced neurotoxicity and
inhibits corticosterone-induced apoptosis in PC12 cells (Zheng et
al., 2010). Hyperoside isolated from Apocynum venetum leaves
increased PC12 cell viability and attenuated corticosterone-
induced intraocular Ca2+ overloading at concentrations of 2.5, 5,
and 10 µg/mL. BDNF and cAMP response element-binding protein
(CREB) expression in PC12 cells was elevated following hyperoside
treatment. Therefore, the activation of the AC-cAMP-CREB signal-
ing pathway is speculated to contribute to the antidepressant effect
of Apocynum venetum (Zheng et al., 2012).
Recently, the effects of Apocynum venetum on neuronal ion
channels have been studied in vitro with a whole-cell voltage-
clamp experiment (Kuo et al., 2011). Apocynum venetum suppresses
voltage-gated Na+ channels (and voltage-gated K+ channels, to a
lesser extent) in a concentration-dependent manner in mouse neu-
roblastoma N2A cells. Na+ channel blockade is associated with
the analgesic efficacy of antidepressants and the blockade of Na +
channels has been proposed to be anxiolytic (Mirza et al., 2005;
Dick et al., 2007; Bourin et al., 2009). Therefore, the Apocynum
venetum-mediated suppression of Na+ currents may contribute to
the antidepressant and anxiolytic properties of this herb. Voltage-
gated K+ channel blockers have been considered as potential
neuroprotective drugs because they are overexpressed at the onset
of neuronal apoptosis (Yu, 2003). The neuroprotective actions of
 W. Xie et al. / Journal of Ethnopharmacology 141 (2012) 1–8
Apocynum venetum may also involve inhibition of neuronal voltage-
gated K+ channels.
Another possibility is that Apocynum venetum acts as an
antioxidant in neurons; it has been shown to inhibit lipid
hydroperoxide-induced ROS production in PC12 cells to a greater
extent than Hypericum perforatum (St. John’s wort) or Ginkgo biloba
L. (Shirai et al., 2005).
A randomized, double-blind, parallel group pilot study show-
ing the effect of Apocynum venetum leaf extract on depression
was conducted in 47 eligible individuals with mild depression.
After 8 weeks of treatment, the Apocynum venetum leaf extract
group showed a significant improvement on Hamilton Depres-
sion Rating Scale (HAMD) questionnaires, suggesting a potential
benefit of Apocynum venetum in individuals with mild depres-
sion. Further analysis revealed that decreased levels of blood
neurotransmitters such as platelet serotonin and plasma 3-
methoxy-4-hydroxyphenylglycol (MHPG) were observed in over
50% of patients treated with Apocynum venetum extract. Further-
more, no severe adverse effects were reported. Thus, Apocynum
venetum extract may be considered as an alternative for indi-
viduals with mild depression, especially because patients with
mild or moderate depression have been difficult to treat with
commonly used medications that are associated with severe side
effects (Clinical Trial Effects of Apocynum venetum Leaf Extract on
Depression and Anxiety {Hamilton Depression Rating Scale}, 2010).
5.6. Anxiolytic effect
A single treatment of Apocynum venetum EtOH extract at doses
of 30 mg/kg and 125 mg/kg to mice markedly increased the time
spent on and the number of entries into open arms in the elevated
plus maze (EPM) test, without inducing an overt change in behav-
ior or inducing motor dysfunction in the open field test, indicating
the putative anxiolytic-like activity of Apocynum venetum extract.
However, no significant activity was observed at a concentration
of 15 mg/kg, 60 mg/kg or 250 mg/kg. This U-shaped dose–response
curve might be attributable to the alternation of specific recep-
tors, as well as the interactions of different receptor systems, which
could alter pharmacological responses. Further evaluation showed
that the effects of Apocynum venetum could be antagonized by the
GABAA receptor antagonist flumazenil and partially blocked by the
unspecific 5-HT1A receptor antagonist WAY-100635, revealing that
Apocynum venetum may act through GABA or 5-HT1A receptors
(Grundmann et al., 2007). Studies of isolated constituents showed
that kaempferol exerts anxiolytic-like activity in the EPM test at
concentrations from 0.02 to 1.0 mg/kg (0.02 and 0.08 mg/kg of
kaempferol are equivalent to 30 and 125 mg/kg of whole Apocynum
venetum extract, respectively). At a concentration of 0.08 mg/kg,
kaempferol functions were inhibited by flumazenil, which implies
a mainly GABA-ergic action at this dose. However, flumazenil failed
to antagonize the 0.02 mg/kg dose. In addition, neither concentra-
tion of kaempferol was inhibited by WAY-100635. This may be
because kaempferol affects a variety of neurotransmitter systems
and enzymes (Grundmann et al., 2009). Further, kaempferol-free
fractions also showed anxiolytic activity in the EMP test, suggesting
further isolation of bioactive ingredients (Grundmann et al., 2009).
6. Safety and drug interactions
The systemic toxicity and safety evaluations of Apocynum
venetum are still inadequate. The acute, subchronic and chronic
toxicities of commercialized Luobuma tea have been evaluated. The
median lethal dose (LD50) of acute oral toxicity of concentrated tea
of Apocynum venetum leaves is more than 10 g/kg (Yu et al., 2006).
Genotoxicity, teratogenic and reproductive studies did not show
7
any risk (Yu and Wang, 2006). In addition, several clinical reports
confirmed that depression patients who took 50 mg of Apocynum
venetum leaf extract per day for periods ranging from 2 weeks to
3.5 years did not experience any side effects. However, additional
toxicology studies and large clinical trials are necessary to assess
the potential of Apocynum venetum as an alternative for treating
other neurologic diseases.
Drug interactions of Apocynum venetum have not been inten-
sively investigated. According to a study from a Japanese research
group, neither single nor multiple administration of Apocynum
venetum at a dose of 3.3 mg/kg changed the dispositions of substrate
drugs nifedipine and methylprednisolone for hepatic cytochrome
P450 (CYP) 3A4 or P-glycoprotein (P-gp) in rats (Kobayashi et al.,
2004). This result implies that Apocynum venetum does not induce
changes in CYP3A4 and P-gp and suggests a limited possibility
of drug interaction. Further investigations regarding the effects of
Apocynum venetum on other CYPs and transporters are necessary.
7. Conclusions
Apocynum venetum has received increasing interest in recent
years, and phytochemical and pharmacological studies have val-
idated the traditional uses of Apocynum venetum. A variety of
pharmacological activities, including antihypertensive, hepatopro-
tective, antidepressant, anxiolytic and antioxidant effects can be
explained by the presence of various flavonols, flavanols and glyco-
sides in this plant. The local use of Apocynum venetum with tobacco
as an agent to detoxify nicotine may receive more interest as a
therapeutic option to detoxify the body from smoking.
There is a need to investigate the biochemical and physiological
mechanisms of Apocynum venetum, especially its cardioprotective,
hepatoprotective and neuroprotective activities. Efforts should also
be made to determine the modes of action, bioavailability, phar-
macokinetics and physiological pathways of specific functional
compounds in Apocynum venetum. Further safety verification and
clinical trials should be performed before it can be integrated into
medicinal practice.
Acknowledgments
This work was supported by the Ministry of Education and
State Administration of Foreign Experts Affairs “overseas teacher”
project (No. MS2011XBNL057) and a grant (No. 01140407) for
returned overseas Chinese Scholars from Northwest A&F Univer-
sity, China.
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