Pharmacological effects of Radix Angelica Sinensis (Danggui) on cerebral infarction.
ABSTRACT Radix Angelica Sinensis, the dried root of Angelica sinensis (Danggui), is a herb used in Chinese medicine to enrich blood, promote blood circulation and modulate the immune system. It is also used to treat chronic constipation of the elderly and debilitated as well as menstrual disorders. Research has demonstrated that Danggui and its active ingredients, as anti-arthrosclerotic, anti-hypertensive, antioxidant anti-inflammatory agents which would limit platelet aggregation, are effective in reducing the size of cerebral infarction and improving neurological deficit scores.
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ABSTRACT: The root of Angelica sinensis (Oliv.) Diels (abbreviated as AS) (Danggui) has a long history in Asian herbal medicine. Recently, it was demonstrated that AS possesses anti-cancer and anti-oxidant activities. Because the transcription factor Nrf2 mediates the expression of many cellular anti-oxidative stress genes, including genes that are involved in phase II drug metabolism and anti-oxidative stress, this study sought to investigate whether pure compounds from AS or an AS extract could activate antioxidant response element (ARE)-mediated gene expression and induce anti-inflammatory activities. Z-Ligustilide (Ligu), 3-butylidenephthalide (Buty) and CO2 supercritical fluid-extracted lipophilic AS extract (SFE) were tested in HepG2-C8 cells stabilized with ARE luciferase reporter gene. Ligu and Buty caused significant toxicity only at 100 μM. All three of the samples induced ARE-luciferase activity; however, SFE at 8.5 µg/mL induced ARE-luciferase activity 2-3 fold more potently than did either of the pure compounds. SFE also significantly increased the endogenous mRNA of Nrf2 and the Nrf2 target anti-oxidative gene NAD(P)H dehydrogenase, quinone 1 (NQO1). The protein expression of NQO1 was also significantly induced by SFE. In RAW 264.7 cells, SFE suppressed LPS-induced IL-1β and TNF-α expression about 2 fold stronger than sulforaphane, whereas both the pure compounds and SFE suppressed inflammatory nitric oxide (NO) production. In summary, our study demonstrates that AS has anti-inflammatory effects and activates the Nrf2 pathway, which protects against oxidative stress. This article is protected by copyright. All rights reserved.Biopharmaceutics & Drug Disposition 05/2013; · 2.09 Impact Factor
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ABSTRACT: The present study was performed to investigate the effects of Jin-Ying-Tang (JYT), a Chinese herbal formula containing Lonicera japonica, Herba taraxaci, Fructus trichosanthis, Fructus forsythia, Radix et rhizoma rhei, Astragalus membranaceus, Angelica sinensis, on rabbit mastitis induced by Staphylococcus aureus. Suckling rabbits were challenged with 1.5 × 10(7) colony forming unit (CFU) of S. aureus at the base of the third pair teats, and they were treated and pretreated with JYT to detect the formula effects. The results showed that JYT could reduce the occurrence of Staphylococcal mastitis in rabbit model. To further investigate the action mechanism of JYT, we examined the leukocyte counts and inflammatory mediator levels such as TNF-α and IL-6 in blood and infected tissue. From histological study and blood analysis, we found that JYT could suppress leukocyte infiltration in infected mammary gland tissue and significantly inhibit the total leukocyte counts and lymphocytes (LYM), monocytes (MON) and granulocytes (GRA) fractions of leukocyte counts in blood. Enzyme-linked immunosorbent assay (ELISA) results showed JYT significantly decreased the TNF-α and IL-6 concentrations in serum and mammary gland. The analysis of these data suggested that JYT effectively inhibited inflammatory responses to reduce the occurrence of mastitis in rabbit model.Immunopharmacology and Immunotoxicology 02/2012; 34(5):786-93. · 1.36 Impact Factor
Pharmacological effects of Radix Angelica Sinensis
(Danggui) on cerebral infarction
Yi-Chian Wu1and Ching-Liang Hsieh1,2,3*
Radix Angelica Sinensis, the dried root of Angelica sinensis (Danggui), is a herb used in Chinese medicine to enrich
blood, promote blood circulation and modulate the immune system. It is also used to treat chronic constipation of
the elderly and debilitated as well as menstrual disorders. Research has demonstrated that Danggui and its active
ingredients, as anti-arthrosclerotic, anti-hypertensive, antioxidant anti-inflammatory agents which would limit platelet
aggregation, are effective in reducing the size of cerebral infarction and improving neurological deficit scores.
Danggui, the dried root of Angelica Sinensis (Radix
Angelica Sinensis), is a commonly used Chinese medic-
inal herb to enrich blood, promote blood circulation and
treat blood deficiency pattern and menstrual disorders
such as dysmenorrhea and irregular menstrual cycle .
Wilasrusmee et al.  reported that Danggui (105 μg/ml)
plays an immunostimulatory role in mitogen-stimulated
murine lymphocytes in vitro. Angelan, a purified polysac-
charide component of Angelica nakai thought to improve
immune function, increases the expression of cytokines
in splenocytes as Angelan enhances and the production
of interleukin-6 (IL-6) and interferon-g(IFN-g) of acti-
vated macrophages, helper T cells and natural killer cells
. The chemical constituents of the Danggui extract are
classified into essential oil and water soluble parts includ-
ing lipid compounds, phenolic compounds, carbohy-
drates, organic acids and other constituents . The
most active ingredients are polysaccharides, Z-Ligustilide
(3-butylidene-4,5-dihydrophthalide) and ferulic acid (4-
This article aims to provide an overview of the pharma-
cological effects of Danggui in reducing the size of cerebral
infarction and improving neurological deficit scores.
We searched Medline, PubMed, Cochrane Library and
the China National Knowledge Infrastructure (Chinese
language database) between 1990 and 2010, using
‘Angelica sinensis’, ‘Danggui’, ‘Angelica polysaccharides’,
‘Z-Ligustilide’, ‘Ferulic acid’ and ‘Ischemic stroke’ as
Vasodilation and improving microcirculation
Nitric oxide (NO) is synthesized with nitric oxide synthase
(NOS) which includes three different isoforms, namely
endothelial NOS (eNOS), neuronal NOS (nNOS) and
inducible NOS (iNOS) . While nNOS and eNOS are
induced under different conditions, their activation relies
on intracellular Ca2+for binding calmodulin [5,6]. Due to
its vasodilative effects, eNOS is considered neuro-protec-
tive . Hypertension and a lack of endothelium-derived
relaxing factor activity are found in eNOS knockout mice
. Moreover, the cerebral infarction size is larger in a
model of eNOS mutant mice with middle cerebral artery
occlusion (MCAo) . Therefore, eNOS has a vasodilation
effect and is neuro-protective by increasing the blood flow
. It is possible that Danggui increases NO formation
and relaxes the endothelium , thereby limiting infarc-
tion size. In rabbits on a high-lipid diet, treatment with
ferulic acid, an active component of Danggui, increases the
generation of NO, thereby inhibiting platelet aggregation
on endothelium and proliferation of smooth muscles and
preventing leucocytes adhering to the endothelium .
Z-Ligustilide (3-butylidene-4,5-dihydrophthalide), a com-
ponent of Danggui, inhibits (4-8 μg/ml) the spontaneous
contraction of isolated rat uterus in a dose-dependent
manner . Moreover, Z-Ligustilide may also inhibit
prostaglandin F-2a, oxytocin, acetylcholine chloride and
potassium depolarization-induced uterine contraction,
* Correspondence: email@example.com
1Department of Chinese Medicine, China Medical University Hospital,
Taichung 40402, Taiwan
Full list of author information is available at the end of the article
Wu and Hsieh Chinese Medicine 2011, 6:32
© 2011 Wu and Hsieh; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
suggesting that Ligustilide modulates the function of uter-
ine tissue and has a non-specific anti-spasmodic effect .
Z-Ligustilide enhances the recovery of conjunctival capil-
lary and venue diameter after dextran T500 administration
to rabbits and increases the number of opened capillaries
as well as blood flow, suggesting that Z-Ligustilide
improves microcirculation .
Ferulic acid is the main organic acid component of
Danggui. Ferulic acid (10-3mol/L) relaxes the phenylephr-
ine-induced contraction of aorta ring in spontaneous on
rat (SHR) whereas the effects of ferulic acid may be
partially blocked by pretreatment of the aorta with NG-
nitro-L-arginine methyl ester (L-NAME, 10-4mol/L)
which inhibits the production of NO from L-arginine .
Ferulic acid (10-3mol/L) reduces the production of throm-
boxane B2in the aorta ring of SHR . Ferulic acid (10-4
mol/L) also significantly reduces the generation of
NADPH-dependent production of the superoxide anion
 and enhances the acetylcholine-induced vasodilation
whereas hydroxyhydroquinone (HHQ) inhibits this effect
. Taken together, ferulic acid reduces blood pressure
in SHR via effects on (1) eNOS; (2) the inhibition of
thromboxane B2to relax aorta ring; (3) reactive oxygen
species (ROS) scavenging activity to increase the availabil-
ity of NO in endothelial cell of aorta .
Stroke is divided into two major groups according to the
cerebral damage, cerebral infarction and cerebral hemor-
rhage. Eighty percent (80%) of stroke patient suffer from
cerebral infarction . Cerebral infarction is mainly
caused by thrombosis, embolism or systemic hemody-
namic hypertension. Atherosclerosis in large and small
arteries is a major contributor to cerebral thrombosis. The
etiology of atherosclerosis and stroke is related to inflam-
mation and genetic factors. Ischemic cerebral infarction
may be prevented by anti-inflammatory agents or the
treatment of vascular diseases, heart diseases and hyper-
A principal contributor to cerebral infarction and ather-
osclerosis is believed to be initiated by an excessive inflam-
matory-fibro-proliferative response . Atherosclerosis
involves growth factors, cytokines and vaso-regulatory fac-
tors such as vascular endothelial growth factor (VEGF),
fibroblast growth factor (FGH), transforming growth fac-
tor-b (TGF-b), interleukin-1 (IL-1) and tumor necrosis
factor -a (TNF-a) [19,20]. Cytokines are both pro- and
anti-atherogenic; for example, IL-1 and TNF-a mediate
the production of monocyte chemoattractant protein-1
(MCP-1) to induce monocyte migration directly into the
intima. By contrast, cytokines can induce NO production
which regulates the vasomotor tone of artery, thereby
influencing the initiation and progression of the
atherosclerosis process . A previous study  found
that nicotine can mediate the development and progres-
sion of atherosclerosis via the inhibition of TGF-b1 and
basic fibroblast growth factor (bFGF). The alteration of
TGB-b activity leads to the atherosclerotic change of ves-
sel wall and increased TGB-b signaling plays a protective
role of atherosclerosis . A study  reported that
bFGF enhances smooth muscle migration and prolifera-
tion via the regulation of interstitial collagenase expression
in the early stages of atherosclerosis. Wang et al. 
found that the levels of TGB-b reduced and those of bFGF
increased in human umbilical vein endothelial cells
damaged by hyperlipidemic serum. Moreover, under elec-
tromicroscopy the morphology of endothelial cell was also
damaged which was reversed by Danggui (20 mg/ml) and
its component of sodium ferulate (0.3 mg/ml). These
results indicate that both Danggui and sodium ferulate
have anti-atherogenic effects . Yu et al.  found that
the levels of total cholesterol (TC, 0.95 mmol/L vs. 11.79
mmol/L), triglyceride (TG) and high density lipoprotein
cholesterol (HDLC) and low density lipoprotein choles-
terol (LDLC) increased in rabbits on a high-lipid diet com-
pared to the control group which was on a normal diet.
After 25% Danggui was administered (i.v.) for four weeks,
the levels of TG decreased from 3.52 mmol/L to 1.68
mmol/L. The plaque area of thoracic aorta was also
reduced after Danggui treatment, from 63.31% to 35.58%
. Moreover, Danggui reduced the increase of the
serum malonyldialdehyde (MDA) levels caused by the
high-lipid diet . In a similar study , after treatment
with sodium ferulate, the plaque area of thoracic aorta was
reduced while the TG level was reduced to 1.75 mmol/L
in rabbits on a high-lipid diet . Moreover, the sodium
ferulate-treated group increased the production of NO
from epithelium cells. Both Danggui and sodium ferulate
inhibit the formation of atherosclerosis because Danggui
reduces the TG and lipid peroxidation levels or increases
NO production, or both.
Anti-platelet aggregation effects
Anti-platelet aggregation agents such as aspirin, ticlopidine
and clopidogrel are widely used to prevent secondary
ischemic stroke [16,26]. A clinical trial  reported that
administration of aspirin within six hours of the onset of
ischemic stroke reduces the patients’ mortality rate.
Danggui dose-dependently inhibited adenosine dipho-
sphate (ADP)-induced platelet aggregation and collagen-
induced platelet . Danggui (20 g/kg) reduced platelet
aggregation by 87.9% in rats with ADP-induced platelet
aggregation and 33.0% in rats with collagen-induced pla-
telet aggregation . Administration of sodium ferulate
(0.2 g/kg, i.v.) reduced ADP-induced platelet aggregation
by 38% in rats while a lower dose (0.1 g/kg) reduced
Wu and Hsieh Chinese Medicine 2011, 6:32
Page 2 of 5
collagen-induced platelet aggregation by 81% . In an
arteriovenous shunt rat model, the wet weight of the
thrombus was reduced to 19.5 mg (46.4 mg in the con-
trol) in rats administered with Z-Ligustilide (10 mg/kg,
p.o.) and 13.6 mg in rats administered with more Z-
Ligustilide (40 mg/kg, p.o.) . The maximal platelet
aggregation was 6.8% and 2.0% in the 10 mg/kg and 40
mg/kg groups respectively while the control was 44.6%
. Compared with warfarin (1.0 mg/kg, p.o.), Z-Ligus-
tilide (10 mg/kg and 40 mg/kg) administered orally for
three days did not increase activated partial thrombo-
plastin time (APTT) and prothrombin time (PT) in a
coagulation time test ex vivo . Danggui and Z-Ligus-
tilide exert anti-platelet aggregation effects.
Pro-inflammatory cytokines, such as IL-1b and TNF-a, are
increased in the brain tissue of transient middle cerebral
artery occlusion (MCAo) rats [29,30]. IL-1 up-regulates
the expression of adhesion molecules such as intercellular
adhesion molecule-1 (ICAM-1), P-selectin and E-selectin
in the endothelium [31,32]. These adhesion molecules
facilitate the translocation of activated leukocytes into the
ischemic core [31,32]. Moreover, nuclear factor-?B (NF-
?B) is also activated in the ischemic core . Both
Sophora japonica L. and paeoniflorin inhibit IL-1b secre-
tion, thereby reducing cerebral infarction size and neuro-
logical deficit . Moreover, paeoniflorin reduces IL-1b,
TNF-a, ICAM-1 and leucocytes . Therefore, anti-
inflammation, such as inhibition of pro-inflammatory
cytokine and ICAM-1, is very important in treating cere-
Ferulic acid (eg 80 and 100 mg/kg, i.v.) reduces the size
of cerebral infarction and neurological deficit scores and
inhibits ICAM-1 and NF-?B expression in transient MCAo
rats . The anti-inflammatory action of ferulic acid is, at
least in part, important in its therapeutic effect on cerebral
infarct . Moreover, ferulic acid (eg 100 mg/kg, i.v.)
exerts anti-inflammatory action by reducing the generation
of 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2’-deoxygua-
nosine (8-OHdG) and apoptosis in the reperfusion period
after cerebral ischemia, thus providing neuroprotection
. This neuro-protection by ferulic acid is thought to
occur via enhancing gamma-aminobutyric acid type B1
(GABAB1) receptor expression to against p38 mitogen acti-
vated protein kinase (MAPK)-mediated NO-induced apop-
tosis . Danggui reduces inflammatory cell infiltration
and TNF-a and TGF-ß1 mRNA expression; it also reduces
TNF-a and TGF-ß1 positive cells in radiation-induced
pneumonitis in mice . Danggui polysaccharides reduce
TNF-a levels in the colon mucosa during intra-colon
enema with 2,4,6-trinitrobenzene sulfonic acid (TNBS) and
ethanol in rats . Both Danggui and ferulic acid exert
Reactive oxygen species (ROS) including the superoxide
anion, hydrogen peroxide and hydroxyl radical are gener-
ated after cerebral ischemia. The ROS affect mitochondrial
function, DNA repair and transcription factors, leading to
apoptosis [37,6]. Superoxide dismutase 1 (SOD1), an
endogenous antioxidant, blocks the early release of cyto-
chrome c from mitochondria and reduces the develop-
ment of apoptosis in focal cerebral ischemic mice .
Apolipoprotein E, via its anti-oxidative effects against cer-
ebral ischemia, is neuro-protective in transient forebrain
ischemia induced by bilateral common carotid artery
occlusion (BCCAo) in mice . Anti-oxidant nutrients
such as vitamin E and Ginkgo biloba extract reduce cere-
bral damage in rodent models of ischemia and reperfusion
. GABABreceptor agonist baclofen may be neuro-pro-
tective via the inhibition of N-methyl-D-asparate (NMDA)
receptor-mediated NO production in brain ischemic injury
. Ferulic acid (100 mg/kg, i.v.) enhanced the expression
of GABAB1in the reperfusion period (three and 24 hours
after ischemia) in rats . Z-ligustilide reduced the size
of cerebral infarction from 22.1% to 11.8% (5 mg/kg, i.p.)
and 2.60% (20 mg/kg, i.p.) . Z-ligustilide reduced the
MDA levels and increased glutathione peroxidase (GSH-
Px) and SOD activities in the ischemia-reperfusion brain
tissues induced by BCCAo in mice . Danggui or its
components or both demonstrate anti-oxidant activity in
ischemia-reperfusion injury models.
Effect of Danggui on cerebral infarction
Danggui (5 g/kg, i.p.) increased blood circulation and
neuronal metabolism in an MCAo rat model . Dang-
gui reduced the size of cerebral infarction, neurological
deficit scores and increased blood flow and SOD activity
in the MCAo rat model . Z-ligustilide reduced cere-
bral infarction size to 10.90% and 3.19% in rats orally
dosed with 20 m/kg or 80 mg/kg respectively (21.08% in
the control group) in a MCAo model . Moreover,
Z-ligustilide (10 mg/kg or 40 mg/kg, p.o.) increased cho-
line acetyltransferase activity and inhibited acetylcholi-
nesterase to improve cognitive function in rats with
hypoperfusion . Our previous study  found that
ferulic acid (80 mg/kg or 100 mg/kg, i.v.) reduced cere-
bral infarction size and neurological deficit scores in
rats. Liu et al.  reported that Danggui (25%, i.v.)
administered to 1040 patients with acute cerebral infarc-
tion improved neuro-function scores and the Barthel
index score more than Salvia miltiorrhiza (78.7% vs.
59.3%). Danggui reduces the size of cerebral infraction
and improves neurological deficit scores.
The effects of Danggui on cerebral infarction are through
multiple pathways, including anti-arthrosclerosis,
Wu and Hsieh Chinese Medicine 2011, 6:32
Page 3 of 5
improving microcirculation, anti-platelet aggregation,
anti-inflammatory and anti-oxidative effects (Table 1).
Danggui may be useful in treating the cerebral infarction
type of stroke.
IL: interleukin; IFN-γ: interferon-γ; AP: polysaccharide component; ALT: serum
alanine transferase; MDA: malondialdehyde; NOS: nitric oxide synthase; CCL4:
carbon tetrachloride; ASP: water-soluble polysaccharide; NO: nitric oxide;
eNOS: endothelial nitric oxide synthase; nNOS: neuronal nitric oxide
synthase;iNOS: inducible nitric oxide synthase; MCAo: middle cerebral artery
occlusion; L-NAME: NG-nitro-L-arginine methyl ester; SHR: spontaneous
hypertensive rat; NADPH:nicotinamide adenine dinucleotide phosphate;
HHQ: hydroxyhydroquinone; ROS: reactive oxygen species; VEGF: vascular
endothelial growth factor; FGH: fibroblast growth factor; TGF-β: transforming
growth factor-β; TNF-α: tumor necrosis factor -α; MCP-1: monocyte
chemoattractant protein-1; bFGF: basic fibroblast growth factor; TC: total
cholesterol; TG: triglyceride; HDLC: high density lipoprotein cholesterol; LDLC:
low density lipoprotein cholesterol; ADP: adenosine diphosphate; APTT:
activated partial thromboplastin time; PT: prothrombin time; ICAM-1:
intracellular adhesion molecule-1; NF-κB: nuclear factor-κB; 4-HNE: 4-hydroxy-
2-nonenal; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; GABAB1: gamma-
aminobutyric acid type B1; MAPK: mitogen activated protein kinase; mRNA:
messenger ribonucleic acid; SOD: superoxide dismutase; NMDA: N-methyl-D-
asparate; GSH-Px: glutathione peroxidase; BCCAo: bilateral carotid artery
This study is supported in part by the Clinical Trial and Research
Center of Excellence (DOH100-TD-B-111-004), Department of Health,
1Department of Chinese Medicine, China Medical University Hospital,
Taichung 40402, Taiwan.2Graduate Institute of Acupuncture Science, China
Medical University, Taichung 40402, Taiwan.3Acupuncture Research Center,
China Medical University, Taichung 40402, Taiwan.
YCW searched the literature, organized the information and wrote the
manuscript. CLH analyzed the information and revised the manuscript. Both
authors read and approved the final version of the manuscript.
The authors declare that they have no competing interests.
Received: 1 March 2011 Accepted: 25 August 2011
Published: 25 August 2011
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reverse the reduction of TGB-b/reverse the increase of bFGF 
reduce the increase of serum malonyldialdehyde (MDA) levels 
sodium ferulateddecrease the levels of triglyceride 
Vasodilatation and improving
increase the formation of NO and mediate the inhibition of calcium influx 
sodium ferulateincrease the generation of NO 
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depolarization-induced muscle contraction 
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inhibit ADP-induced and collagen-induced platelet aggregation 
Anti-platelet aggregation effects
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Cite this article as: Wu and Hsieh: Pharmacological effects of Radix
Angelica Sinensis (Danggui) on cerebral infarction. Chinese Medicine 2011
Wu and Hsieh Chinese Medicine 2011, 6:32
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