Pharmacological effects of Radix Angelica Sinensis (Dang-qui) on
cerebral infarction
Yi-Chian Wu1 and Ching-Liang Hsieh1, 2, 3 *
1
Department of Chinese Medicine, China Medical University Hospital, Taichung,
40402, Taiwan
2
Graduate Institute of Acupuncture Science, China Medical University, Taichung,
40402, Taiwan
3
Acupuncture Research Center, China Medical University, Taichung, 40402, Taiwan
*
Corresponding author:
Ching-Liang Hsieh
Graduate Institute of Acupuncture Science
China Medical University
91 Hsueh-Shih Road
Taichung, 40402, Taiwan
E-mail addresses: [email protected]
TEL: 886-4-22053366 (ext. 3600)
Abstract
Dang-qui, the dried root of Angelica Sinensis, is a Chinese herb used to enrich blood,
promote blood circulation, modulate the immune system, as an emollient and laxative
for chronic constipation of the aged and debilitated, and treat female menstrual
disorders. Dang-gui and its active ingredients had been proved effective on cerebral
infarction in many researches. Dang-gui treats cerebral infarction type of stroke is
through its anti-arthrosclerosis and anti-hypertension effect to prevent the occurrence
of cerebral infarction, and through its anti-platelet aggregation, anti-inflammation and
anti-oxidation to reduce cerebral infarction size and improve neurological deficit
score. Therefore, Dang-qui is mediated via multiple pathways including
anti-atherosclerosis, improving microcirculation, anti-platelet aggregation,
anti-inflammatory, and increasing anti-oxidant system activity to improve cerebral
infarction.
Key words: Angelica Sinensis (Dang-gui); Angelica polysaccharides; Z-Ligustilide;
Review Background
Dang-Gui, the dried root of Angelica Sinensis, is one of most common use Chinese
herbs. According to Traditional Chinese medicine recordings, Dang-gui has the action
of enrich blood and promoting blood circulation and is used to treat blood deficiency
pattern and to treat menstruction disorders such as dysmenorrheal, irregular
menstruction cycle [1]. Wilasrusmee et al. (2002) find that Dang-gui (105 µg/ml)
increases average [3H] thymidine incorporation counts per minute from 8524.6 to
16007.3 (87%) plays as an immunostimulatory role in mitogen-stimulated murine
lymphocytes in vitro [2], and is also as an emollient and laxative for chronic
constipation of the aged and debilitated [1]. Angelan is a purified polysaccharide
component of Angelica Nakai of Umbelliferae includings Dang-qui. Angelan (100
µg/ml) may increase the expression of cytokines in splenocytes. Angelan may rapidly
enhance and maintain thereafter production of interleukin-6 (IL-6) and
interferon-γ(IFN-γ) of activated macrophage, helper T cells and natural killer cells,
whereas the increase of IL-2 is gradually, and IL-4 increase is affected only a few hrs
[3]. The polysaccharide component (AP) of Dang-qui (75 mg/kg) orally at 6 and 1 hr
prior to acetaminophen administration may decrease serum alanine transferase (ALT)
hepatic malondialdehyde (MDA) in mice with acetaminophern-induced hepatic injury,
whereas the AP (50 mg/kg or 75 mg/kg) cannot affect ALT, nitric oxide synthase
(NOS) and glutathione concentration in mice or rat with carbon tetrachloride
(CCl4)-induced liver damage [4]. Therefore, AP of Dang-qui is a selective protection
to liver.). The crude water-soluble polysaccharide (ASP) component of Dang-qui can
be separated into the three main fraction of ASP1 (neutral polysaccharide), and ASP2
and ASP3 (acid polysaccharide). The pretreatment with ASP3 fraction of ASP at 200
mg/kg/day for 7 day may increase peripheral leucocytes counts to 85.7%, and also
may increase lymphocytes counts to 99.14% compared to control in 3.0 Gy gamma
irradiated mice. In addition, pretreatment with ASP3 at 50 mg/kg, and at 200 mg/kg
may produce inhibition rate of peripheral lymphocytes apoptosis is 11.50 and 44.78%,
respectively, compared to control at 12 hr after irradiation in mice [5], suggesting that
ASP3 component of Dang-qui may modulate apoptosis process and plays a
radio-protective effect.
The chemical constituents of the Dang-gui extract are classified into essential oil
and water soluble parts, including lipid compounds, phenolic compounds,
carbohydrates, organic acids, and other constituents [6]. The most active ingredients
are polysaccharides, Z-Ligustilide (3-butylidene-4,5-dihydrophthalide) and ferulic
the the effects and mechanisms in how does Dang-gui reduce cerebral infarction size
and neurological deficit. We searched the databases including Medline, PubMed,
Cochrane Library and Chinese language database namely China National Knowledge
Infrastructure between 1990 and 2010, using Angelica Sinensis, Dang-gui, Angelica
polysaccharides, Z-Ligustilide, Ferulic acid, and ischemic stroke as keywords.
Pharmacology
Vasodilation and improving microcirculation
Nitric oxide (NO) is synthesized by NOS, and the three different isoforms include
endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS).
Although nNOS and eNOS are induced by different condition, their activation needs
intracellular Ca2+ for binding calmodulation [7, 8]. eNOS is considered as
neuro-protection due to its vasodilative effect [8]. Hypertension and lack
endothelium-derived relaxing factor activity is finds in eNOS knockout mice. In
addition, the cerebral infarction size is larger in eNOS mutant mice with middle
cerebral artery occlusion (MCAo) model. Therefore, eNOS has a vasodilatation effect
and increase blood flow plays as neuro-protection [9]. Dang-qui can increase the
formation of NO to cause relaxation of endothelium, and it also can mediate the
of ferulic acid can increase the generation of NO to inhibit platelet aggregation of
endothelial cells and proliferation of smooth muscle, and also can prevent leucocytes
adhesion to endothelium in hyperlipid diet-treated rabbit [11]. Therefore, Dang-qui
enhances the generation of NO cause vasodilatation acts a neuroprotection..
Ligustilide (3-butylidene-4,5-dihydrophthalide), a component of Dang-qui, at 4-8
µg/ml may inhibit the spontaneous contraction of isolated rat uterus, and this effect is
dose-dependent. In addition, Ligustilide also may inhibit prostaglandin F-2α, oxytocin,
acetylcholine chloride, and potassium depolarization-induced uterine contraction,
therefore, suggesting that Ligustilide has a modulator function to uterus and plays a
non-specific anti-spasmodic effect [12]. Ligustilide can enhance the recovery of
conjunctival capillary and venue diameter to 92.4% and 85% of original diameter at
30 min after dextran T500 administration in rabbit, and also can increase the number
of opened capillary and can increase blood flow speeds, therefore, suggesting
Ligustilide can improve microcirculation [13]. To sum up, Ligustilide can inhibit
constriction of smooth muscle and plays an anti-spasmodic effect to enhance blood
flow and to improve microcirculation.
Ferulic acid is the main organic acids component of Dang-qui. Ferulic acid
(10-3 mol/L) can relax phenylephrine-induced contraction of aorta ring in spontaneous
by removing the endothelium of aorta or by NG-nitro-L-arginine methyl ester
(L-NAME, 10-4 mol/L) pretreatment of the aorta [14]. Ferulic acid (10-3 mol/L) can
reduce the production of thromboxane B2 in aorta ring of spontaneous hypertensive
rat (SHR) [14]. Ferulic acid (10-4 mol/L) also can significantly reduce the generation
of NADPH-dependent production of superoxide anion [14], and ferulic acid also can
enhance acetylcholine-induced vasodilatation, whereas hydroxyhydroquinone (HHQ)
can mediate via superoxide anion inhibit this potentiate effect of ferulic acid [14].
Taken together, the mechanisms of ferulic acid reducing blood pressure in SHR
possibly involves to: 1) eNOS; 2) through the inhibition of thromboxane B2 to relax
aorta ring; 3) reactive oxygen species (ROS) scavenging activity to increase the
availability of NO in endothelial cell of aorta [14].
Anti-arthrosclerosis effects
Stroke divided into mainly tow type of cerebral infraction and cerebral hemorrhage,
and 80% of stroke patient suffer from cerebral infarction [15]. The main cause of
cerebral infarction includes thrombosis, embolism or systemic hemodynamic
hypotension. Atherosclerotic change of large and small arteries is a major contributor
of cerebral thrombosis. The etiology of atherosclerosis and stroke is related to
through anti-inflammation and treatment for vascular diseases, heart diseases and
hypertension [16, 17, 18].
Atherosclerosis is a principal contributor to cerebral infarction, and the
development of atherosclerosis is due to initial endothelium and smooth muscle of the
arterial wall insult results in an excessive inflammatory-fibro-proliferative response.
The process of atherosclerosis involves to a lot of growth factor, cytokine and
vaso-regulatory factor such as vascular endothelial growth factor (VEGF), fibroblast
growth factor (FGH), transforming growth factor-β (TGF-β), interleukin-1 (IL-1) and
tumor necrosis factor –α (TNF-α) [19, 20]. Cytokine can play both pro- and
anti-athrogenic role , for example, IL-1 and TNF-α can mediate via the production of
monocyte chemoattractant protein-1 (MCP-1) to induce monocyte migrates directly
into the intima. In contrast, cytokine also can induce a vasodilatory NO to regular
vasomotor tone of artery; therefore, cytokine can influence initiation and progression
of atherosclerosis process [20]. A study finds that nicotine mediates via the regulation
of TGF-β1 and Basic fibroblast growth factor (bFGF) production and release to play a
critical role in the development and progression of arteriosclerosis [21] . The
reduction of TGB-β signaling cause the atherosclerotic change of vessel wall, and the
increase of TGB-β signaling can plays as an athero-protective because the levels of
stages of atherosclerosis can mediate via the regulation of interstitial collagenase
expression to enhance smooth muscle migration and proliferation [23]. The
morphology endothelial cell occurs damage is observed by electro-microscopy, and
the levels of TGB-β reduces from 1959 to 1018 optical density, and the levels of
bFGF increase from 1256 to 1488 optical density in the hyper-lipidemic serum treated
human umbilical vein endothelial cells. Both Dang-qui (20 mg/ml) and its component
of sodium ferulate (0.3 mg/ml) can reverse this damage of endothelial cells. Dan-qui
can reverse this reduction of TGB-β to 1897, and also can reverse this increase of
bFGF to 1120; Sodium ferulate can reverse this reduction of TGB-β to 1938, and also
can reverse this increase of bFGF to 903. Taken together, both Dang-qui and its
component of sodium ferulate have anti-atherogenic effect [24]. Yu et al.(2000) find
that the levels of total cholesterol (TC, 0.95 vs 11.79 mmol/L), triglyceride (TG, 0.87
vs 3.52 mmol/L), high density lipoprotein cholesterol (HDLC, 0.46 vs 1.63 mmol/L)
and low density lipoprotein cholesterol (LDLC, 0.52 vs 8.23 mmol/L) increased
compared to normal control group in high lipid diet-treated rabbits. The levels of TG
decrease to 1.68 mmol/L after 25% Dang-qui intra-venous administration for 4 weeks.
The plaque area of thoracic aorta also reduces from 63.31% to 35.58% after Dang-qui
treatment. In addition, Dang-qui also can reduce the increase of serum
of thoracic aorta is 23.2%, TG is 1.75 mmol/L in the sodium ferulated-treated group.
In addition, the sodium ferulated also can increase the reduction of NO production
[11]. Therefore, both Dang-qui and its component of sodium ferulate can inhibit the
formation of atherosclerosis, and this effect of Dang-qui has relationship to its
reducing TG and lipid peroxidation level, or increasing NO.
Anti-platelet aggregation effects
Anti-platelet agent such as Aspirin, Ticlopidine and Clopidogrel had been widely used
to the prevention of secondary ischemic stroke [16, 26]. A Multicentre Acute Stroke
Trial-Italy reports that administration of aspirin with 6 hrs of ischemic stroke onset
can reduce mortality rate [26].
Dang-qui at 200 mg/ml and 500 mg/ml can inhibit ADP-induce rat platelet
aggregation, and the inhibition rate is 30 and 75%, respectively. The inhibition rate is
48, 66 and 88%, respectively, in Dang-qui at 200, 300 and 500 mg/ml on
collagen-induced rat platelet aggregation. The intravenous administration of Dang-qui
20 g.kg can produced an inhibition rate of 87.9% in ADP-induced platelet aggregation,
and inhibition rate of 33.0% in collagen-induced platelet aggregation in rat [27].
Similar effect also is seen in sodium ferulate, intravenous administration of sodium
aggregation in rat, and sodium ferulate at 0.1g/kg can produce an inhibition rate of
81% in collagen-induced platelet aggregation [27]. Pretreatment with Z-Ligustilide
(10 mg and 40 mg/kg) orally for three days can reduce wet weight of thrombus from
46.4 mg in the control to 19.5 mg and to 13.6 mg in the arteriovenous shunt rat model
[28]. The maximal platelet aggregation is 6.8% in the 10 mg/kg group and 2.0% in the
40 mg/kg group (pretreatment with Z-Ligustilide orally three days in rat) are lower
than 44.6% in the control group in ADP-induced platelet aggregation ex vivo [28],
whereas Z-Ligustilide (10 mg/kg and 40 mg/kg) orally three days cannot like warfarin
(1.0 mg/kg, p.o.) affect activated partial thromboplastin time (APTT) and prothrombin
time (PT) in coagulation time test ex vivo [28]. To sum up, Dang-qui and its
component of Z-Ligustilide have anti-platelet aggregation effect.
Anti-inflammatory effects
The pro-inflammatory cytokine such as IL-1β, TNF-α increase in transient MCAo rats
[29, 30], and cytokine IL-1 can up-regular expression of adhesion molecule such as
intercellular adhesion molecule-1 (ICAM-1), P-selectins and E-selectins expression in
the endothelium [31, 32]. This adhesion molecular can facilitate activated leukocytes
into the ischemic core [31, 32]. In addition, nuclear factor-κB (NF-κB) also is
can reduce cerebral infarction size and neurological deficit. The Sophora Japonica L
also can reduce IL-1β [29], and paeoniflorin also can reduce IL-1β, TNF-α, ICAM-1
and leucocytes [30]. Therefore, anti-inflammation such as inhibition of
pro-inflammatory cytokine and ICAM-1 plays a critical role in treating cerebral
infarction.
Ferulic acid at 80 and at 100 mg/kg iv can reduce cerebral infarction size and
neurological deficit, and also can inhibit ICAM-1 and NF-κB expression in transient
MCAo rats, therefore, its anti-inflammatory action plays, at least, partly an important
role in the therapeutic effect to cerebral infarct [33]. In addition, ferulic acid (100
mg/kg iv) can mediate its anti-inflammation to reduce the generation of
4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2’-deoxyguanosine (8-OHdG) and
apoptosis in the reperfusion period after cerebral ischemia and provide a
neuro-protection [32]. This neuro-protection of ferulic acid is through enhancing
gamma-aminobutyric acid type B1 (GABAB1) receptor expression to against p38
mitogen activated protein kinase (MAPK)-mediated NO-induced apoptosis [34].
Dang-qui reduce inflammatory cells infiltration, and also reduce TNF-α and TGF-ß1
mRNA expression and reduce TNF-α and TGF-ß1 positive cells in radiation-induced
pneumonitis in mice [35]. Dang-qui polysaccharides (400 mg/kg and 800 mg/kg) can
2,4,6-trinitrobenzene sulfonic acid (TNBS) and ethanol rat [36]. Taken together, both
Dang-qui and its component of ferulic acid have anti-inflammation effect.
Anti-oxidative effects
ROS including superoxide anion, hydrogen peroxide, and hydroxyl radical is
generated during the period after cerebral ischemia. These ROS can cause neuronal
cells damage because they can affect mitochondria function, DNA repair and
transcription factors results in apoptosis after cerebral ischemia [37, 8]. Recurrent
studies find that superoxide dismutase 1 (SOD1), an endogenous antioxidant, block
the early release of cytochrome c in mitochondria and reduce development of
apoptosis in focal cerebral ischemic mice [38], and apolipoprotein E is through its
anti-oxidation to against cerebral ischemia plays a neuro-protective effect in
transient forebrain ischemia induced by bilateral common carotid artery occlusion
(BCCAo) mice [39]. Anti-oxidant nutrients such as vitamin E, Ginkgo biloba extract
reduces cerebral damage in rodent model with ischemia and reperfusion [40].
GABAB receptor agonist baclofen may play a neuro-protection through the
inhibition of N-methyl-D-asparate (NMDA) receptor-mediated NO production in
brain ischemic injury [41]. Ferulic acid (100 mg/kg iv.) enhances the expression of
reduces cerebral infarction size from 22.1% to 11.8% at 5 mg/kg i.p, and to 2.60% at
20 mg/kg i.p.. Z-ligustilide also can reduce MDA levels and can increase glutathione
peroxidase (GSH-Px) and SOD activities in the ischemia–reperfusion brain tissues
induced by BCCAo in mice [42]. To sum up, Dang-qui has anti-oxidation effect.
Effect on Dang-qui on cerebral infarction: basic and clinical study
Liu et al. (2004) reports that Dan-qui (25%, i.v.) has greater improvement in
neuro-function scores and Barthel index score than compound salvia (78.7% vs 59.3%)
in 1040 patients with acute cerebral infarction [43]. Dang-qui (5 g/kg, i.p.) can
increase blood circulation and neuronal metabolism [44], and Dang-qui can reduce
cerebral infarction size, neurological deficit, and can increase blood flow and SOD
activity in MCAo rat model [45]. Z-ligustilide can reduce cerebral infarction size to
10.90% and 3.19% in 20 m/kg or 80 mg/kg orally, these reduce is greater than in the
control that reduce cerebral infarction size to 21.08% in rat with MCAo model [46].
In addition, Z-ligustilide (10 mg/kg or 40 mg/kg orally) also can mediate via
increasing choline acetyltransferase activity and inhibiting acetylcholinesterase to
improve cognitive function in rats with hypo-perfusion [47]. Ferulic acid (80 mg/kg
or 100 mg/kg i.v.) reduces cerebral infarction size and neurological deficit scores had
cerebral infraction size and also can improve neurological deficit scores; therefore it
can be used to cerebral infarction type of stroke.
Conclusion
Dang-qui prevent and treat cerebral infarction is through multiple pathways including
anti-arthrosclerosis, improving microcirculation, anti-platelet aggregation,
anti-inflammatory and anti-oxidative effects (Table 1).
Abbreviations
IL : interleukin ; IFN-γ : interferon-γ ; AP : the 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;
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 occlusion.
Competing interests
The authors declare that they have no competing interests.
Author’ contributions
YCW searched the literature, organized the data and wrote the manuscript. CLH
analyzed the data and revised the manuscript . Both author authors read and approved
Acknowledgements
This study is supported in part by Taiwan Department of Health Clinical Trial and
Research Center of Excellence (DOH100-TD-B- 111-004).
Author Detail
1
Department 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,
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Table 1. Possible pharmacological actions of Radix Angelica Sinensis on cerebral infarction
pharmacological actions Related components Possible mechanisms Dang-qui and sodium
ferulate
reverse the reduction of TGB-β / reverse the increase of bFGF [24]
Dang-qui reduce the increase of serum
malonyldialdehyde (MDA) levels [25] anti-arthrosclerosis effects
sodium ferulated decrease the levels of triglyceride [11] Dang-qui increase the formation of NO and
mediate the inhibition of calcium influx [10]
sodium ferulate increase the generation of NO [11] Ligustilide inhibit prostaglandin F-2α, oxytocin,
acetylcholine chloride, and potassium depolarization-induced muscle contraction [12]
Ligustilide increase the number of opened capillary and the speed of blood flow [13] vasodilatation and
improving microcirculation effects
Ferulic acid enhance acetylcholine-induced
vasodilatation and reduce the production of thromboxane B2 [14]
Dang-qui and sodium ferulate
inhibit ADP-induced and
collagen-induced platelet aggregation [27]
anti-platelet aggregation effects
Z-Ligustilide inhibit ADP-induced platelet aggregation [28]
Ferulic acid inhibit ICAM-1 and NF-κB expression [33]
Ferulic acid enhance gamma-aminobutyric acid type B1 (GABAB1) receptor expression [34]
Dang-qui reduce TNF-α and TGF-ß1 mRNA expression [35]
anti-inflammatory effects
Dang-qui polysaccharides
reduce TNF-α levels [36]
anti-oxidative effects Ferulic acid reduce the generation of
NADPH-dependent production of superoxide anion [14]
Ferulic acid enhances the expression of GABAB1
receptor expression [34] Z-ligustilide reduce MDA levels and increase
