How would composite traditional Chinese medicine protect the brain--an example of the composite formula "Pien Tze Huang".
ABSTRACT Chinese medicine has a long history of several thousand years. The main form of Traditional Chinese Medicine (TCM) is composite, i.e. a mixture of up to 10 medicinal products. Thus a composite prescription of 4-5 kinds of Chinese medicinal products may contain several hundred kinds of chemical composition. The active ingredients and clinical efficacy of which are difficult to characterize. We aim to review the Chinese literature of TCMs with neuroprotective effects. We illustrate with our study on Pien Tze Huang (PZH) the use of in vivo tests in the study of composite TCM. Our results show evidence that PZH might have neuropreventive effects in rats.
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ABSTRACT: Among hundreds of formulae of Chinese herbal prescriptions and recently extracted active components from the herbs, some of which had demonstrated their functions on nervous system. For the last decade or more, Gingko biloba and Polygala tenuifolia were widely studied for their beneficial effects against damage to the brain. Two compounds extracted from Apium graveolens and Rhizoma coptidis, butylphthalide and berberine, respectively, received much attention recently as potential neuroprotective agents. In this review, the two traditionally used herbs and the two relatively new compounds will be discussed with regard to their potential advantages in alleviating brain and other relevant ailments.Evidence-based complementary and alternative medicine : eCAM. 01/2014; 2014:682717.
3590 Current Medicinal Chemistry, 2011, 18, 3590-3594
0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
How Would Composite Traditional Chinese Medicine Protect the Brain – An Exam-
ple of the Composite Formula “Pien Tze Huang”
L. Zhang1,2, W.P. Lam1, L. Lü3, Y.-X.J. Wang4, Y.W. Wong1, L.H. Lam1, H.C. Tang1, M.S. Wai1, Y.T. Mak1,
M. Wang2 and D.T. Yew*,1
1Brain Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong
2Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
3Department of Anatomy, School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
4Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin,
Abstract: Chinese medicine has a long history of several thousand years. The main form of Traditional Chinese Medicine (TCM) is
composite, i.e. a mixture of up to 10 medicinal products. Thus a composite prescription of 4-5 kinds of Chinese medicinal products may
contain several hundred kinds of chemical composition. The active ingredients and clinical efficacy of which are difficult to characterize.
We aim to review the Chinese literature of TCMs with neuroprotective effects. We illustrate with our study on Pien Tze Huang (PZH) the
use of in vivo tests in the study of composite TCM. Our results show evidence that PZH might have neuropreventive effects in rats.
Keywords: Cerebral ischemia, cerebral stroke, neuroprotection, composite traditional Chinese Medicine, Pien Tze Huang, Ginkgo Biloba,
Angong Niuhuang Wan, Compound Danshen Dripping Pill, water maze, functional magnetic resonance imaging.
Chinese medicine has a long history of several thousand years.
The main form of Traditional Chinese Medicine (TCM) is compos-
ite, i.e. a mixture of several, four or five, or up to 10 medicinal
products . Despite the use of scientific methods in recent years,
their therapeutic effects and mechanisms of action are difficult to
document [2-4]. Since a composite prescription of 4-5 kinds of
Chinese medicinal products may contain several hundred kinds of
chemical composition, the active ingredients and clinical efficacy of
such composite TCMs are difficult to characterize [4-6], and their
purposed effectiveness of TCMs has often been questioned [7-10].
Pien Tze Huang (PZH) is an example of composite TCM: the for-
mulation of PZH contains musk, calculus bovis, snake’s gall, and
Tienchi which singly and/or in combination, could have anti-
edematous, anti-inflammatory and anti-thrombotic effects [11, 12].
In this article, we review TCMs which claim to have protective
effects on the central nervous system (CNS). We then illustrate the
study of TCM with PZH.
COMPOSITE TRADITIONAL CHINESE MEDICINE
TCM prescriptions are usually in the form of a composite of
several medicinal products . The idea of composite TCM is
multi-target therapy; in which not only the target tissue or organ
causing the disease but also other tissues or organs that are relevant
to the disease are treated, i.e. a holistic approach to treatment [1,
13]. The advantage of this kind of treatment is that the one compo-
nent treats the diseased tissue or organ, while the other components
might promote the functions of relevant tissues and organs to en-
hance the overall therapeutic effect of the TCM. Different ingredi-
ents could have synergistic effects . For example, pretreatment
for the treatment of cardiovascular and cerebrovascular diseases
would select one or more from the following: miltiorrhizae, no-
toginseng, ginseng, carthami, angelica . Often, these prescrip-
tions are ancient formula of over thousand years of history. Nowa-
days, many such composite prescriptions, for example PZH, are
manufactured in capsule, tablet or injection form for more conven-
*Address correspondence to this author at the Brain Research Centre, School of Bio-
medical Sciences, The Chinese University of Hong Kong, Shatin, New Territories,
Hong Kong, China; Tel: (852) 26096869; Fax: (852) 26035123;
While composite TCMs are popular in China and among over-
seas Chinese, the complex nature of the ingredients prohibit their
use in Western medicine as the active ingredients of such composite
TCMs and their clinical efficacy are difficult to characterize, as
well as because of questionable effectiveness. For example, TCM
has been used for stroke treatment in China for a long time . A
meta-analysis of 191 trials of 22 TCMs reported a strikingly large
and significant positive effect (odds ratio 3.4, 95% confident inter-
val 3.1 to 3.6) of all treatments on cerebral stroke . However, the
authors cautioned that due to the overall uncertain methodological
quality of these trials there was insufficient evidence to determine
the effectiveness of TCM in ischemic stroke [2, 3]. In recent dec-
ades, scientific methods including laboratory testing and clinical
trials are used to elucidate the effectiveness and mechanisms of
TCMs, however, despite these efforts, the popularity remains ques-
tionable in the West [13, 16]. Furthermore, most of these studies are
mainly published in Chinese apart from only few in English [17-
19], which hinders the circulation and creditability of the research
TCM FOR CNS DISEASES
We have a strong interest in using TCM for treatment of CNS
diseases, since many CNS conditions such as cerebral stroke and
neurodegeneration have as yet no effective treatment in the Western
medicine [20, 21]. On the other hand, there are many TCMs pro-
posed to have therapeutic or protective effects on such conditions.
We searched literatures and identified 71 oral simple TCMs (i.e.
one medicinal product), 161 oral composite TCMs, 16 injectable
simple TCM, and 12 injectable composite TCMs from the database
of Chinese literature using keywords of TCM, nervous system,
protection and neuroprotection from 1981 to present, for having
therapeutic or protective effects on CNS  (Table 1 shows se-
lected examples). We describe three examples in the following
The extract from the leaves of the Ginkgo Biloba tree, labeled
EGb761, is one of the most widely used medicinal products in the
West . Both the seeds and leaves have been used in Chinese
folk medicine for thousands of years in treating lung and kidney
disorders such as tuberculosis and asthma . Extracted from the
Traditional Chinese Medicine for Neuroprotection Current Medicinal Chemistry, 2011 Vol. 18, No. 23 3591
Ginkgo Biloba leaves, EGb761 is a standardized mixture consisting
of two major components, 24% of the flavonoids glycosides (pri-
marily quercetin, kaempferol and isorhamnetin), and 6% of the
terpene lactones (3.1% of ginkgolides A, B and C, and 2.9% of
bilobalide), first developed by the French company Beaufour-Ipsen
in 1975 and then in other countries as an ethical drug under the
trade names as Rokan®, Tanakan®, or Tebonin® [26, 26]. How-
ever, EGb761 has not been approved for use as a drug by the Food
and Drug Administration (FDA) of the United States of America.
Rather it is marketed as a dietary supplement, under the name Gin-
gold . Nevertheless, EGb761 has become one of the most
widely used medicinal products in the West for a range of neuro-
logical and vascular disorders including dementia, arterial occlu-
sion, ischemia, retinal deficit, depression, Parkinson’s disease, as
well as normal aging [23, 24, 28-31], in spite of conflicting evi-
dence about the benefits of Ginkgo leaf extract [32-36]. EGb761’s
physiological and psychological benefits are thought to be based on
its actions on neurotransmitter regulation, its neuroprotective ef-
fects against neuronal cell death, the improvement of microcircula-
tion, and its antioxidant activity [26, 37]. With our own studies, we
have elucidated the possible general molecular mechanisms of how
EGb761 exerts its neuroprotective effects, which involves vascular
effects, anti-apoptosis, anti- oxidative stress, and neurotransmitter
regulation [23, 38-42]. However, the overall mechanism of its
therapeutic effect on the CNS remains uncertain [43-45].
Angong Niuhuang Wan
Angong Niuhuang Wan is a commonly used TCM for ‘toxin
elimination’ with a history of two thousand years [46-48]. It is a
composite TCM manufactured by Tong Ren Tang (Beijing, China)
containing 12 medicinal products including niuhuang (Calculus
bovis), xi jiao (rhinoceros horn), zedoary, musk, huanglian (Chi-
nese goldthread), pearl powder . All these medicinal products
are well-known for ‘clearing away toxins’ [11, 12]. Some ingredi-
ents such as huanglian are used as an antibiotic and antiviral .
Angong Niuhuang Wan is claimed to be beneficial for cardiovascu-
lar and cerebrovascular diseases . Indeed, Angong Niuhuang
Wan has been used in the treatment of acute intracerebral hemor-
rhage and other cerebral disorders . Studies have been at-
tempted to analyze the exact chemical compositions of Angong
Niuhuang Wan [51, 52]. However, its active ingredients remain
Compound Danshen Dripping Pill (Fufang Danshen Di Wan)
The Compound Danshen Dripping Pill (CDDP) is a well-
known TCM used for the treatment of cardiovascular diseases in
China [53, 54]. It is composed of three main ingredients, Danshen,
Borneol and Sanchi. CDDP is the first TCM which has obtained a
FDA approval for Phase II clinical trials [55, 56]. There are quite a
Selected TCMs with Neuroprotection Effect Searched from the Database of Chinese Literature
(A) List of some common single TCMs.
Name Active components
Danshen root (丹参)
Chinese angelica (当?)
Liquorice root (甘草)
Lobed kudzuvine root (葛根)
Kadsura pepper twig and leaf (海?藤)
Mongolian milkvetch root (黄芪)
Baikal skullcap root (黄芩)
Lucid ganoderma (灵芝)
Forest musk (麝香)
Ginkgo leaf (?杏叶)
Szechwan lovage rhizome (川芎)
Shortscape fleabane herb (灯?花)
tanshinone, salvianolic acid, protocatechualdehyde, propanoid acid
ligustilide, ferulic acid, angelica polysaccharides
glycyrrhizic acid, flavonone, chalcone
Panax notoginsenosidum, ginsenoside Rb1, Rg1, flavonoid glycoside
flavonoid glycoside, ginkgolide, Bilobalide
ligustrazine, ferulic acid
(B) List of some common composite TCMs.
Angong Niuhuang Wan (安?牛黄丸)
Cardiotonic pill, Compound Danshen dripping pills (复方丹参滴丸)
Compound Ginkgo Biloba (?杏叶复方)
(C) List of some common injection prescriptions.
Single TCM Composite TCM
Gingko extract (??????) Compound Danshen (???????)
3592 Current Medicinal Chemistry, 2011 Vol. 18, No. 23
Zhang et al.
number of publications in English literature reporting the use of
CDDP or Danshen in clinical and animal studies for the treatment
of heart related conditions [2, 57-63], as well as studies using cell
cultures [64-66]. Furthermore, some studies reported the details of
the active chemical constituents found in Danshen using different
advanced analytical techniques [55, 67-71]. The proposed mecha-
nisms of CDPP or Danshen include anti-coagulation , reduction
of adhesion molecules [58, 62, 66], modulation of functions of
platelet , and anti-oxidation . CDDP or Danshen is one of
the most thoroughly studied composite TCMs , thought it has
still not been approved by FDA as a prescribed drug .
Pien Tze Huang
Pien Tze Huang (PZH) is a composite TCM commonly used for
the treatment of liver diseases, cancer, and inflammation . PZH
has four main ingredients: musk, calculus bovis (gallstone of the
ox), snake’s gall, and Tienchi (the root of Panax notoginseng – a
type of ginseng) which, according to Chinese herbal documenta-
tion, singly and/or in combination has anti-edematous, anti-
inflammatory and anti- thrombotic effects [11, 12]. In fact, musk
and calculus bovis are also the main ingredients of Angong Niu-
huang Wan. We have previously shown PZH could protect the liver
from carbon tetrachloride damage, which might lead to the devel-
opment of hepatomas , and subsequently have shown the anti-
cancer activity of PZH in neuroblastoma cultures . Previous
studies have shown that ginseng extracts could effectively decrease
the release of endothelin in cell culture  and inhibit the prolif-
eration of vascular smooth muscle cells , while endothelial cell
damage is the initial step of thrombosis and arteriosclerosis in car-
diovascular disorders. Muscone, an active substance of musk, may
reduce the level of endothelin and size in rats with experimental
myocardial infarct [70, 77]. Therefore, both Tienchi and muscone
might protect blood vessel endothelium resulting in less vasogenic
In view of this evidence, we hypothesized that PZH might have
neuro-preventive effects on cerebral ischemia and/or stroke. PZH is
a composite TCM which, like other TCMs, has therapeutic effects
that are difficult to document [2-4]. We investigated PZH using
direct in vivo water maze and functional magnetic resonance imag-
ing (fMRI) studies using experimental animals to evaluate whether
the effects were indeed real. Specifically, we aimed to evaluate in
vivo whether PZH could alleviate the consequences of cerebral
stroke and ischemia in spontaneously hypertensive rat (SHR) and
stroke prone SHR (SHRsp) [78, 79].
Water maze results showed that SHR received PZH treatment
before ischemia showed significant improvement (p<0.05) in the
escape latency as compared with the ischemic control SHR without
PZH treatment (Fig. 1). This suggested that PZH could protect SHR
from memory damage caused by ischemia. fMRI experiment found
that both the groups with ischemia with PZH treatment and
ischemic control groups displayed larger activated volumes in re-
sponse to the tail stimulus as compared to the sham operation con-
trol group (Fig. 2). The activated brain areas were significantly
increased upon a 500 g weight stimulus onto the tail. However,
there was no significant difference between the ischemia with PZH
treatment group and ischemic control group suggesting PZH might
not have an effect on the prevention of this functional damage. For
SHRsp which develop stroke spontaneously, results suggest that
PZH treatment before the onset of stroke significantly lengthened
(p<0.05) the survival of the animals after stroke. In addition, PZH
may lessen the severity of stroke but could not prevent the progress
of stroke and the subsequent fatality of the rats.
Fig. (2). Functional magnetic resonance imaging (fMRI) analysis of brain
activations was performed in ischemia with PZH treatment, ischemia con-
trol, and sham operation control groups of SHR two weeks after the ligation.
fMRI scans were acquired with tail stimulus of a weight of 500 g. The acti-
vated volumes were significantly increased in the ischemia with PZH treat-
ment group (115.2?70.0, p=0.0203) and the ischemia control group
(135.8?118.5, p=0.049) as compared to the sham operation group
(35.1?17.3). This suggested that while there was significant damage to the
functional integrity caused by ischemia to the brain, PZH treatment as tested
by fMRI might not show any effect on the prevention of this functional
damage. Data were the means ± standard deviations of activation volumes
The two in vivo tests, the water maze and the fMRI, showed
discrepant results: the differences between the ischemia with PZH
treatment and ischemic control groups were significant in water
maze tests but not on fMRI results. The reasons could be two-fold:
first, the water maze test is a test of spatial learning and memory
test for the prefrontal cortex, a specific brain region, while the fMRI
tests the whole brain. Secondly, the water maze and fMRI test dif-
ferent functional aspects of the brain, and test for memory and sen-
sory functions respectively. The loss of a single functional integrity
may not necessarily occur with the loss of another. PZH treatment
may have protected the memory and spatial orientation ability, as
shown in the water maze test, but might not be able to prevent brain
cells from losing certain functions such as sensory functions, as
recorded by fMRI. It is also possible that PZH might prevent dam-
age or injury caused by ischemia to the prefrontal cortex and could
therefore improve performance of the SHR group with ischemia
and PZH treatment in water maze test, but this result might not be
observed in fMRI testing of the whole brain.
Fig. (1). Water maze test results of ischemia with Pien Tze Huang (PZH)
treatment and ischemia control SHR before and after training. On day 5,
after the training period, the escape latency of the ischemia with PZH treat-
ment group was significantly shorter (p=0.00016) than the ischemia control
group. This suggested that PZH could protect the rats from memory damage
caused by the ischemia. Data were the means ± standard deviations.
Day 1Day 5Day 1Day 5
Ischemia controlIschemia with PTH treatment
Escape latency (seconds)
*P<0.05 vs the ischemia control group of Day 5.
Ischemia controlIschemia with PTH
Activation volume (mm3)
* p<0.05 vs the sham operation control group.
Traditional Chinese Medicine for Neuroprotection Current Medicinal Chemistry, 2011 Vol. 18, No. 23 3593
We further examined preventive effect of PZH on stroke using
SHRsp in another in vivo test of PZH. PZH did not prevent the
progression of stroke and the subsequent fatality, however, PZH
apparently could make the stroke slightly less severe and signifi-
cantly delay death after stroke had occurred. This is important in
two ways: firstly, we provided no clinical treatment to the rats after
stroke had occurred, but this is certainly not the case for human
patients who have suffered a stroke. Therefore, the lesser severity
of stroke and significant delay in death would afford a better out-
come for human patients. Secondly, stroke in SHRsp is almost un-
avoidable and imminent, whereas in humans, stroke is not a definite
outcome, even in hypertensive patients . Due to this difference
in the nature of stroke in SHRsp and humans, we may speculate and
anticipate that the preventive effects of PZH on human cases of
stroke could possibly be very significantly beneficial in the out-
come. In conclusion, PZH showed significant neuropreventive ef-
fects in limiting the damage caused by ischemia and stroke in rats
with hypertension. This provides evidence that PZH might have
similar preventive or prophylactic effects in high-risk human pa-
tients. Further studies are required to more clearly define these ef-
Pien Tze Huang (PZH) is a composite TCM which, like other
TCMs, has therapeutic effects that have been considered to be are
difficult to document [2-4]. Our study investigated the possible
effects of a TCM, PZH in this case, in whole animals, and was able
to reveal that the proposed effects are real.
We thank Ms. E. Lucy Forster for her critical review of the
English of the manuscript. This study was funded by Zhang Long
Industrial Company Limited, Hong Kong.
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Received: March 03, 2011
Revised: June 08, 2011 Accepted: June 10, 2011