Author’s Accepted Manuscript

The rhizome of Gastrodia elata Blume - an

ethnopharmacological review

Hong-Dan Zhan, Hai-Yu Zhou, Xin-Liang Du,

Yun-Peng Sui, Wei-hao Wang, Li Dai, Feng Sui,
Hai-Ru Huo, Ting-Liang Jiang
www.elsevier.com/locate/jep

PII: S0378-8741(16)30417-2
DOI: http://dx.doi.org/10.1016/j.jep.2016.06.057
Reference: JEP10259
To appear in: Journal of Ethnopharmacology
Received date: 13 November 2015
Revised date: 22 June 2016
Accepted date: 24 June 2016
Cite this article as: Hong-Dan Zhan, Hai-Yu Zhou, Xin-Liang Du, Yun-Peng Sui,
Wei-hao Wang, Li Dai, Feng Sui, Hai-Ru Huo and Ting-Liang Jiang, The
rhizome of Gastrodia elata Blume - an ethnopharmacological review, Journal of
Ethnopharmacology, http://dx.doi.org/10.1016/j.jep.2016.06.057
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The rhizome of Gastrodia elata Blume - an ethnopharmacological
review
Hong-Dan Zhan1, Hai-Yu Zhou1, Xin-Liang Du2, Yun-Peng Sui3, Wei-hao Wang1, Li Dai1, Feng
Sui1*, Hai-Ru Huo1* Ting-Liang Jiang1

1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing
100700, China; 2. Graduate School of China Academy of Chinese Medical Sciences, Beijing
100700, China; 3. Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.

ABSTRACT
Ethnopharmacological relevance: Gastrodia elata Blume (Orchidaceae) is
commonly called Tian ma in Chinese and mainly distributed in the mountainous areas
of eastern Asia, such as China, Korea, Japan and India. It is an extensively used
traditional Chinese herbal medicine in the clinical practice of traditional Chinese
medicine, to treat headache, migraine, dizziness, epilepsy, infantile convulsion, tetany
and so on. The present paper reviews the advancements in investigation of botany and
ethnopharmacology, phytochemistry, pharmacology, toxicology and quality control of
Gastrodia elata Blume. Finally, the possible tendency and perspective for future
investigation of this plant are also put forward.
Materials and methods: The information on Gastrodia elata Blume was
collected via piles of resources including classic books about Chinese herbal medicine,
and scientific databases including Pubmed, Google Scholar, ACS, Web of science,
ScienceDirect databases, CNKI and others. Plant taxonomy was validated by the
databases “The Plant List”, and “Mansfeld's Encyclopedia”.
Results: Over 81 compounds from this plant have been isolated and identified,
phenolics and polysaccharides are generally considered as the characteristic and
active constituents of Gastrodia elata Blume. Its active compounds possess
wide-reaching biological activities, including sedative, hypnotic, antiepileptic,
anticonvulsive, antianxietic, antidepressant, neuroprotective, antipsychotic,
anti-vertigo, circulatory system modulating, anti-inflammationary, analgesic,
antioxidative, memory-improving and antiaging, antivirus and antitumor effects.
Conclusion: Despite the publication of various papers on Gastrodia elata Blume,
there is still, however, the need for definitive research and clarification of other
bioactive compounds using bioactivity-guided isolation strategies, and the possible
mechanism of action as well as potential synergistic or antagonistic effects of
multi-component mixtures derived from Gastrodia elata Blume need to be evaluated.
It is also necessary and important to do more quality control and toxicological study
on human subjects in order to maintain its efficacy stable in the body and validate its
safety in clinical uses. In addition, more investigations on other parts of this plant
beyond the tubers are needed. Further studies on Gastrodia elata Blume will lead to
the development of new drugs and therapeutics for various diseases, and how to
utilize it better should be paid more attention to.
*Corresponding author. Tel.: +86 10 64041008; fax: +86 10 64041008. E-mail addresses:
fsui@icmm.ac.cn (F. Sui), hrhuo@icmm.ac.cn (H.-R. Huo).
1
Chemical compounds studied in this article

 Gastrodin (PubChem CID: 115067);

 Hydroxybenzyl alcohol (PubChem CID: 125);
 4-hydroxybenzaldehyde (PubChem CID: 126);
 Vanillyl alcohol (PubChem CID: 62348);
 Vanillin (PubChem CID: 1183);
 Parishin (PubChem CID: 44421666);
 Parishin B (PubChem CID: 44715528);
 Parishin C (PubChem CID: 46173915);
 β-sitosterol (PubChem CID: 222284);
 Gastrodamine (PubChem CID: 5702160)

Keywords: Gastrodia elata Blume; Tian ma; Ethnopharmacology; Phytochemistry;

Pharmacology; Clinical applications

Contents
1. Introduction ....................................................................................................................... 3
2. Botany and ethnopharmacology ......................................................................................... 3
2.1. Botany ..................................................................................................................... 3
2.2. Ethnopharmacology ................................................................................................ 3
3. Phytochemistry................................................................................................................... 3
3.1. Phenolics and its glycosides .................................................................................... 3
3.2. Polysaccharides ....................................................................................................... 3
3.3. Sterol and organic acids .......................................................................................... 3
3.4. Other compounds .................................................................................................... 3
4. Pharmacological activities ................................................................................................. 3
4.1. Sedative and hypnotic activities .............................................................................. 3
4.2. Antiepileptic and anticonvulsive activities.............................................................. 3
4.3. Anti-anxiety and antidepressant activities ............................................................... 3
4.4. Neuroprotective activities ....................................................................................... 3
4.4.1. Protection of neuronal cells and anti-apoptoticaction activities ................. 3
4.4.2. Anti-oxidative activities ............................................................................. 3
4.4.3. Protection of neuro-synaptic plasticity ....................................................... 3
4.5. Anti-cardio-cerebral-vascular diseases activities .................................................... 3
4.6. Antipsychotic activities ........................................................................................... 3
4.7. Anti-vertigo activities.............................................................................................. 3
4.8. Effect on circulatory system .................................................................................... 3
4.8.1. Anticoagulant and antithrombotic activities ............................................... 3
4.8.2. Anti-atherosclerotic activities .................................................................... 3
4.8.3. Antihypertensive activities ......................................................................... 3

2
 4.9. Anti-inflammatory and analgesic activities ............................................................. 3
4.10. Improve memory and anti-aging activities ............................................................ 3
4.11. Antivirus and antitumor activities ......................................................................... 3
4.12. Other pharmacological activities ........................................................................... 3
5. Quality control ................................................................................................................... 3
6. Toxicology ......................................................................................................................... 3
7. Concluding remarks ........................................................................................................... 3
Acknowledgments ..................................................................................................................... 3
References ................................................................................................................................. 3

Introduction

3
Gastrodia elata Blume (G. elata, Orchidaceae), commonly called Tian ma (天麻) in
Chinese, is a perennial parasitic herb also called Chi jian (赤箭) or Ming tian ma (明
天麻). It is considered as a top grade herbal medicine that has been used for a long
history described to enter the liver meridian in the Shennong’s Classic of Materia
Medica (Shen nong ben cao jing). Generally, after the beginning of winter to the
following year before the Tomb-sweeping Day, excavate the rhizome of G. elata, wash
it immediately, and braise it well and then dry it at low temperature for the clinical use
(Chinese Pharmacopoeia Commission, 2015).
G. elata has nine synonyms (G. elata f. alba S.Chow, G. elata f. elata, G. elata f.
flavida S.Chow, G. elata f. glauca S.Chow, G. elata var. gracilis Pamp., G. elata var.
pallens Kitag., G. elata f. pilifera Tuyama, G. elata f. viridis (Makino) Makino, and G.
elata var. viridis (Makino) Makino) (The Plant List., 2013). To search by using these
nine names, only two Chinese articles (Jiang et al., 2001; Zhang et al., 2014)
regarding Gastrodia elata f. elata, and one English article (Wang et al., 2007)
covering Gastrodia elata f. glauca S.Chow were obtained. However, it was found that
G. elata was used in more than 200 publications (both in English and Chinese). There
are also many Chinese articles in which the plant was just defined as Tian ma (Li et al.,
2015; Luo et al., 2012) To communicate more effectively and internationally, it is
suggested that G. elata should be used instead of Tian ma in all publications in the
future.
Currently, over 81 compounds from this plant have been isolated and identified,
and they are phenolics, polysaccharides, sterols and organic acids, and so on.
(Ojemann et al., 2006). In the theory of traditional Chinese medicine (TCM), G. elata
is considered to suppress the hyperactive liver, arrest endogenous wind and stop
tetany. In the aspect of clinical practice, G. elata is mainly applied for neurasthenia,
insomnia, dizziness, epilepsy, convulsions, nervous headache, Alzheimer's disease,
hypertensive and others (Hou et al., 2012). Modern pharmacological experiments
have demonstrated that the extracts of G. elata or its active compounds possess
wide-reaching biological activities, including antitumor, anti-virus,
memory-improving, antioxidation, and anti-aging actions (Huang et al., 1985; Heo et
al., 2007; Hu et al., 2014). It is commonly used in traditional medicine as a tonic and
aphrodisiac in China and other Asian countries as well as used as a functional food by
adding to alcoholic beverages or porridge to improve sexual potency and vision and to
prevent abortion (Zhang, 1981).
A large number of investigations have been conducted on G. elata in the past few
decades, but only a short review of G. elata as a herbal medicine has been published
by Chen et al. (Chen and Sheen, 2011), in which its biological activities and
antidepressant mechanisms are briefly mentioned, and another review written by Jang
et al. (Jang et al., 2015), in which only the neuropharmacological potential of G. elata
was covered. In this review, using various databases search and library search to
4
provide constructive information on the ethnopharmacology, phytochemistry,
pharmacology, toxicology and quality control of G. elata as well as the
structure-activity relationships of the active ingerdients derived from G. elata, aims to
coherently unite these aspects and to encourage further research.

2. Botany and ethnopharmacology

2.1. Botany

G. elata (Fig. 1) belongs to the genus Gastrodia, family Compositae. There are
about twenty-two species in the genus Gastrodia, and most of the species grow in
China (Table 1). However, only G. elata is used as medicinal material in the clinical
practice of TCM and registered in the Pharmacopeia of People’s Republic of China.
G. elata is found primarily in eastern Asia, specifically in the mountainous areas of
China, Korea, Japan and India (Shuan and Chen, 1983; Jones, 1991). Characterized
by a fleshy tuber or coralloid underground stem and absence of leaves, it grows in the
forest at 400-3200 meters above sea level and has a complex relationship with the
fungus Armillaria mellea, which invades the sprouted tuber and provides nutrients
and energy (Wang, et al., 2007). The plant lives underground during its life cycle
except for florescence. Four subspecies, including G. elata Bl. f. elata, G. elata Bl. f.
flavida S.chow, G. elata Bl. f. glauca S. chow and G. elata Bl. f. viridis Makino have
been found in G. elata species (Zhou et al., 1987). Except for the subspecies of G.
elata Bl. f. viridis Makino which is becoming increasingly rare in the wild, the other
three subspecies have successfully been cultivated in fields both in China and other
countries such as Korea (Lee et al., 2014). Recent studies have shown that G. elata is a
small genus composed of 16-31species (Table 1). Among them, the most abundant
species is distributed in Taiwan (Chung and Hsu, 2006; Dressler, 1993; Meng et al.,
2007). As the unique botanical characters, G. elata grows to the height of 60-100 cm
and the whole plant does not contain chlorophyll. The tubers of G. elata are pachyntic,
oblong, about 10 cm long and its diameter is 3-4.5 cm. The stems are vertical,
cylindrical, and red. The leaves are scalelike, membranous, 1-2 cm long, nervulose.
Its inflorescence is fringy raceme, 10-30 cm long and golden colored (Chinese
materia medica, 1999).
G. elata is harvested in winter or spring; the excavated in winter is named
Gastrodia hiemalis T. P Lin, the quality of which is relatively excellent, and the
dredged in spring is called Gastrodia fontinalis T. P Lin, the quality of which is
inferior to Gastrodia hiemalis (Lei et al, 2015). After digged out, removed the stems
and fibrous root, washed the dirt, soaked in water and wiped off the coarse skin, then
soaked in water or alum, next boiled or steamed and when the white dots in the center
dispeared, took it out and dried it (Chinese materia medica, 1999).
The dried tubers are oval shaped, long, slightly flat, and exhibit signs of shrinkage
and bending. The residual stem base at one end, commonly known as "Ying ge zui" is
red to reddish brown in colour, and the other end has rounded root marks. They are
6-10cm long, 2-5cm in diameter, and 0.9-2cm thick. Its surface is yellowish-white to
yellowish-brown and translucent. It has residual flakes of the light coloured skin, lots

5
No. Name Distribution Part of herb used Medicinal uses References

of longitudinal wrinkles, fibrous scar lines and an amount of less visible annulus.
Gastrodia hiemalis is with tenuous and less wrinkles and Gastrodia fontinalis is with
thick wrinkles. Both of their textures are hard and not easy to be fractured (Chinese
materia medica, 1999).
In China, wild G. elata is naturally distributed in many provinces. These provinces
include Sichuan, Guizhou, Yunnan, Shanxi, Hubei, Gansu, Anhui, Henan, Jiangxi,
Hunan, Guangxi, Jilin province and so on. Within these areas, G. elata growing in the
western Guizhou, southen Sichuan, northeast of Yunnan and Changbai mountain areas
are generally regarded as being of high quality. However, the extensive urbanization
of China as a whole has led to serious habitat fragmentation, which may in turn lead
to gradual loss of wild G. elata. Further adding insult to this injury is the current
exploitation of the limited resources of G. elata (Chinese materia medica, 1999).
These wrong actions will lead to the heavy shortages of wild G. elata, which are
actually more valuable than the cultivated ones in biological activities. As such, some
urgent conservation measures should be taken to protect the G. elata’ natural habitat,
in order to guarantee the long-term application of this herbal medicine.

Table 1 The ascertained species in the genus Gastrodia.

6
1 G. elata Bl. Most regions of Rhizome Treating dizziness, Shuan and Chen(1983); Flora
China limb numbness, of China (2004)
infantile convulsion,
epilepsy, tetanus,
hypertension, etc
2 Gastrodia fontinalis T. P Taiwan, Yunnan, Rhizome Treating dizziness, Flora of China (2004)
Lin. Sichuan, Guizhou limb numbness,
and Hubei in infantile convulsion,
China epilepsy, tetanus,
hypertension, etc

3 Gastrodia hiemalis T. P Taiwan, Yunnan, Rhizome Treating dizziness, Flora of China (2004)
Lin Sichuan, Guizhou limb numbness,
and Hubei in infantile convulsion,
China epilepsy, tetanus,
hypertension, etc

4 G. elata Bl. form. glauca Western of Not mentioned Not mentioned Shuan and Chen (1983); Flora
S. Chow Guizhou, of China (2004); Chen et al.
Northeast to the (2005); Tang (2013)
northwest of
Yunnan in China
5 G. elata Bl. f. alba S. Northwest Not mentioned Not mentioned Shuan and Chen (1983); Flora
Chow Yunnan in China of China (2004)
6 G. elata Bl. f. favida S. Henan, Hubei, Not mentioned Not mentioned Shuan and Chen (1983); Flora
Chow Western Guizhou, of China (2004); Tang (2013)
Northeast Yunnan
in China
7 Gastrodia angusta S. Southeastern Not mentioned Not mentioned Shuan and Chen (1983); Flora
Chou & S. C. Chen Yunnan, Sichuan, of China (2004); Chen et al.
Shanxi in China (2015)
8 Gastrodia tuberculata F. Central Yunnan Not mentioned Not mentioned Shuan and Chen (1983); Liu
Y. Liu & S. C. Chen in China et al. (1983); Flora of China
(2004); Chen et al. (2015)
9 Gastrodia menghaiensis Southern Yunnan Not mentioned Not mentioned Tsi and Chen (1994); Flora of
Z. H. Tsi & S. C. Chen in China China (2004); Chen et al.
(2015)
10 Gatrodia wuyishanensis Wuyi mountain of Not mentioned Not mentioned Li and Liu (2007)
D. M. Li & C. D. Liu Fujian province
in China

11 Gastrodia gracilis Bl. Northern Not mentioned Not mentioned Shuan and Chen (1983); Flora
Taiwan, Yunnan, of China (2004); Chen et al.
Sichuan, Guizhou (2015)
and Hubei in
China
12 Gastrodia javanica (Bl.) Southern Taiwan Not mentioned Not mentioned Yokota (1998); Flora of China
Lindl. (2004); Aoyama and Yokota
(2012)
13 Gastrodia flabilabella S. Central Taiwan Not mentioned Not mentioned
S. Ying Flora of China (2004); Lok
and Ang (2009); Lai (2012)
14 Gastrodia peichatieniana Northern Taiwan Not mentioned Not mentioned Flora of China (2004); Tian et
S. S. Ying al. (2010)
15 Gastrodia autumnalis T. Northern Taiwan Not mentioned Not mentioned Flora of China (2004)
P Lin

16 G. elata Bl. f. elata Huanghe valley Not mentioned Not mentioned Shuan and Chen (1983); Flora
and Changjiang of China (2004); Chen et al.
valley in China (2005); Tang (2013)

17 G. elata Bl. f. viridis Northeast to Not mentioned Not mentioned Shuan and Chen (1983); Flora
(Makino) Makino southwest of China (2004); Chen et al.
provinces in (2005); Tang (2013)
China
18 Gastrodia confuse Honda Central Taiwan; Not mentioned Not mentioned Flora of China (2004);
& Tuyama Yunnan in Yang et al. (2013)
China
19 Gastrodia appendiculata Taiwan Not mentioned Not mentioned Yeh et al. (2011)
C. S. Leou & N. J.
Chung
20 Gastrodia shimuzuana Northern Taiwan Not mentioned Not mentioned Tuyama (1982); Flora of
Tuyama in Acta Phytotax China (2004); Chung and
Hsu (2006)
21 Gastrodia elata Shanxi Not mentioned Not mentioned Zhang and Ji (2010)
var.obovata Y.J.Zhang

7
 A B

C D

Fig.1 G. elata. (A) seedlings, (B) stem and flowers, (C) dried tubers, and (D)
decoction pieces.

2.2. Ethnopharmacology

With an extensive scope of biological and pharmacological effects, G. elata has

been traditionally used in China for centuries with the dried rhizome (tuber) as the
useful part. G. elata was initially recorded in the Shennong’s Classic of Materia
written in the period of the Warring States and the Qin and Han Dynasties. In this
monograph, G. elata was classified as a “top grade” drug with rejuvenating effect, no
toxic and thus can be long-term used without harm. This monograph described that
long-time treatment with Gastrodiae elata can tonify qi and strength the body, nourish
yin, enhance health, rejuvenate the body, and prolong life (Gu and Yang, 2013).
G. elata is also recorded in many other traditional Chinese medicine classics,
including the Variorum of the Shennong’s Classic of Materia Medica (Shen nong ben
cao jing ji zhu) and the Newly Revised Materia Medica (Xin xiu ben cao). The content
of them is the same as that of Shennong’s Classic of Materia Medica (Chinese materia
medica, 1999). In Compendium of Materia Medica (Ben cao gang mu), another
8
monograph of TCM, G. elata is charactered as a medicine improving liver meridian
and is called “Ding feng cao” as a marvelous medicine in the treatment of the diseases
caused by the invasion of wind (Li, 2011).
In accordance with the authoritative textbook of Chinese pharmacy, G. elata is
sweet in flavor, neutral in nature and attributive to the liver channel. G. elata is
described possessing the power to suppress hyperactive liver for calming endogenous
wind, dredge the meridians and relieve pain. In the clinical practice, G. elata is
primarily applied for dizziness, epilepsy, convulsion, numbness of the limbs,
rheumatic arthralgia and headaches by combining with other botanical drugs based on
the TCM theory (Chinese materia medica, 1999).
On account of its wonderful and specific clinical effects, lots of classic
formulations including G. elata created by the ancient famed doctors were spread
generation after generation through the refined clinical verification for centuries. For
example, Gastrodia and Uncaria decoction was used to treat neurodegenerative
disease, such as stroke, brain trauma, and spinal cord injury, Huntington's disease,
Alzheimer's disease (AD), and Parkinson's disease (PD) diseases, etc. (Chik et al.,
2013). Banxia Baizhu Tianma Decoction was mainly used to treat vertigo in the past,
and now it was also used to treat spontaneous hypertensive, vomiting, diarrhea,
tinnitus, deafness, migraine headache, stroke, dementia, epilepsy, etc. (Jiang et al.,
2011; Dong, 2012).
Nowadays, a lot of prescriptions containing G. elata (Table 2) have been applied in
the forms of injection, granule, pill and capsule. For example, Tianma Injection was
used to treat 53 patients with vertebral basilar artery insufficiency with the total
efficiency significantly higher than that of the control group (He et al., 2014). Qiangli
Tianma Duzhong Capsule was prescribed for the treatment of acute cerebral
infarctions for 36 patients for 28 days, and the obviously effective rate and response
rate for the treatment group are 66.67% and 90.00% respectively (Shen et al., 2006).
Another study was also conducted to evaluate the clinical effect and safety of
Tianmasu Injection in treating vertigo symptom, and the results showed that the
significantly effective rate and total effective rate for the tested groups were higher
than for the control group (P<0.05) (Gao, 2012). Furthermore, it is also reported that
Tianma preparations can be used in combination with other drugs to prevent and treat
more diseases or increase therapeutic effects. For instance, Tianmasu Injection was
used to treat diabetic neuropathy in combination with Kudiezi Injection with an
affirmative effect that is superior to the chemical drugs (Wei and Cui, 2012). Banxia
Baizhu Tianma Decoction was effective to treat vertebral-basilar artery insufficiency
(VBI) when combined with Shuxuening Injection (Chen, 2010).
G. elata not only contains phenolics and polysaccharides that can produce
pharmacological activities, but also have a variety of trace elements and amino acids.

9
 So it has a high nourishing and edible value and is often used to make medicinal food
in folk, such as “Stewd black-bone chicken with Tianma”, a traditional dish in Yunnan
province of China that can be used to treat deficiency of both qi and blood or
postpartum blood deficiency characterized by dizziness, anemia and hypotension.
“Tianma sleeping porridge” possesses medical functions of improving brain and
bodies, sedative and sleeping effects, and can thus be used to treat stubborn sex,
insomnia, dizziness, and forgetfulness. “Tianma steamed egg” used to treat dizziness,
neurasthenia, etc. “Tianma stewed pig brain” has enriching essence and marrow effect,
and is often used for headache, dizziness, easily angry, palpitations, and insomnia
insulted by liver fire. (Zhao et al., 2013). In addition, a lot of G. elata health care
products have been developed and sell well in China, such as Tianma health wine,
Tianma health drinks, Tianma candy and so on (Li et al., 2002; Xiao et al., 2009).
Influenced by the traditional Chinese culture and the medical system of TCM,
application of G. elata as a therapeutic botanical drug is now popular in many Asian
countries, especially in South Korea and Japan. In view of this fact, this plant is
currently cultivated in a number of cultivation regions distributed in different cities of
Korea (such as Chuncheon, Gimcheon, Muju, Sangju, and Asan) (Lee et al., 2014).
While in Japan, Kampo, a traditional Japanese medicine, is widely practised and is
fully integrated into the modern health-care system. In the clinical practice of Kampo,
G. elata is used alone or in combination under the direction of Kampo theory similar
to the basic theory of TCM (Yu et al., 2006).

Table 2 The traditional and clinical usages of G. elata in China.

Formulation Dosage Compositions Efficacy and application References
name form
Tian Ma Gou Decoction Rhizoma Gastrodiae, Calm liver wind,clear heat, Zabing Zhengzhi Xinyi
Teng Yin Ramulus Uncariae cum promote blood circulation,
Uncis, Conncha tonify liver and kidney,
Haliotidis,Radix indicated for liver-yang
Scutellariae,Radix hyperactivity and wind
Cyathulae, Eucommia syndrome caused by
Ulmoides, Herba liver-yang.
Leonuri,Tuber Fleeceflower
stem.

Xing Pi Wan Pill Cortex magnoliae officinalis, Indicated for infantile Puji Benshifang
Atractylodes Macrocephala chronic spleen wind,
Koidz, Brimstone, Rhizoma trapped lethargy after
Gastrodiae, Scorpion, Radix vomit, potentially causing
Saposhnikoviae Chinese seizures.
cinnamon, Ginseng.

Yu Zhen San Powder Rhizpma Arisaematis, Dispel pathogenic wind Waike Zhengzong
Radix Ledebouriellae Radix and eliminate phlegm,
Angelicae Dahuricae, prevent convulsions and
Rhizoma Gastrodiae, spasm, indicated for
Rhizoma seu Radix tetanus.
Notopterygii, Rhizoma
Aconiti praeparatae.
Ban Xia Bai Decoction Dry dampness and Yi xue Xinwu
Zhu Tian Ma Pinellia ternate, Atractylodes eliminate phlegm, calme
Tang Macrocephala Koidz, liver wind, indicated for

10
 Rhizoma Gastrodiae, the wind-phlegm
Pericarpium Citri syndrome.
Reticulatae, Poria cocos,
Radix Glycyrrhizae, Fresh
Ginger, Fructus Jujubae.
a
Qin Jiao Tian Decoction Gentiana Macrophylla Pall., Strengthen body resistance Yi xue Xinwu
Ma Tang Rhizoma Gastrodiae, and eliminate evil, relieve
Rhizoma et Radix pain, dredge the palsy and
Notopterygii, Pericarpium relieve pain, attending
Citri Reticulatae, Radix rheumatism pain, adverse
Angelica Sinensis, Rhizoma joint flexion and
Ligustici Chuanxiong, Radix extension.
Glycyrrhizae preparata,
Fresh Ginger, Ramulus Mori

Tian Ma Wan Pill,capsul Rhizoma Gastrodiae, Dispel wind and eliminate Zhongguo Yaodian
e Rhizoma seu Radix dampness, relax muscles
Notopterygii, Radix and tendons, remove
Angelicae Dahuricae, obstruction from
Cortex Eucommiae, meridians, indicated to
Achyranthis Bidentatae treat hemplegia spasm ，
Radix, Rhizoma Dioscoreae numbness of extremities
Hypoglaucae, Radix Aconiti and aching lumbus and leg
preparata, Radix Angelica pain.
Sinensis, Radix
Rehmanniae, Radix
Scrophulariae .

Tian Ma Tou Pill Rhizoma Gastrodiae, Radix Nourish the blood to Zhongguo Yaodian
Tong Pian Angelicae Dahuricae, expel wind, eliminate cold
Rhizoma Ligustici stop pain, to treat
Chuanxiong, Herba wind-cold headache, or
Schizonepetae, Radix headache due to deficiency
Angelica Sinensis, Resina of blood and blood stasis
Olibani. headache.

Tian Ma Shou Pill,capusl Rhizoma Gastrodiae, Radix Tonify yin and replenish Zhongguo Yaodian
Wu Pian e Angelicae Dahuricae, the kidney, nourish blood
Polygonum Multiflorum, for calming endogenous
Radix Rehmanniae wind, liver-kidney yin
praeparata, Radix Salviae deficiency caused by
Miltiorrhizae, Rhizoma dizziness,
Ligustici Chuanxiong, headache ,tinnitus,
Tribulus Terrestris mouth-bitterness,
praeparata, Mulberry Leaf, throat-drying, soreness and
Herba Ecliptae, Fructus weakness of waist and
Ligustri Lucidi, Radix knees, alopecia, poliothrix
Paeoniae Alba, Rhizoma and angioneurotic
Polygonati, Radix headache, seborrheic
Glycyrrhizae. aiopecia and so on.

Tian Ma Qu Pill Rhizoma Gastrodiae, Tonify kidney, nourish Zhongguo Yaodian

Feng Bu Pian Angelica sinensis, Radix liver, dispel dampness and
Aconiti praeparatae, Cortex relieve pain, to treat the
Eucommiae, Radix deficiency of liver and
Angelicae Pubescentis, kidney caused by
Poria, Radix cyathulae, dizziness, tinnitus, muscle
Radix Rehmanniae,Cortex spasm, arthralgia and the
Cinnamoni, Rhizoma seu numbness of limbs.
Radix Notopterygii,Radix
Scrophulariae

Approved by China Food and Drug Administration (CFDA)

11
Tian Ma Su Injection Gastrodin
Zhu She Ye Used for neurasthenia,
neurasthenia syndrome,
a
angioneurotic headache CFDA
disorder, traumatic brain
syndrome, vertigo meniere
disease, medicinal with
dizziness, vertigo, sudden
deafness, vestibular
neuronitis, vertebral
basilar artery blood supply
deficiency, etc.
a
Tian Ma Zhui Plaster Rhizoma Gastrodiae, Radix Dispel wind and eliminate CFDA
Feng Gao Aconiti Kusenzoffii, Radix dampness, promote blood
aconite, Radix Aconiti circulation to remove
preparata, Radix Clematidis, meridian obstruction,
Herba Ephedrae, Radix eliminate cold to stop pain.
Saposhnikoviae, pine nodular
branch, Ramulus mori,
zaocys dhumnade, Flos
Carthami, Resina Olibani.
Borneol, etc.
a
Tian Ma Pill Rhizoma Gastrodiae, Radix Dispel wind and eliminate CFDA
Zhuang Gu Angelicae Dahuricae, dampness, promote blood
Wan Leopard bone, Ginseng, circulation, reinforce liver
Herba Asari, Cornu cervi and kidney, strengthen the
pantotrichum, Cortex lumbus and knees,
Eucommiae, Cortex indicated for the
Acanthopanacis, Radix rheumatism, headache,
Gentianae dizziness, rheumatism
Macrophyllae,Herba pain, lumbar debility,
Siegesbeckiae, Radix numbness of limbs.
Saposhnikoviae, Radix
angelica sinensis, Rhizoma
Ligustici Chuanxiong,
Radix Stephaniae Tetrandrae,
Ramulus Mori, Radix
Angelicae Dahuricae,
Ligusticum sinense Oliv,
Rhizoma seu Radix
Notopterygii, Geranium
wilfordii, Hedera Helix.
a
Tian Ma Xing Capsule Rhizoma Nourish liver and kidney, CFDA
Nao Jiao Gastrodiae ,Pheretima, dredge the meridians and
Nang Rhizoma Acori Tatarinowii, relieve pain, indicated for
Radix Polygala, Radix headache, dizziness,
Rehmanniae Preparata, memory loss, insomnia,
Herba Cistanche unresponsive, tinnitus and
lumbar acid caused by
kidney deficiency.
a
Qiang Li Tian Pill, Rhizoma Gastrodiae, Cortex Expel the wind and CFDA
Ma Du Zhong capuse Eucommiae, Radix angelica promote blood circulation,
Wan sinensis, Rhizoma seu Radix relieve swelling and pain,
Notopterygii, Radix indicated for series of
Angelicae Dahuricae, Radix symptoms caused by
Rehmanniae, Radix stroke.
Cyathulae, Viscum
Coloratum,Radix aconiti
kusnezoffi preparata, Radix
Aconiti preparata,Ligusticum
sinense Oliv, Radix
Scrophulariae .

12
 a
Tian Ma Tou Pill,capsul Rhizoma Gastrodiae, Radix Nourish Yin and suppress CFDA
Feng Ling e, Achyranthis Bidentatae, Yang, dispel the wind,
Pian chewable Radix scrophulariae, strengthen muscles and
tablet Rhizoma rehmanniae, Radix bones, indicated for
Angelica sinensis Cortex stubborn headache,
Eucommiae, Rhizoma chronic lumbocrural pain,
Ligustici Chuanxiong, long-term numbness in the
Viscum Coloratum, Flos hands and feet.
Chrysanthemi Indici,
Ramulus uncariae cum uncis.
a
Ren Sen Tian Medicinal Rhizoma Gastrodiae, Tonify Qi and promote CFDA
Ma Yao Jiu liquor Ginseng, Radix Astragali, blood circulation, relieve
Radix Cyathulae, Rhizoma swelling and pain,
Dioscoreae Nipponicae, Flos indicated for all kinds of
Cartham. joint pain, waist and leg
pain, numbness of limbs.
a
Cited from the website: http://www.sda.com.cn (The website of China Food and
Drug Administration)

3. Phytochemistry
Up to now, many chemical components (Table 3), for instance, gastrodins,
4-hydroxybenzyl alcohols, vanillyl alcohols, vanillins, polysaccharides, sterols and
orgnic acids, have been isolated from G. elata. Among them, gastrodin and its
aglycone gastrodigenin (4-hydroxybenzyl alcohols) are considered as the
characteristic and main active constituents of G. elata. The content of total phenolics
in G. elata was detected by using the method of Folin-Ciocaileu colorimetry, and
found that total phenols reached 0.0485% (Xiong et al., 2013). The polysaccharides
content of G. elata produced in Yunnan province of China was determined by the
phenol-sulfuric acid method, and showed that the highest content was 21.6% (Wang et
al, 2011). In addition, the detection results for gastrodin, amino acid and total
flavonoids demonstrated that their biggest contents were 0.24%, 1.92% and 0.24%
respectively (Cheng et al., 2009). Other chemical constituents derived from G. elata
have not been determined (Fig.2).

1. Total phenolics (0.0485%)

2. Total polysaccharides (21.6%)
3. Total flavonoids (0.235%)
4. Total amino acids (1.92%）
5. Gastrodin (0.240%)
6. β-sitosterol (0.113%)
7. Not determined (77.8%)

13
 90
80
70
60
50
40
30
20
10
0
1 2 3 4 5 6 7

Fig. 2 Contents of the chemical components from G. elata

Table 3 The compounds isolated from G. elata

Classification No. Chemical component Part of plant References
Phenolics 1 Parishin Rhizome Lin et al.(1996）
2~3 Parishin B~C Rhizome Lin et al.(1996）
4~5 Parishin D~E Rhizome Yang et al.(2006）
6~7 Parishin F~G Rhizome Wang et al.(2012）
8~23 Parishin H Rhizome Li et al.(2015)
24 Vanillin Rhizome Kim et al. (2007)
25 Vanillyl alcohol Rhizome Kim et al.((2011)
26 Gastrodigenin Rhizome Choi et al.(2006)
27 4-hydroxybenzyl methy lether Rhizome Taguchi et al.(1981)
28 (4-methoxyphenyl)methanol Rhizome Rohmann et al.(1961)
29 Benzyl alcohol Rhizome Jang et al.(2010)
30 4-hydroxy-3-methoxybenzoic acid Rhizome Jang et al.(2010)
31 4-hydroxybenzyl alcohol Rhizome Noda et al.(1995)
32 4-hydroxybenzaldehyde Rhizome Noda et al.(1995)
33 4-hydroxybenzyl ethyl ether Rhizome Yang et al.(2006）
34 4-(4’-hydroxybenzyl)phenol Rhizome Yang et al.(2006）
4-[4'-(4"-hydroxybenzyloxy)benzyloxy]benzyl Hye et al.(1998）
35 Rhizome
methyl ether
36 1-furan-2-yl-2-(4-hydroxyphenyl)-ethanone Rhizome Lee et al.(2007)
5-(4-hydroxybenzyloxymethyl)-furan-2-carbaldeh Lee et al.(2007)
37 Rhizome
yde
38 2,4-Bis(4-hydroxybenzyl)phenol Rhizome Han et al.(2011)
5-[4'-(4"-hydroxybenzyl)-30-hydroxybenzyloxyme Huang et al.(2014)
39 Rhizome
thyl]-furan-2-carbaldehyde
40 4-butoxyphenylmethanol Rhizome Rohmann et al.(1961)
41 4,4'-methylenediphenol Rhizome Ma et al.(2015)
42 4,4'-sulfinylbis(methylene) diphenol Rhizome Yun et al.(1997)
43 4,4'-Dihydroxybenzyl sulfone Rhizome Mi et al.(2004)
44 Bis(4-hydroxybenzyl)sulfide Rhizome Huang et al.(2007)
45 4-(ethoxymethyl)-glucopyranosyl-phenol Rhizome Ma et al.(2015)
46 4-O-glucopyranosyl-benzaldehyde Rhizome Ma et al.(2015)
47 Gastrodin Rhizome Baek et al.(1999)
48 Gastrodin A Rhizome Li et al.(2007)

14
 49 Gastrodin B Rhizome Zhang et al.(2013)
50 Gastrol A Rhizome Li et al.(2007)
51 Gastrol B Rhizome Zhang et al.(2013)
52 5- hydroxymethyl-2-furancarboxaldehyde Rhizome Mi et al.(2004)
53 Cirsiumaldehyde Rhizome Yun et al.(1997）
54 p-Ethoxymethyl phenyI-O-β-D-glucoside Rhizome Huang et al.(2006）
55 N-(p-hydroxybenzyl)-adenosine Rhizome Huang et al.(2006）
56 N6-(4-hydroxybenzyl)adenine riboside Rhizome Huang et al.(2007)
N6-(3-methoxyl-4-hydroxybenzyl) adenine Shi et al.(2014)
57 Rhizome
riboside
1-furan-2-yl-2-(4-hydroxy-phenyl)-ethane-1, Li et al.(2014）
58 Rhizome
2-dione
4-hydroxy 3 - 4-hydroxybenzyl) benzyl methyl Wang et al.(2012）
59 Rhizome
ether
Polysaccharid Qiu et al.(2007）
60 AGEW Rhizome
es
61 WGEW Rhizome Qiu et al.(2007）
62 WSS25 Rhizome Chen et al.(2007）
63 WSS45 Rhizome Tong K et al.(2010）
64 Adenosine glucoside Rhizome Wang et al.(2007）
65 Gastrodin isomer Rhizome Wang et al.(2007）
4-(methoxymethyl) Wang et al.(2012）
66 Rhizome
phenyl-1-O-β-D-glucopyranoside
67 Trimethylcitryl-b-D-galactopyranoside Rhizome Choi et al.(2006）
68 5-(hydroxymethyl)-furfural Rhizome Ishida et al.(1996）
69 5-(hydroxymethyl)-2-furaldehyde Rhizome Huang et al.(2014）
Sterols 70 β-sitosterol Rhizome Lee et al.(2007）
71 β-sitosterol glucoside Rhizome Lee et al.(2007）
72 3-O-(4'-Hydroxybenzyl)-13-sitosterol Rhizome Yun et al.(1998）
Organic acids 73 L-pyroglutamic acid Rhizome Hao et al.(2000）
74 6-methyl citrate Rhizome Hao et al.(2000）
75 1,5-dimethyl citrate Rhizome Hao et al.(2000）
76 Docosanoic acid oxiranylmethyl ester Aerial Part Liu et al.(2002）
Other Hao et al.(2000）
77 Gastrodamine Rhizome
components
78 N2-(p-hydroxybenzyl) guanosine Rhizome Wang et al.(2009）
79 P-hydroxybenzyl guanosine Rhizome Wang et al.(2007）
80 P-hydroxybenzyl adenosine Rhizome Wang et al.(2007）
81 S-(4-hydroxybenzyl)glutathione Rhizome Andersson et al.(1995）

3.1. Phenolics and its glycosides

G. elata contains several of ingredients that have previously been characterized.

Biological and biochemical activities of these constituents are investigated in lots of assays.
Recent studies have confirmed the presence of abundant phenolics in G. elata, which have
been thought to be the active components of this botanical drug. According to the
structures (Fig. 3), these compounds have a unique structure with variants of
4-hydroxybenzyl alcohol with gastrodin (Zhou et al., 1979) and 4-hydroxybenzyl alcohols
(4-HA) as principal active constituents. Gastrodin is the phenolic glucoside of 4-HA and is
chosen as one of the standard compounds to evaluate the quality of G. elata and G. elata
-including preparations due to its extensive pharmacological actions and unique

15
mechanisms. The phenolics constituents were reported to have prominent neuroprotective,
anti-inflammatory, anti-oxidant actions and many others (Lee et al., 2012a; Han et al., 2014;
Sun et al., 2012).

O OH
O OH
CH2 O O
C O OH CH2 O O
OH C O OH
H2C O
OH H2C O OH
OH
HO C C O CH2 O O OH OH
OH HO C C O CH2 O O
H2C OH OH
C O OH OH H2C OH
CH2 O O COOH OH
O OH
OH
OH

1 2

O OH
O
CH2 O O
CH2 OH
C O OH
OH C O
H2C
H2C
OH
HO C COOH
HO C COOH

H2C
OH H2C
C O
C O
CH2 O O
O OH CH2 OH
O
OH
OH
3 4
O OH
CH2 O O
C O OH
H2C OH
OH
HO C COOH

H2C
COOH
5
O OH
OH
CH2 O O
OH O
C O
OH OH
H2C O
OH
OH O
OH
HO C C O CH2 O O
OH
H2C OH
C O OH OH

CH2 O O
O OH
OH
OH
6
COOH O OH
H2C O CH2 O O
OH C O OH
HO C C O CH2 O H2 C O OH
O
OH OH OH
H2C OH HO C C O CH2 O O
COOH OH
OH
H2 C 16 OH
COOH OH
OCH3
 7 8

O OH
CH2 O O OH
C O OH O
O OH
H2 C O
OH
OH OH
OH
HO C C O CH2 O O
OH
H2 C OH
COOH OH
9 OCH3

O OH
COOH CH2 O O
H2C O OH
C O
OH OH
H2C O
HO C C O CH2 O O OH OH
OH
HO C C O CH2 O O
H2C OH
OH
C O OH OH
OCH3 H2C
CH3 C O OH
O
CH3
10 OCH3 O 11

OH O OH
O
CH2 O O CH2 O O
OH C O OH
C O
OH H2C OH
H2C O
OH OH OH
HO C C O CH2 O O HO C COOH
OH
H2C OH H2C
OH C O OH
C O OH
CH2 O O CH2 O O
O OH
O OH
OH
OH
OH
OH
12 13

O OH O
CH2 CH3
O O
C O OH C O
H2C O OH H2C O
OH
OH
HO C C O CH2 O O
HO C C O CH3
OH
H2C OH
H2C
C O OH
C O
CH3
CH3 O
O
14 15

O OH
OH
CH2 O O OH
OH O
OH O
C O OH
O
H2C O O
OH
OH OH
OH
HO C C O CH3
17
H2C
C O
CH3
O
 16

O
CH3
C O
H2C O
OH
OH
HO C C O CH2 O O OH
OH O
OH O
O OH
H2C O
OH
C O OH OH
OH
CH3
O
17

O OH
CH2 O O
C O OH
H2C O OH
OH OH
HO C C O CH2 O O
OH
H2C OH
C O OH OH
CH2 OCH2 O O
O OH
OH
OH

18

O OH
CH2 O O
C O OH
H2 C O OH
OH OH
HO C C O CH2 OCH2 O O
OH

H2 C OH
C O OH OH

CH2 O O
O OH
OH
OH

19

O OH OH
O
CH2 O O CH2 O O
C O OH OH
C O
H2C O OH OH
H2C O
OH OH OH
HO C C O CH2 OH HO C C O CH2 O O
OH
H2C H2C OH
C O OH C O OH
CH2 O O CH2 OH
O OH 18
O
OH
OH
 20 21

O OH
CH2 O O
C O OH
H2C O OH
OH OH
HO C C O CH2 O O OH
OH O
H2C O OH
C O OH OH

COOH OH
O
22

COOH
H2C O CHO
OH
HO C C O CH2 O O
OH OH
H2C OH
C O OH
OCH3 HO
CH2 OH
O
OH OCH3

23 24 25

CH2OH OH
CH2OH

HO

OCH3

OCH3
OH

26 27 28 29

COOH CH2OCH2 CH3

HO HO

OH O
H3CO

OH OH
H

30 31 32 33

HO H2C OH

34

HO CH2O CH2O CH2OCH3

19
 35

OH O
O O
O
O
H

OH
36 37

O CHO

HO HO OH

HO OH

38 39

HO OH
O

HO

40 41

HO OH HO OH
O
O O

S
S

42 43

OH O
HO CH2SH2C OH
O
HO
HO O
HO

44 45

OH
H O
O
OH
HO O
HO
HO
O O
HO
OH OH
CH2 OH O
O
O OH
HO OH
HO O HO
HO CH2OH
OH

46 47 48

20
 OH

O
HO OH
HO O
HO

49

HOH2C O

OH OH

50
OH

HO O
HO H

O
O
O

51 52

H H HO

O O

O O OH
O O O

OH

53 OH 54

N
OCH3
N NH
HN
OH
HO
O N
N N N OH

HO N
N
O
HO
OH

55 OH OH 56

HO
NH
21
N
N

N
N
 OH
O

57 58

HO HO

59
Fig.3 The structures of phenolics from G. elata.

3.2. Polysaccharides

Apart from above-mentioned phenolics and its glycosides (Fig. 4),

polysaccharides are also a class of important ingredient of G. elata due to their certain
pharmacological activities. Recently, more than ten kinds of polysaccharides have
been discovered, such as GE-I, GE-II, WGEW, AGEW (Qiu et al., 2007), GBP-I and
GEP-I. Its main structure is 1→6 keyed branched chain of α-(1→4)-D-glucan, GPSa,
and GBII (Hong et al., 2010), and most of these polysaccharides contain
α-(1→4)-D-glucan. Some of them have been evidenced to have anti-dengue virus
bioactivities (Tong et al., 2010; Qiu et al., 2007). What is more, some
structure-activity relationship study has been conducted, demonstrating that the
glycoside from Gastrodia possesses inhibitory activity on GABA transaminase which
degrades GABA (γ-aminobutyric acid), a major CNS inhibitory neurotransmitter
(Choi and Lee, 2006) and has anti-angiogenesis effect (Chen et al., 2012).
HO
HO
OH
OH

OR
OR
HO
O HO
O

O
O
OH
OH

OR
OR
HO
O HO
O

x
x
O
O
OR
OR
O
O O
O O O
O O O
HO HO O
OH HO HO
OH OH
OH
y n y n
H(x+y=14)
H(x+y=16)

22
 60 61

HO HO
OH OH

OR OR

HO HO
O O

O O
OH OH

OR OR

HO HO
O O

x x
O O
OR OR
O O
O O
O O O O
O O
HO HO HO HO
OH OH
OH OH
y n y n
R=SO or H(x+y=16) R=SO32- or H(x+y=16)

62 63

OH
O O NH2
OH
OH
OH N O
N O
OH
OH

N HO OH
N O OH
HOH2C

OH
OH
64 65
O
HO
O
C O CH 3
HO O OH
HO OH O
HO
O
O C C O CH3
O HO
O
OH
66 67 C O CH3
O

O O CHO
OH
H HO

68 69
Fig.4 The structures of polysaccharides from G. elata.

23
3.3. Sterol and organic acids

There are relatively few reports on sterol and organic acids constituents in G. elata
(Fig. 5). Organic acids include citric acid, succinic acid (Zhou et al., 1979), palmitic
acid (Wang et al., 2003), L-pyroglutamic acid, 6-methyl citrate, 1,5-dimethyl citrate
(Hao et al., 2000), M-hydroxyhenzoic acid, syringic acid, protocatechu acid (Wu et al.,
2013) and citric acid mono-ethyl ester (Wang et al., 2009). Sterols contain β-sitosterol,
4-hydroxy benzyl-β-sitosterol, daucosterol (Wang et al., 2006) and
3-O-(4'-hydroxybenzyl)-β-sitosterol (Yun-Choi et al., 1998). Perhaps due to it's low
content in G. elata, its pharmacological action has been little investigated.

O
H2C COOH
O H2C C O CH3
O N COOH HO C C O CH3
HO C COOH
H H 2C COOH
H2C C O CH3

70 71 72

O
O
CH3CH2(CH2)17CH2CH2 C OCH2 HC CH2

HO

73 74

OH
O O

OH
OH
OH HO CH2O

75 76

Fig.5 The structures of sterol and organic acids from G. elata.

24
3.4. Other compounds

In addition, many other constituents (Fig. 6) were isolated from G. elata, such as
4-(methylsulfinylmethyl) phenol, dioctyl phthalate, grossamide (Wang et al., 2013),
4-thoxybenzyl alcohol, anisic alcohol, bis (3, 4-dihydroxyphenyl) methane,
4-(methoxymenthyl) benzene-1, 2-diol (Duan et al., 2013) and gastrodamine
[di-(p-hydroxyl benzyl) hydroxylamine] (Hao et al., 2000). Chitinase and β-1,
3-glueanase, isolated and purified from the primary corn of G. elata, are shown to
have the activity of inhibiting the growth of Trichoderma viride (Yang and Hu, 1990).
What’s more, S-(4-hydroxybenzyl) glutathione was isolated as the major principle
responsible for inhibition of the in vitro binding of kainic acid to brain glutamate
receptors by water extracts of G. elata (Andersson et al., 1995). Furthermore,
gastrodin antifungal proteins (GAFPs, also known as gastrodianins) isolated from the
cortex of the terminal corm of G. elata show a strong fungistatic activity against a
broad spectrum of fungi (Hu et al., 1988; Hu et al., 1994; Hu et al., 1999).
G. elata also contains adenine, adenine nucleoside, AmD2-9, AmD2-20, AmD2-28
and many kinds of amino acids. (Xie et al., 2004). Among trace elements, the content
of Fe in G. elata is the highest, followed by Cr, Zn, Mn, Cu, and Se. These essential
trace elements have the effects to delay aging and prevention and control of diseases
(Fan et al., 1991a; Fan et al., 1991b; Li et al., 2015). Some phenolic components are
separated from the fresh G. elata as well, such as, gastrodin,
4-hydroxybenzenemethanol, p-hydroxy benzaldehyde, 4,4'-dihydroxy-Biphenyl
methane, 4, 4'-dihydroxy-dibenzyl ether, 3,4-dihydroxy-benzaldehyde,
4-ethoxymethyl phenyl, 4'-hydroxy benzyl ether, 4-ethoxymethyl phenol and parishin
( Zhou et al., 1979; Zhou et al., 1980a; Zhou et al., 1980b; Zhou et al., 1981). Among
them, gastrodin and 4-hydroxybenzenemethanol, can produce strong sedative and
hypnotic effects (Deng and Mo, 1979; Deng and Mo, 1980).

HO CH2 N CH2 OH

OH
77

O
O

N
N HN
N

N
H2N HO CH2 H2N N
H3CO N O
N
O HOH2C
H2C

HO

OH
OH
OH
OH

78 79

HO
HO CH2 NH2

25
N
N

S
N O H
N
O
 80 81

Fig.6. The structures of other compounds from G. elata.

4. Pharmacological activities

4.1. Sedative and hypnotic activities

Up to date, only two active ingredients, N6-(4-hydroxybenzyl) adenine riboside

(NHBA, 0.2, 1 and 5 mg/kg i.p.) and its analog N6-(3-methoxyl-4-hydroxybenzyl)
adenine riboside (B2, 1 or 5 mg/kg, i.p.), isolated from G. elata, are reported to have
significant sedative and hypnotic effects. Further study showed that the molecular
mechanism of action for NHBA might be closely related to the activation of
adenosine A1/A2A receptors and stimulation to the sleep center in the ventrolateral
preoptic area (VLPO) (Zhang et al., 2012), but the molecular mechanism of B2
remains to be determined (Shi et al., 2014).

4.2. Antiepileptic and anticonvulsive activities

The aqueous extracts of G. elata can regulate the activator protein 1 (AP-1)
expression, thus to further modulate the neuronal plasticity and apoptosis, via the JNK
signaling pathway in KA-induced epilepsy (Hsieh et al., 2007). At the same time, the
methanol extract of G. elata was shown to inhibit the recovery time and severity of
PTZ-induced convulsion rats, and this action might be realized by increasing the
GABA content of brain (Hsieh et al., 2007). In addition, 4-hydroxybenzaldehyde
(4-HBA), a kind of active component of G. elata, demonstrated an anti-oxidative
effect and positive modulation of GABA, which contributes to its antiepileptic and
anticonvulsive activity (Ha et al., 2000)

4.3. Anti-anxiety and antidepressant activities

Oral administration of aqueous G. elata extract or injection of its phenolic

constituents, 4-HA and 4-HBA, can significantly increase the percentage of the time
spent and arm entries into the open arms of the elevated plus maze (EPM) in mice.
This observation suggests that they possess the anxiolytic-like effects (Jung et al.,
2006). Furthermore, 75% ethanol extract of G. elata exerted antidepressant-like effect

26
comparable to that of fluoxetine in an experimental animal model (Zhou et al., 2006);
the Slit−Robo pathway and neuronal cytoskeleton remodeling are possibly key
players associated with the antidepressive-like effect of G. elata (Lin et al., 2014). At
the same time, in a forced-swimming test (FST), G. elata showed antidepressant-like
effect; the possible mechanism might be via regulating both the serotonergic and
dopaminergic systems (Chen et al., 2009) or modulating the turnover of DA in rats
(Chen et al., 2012).

4.4. Neuroprotective activities

4.4.1. Protection of neuronal cells and anti-apoptoticaction activities

Both in vitro and in vivo studies of G. elata extracts or its ingredients on the
neuroprotective activities had been conducted in the past few years. In an in vitro
experiment, chloroform, methanol or ethanol extracts of G. elata, as well as the pure
compounds gastrodin and 4-HBA, were shown to protect against β-amyloid insult,
which is one of the major recognized causes for the onset of AD. It was also reported
that G. elata has a protective effect on pheo-chromocytoma cells (PC12), primary
neuronal cells and BV2 microglia cells; the protective mechanism to BV2 microglia
cells is suggested to be the induction of the chaperone ER stress protein GRP78 (Lee
et al., 2012a; Kim et al., 2007a; Kim et al., 2011a). Furthermore, 50% alcohol extract
of G. elata has a protective effect against neuronal damage in kainic acid-treated rats
by reducing neuronal nitric oxide synthase, microglia activation and apoptosis (Hsieh
et al., 2005). Not only organic solvent extracts but also the aqueous extracts of G. elata
were shown to reduce the β-amyloid-induced neurotoxicity through inhibition of
apoptosis and reduction of oxidative stress in both Drosophila and PC12 Cells (Ng et
al., 2013). These results strongly suggest that G. elata could be further developed as a
promising herbal agent for neuroprotection and novel adjuvant therapies for
Alzheimer’s disease.
In addition, gastrodin, an active ingredient from G. elata, could induce heme
oxygenase-1 (HO-1) expression through activation of p38 MAPK/Nrf2 signaling
pathway, thus protecting human dopaminergic SH-SY5Y cells from
1-methyl-4-phenylpyridinium MPP+-induced oxidative cytotoxicity (Jiang et al., 2014)
and up-regulating the decreased striatal dopamine (DA) content in IDPN-induced rats
and down-regulating the elevated striatal DA content in apo-induced rats (Zhang and
Li, 2015). Moreover, gastrodin could significantly and dose-dependently protect
dopaminergic neurons against neurotoxicity to prevent dopamine depletion and
reduce reactive astrogliosis, and is also effective in preventing neuronal apoptosis by
attenuating antioxidant and antiapoptotic activities in these brain areas in
experimental PD models (Kumar et al., 2013). These results suggest that it has the
potential to be developed as a clinical drug to ameliorate PD symptoms of patients.
Other ingredients, such as vanillyl alcohol, was also found to protect
dopaminergic MN9D cells against MPP+-induced apoptosis by relieving oxidative
stress and modulating the apoptotic process (Kim et al., 2011b). Bis (4-hydroxybenzyl)
sulfide (BIS) and NHBA demonstrated the ability to prevent serum

27
deprivation-induced apoptosis in PC12 cells, in a concentration-dependent manner,
and the ability to bind the adenosine A2Areceptor (A2A-R) gene that is highly
expressed in GABA striopallidal neurons (Huang et al., 2007).

4.4.2. Anti-oxidative activities

It is found that methanol extracts from G. elata also possess a potent

neuroprotective effect against oxidative glutamate toxicity in HT22 cells through
up-regulating the function of PI3K signaling pathway in association with
brain-derived neurotrophic factor (BDNF), indicating that it may be a useful
therapeutic agent for the treatment of oxidative neuronal death (Han et al., 2014).
Furthermore, gastrodin (100 or 200 mg/ml) can effectively resist hypoxia-induced
neurotoxicity in cultured rat cortical neurons, and this mechanism may involve a
down-regulation of the extracellular glutamate level (Xu et al., 2007). In addition,
vanillin, 4-hydroxybenzyl aldehyde (4-HBAL) and 4-HBA can significantly inhibit
oxidative stress and excitotoxicity, and suppress neuronal death in CA1 region (Kim
et al., 2007b).

4.4.3. Protection of neuro-synaptic plasticity

The solution of G. elata in deionized water may promote neuro-regenerative

processes via controlling chaperone/proteasomal degradation pathways (such as
CALR, FKBP3/4, HSP70/90) (Ramachandran et al., 2012). Moreover, it also
exhibited a significant inhibition on stress-related proteins and neuroprotective genes
such as Nxn, Dbnl, Mobkl3, Clic4, Mki67 and Bax with various regenerative
modalities and capacities related to neuro-synaptic plasticity (Manavalan et al., 2012a)
and protected against lead-induced impairments on synaptic plasticity in the
hippocampal CA1 region, like LTP, PPF, and I/O functions (three electrophysiological
parameters for evaluation of synaptic plasticity) (Yong et al., 2009).

4.5. Anti-cardio-cerebral-vascular diseases activities

G. elata also played an important role in the protection against cerebral ischemia.
The water extract of G. elata was found to contribute to the improvement of synaptic
plasticity and neurorestorative processes by regulating the brain proteome (Manavala
et al., 2012b), and thus might be beneficial to neurodegenerative diseases.
As one of the main effective constituents of G. elata, gastrodin was demonstrated
to markedly decrease the infarct volume and edema volume, improve the neurological
functions on cerebral ischemic injury in rats caused by transient middle cerebral
arterial occlusion (MCAO) and also significantly inhibit oxygen/glucose deprivation
(OGD) and glutamate-induced neuronal cell death and reduce the extracellular
glutamate level following OGD. Moreover, it can significantly inhibit the increase of
OGD-induced Ca2+ and NO (Zeng et al., 2006). Meanwhile, 4-HA, the aglycone of
gastrodin, can reduce cerebral infarct volumes in a murine model of focal brain
ischemia/reperfusion (Elodie et al., 2009). It also ameliorated ischemic injury induced

28
by transient focal cerebral ischemia in rats, and this neuroprotective effect may partly
relate to attenuating apoptosis pathway (Yu et al., 2009). In addition, p-hydroxybenzyl
alcohol (p-HBA) was found to protect against brain damage by modulating
cytoprotective genes, for instance, protein disulphide isomerase (PDI), nuclear
factor-E2-related factor2 (Nrf2), and neurotrophic factors (Kam et al., 2011).

4.6. Antipsychotic activities

5-HT1A receptor has been recently regarded as an important therapeutic target of

schizophrenia. GR extract was demonstrated to affect phencyclidine (PCP)-induced
abnormal behavior in mice, which may be mediated via activation of 5-HT1A receptor
(Shin et al., 2011). As one of the main effective constituents of G. elata, parishin C
also showed high affinity with 5-HT1A receptor as a 5-HT1A-agonist in an
8-OH-DPAT–stimulated [35S] GTP-γS binding assay (Shin et al., 2010).

4.7. Anti-vertigo activities

It was demonstrated that polysaccharides of G. elata could improve food intake of

vertiginous mice caused by machinery rotation, and also obviously shorten the
escaping time of electrical shock in maze experiment and jumping platform test (Lei
et al., 2006). However, the exact molecular mechanisms of their actions still remain to
be determined.

4.8. Effect on circulatory system

4.8.1. Anticoagulant and antithrombotic activities

Gastrodin has anticoagulant activity and the mechanism mainly involves its
interference with the knob-to-hole interactions between fibrin molecules, thereby
effectively inhibiting the formation of clots and decreasing the risk of thrombosis (Liu
et al., 2006). Futhermore, polysaccharide 2-1 from G. elata has remarkable effects of
anticoagulation and antithrembosis (Ding et al., 2007). This result suggested that it
may be one of the main components from G. elata for antithrombosis.

4.8.2. Anti-atherosclerotic activities

It was found that the ethanol extract of G. elata can suppress the endothelial
extracellular matrix degradation induced by tumor necrosis factor (TNF)-α, and
decrease TNF-α-induced increase of matrix metalloproteinase (MMP)-2/-9 activities
(Jung et al., 2009). These observations provide new insights into the
pathophysiological mechanisms for the anti-atherosclerotic properties of G. elata in
vascular diseases.

4.8.3. Antihypertensive activities

It was evidenced that acidic polysaccharides isolated from G. elata could reduce

29
hypertension and improve serum lipid levels in spontaneously hypertensive rats (SHR)
produced by a high-fat diet (Lee et al., 2012b), but the mechanism of this effect still
remains to be further studied.

4.9. Anti-inflammatory and analgesic activities

Phenolic compounds are a kind of important component that can be extracted

from G. elata and possess anti-inflammatory and analgesic properties via inhibiting
COX activity. It was also demonstrated that both C-4 hydroxy and C-3 methoxy
radicals of benzyl aldehyde from G. elata play an important role in anti-inflammatory
effects (Lee et al., 2006). Moreover, the ethanol extract of G. elata was found to
inhibit NO production in vivo and in vitro as well as the mRNA expression of
inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) upon
stimulation by lipopolysaccharide (LPS) in RAW264.7 macrophages (Ahn et al.,
2007). At the same time, it could also suppress TNF-α-induced vascular inflammatory
process via inhibition of oxidative stress and NF-κB activation in HUVEC (Hwang et
al., 2009), presenting anti-angiogenic, anti-inflammatory and analgesic activities. In
addition, gastrodin was shown to decrease sodium currents and enhance potassium
currents in diabetic small DRG neurons (Sun et al., 2012). These results indicate that
it may be effective in the treatment of painful diabetic neuropathy (PDN).

4.10. Improve memory and anti-aging activities

Oral administration of G. elata powder mixed with drinking water can effectively
improve memory functions and normalize GABA levels in rats exposed to AlCl3
suffering from deficits in learning and memory, accompanied by increase in GABA
levels in the neocortex (He et al., 2008). But, it might not decrease the content of
brain cortex aluminum of rats (Niu et al., 2004) though could ameliorate the learning
and memory deficits induced by forced swimming (Chen et al., 2011). In addition,
gastrodin was found to improve memory impairments in the Morris water maze test
and probe test, and attenuate Aβ deposition and glial activation in brains of mice (Hu
et al., 2014), suggesting that gastrodin exerted neuroprotective activity via
anti-inflammatory and anti-amyloidogenic effects.
It was evidenced that the antioxidant effect of G. elata extract in the rat brain,
another important biological function of the herb, may result from the actions of
p-HBA and other phenolic compounds such as vanillin at the cellular and molecular
level (Liu and Mori, 1993). The order of antioxidation potency was as follows:
hydroxybenzyl alcohol > vanillyl alcohol > vanillin > hydroxybenzaldehyde (Jung et
al., 2007). Thus G. elata and its main constituents may have a potential in treating
neurological disease through the inhibition on lipid peroxidation in the brain.

4.11. Antivirus and antitumor activities

Two glucans, WGEW and AGEW, isolated from G. elata and its sulfated derivatives
(such as WSS25 and WSS45) were all shown to have strong anti-dengue virus

30
bioactivities. However, the study on structure-activity relationships (SAR) between
the polysaccharides and their sulfated derivatives showed that the higher the degree of
substitution is, the more potent the impact on the dengue virus infection would be
(Qiu et al., 2007; Tong et al., 2010). Furthemore, G. elata extract may have the
potential to alleviate tumorigenesis by a GTP-Ras-dependent pathway (Heo et al.,
2007); although the precise molecular mechanisms are still unclear. Another study
demonstrated that gastrodin could promote NF-κB-mediated gene transcription in
CD4+ T cells that is implicated in its anticancer immunomodulatory properties (Shu
et al., 2013). However, further studies are required to determine its specific anticancer
actions.

4.12. Other pharmacological activities

Besides above-mentioned activities, G. elata has been shown to exert other

pharmacological effects. In a study on anti-huntingtin aggregations, 70% methanol
extracts of G. elata was demonstrated to prevent mutant huntingtin aggregations in
PC12 cells in a model of Huntington's disease (HD) and was demonstrated to increase
proteasomal activity by targeting the A2A-R through protein kinase A
(PKA)-dependent pathway (Huang et al., 2011). Studies on laboratory mice have
shown that 30% methanol extract of G. elata protects the gastric mucosa against water
immersion restraint (WIR)-induced gastric damage, at least in part by decreasing NO
levels via suppression of iNOS mRNA expression (Park et al., 2007). Gastrodin was
also found to prevent steroid-induced osteonecrosis of the femoral head in rats by
anti-apoptosis and was found to protect against osteoporosis linking to a reduction in
reactive oxygen species (Zheng et al., 2014; Huang et al., 2014). Another study found
that gastrodin has a protective potential in targeting cardiac hypertrophy and fibrosis
through suppression of ERK1/2 signaling (Shu et al., 2012). Besides, BIS, isolated
from G. elata was found possessing anti-melanogenesis ability (Chen et al., 2015).
Furthermore, the C-4 hydroxy and C-3 methoxy radicals in benzyl alcohols and
aldehydes (such as 4-hydroxy-3-methoxybenzyl alcohol,
4-hydroxy-3-methoxybenzoic acid, etc.) play important roles in mediating the
anti-asthmatic activities of phenolic compounds obtained from the dried roots of G.
elata (Jang et al., 2010). In a recent study, water and ethanol extracts of GR were
demonstrated to ameliorate dyslipidemia, hypertension, and insulin resistance. Thus it
may be a beneficial therapeutic approach for metabolic syndrome (Kho et al., 2014;
Teong et al., 2011). It was also found that the water extract mainly reduced insulin
resistance as a result of the action of 4-HBA and vanillin contained in G. elata (Park et
al., 2011).
All in all, the experimental results that G. elata has remarkable effects on nervous
system, cardiocerebral vascular system and blood circulation system have powerfully
supported the traditional use of it as a neuroprotective, sedative, hypnotic,
anti-epileptic, anti-convulsive, anti-anxiety, anti-depressant and blood circulation
regulating herbal medicine. Furthermore, besides its traditional use for nervous
system, modern pharmacological experiments have shown more other activities, such
as anti-tumor, anti-virus, memory-improving, anti-aging, etc. Although the
31
 mechanisms of some of these activities have not been fully clear, there has already
been a clue that the therapeutic effectiveness of G. elata on a variety of disorders is
somewhat based on its wide-reaching biological activities.

Table 4 Bioactivities of the extracts and compounds from G. elata.

Pharmacological Extract/Compound Types Testing subjects Dose Effects References

activities
N6-(3-methoxyl-4-hyd in vivo male ICR mice 1, 5 mg/kg shortened the sleep Zhang et al.,
Sedative and roxybenzyl) adenine i.p. latency, prolonged 2012
hypnotic activities riboside (B2) NREM sleep and
shortened wakefulness

N6-(4-hydroxybenzyl) in vivo adult male ICR 0.2, 1, 5 decreased wakefulness Shi et al., 2014
adenine riboside mice-treated with mg/kg time and increased
(NHBA) sodium i.p. NREM sleep time
pentobarbital
aqueous extracts of G. in vivo male SD rats 0.5, 1.0 regulated the AP-1 Hsieh et al.,
elata –treated with kainic g/kg/day expression via the JNK 2007
Antiepileptic and
acid (KA) for 2 signaling pathway
anticonvulsive
weeks
activities
p.o.

4-HBA in vivo male SD rats 500 mg/kg inhibited the recovery Ha et al., 2000
–treated with p.o. time and severity,
pentylenetetrazole increased the brain
(PTZ) GABA contents

Anti-anxiety and aqueous extracts of G. in vivo elevated plus maze 50, 100, increased the percentage Jung et al.,
antidepressant elata (EPM) in male ICR 200, 400 of time spent and arm 2006
activities mice mg/kg p.o. entries into the open
arms of the EPM
4-HA in vivo the same as above 5, 10, 25, the same as above Jung et al.,
50, 100 2006
mg/kg i.p.

4-HBA in vivo the same as above 5, 10, 25, the same as above Jung et al.,
50, 100 2006
mg/kg i.p.
75% ethanol extracts in vivo behavioral models 100, 200, reduced the immobility Zhou et al.,
of G. elata of male kunming 300 mg/kg duration in FST and TST 2006
mice p.o.
aqueous extracts of G. in vivo male SD rats 500 mg/kg down-regulated Lin et al., 2014
elata p.o. Slit-Robo pathway
mediating neuronal
cytoskeletal remodeling
processes
aqueous extracts of G. in vivo using 0.5, 1.0 regulated serotonin and Chen et al.,
elata forced-swimming g/kg p.o. dopamine concentration 2009
test as an animal and their metabolism
model of depression
(6 weeks old male
SD rats)
water extracts of G. in vivo 6 weeks old male 1.0 g/kg decreased the turnover Chen et al.,
elata SD rats p.o. of DA in striatum 2012

Neuroprotective
activities

32
Protection of chloroform, methanol in vitro BV2 mouse 1 mg/ml against Lee et al.,
neuronal cells and or ethanol extracts of microglial cells- β-amyloid-induced cell 2012a; Kim et
anti-apoptotic G. elata, gastrodin, or treated with death, possibly through al., 2007a;
activities 4-HBA β-amyloid the enhancement of Kim et al.,
protein folding 2011a
machinery of a
representative protein,
GRP78, and the
regulation of CHOP in
BV2 mouse microglial
cells
50% alcohol extracts in vivo adult male SD 0.5, 1.0 mediated the suppression Hsieh et al.,
of G. elata rats-treated with g/kg of nNOS and microglia 2005
KA injection p.o. activation
aqueous extracts of G. in vivo drosophila 1 , 5 mg/g upregulated the Ng et al., 2013
elata and in and PC12 cells- 250-1000 enzymatic activities of
vitro treated with µg/ml catalase, superoxide
β-amyloid dismutase, and
glutathione peroxidase

gastrodin in vitro human 1, 5, up-regulated heme Jiang et al.,

dopaminergic 25 µM oxygenase-1 (HO-1) 2014
cells-treated with expression through
MPP+ activation of p38
MAPK/Nrf2 signaling
pathway
gastrodin in vivo Wistar rats (male, 4 20 increased the Zhang and Li,
weeks old)-treated mg/kg/day down-regulated striatal 2015
with apomorphine intraperito DA content in
(Apo) neal IDPN-induced rats,
injection decreased the
up-regulated striatal DA
content in Apo-induced
rats
gastrodin in vitro six-week-old male 10, 30, 60 prevented the ROS Kumar et al.,
and in C57BL/6 mg/kg generation; augmented 2013
vivo mice and 1, 5, and SOD activity; regulated
human 25 µM Bax/Bcl-2 mRNA,
dopaminergic caspase-3, and cleaved
SH-SY5Y poly (ADP-ribose)
cells-treated with polymerase (PARP)
MPP+

vanillyl alcohol in vitro MN9D 10, 100, attenuated the Kim et al.,
dopaminergic 200 µg/m elevation of ROS levels, 2011
cells-treated with l decreased the Bax/Bcl-2
MPP+ ratio and poly
(ADP-ribose)polymerase
proteolysis
BIS and NHBA in vitro PC12 cell 1×10-10 to prevent serum Huang et al.,
ischemic/hypoxic -5
deprivation-induced 2007
model 1×10 M apoptosis in PC12 cells
and to bind A2A-R
Anti-oxidative methanol extracts of in vitro HT22 hippocampal 0.1 to 30 up-regulated the PI3K Han et al.,
activities G. elata cells-treated with g/ml signaling pathway and 2014
glutamate(5 mM) inhibited production of
ROS
gastrodin in vitro rat cortical neurons 100, 200 inhibited the Xu et al., 2007
treated with mg/ml extracellular glutamate
hypoxia level induced by NMDA
insult

33
 Vanillin, 4-HBAL and in vivo hippocampal CA1 40 mg/kg Suppressed neuronal Kim et al.,
4-HBA cell death i.p. death in CA1 region. 2007b
following global after global ischemia
ischemia
Protection of supernatant of in vitro human neuronal 1 mg/ml controlled Ramachandran
neuro-synaptic powdered Tianma in SH-SY5Y cells per well chaperone/proteasomal et al., 2012
plasticity water degradation pathways
(e.g. CALR, FKBP3/4,
HSP70/90) and
mobilized
neuro-protective genes
(such as AIP5) as well as
modulated other proteins
(RTN1/4, NCAM,
PACSIN2, and
PDLIM1/5)
supernatant of G. elata in vivo mouse neuronal 1 mg/ml inhibited stress-related Manavalan et
powder in water N2a cells per well proteins and mobilized al., 2012a
neuroprotective genes
such as Nxn, Dbnl,
Mobkl3, Clic4, Mki67
and Bax

gastrodin in vitro wistar rats on 50, 100, relieved LTP, PPF, and Yong et al.,
postnatal day 22 200, 400 I/O functions were 2009
mg/kg/d impaired in lead-exposed
intraperito rats
neally
injection
Anti-cardio-cerebr supernatant of G. elata in vivo one-year-old male 2.5 modulated the brain Manavala et
al-vascular powder in water Wistar Kyoto rats g/kg/day protein metabolism at the al., 2012b
diseases activities brain tissue for 3 proteome level
months
p.o.
phenolic glucoside in vitro transient middle 50, 100 inhibited the Zeng et al.,
gastrodin cerebral arterial mg/kg OGD-induced Ca2+and 2006
occlusion (MCAO) (intraperit NO increases
model and rat oneal
hippocampal injection)
neurons injuried 15, 30 µg
byoxygen/glucose /ml
deprivation (OGD)
or glutamate

4-HBA in vivo C57 black J6 mice 25 mg/kg reduced total, cortical Elodie et al.,
MCAO model i.e. and sub-cortical infarct 2009
volumes by 42%, 28%
and 55%

4-HBA in vivo cerebral ischemic 25, 50 increased the expression Yu et al., 2009
injury rats mg/kg of Bcl-2 and inhibited
p.o. the activation of
caspase-3 ultimately

p-HBA in vitro female SD rats 25 mg/kg modulated cytoprotective Kam et al.,

and in MCAO model p.o. genes, such as Nrf2 2011
vivo and PDI, and
neurotrophic factors

Antipsychotic supernatant of G. elata in vivo male C57BL/6J 500 , 1000 mediated via activation Shin et al.,
activities in 0.5% mice or male mg/kg/day of 5-HT1A in mice. 2011
carboxymethylcellulos ICR mice- treated p.o.
e with Phencyclidine

34
 Parishin C in vivo male C57BL/6J 25, 50, activated 5-HT1A Shin et al.,
mice or male ICR 100 mg/kg receptors 2010
mice /day i.p.

Anti-vertigo polysaccharides of G. in vivo male Kunming mice 50, 10, obviously shortened the Lei et al., 2006
activities elata 200 mg/kg escaping time of
p.o. electrical shock and
increase food intake of
mice
Effect on
circulatory system
Anticoagulant and gastrodin in vivo rats 7.5, 15, 30 interference with the Liu et al., 2006
antithrombotic mg /kg knob-to-hole interactions
activities tail between fibrin molecules
intravenou
s injection
polysaccharide 2-1 in vitro male Kunming mice 10, 20, 40 remarkably prolonged Ding et al.,
from G. elata and in and Wisatr rats and 30, CT and BT, increased 2007
vivo 60, 120 bleeding capacity
mg/kg
intraperito
neal
injection

Antihypertensive acidic polysaccharides in vivo spontaneously 6 mg/kg decreased blood pressure Lee et al.,
activities hypertensive rats p.o. and serum lipid levels 2012
modle

Anti-inflammatoy phenolic compounds in vivo pathogen-free 12.5, 25, had anti-inflammatory Lee et al.,
and analgesic male SD rats- 50 mg/kg and analgesic 2006
activities treated with p.o. properties and inhibited
carrageenan COX activity and
silica-induced ROS
generation in a
dose-dependent manner

ethanol extracts of G. in vivo male ICR 50, 100, inhibited NO production Ahn et al.,
elata and in mice-treated with 200 mg/kg 2007
vitro 0.7% acetic acid p.o.
and 0, 0.25,
RAW264.7 0.5, 1.0
macrophages mg/ml
treated with LPS
99.0%ethanol extracts in vivo human 1, 10, 50 inhibited oxidative stress Hwang et al.,
of G. elata umbilical vein µg/ml and NF-κB activation 2009
endothelial cells
gastrodin in vivo rats-treated with 5, 10 ,20 decreased transient Sun et al.,
streptozotocin mg/kg sodium currents, 2012
(STZ) intraperito increased potassium
neal currents in diabetic small
injection DRG neurons

Improve memory G. elata powder in vivo adult male SD 0.4 g/kg decreased Al He et al., 2008
and anti-aging mixed in the water rats-treated with p.o. concentrations in the
activities aluminum chloride neocortex and increased
(5 or 10 mg/kg/day in cortical GABA levels
(i.p.) for 2 months)

water decoction of G. in vivo male Wistar rats- 4 g/kg/d increased the expression Hu et al., 2003
elata treated with lead p.o. of c-fos mRNA in
acetate(0.2 or 0.1 hippoeampus and
g/kg/d) cerebellum
water extracts of G. in vivo four-week-old male 0.5, 1.0 improved retention by Chen et al.,

35
 elata SD rats learning g/kg p.o. shortening escape 2011
deficits model latency in the first test
session and increasing
the time in searching the
target zone during the
probe test
methanol extract of G. in vivo SD rats-treated with 0.4g/kg regulated the cholinergic Niu et al.,
elata aluminum p.o. system and the 2004
monoaminergic system.

p-HBA ,Vanillin in vitro rats brain tissue 0, 0.0025, a dose-dependent Liu and Mori,
(8-week-old male 0.025, inhibition on Fe 1993
SD rats-treated with 0.25, 2.5% ( Ⅱ )-H2O2-induced
Fe(Ⅱ)-H2O2) damage to benzoate,
deoxyribose, glutamic
acid, 2-aminabutyric acid
and methionine, as well
as benzoate
hydroxylation

ether fraction of in vivo male Mongolian 500 inhibited Jung et al.,

the methanol gerbils-treated with mg/kg/day auto-peroxidation and 2007
extract of G. elata, H2O2 for 2 H2O2-induced lipid
vanillin, vanillyl weeks p.o. peroxidation; the order
alcohol, of antioxidation
hydroxybenzaldehyde potency was as follows:
and hydroxybenzyl hydroxybenzyl alcohol
alcohol >vanillyl
alcohol >vanillin >
hydroxybenzaldehyde

Antivirus and WSS45 in vitro BHK cells-treated 0.1, 1, 10 inhibited DV2 infection Tong et al.,
antitumor with DV2 infection µg/ml in BHK cells with an 2010
activities EC50 value of 0.68±0.17
µg/ml, mainly interfered
with virus adsorption
WGEW and AGEW in vitro C6/36 cells 0.6 g the higher the DS is, the Qiu et al.,
WGEW, more potent the impact 2007
1.8 g on the dengue virus
AGEW infection would be

99.0% ethanol extract in vitro primary cultured 30, 100 alleviated tumorigenesis, Lee et al.,
of G. elata HUVEC and μg/ml by a GTP-Ras-dependent 2009
endothelial pathway
cell-treated
withnecrosis
factor-alpha
methanol extracts of in vitro murine melanoma 30, 100 alleviated tumorigenesis Heo et al.,
G. elata cell line B16-F1 μg/ml in a dose-dependent 2007
and human manner, by a
umbilical vein GTP-Ras-dependent
endothelial pathway; but the
cells (HUVECs) precise molecular
mechanisms are still
being examined

Other 70% MeOH extracts in vitro Rat PCl2 cells 0 to 500 prevented mutant Htt Huang et al.,
pharmacological of G. elata μg/ml aggregations targeting 2011
activities the A2A-R through
PICA-dependent
pathway.

36
 30% methanol in vivo mouse water 20 ml/kg decreased in serum and Park et al.,
extracts of G. elata and in immersion restraint p.o. gastric musoca nitric 2007
vitro (WIR) 30 μg/ml oxide (NO) levels to 50
stress-induced and 28%, respectively
gastric lesion model

gastrodin in vitro hBMMSCs and 0.1, 1, 10 increased mRNA and Zheng et al.,
RAW264.7 μM protein expression of 2014; Huang
cells-treated with Bax, Bcl-2, and et al., 2014
H2O2 Caspase-3, decreased the
Bcl-2 mRNA and protein
expression levels
gastrodin in vivo adult male C57/B6 100 attenuated fibrosis and Shu et al.,
mice mg/kg/day collagen synthesis 2012
p.o. through abrogating
ERK1/2 signaling
pathway
BIS in vivo zebrafish 5, 50 μM the molecular modeling Chen et al.,
demonstrates that the 2015
sulfur atom of BIS
coordinating with the
copper ions in the active
site of tyrosinase is
essential for mushroom
tyrosinase inhibition and
the ability of diminishing
the human melanin
synthesis
4-hydroxy-3-methoxy in vivo male dunkin- 12.5, 25, the C-4 hydroxy and C-3 Jang et al.,
benzyl alcohol hartley guinea pigs 50 mg/kg methoxy radicals in 2010
p.o. benzyl alcohols and
aldehydes play important
roles in mediating the
anti-asthmatic activities

water extracts of G. in vivo male SD rats 0.3, 1.0 reduced insulin Park et al.,
elata g/kg p.o. resistance by decreasing 2011
fat accumulation in
adipocytes by activating
fat oxidation and
potentiating leptin
signaling in diet-induced
obese rats
ethanol extracts of G. in vivo six-to-seven-week-o 2.5 g/kg isoprenaline Teong et al.,
elata ld male SD rats for 7 (IPNA)-induced 2011
weeks p.o. relaxation remained
unchanged in –UE strips
after Tianma treatment,
but the potency of IPNA
was lower in
Tianma-treated +UE
strips in the longitudinal
direction

5. Quality control

G. elata can be found all over China and its broad distribution determines its
quality variations among the different producing areas. Up to date, there are almost
ten representative national GAP (Good Agricultural Practice) bases located in Yunnan,
Sichuan, Guizhou, Shanxi and Hubei province. G. elata is one of the botanical drugs

37
that is most prone to adulteration due to its high economic value and there are many
instances of fakes on the market. In the Pharmacopeia of Peoples Republic of China,
qualitative identification by thin layer chromatography (TLC) and determination of
content by high performance liquid chromatography (HPLC) are mainly used to
evaluate the quality of G. elata. Gastrodin is chosen as the marker component to
control the quality of G. elata, and it’s required that the content of gastrodin should be
no less than 0.2% with the specified methods (Chinese Pharmacopoeia Commission,
2015). However, using only one ingredient as the marker might not be sufficient to
fully clarify the quality of G. elata due to its complex constituents and multifarious
pharmacological activities. In fact, more important bioactive constituents should be
integrated into the quality control system of G. elata. Encouragingly, in recent years,
the method of HPLC fingerprinting has been developed to describe the chemical
constituents and to control the quality of many Chinese herbs, as well as to evaluate
the quality of G. elata from different producing areas (Wang et al., 2006b).

6. Toxicology

Clinical reports on the toxicity of G. elata are relatively few. It was found that
gastrodin was capable of repressing transplanted H22 ascitic hepatic tumor cell
growth in vivo with low toxicity (Shu et al., 2013). But according to a recent report,
intramuscular injection of gastrodin could cause severe allergic reactions and even
allergic shock (Hou and Fang, 2012). Subcutaneous injection of Tianma Injection at
the dose of 75g/kg, mice were shown to be quiet without other behavioral changes.
However, intravenous injection of Tianma Injection, LD50 of the mice is 39.8g/kg
(36.5g/kg-43.5g/kg), but intravenous injection of 1000 mg/kg glycosides from G. elata,
no obvious toxic reaction was observed (Huang and Wang, 1985). BIS was found to
be a strong competitive inhibitor against mushroom tyrosinase, and an in vivo
zebrafish assay reveals that BIS can effectively reduce melanogenesis with no serious
side effects. But in an acute oral toxicity study with mice, it was shown to be free of
discernable cytotoxicity (Chen et al., 2015).

7. Concluding remarks

A large number of investigations of G. elata have been carried out due to its wide
use in the healthcare as well as in the clinical pratice of TCM in both China and some
Asian countries. To date, more than 81 compounds have been isolated from G. elata,
predominantly phenolics and its glycosides, polysaccharides, sterols and organic acids.
Among these ingredients, phenolics and their glycosides have been proven to be
closely linked to the pharmacological activities of G. elata. As one of the main
active ingredients, gastrodin was shown to possess a variety of actions such as protect
ion of neuronal cells, anti-apoptotic, anti-oxidative, anticoagulant and antithrombotic,
anti-inflammatory, anti-aging and analgesic activities. Although the in vitro and in
vivo studies have provided evidence strongly indicating that G. elata is useful in many
diseases, pharmacological research validating its traditional uses is still limited.

38
 To date, most of the studies that have been performed on G. elata were based on its
total extracts (mostly poorly characterized), more promising natural chemical
compounds-especially the trace amount but highly effective ingredients, should be
extracted and purified with the most advanced chemical technologies. In addition,
more studies regarding pharmacodynamics and pharmacokinetics should be conducted
using the key natural ingredients derived from this plant in order to clarify the
pharmacological mechanism of action and to search for the metabolites responsible
for the activities of G. elata. Furthermore, the current study on the phytochemistry of
this plant were mainly targeting on its tubers while studies on other parts, such as
stem and leaves, are still lacking. In Compendium of Materia Medica (Ben cao gang
mu), both stem and leaves of G. elata are regarded as medicinal parts entering liver
meridian and also effective in treatment of the diseases caused by invasion of the
wind. Therefore, more investigations on the chemical composition and
pharmacological actions of these medicinal parts should be encouraged.
The current price for G. elata is becoming higher and higher due to its increasing
demand in the herbal market, especially the wild sources of G. elata are dwindling
dramatically due to exhaustive exploitation. This thus raises concerns about the
possible delibrate confusion of this herbal drug with others, such as mirabills jalapa L.
(family nyctaginaceae), ahlia plnnata Cav. (family compositae), canna edulis
Ker.(family cannaceae), cacalia tangutica (Fr.) H.M. (family composltae) and
cacalla davidll (Fr.) H.M.(family compositae). Though quite similar in appearance of
dried roots or tubers, their contents in the active ingredients and bioactivities vary
greatly. Thus, how to exclusively and accurately monitor and evaluate the quality of
samples, by detection of multiple active ingredients instead of only one, to identify G.
elata from its confusing herbs to ensure and maintain its clinical efficacy and
pharmaceutical stability, should be further studied.

Acknowledgments
This work was supported by grants from the National Natural Science Foundation of
China (81274112; 81373986; 81473372; 81403322; 81403125), Beijing Municipal
Natural Science Foundation (7152106), Inheritance Program of China Academy of
Chinese Medical Sciences (CM2014GD3002) and Voluntary Program of China
Academy of Chinese Medical Sciences (ZZ2014056).

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Graphical Abstract

pharmacological properties Phytochemicals

Sedative and hypnotic activities Phenolics and its glycosides
Antiepileptic and anticonvulsive Polysaccharides
Anti-anxiety and antidepressant Sterol and organic acids
Neuroprotective activities Other compounds
Antivascular diseases
Other activities

Traditional uses
Dizziness
Epilepsy
Convulsion
Numbness of the limbs
Rheumatic arthralgia
Headaches
Gastrodia elata Blume

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