The Rhizome of Gastrodia Elata Blume – an Ethnopharmacological Review

Journal of Ethnopharmacology 189 (2016) 361–385

Contents lists available at ScienceDirect

Journal of Ethnopharmacology

journal homepage: www.elsevier.com/locate/jep

Review The rhizome of Gastrodia elata Blume – An ethnopharmacological review

Hong-Dan Zhan a,1, Hai-Yu Zhou a,1, Yun-Peng Sui b,1, Xin-Liang Du c,1, Wei-hao Wang a, Li Dai a, Feng Sui a,n, Hai-Ru Huo a,n, Ting-Liang Jiang a a Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China b Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China c Graduate School of China Academy of Chinese Medical Sciences, Beijing 100700, China article info abstract

Article history: Ethnopharmacological relevance: Gastrodia elata Blume (Orchidaceae) is commonly called Tian ma in Received 13 November 2015 Chinese and mainly distributed in the mountainous areas of eastern Asia, such as China, Korea, Japan and Received in revised form India. It is an extensively used traditional Chinese herbal medicine in the clinical practice of traditional 22 June 2016 Chinese medicine, to treat headache, migraine, dizziness, epilepsy, infantile convulsion, tetany and so on. Accepted 24 June 2016 The present paper reviews the advancements in investigation of botany and ethnopharmacology, phy- Available online 1 July 2016 tochemistry, pharmacology, toxicology and quality control of Gastrodia elata Blume. Finally, the possible Keywords: tendency and perspective for future investigation of this plant are also put forward. Gastrodia elata Blume Materials and methods: The information on Gastrodia elata Blume was collected via piles of resources Tian ma including classic books about Chinese herbal medicine, and scientific databases including Pubmed, Ethnopharmacology Google Scholar, ACS, Web of science, ScienceDirect databases, CNKI and others. Plant taxonomy was Phytochemistry “ ” “ ’ ” Pharmacology validated by the databases The Plant List , and Mansfeld s Encyclopedia . Clinical applications 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 Chemical compounds studied in this article: Blume. Its active compounds possess wide-reaching biological activities, including sedative, hypnotic, Gastrodin (PubChem CID: 115067) antiepileptic, anticonvulsive, antianxietic, antidepressant, neuroprotective, antipsychotic, anti-vertigo, Hydroxybenzyl alcohol (PubChem CID: 125) circulatory system modulating, anti-inflammationary, analgesic, antioxidative, memory-improving and 4-hydroxybenzaldehyde (PubChem CID: antiaging, antivirus and antitumor effects. 126) Vanillyl alcohol (PubChem CID: 62348) Conclusion: Despite the publication of various papers on Gastrodia elata Blume, there is still, however, the Vanillin (PubChem CID: 1183) need for definitive research and clarification of other bioactive compounds using bioactivity-guided Parishin (PubChem CID: 44421666) isolation strategies, and the possible mechanism of action as well as potential synergistic or antagonistic Parishin B (PubChem CID: 44715528) effects of multi-component mixtures derived from Gastrodia elata Blume need to be evaluated. It is also Parishin C (PubChem CID: 46173915) necessary and important to do more quality control and toxicological study on human subjects in order β -sitosterol (PubChem CID: 222284) to maintain its efficacy stable in the body and validate its safety in clinical uses. In addition, more in- Gastrodamine (PubChem CID: 5702160) vestigations 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. & 2016 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction ...... 362 2. Botany and ethnopharmacology ...... 362 2.1. Botany...... 362

n Corresponding authors. E-mail addresses: [email protected] (F. Sui), [email protected] (H.-R. Huo). 1 These authors contributed equally to this paper. http://dx.doi.org/10.1016/j.jep.2016.06.057 0378-8741/& 2016 Elsevier Ireland Ltd. All rights reserved. 362 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

2.2. Ethnopharmacology...... 365 3. Phytochemistry ...... 365 3.1. Phenolics and its glycosides ...... 365 3.2. Polysaccharides ...... 367 3.3. Sterol and organic acids ...... 367 3.4. Other compounds ...... 367 4. Pharmacological activities ...... 368 4.1. Sedative and hypnotic activities ...... 368 4.2. Antiepileptic and anticonvulsive activities ...... 369 4.3. Anti-anxiety and antidepressant activities ...... 369 4.4. Neuroprotective activities ...... 369 4.4.1. Protection of neuronal cells and anti-apoptotic action activities...... 369 4.4.2. Anti-oxidative activities...... 369 4.4.3. Protection of neuro-synaptic plasticity ...... 369 4.5. Anti-cardio-cerebral-vascular diseases activities ...... 373 4.6. Antipsychotic activities ...... 373 4.7. Anti-vertigo activities ...... 374 4.8. Effect on circulatory system ...... 374 4.8.1. Anticoagulant and antithrombotic activities...... 374 4.8.2. Anti-atherosclerotic activities ...... 374 4.8.3. Antihypertensive activities ...... 374 4.9. Anti-inﬂammatory and analgesic activities ...... 375 4.10. Improve memory and anti-aging activities...... 375 4.11. Antivirus and antitumor activities ...... 376 4.12. Other pharmacological activities...... 376 5. Quality control...... 378 6. Toxicology...... 379 7. Concluding remarks...... 379 Acknowledgments...... 383 References...... 383

1. Introduction others (Hou et al., 2012). Modern pharmacological experiments have demonstrated that the extracts of G. elata or its active com- Gastrodia elata Blume (G. elata, Orchidaceae), commonly called pounds possess wide-reaching biological activities, including an- Tian ma (天麻) in Chinese, is a perennial parasitic herb also called titumor, anti-virus, memory-improving, antioxidation, and anti- Chi jian (赤箭)orMing tian ma (明天麻). It is considered as a top aging actions (Huang et al., 1985; Heo et al., 2007; Hu et al., 2014). grade herbal medicine that has been used for a long history de- It is commonly used in traditional medicine as a tonic and aph- scribed to enter the liver meridian in the Shennong's Classic of rodisiac in China and other Asian countries as well as used as a Materia Medica (Shen nong ben cao jing). Generally, after the be- functional food by adding to alcoholic beverages or porridge to ginning of winter to the following year before the Tomb-sweeping improve sexual potency and vision and to prevent abortion Day, excavate the rhizome of G. elata, wash it immediately, and (Zhang, 1981). braise it well and then dry it at low temperature for the clinical use A large number of investigations have been conducted on G. (Chinese Pharmacopoeia Commission, 2015). elata in the past few decades, but only a short review of G. elata as G. elata has nine synonyms (G. elata f. alba S. Chow, G. elata f. a herbal medicine has been published by Chen and Sheen (2011), elata, G. elata f. flavida S. Chow, G. elata f. glauca S. Chow, G. elata in which its biological activities and antidepressant mechanisms var. gracilis Pamp., G. elata var. pallens Kitag., G. elata f. pilifera are briefly mentioned, and another review written by Jang et al. Tuyama, G. elata f. viridis (Makino) Makino, and G. elata var. viridis (2015), in which only the neuropharmacological potential of G. (Makino) Makino) (The Plant List., 2013). To search by using these elata was covered. In this review, using various databases search nine names, only two Chinese articles (Jiang et al., 2001; Zhang and library search to provide constructive information on the et al., 2014) regarding Gastrodia elata f. elata, and one English ar- ethnopharmacology, phytochemistry, pharmacology, toxicology ticle (Wang et al., 2007a,b) covering Gastrodia elata f. glauca S. and quality control of G. elata as well as the structure-activity re- Chow were obtained. However, it was found that G. elata was used lationships of the active ingredients derived from G. elata, aims to in more than 200 publications (both in English and Chinese). There coherently unite these aspects and to encourage further research. are also many Chinese articles in which the plant was just defined as Tian ma (Li et al., 2015a,b; Luo et al., 2012). To communicate more effectively and internationally, it is suggested that G. elata 2. Botany and ethnopharmacology should be used instead of Tian ma in all publications in the future. Currently, over 81 compounds from this plant have been iso- 2.1. Botany lated and identified, and they are phenolics, polysaccharides, sterols and organic acids, and so on. (Ojemann et al., 2006). In the G. elata (Fig. 1) belongs to the genus Gastrodia, family Compo- theory of traditional Chinese medicine (TCM), G. elata is con- sitae. There are about 22 species in the genus Gastrodia, and most sidered to suppress the hyperactive liver, arrest endogenous wind of the species grow in China (Table 1). However, only G. elata is and stop tetany. In the aspect of clinical practice, G. elata is mainly used as medicinal material in the clinical practice of TCM and applied for neurasthenia, insomnia, dizziness, epilepsy, convul- registered in the Pharmacopeia of People's Republic of China. sions, nervous headache, Alzheimer’s disease, hypertensive and G. elata is found primarily in eastern Asia, specifically in the H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 363

A B

C D

Fig. 1. G. elata. (A) Seedlings, (B) stem and flowers, (C) dried tubers, and (D) decoction pieces. mountainous areas of China, Korea, Japan and India (Shuan and hiemalis (Lei et al., 2015). After digged out, removed the stems and Chen, 1983; Jones, 1991). Characterized by a fleshy tuber or cor- fibrous root, washed the dirt, soaked in water and wiped off the alloid underground stem and absence of leaves, it grows in the coarse skin, then soaked in water or alum, next boiled or steamed forest at 400–3200 m above sea level and has a complex re- and when the white dots in the center disappeared, took it out and lationship with the fungus Armillaria mellea, which invades the dried it (Chinese materia medica, 1999). sprouted tuber and provides nutrients and energy (Wang et al., The dried tubers are oval shaped, long, slightly flat, and exhibit 2007a,b). The plant lives underground during its life cycle except signs of shrinkage and bending. The residual stem base at one end, for florescence. Four subspecies, including G. elata Bl. f. elata, G. commonly known as “Ying ge zui” is red to reddish brown in color, elata Bl. f. flavida S.chow, G. elata Bl. f. glauca S. chow and G. elata and the other end has rounded root marks. They are 6–10 cm long, Bl. f. viridis Makino have been found in G. elata species (Zhou et al., 2–5 cm in diameter, and 0.9–2 cm thick. Its surface is yellowish- 1987). Except for the subspecies of G. elata Bl. f. viridis Makino white to yellowish-brown and translucent. It has residual flakes of which is becoming increasingly rare in the wild, the other three the light colored skin, lots of longitudinal wrinkles, fibrous scar subspecies have successfully been cultivated in fields both in China lines and an amount of less visible annulus. Gastrodia hiemalis is and other countries such as Korea (Lee et al., 2014). Recent studies with tenuous and less wrinkles and Gastrodia fontinalis is with have shown that G. elata is a small genus composed of 16–31 thick wrinkles. Both of their textures are hard and not easy to be species (Table 1). Among them, the most abundant species is fractured (Chinese materia medica, 1999). distributed in Taiwan (Chung and Hsu, 2006; Dressler, 1993; Meng In China, wild G. elata is naturally distributed in many pro- et al., 2007). As the unique botanical characters, G. elata grows to vinces. These provinces include Sichuan, Guizhou, Yunnan, Shanxi, the height of 60–100 cm and the whole plant does not contain Hubei, Gansu, Anhui, Henan, Jiangxi, Hunan, Guangxi, Jilin province chlorophyll. The tubers of G. elata are pachyntic, oblong, about and so on. Within these areas, G. elata growing in the western 10 cm long and its diameter is 3–4.5 cm. The stems are vertical, Guizhou, southern Sichuan, northeast of Yunnan and Changbai cylindrical, and red. The leaves are scalelike, membranous, 1–2cm mountain areas are generally regarded as being of high quality. long, nervulose. Its inflorescence is fringy raceme, 10–30 cm long However, the extensive urbanization of China as a whole has led to and golden colored (Chinese materia medica, 1999). serious habitat fragmentation, which may in turn lead to gradual G. elata is harvested in winter or spring; the excavated in winter loss of wild G. elata. Further adding insult to this injury is the is named Gastrodia hiemalis T. P Lin, the quality of which is rela- current exploitation of the limited resources of G. elata (Chinese tively excellent, and the dredged in spring is called Gastrodia materia medica, 1999). These wrong actions will lead to the heavy fontinalis T. P Lin, the quality of which is inferior to Gastrodia shortages of wild G. elata, which are actually more valuable than 364

Table 1 The ascertained species in the genus Gastrodia.

No. Name Distribution Part of herb used Medicinal uses References

1 G. elata Bl. Most regions of China Rhizome Treating dizziness, limb numbness, infantile convul- Shuan and Chen (1983), Flora of China (2004) sion, epilepsy, tetanus, hypertension, etc. 2 Gastrodia fontinalis T. P Lin. Taiwan, Yunnan, Sichuan, Guizhou and Rhizome Treating dizziness, limb numbness, infantile convul- Flora of China (2004) Hubei in China sion, epilepsy, tetanus, hypertension, etc. 3 Gastrodia hiemalis T. P Lin Taiwan, Yunnan, Sichuan, Guizhou and Rhizome Treating dizziness, limb numbness, infantile convul- Flora of China (2004)

Hubei in China sion, epilepsy, tetanus, hypertension, etc. 361 (2016) 189 Ethnopharmacology of Journal / al. et Zhan H.-D. 4 G. elata Bl. form. glauca S. Chow Western of Guizhou, Northeast to the Not mentioned Not mentioned Shuan and Chen (1983), Flora of China (2004), Chen et al. northwest of Yunnan in China (2005), Tang (2013) 5 G. elata Bl. f. alba S. Chow Northwest Yunnan in China Not mentioned Not mentioned Shuan and Chen (1983), Flora of China (2004) 6 G. elata Bl. f. favida S. Chow Henan, Hubei, Western Guizhou, North- Not mentioned Not mentioned Shuan and Chen (1983), Flora of China (2004), Tang (2013) east Yunnan in China 7 Gastrodia angusta S. Chou & S. C. Southeastern Yunnan, Sichuan, Shanxi in Not mentioned Not mentioned Shuan and Chen (1983), Flora of China (2004), W.C. Chen et al. Chen China (2015), J.S. Chen et al. (2015) 8 Gastrodia tuberculata F. Y. Liu & S. Central Yunnan in China Not mentioned Not mentioned Shuan and Chen (1983), Liu et al. (1983), Flora of China (2004), C. Chen J.S. Chen et al. (2015), W.C. Chen et al. (2015) 9 Gastrodia menghaiensis Z. H. Tsi & Southern Yunnan in China Not mentioned Not mentioned Tsi and Chen (1994), Flora of China (2004), J.S. Chen et al. S. C. Chen Wuyi mountain of Fujian province in Not mentioned Not mentioned(2015) Li and, LiuW.C. (2007) Chen et al. (2015) 10 GastrodiaC. D. Liu wuyishanensis D. M. Li & China 11 Gastrodia gracilis Bl. Northern Not mentioned Not mentioned Shuan and Chen (1983), Flora of China (2004), J.S. Chen et al. Taiwan, Yunnan, Sichuan, Guizhou and (2015), W.C. Chen et al. (2015) Hubei in China 12 Gastrodia javanica (Bl.) Lindl. Southern Taiwan Not mentioned Not mentioned Yokota (1998), Flora of China (2004), Aoyama and Yokota (2012) 13 Gastrodia ﬂabilabella S. S. Ying Central Taiwan Not mentioned Not mentioned Flora of China (2004), Lok et al. (2009), Lai (2012) 14 Gastrodia peichatieniana S. S. Ying Northern Taiwan Not mentioned Not mentioned Flora of China (2004), Tian et al. (2010) 15 Gastrodia autumnalis T. P Lin Northern Taiwan Not mentioned Not mentioned Flora of China (2004) – 16 G. elata Bl. f. elata Huanghe valley and Changjiang valley in Not mentioned Not mentioned Shuan and Chen (1983), Flora of China (2004), Chen et al. 385 China (2005), Tang (2013) 17 G. elata Bl. f. viridis (Makino) Northeast to southwest provinces in China Not mentioned Not mentioned Shuan and Chen (1983), Flora of China (2004), Chen et al. Makino (2005), Tang (2013)

18 Gastrodia confuse Honda & Tuyama Central Taiwan; Yunnan in China Not mentioned Not mentioned Flora of China (2004), Yang et al. (2013) 19 Gastrodia appendiculata C. S. Leou Taiwan Not mentioned Not mentioned Yeh et al. (2011) & N. J. Chung 20 Gastrodia shimuzuana Tuyama in Northern Taiwan Not mentioned Not mentioned Tuyama (1982), Flora of China (2004), Chung and Hsu (2006) Acta Phytotax Shanxi Not mentioned Not mentioned Zhang and Ji (2010) 21 ZhangGastrodia elata var.obovata Y.J. H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 365 the cultivated ones in biological activities. As such, some urgent treat diabetic neuropathy in combination with Kudiezi Injection conservation measures should be taken to protect the G. elata’ with an affirmative effect that is superior to the chemical drugs natural habitat, in order to guarantee the long-term application of (Wei and Cui, 2012). Banxia Baizhu Tianma Decoction was effective this herbal medicine. to treat vertebral-basilar artery insufficiency (VBI) when combined with Shuxuening Injection (Chen, 2010). 2.2. Ethnopharmacology G. elata not only contains phenolics and polysaccharides that can produce pharmacological activities, but also have a variety of With an extensive scope of biological and pharmacological ef- trace elements and amino acids. So it has a high nourishing and fects, G. elata has been traditionally used in China for centuries edible value and is often used to make medicinal food in folk, such with the dried rhizome (tuber) as the useful part. G. elata was as “Stewd black-bone chicken with Tianma”, a traditional dish in initially recorded in the Shennong's Classic of Materia written in Yunnan province of China that can be used to treat deficiency of the period of the Warring States and the Qin and Han Dynasties. In both qi and blood or postpartum blood deficiency characterized by this monograph, G. elata was classified as a “top grade” drug with dizziness, anemia and hypotension. “Tianma sleeping porridge” rejuvenating effect, no toxic and thus can be long-term used possesses medical functions of improving brain and bodies, se- without harm. This monograph described that long-time treat- dative and sleeping effects, and can thus be used to treat stubborn ment with Gastrodiae elata can tonify qi and strength the body, sex, insomnia, dizziness, and forgetfulness. “Tianma steamed egg” nourish yin, enhance health, rejuvenate the body, and prolong life used to treat dizziness, neurasthenia, etc. “Tianma stewed pig (Gu and Yang, 2013). brain” has enriching essence and marrow effect, and is often used G. elata is also recorded in many other traditional Chinese for headache, dizziness, easily angry, palpitations, and insomnia medicine classics, including the Variorum of the Shennong's insulted by liver fire. (Zhao et al., 2013). In addition, a lot of G. elata Classic of Materia Medica (Shen nong ben cao jing ji zhu) and the health care products have been developed and sell well in China, Newly Revised Materia Medica (Xin xiu ben cao). The content of such as Tianma health wine, Tianma health drinks, Tianma candy them is the same as that of Shennong's Classic of Materia Medica and so on (Li et al., 2002; Xiao et al., 2009). (Chinese materia medica, 1999). In Compendium of Materia Influenced by the traditional Chinese culture and the medical Medica (Ben cao gang mu), another monograph of TCM, G. elata is system of TCM, application of G. elata as a therapeutic botanical charactered as a medicine improving liver meridian and is called drug is now popular in many Asian countries, especially in South “Ding feng cao” as a marvelous medicine in the treatment of the Korea and Japan. In view of this fact, this plant is currently culti- diseases caused by the invasion of wind (Li, 2011). vated in a number of cultivation regions distributed in different In accordance with the authoritative textbook of Chinese cities of Korea (such as Chuncheon, Gimcheon, Muju, Sangju, and pharmacy, G. elata is sweet in flavor, neutral in nature and attri- Asan) (Lee et al., 2014). While in Japan, Kampo, a traditional Ja- butive to the liver channel. G. elata is described possessing the panese medicine, is widely practised and is fully integrated into power to suppress hyperactive liver for calming endogenous wind, the modern health-care system. In the clinical practice of Kampo, dredge the meridians and relieve pain. In the clinical practice, G. G. elata is used alone or in combination under the direction of elata is primarily applied for dizziness, epilepsy, convulsion, Kampo theory similar to the basic theory of TCM (Yu et al., 2006). numbness of the limbs, rheumatic arthralgia and headaches by combining with other botanical drugs based on the TCM theory (Chinese materia medica, 1999). 3. Phytochemistry On account of its wonderful and specific clinical effects, lots of classic formulations including G. elata created by the ancient Up to now, many chemical components (Table 3), for instance, famed doctors were spread generation after generation through gastrodins, 4-hydroxybenzyl alcohols, vanillyl alcohols, vanillins, the refined clinical verification for centuries. For example, Gas- polysaccharides, sterols and organic acids, have been isolated from trodia and Uncaria decoction was used to treat neurodegenerative G. elata. Among them, gastrodin and its aglycone gastrodigenin (4- disease, such as stroke, brain trauma, and spinal cord injury, hydroxybenzyl alcohols) are considered as the characteristic and Huntington’s disease, Alzheimer’s disease (AD), and Parkinson’s main active constituents of G. elata. The content of total phenolics disease (PD) diseases, etc. (Chik et al., 2013). Banxia Baizhu Tianma in G. elata was detected by using the method of Folin-Ciocaileu Decoction was mainly used to treat vertigo in the past, and now it colorimetry, and found that total phenols reached 0.0485% (Xiong was also used to treat spontaneous hypertensive, vomiting, diar- et al., 2013). The polysaccharides content of G. elata produced in rhea, tinnitus, deafness, migraine headache, stroke, dementia, Yunnan province of China was determined by the phenol-sulfuric epilepsy, etc. (Jiang et al., 2011; Dong, 2012). acid method, and showed that the highest content was 21.6% Nowadays, a lot of prescriptions containing G. elata (Table 2) (Wang et al., 2011). In addition, the detection results for gastrodin, have been applied in the forms of injection, granule, pill and amino acid and total flavonoids demonstrated that their biggest capsule. For example, Tianma Injection was used to treat 53 pa- contents were 0.24%, 1.92% and 0.24% respectively (Cheng et al., tients with vertebral basilar artery insufficiency with the total ef- 2009). Other chemical constituents derived from G. elata have not ficiency significantly higher than that of the control group (He been determined (Fig. 2). et al., 2014). Qiangli Tianma Duzhong Capsule was prescribed for the treatment of acute cerebral infarctions for 36 patients for 28 3.1. Phenolics and its glycosides days, and the obviously effective rate and response rate for the treatment group are 66.67% and 90.00% respectively (Shen et al., G. elata contains several of ingredients that have previously 2006). Another study was also conducted to evaluate the clinical been characterized. Biological and biochemical activities of these effect and safety of Tianmasu Injection in treating vertigo symp- constituents are investigated in lots of assays. Recent studies have tom, and the results showed that the significantly effective rate confirmed the presence of abundant phenolics in G. elata, which and total effective rate for the tested groups were higher than for have been thought to be the active components of this botanical the control group (Po0.05) (Gao, 2012). Furthermore, it is also drug. According to the structures (Fig. 3), these compounds have a reported that Tianma preparations can be used in combination unique structure with variants of 4-hydroxybenzyl alcohol with with other drugs to prevent and treat more diseases or increase gastrodin (Zhou et al., 1979a,b) and 4-hydroxybenzyl alcohols (4- therapeutic effects. For instance, Tianmasu Injection was used to HA) as principal active constituents. Gastrodin is the phenolic Table 2 366 The traditional and clinical usages of G. elata in China.

Formulation name Dosage form Compositions Efﬁcacy and application References

Tian Ma Gou Teng Yin Decoction Rhizoma Gastrodiae, Ramulus Uncariae cum Uncis, Concha Haliotidis, Radix Calm liver wind, clear heat, promote blood circulation, tonify liver and Zabing Zhengzhi Scutellariae, Radix Cyathulae, Eucommia ulmoides, Herba Leonuri, Tuber kidney, indicated for liver-yang hyperactivity and wind syndrome caused Xinyi Fleeceflower stem. by liver-yang. Xing Pi Wan Pill Cortex magnoliae officinalis, Indicated for infantile chronic spleen wind, trapped lethargy after vomit, Puji Benshifang Atractylodes Macrocephala Koidz, Brimstone, Rhizoma Gastrodiae, Scor- potentially causing seizures. pion, Radix Saposhnikoviae Chinese cinnamon, Ginseng. Yu Zhen San Powder Rhizpma Arisaematis, Radix Ledebouriellae Radix Angelicae Dahuricae, Dispel pathogenic wind and eliminate phlegm, prevent convulsions and Waike Zhengzong Rhizoma Gastrodiae, Rhizoma seu Radix Notopterygii, Rhizoma Aconiti spasm, indicated for tetanus. praeparatae. Ban Xia Bai Zhu Tian Ma Decoction Pinellia ternate, Atractylodes Macrocephala Koidz, Rhizoma Gastrodiae, Dry dampness and eliminate phlegm, calme liver wind, indicated for the Yi xue Xinwu Tang Pericarpium Citri Reticulatae, Poria cocos, Radix Glycyrrhizae, Fresh Ginger, wind-phlegm syndrome. Fructus Jujubae. a Qin Jiao Tian Ma Tang Decoction Gentiana macrophylla Pall., Rhizoma Gastrodiae, Rhizoma et Radix No- Strengthen body resistance and eliminate evil, relieve pain, dredge the Yi xue Xinwu 361 (2016) 189 Ethnopharmacology of Journal / al. et Zhan H.-D. topterygii, Pericarpium Citri Reticulatae, Radix Angelica Sinensis, Rhizoma palsy and relieve pain, attending rheumatism pain, adverse joint flexion Ligustici Chuanxiong, Radix Glycyrrhizae preparata, Fresh Ginger, Ramulus and extension. Tian Ma Wan Pill, capsuleMori Rhizoma Gastrodiae, Rhizoma seu Radix Notopterygii, Radix Angelicae Da- Dispel wind and eliminate dampness, relax muscles and tendons, remove Zhongguo Yaodian huricae, Cortex Eucommiae, Achyranthis Bidentatae Radix, Rhizoma Dios- obstruction from meridians, indicated to treat hemplegia spasm, numb- coreae Hypoglaucae, Radix Aconiti preparata, Radix Angelica Sinensis, Radix ness of extremities and aching lumbus and leg pain. Rehmanniae, Radix Scrophulariae. Tian Ma Tou Tong Pian Pill Rhizoma Gastrodiae, Radix Angelicae Dahuricae, Rhizoma Ligustici Chuan- Nourish the blood to expel wind, eliminate cold stop pain, to treat wind- Zhongguo Yaodian xiong, Herba Schizonepetae, Radix Angelica Sinensis, Resina Olibani. cold headache, or headache due to deficiency of blood and blood stasis headache. Tian Ma Shou Wu Pian Pill, capsule Rhizoma Gastrodiae, Radix Angelicae Dahuricae, Polygonum Multiflorum, Tonify yin and replenish the kidney, nourish blood for calming endogenous Zhongguo Yaodian Radix Rehmanniae praeparata, Radix Salviae Miltiorrhizae, Rhizoma Ligustici wind, liver-kidney yin deficiency caused by dizziness, headache, tinnitus, Chuanxiong, Tribulus terrestris praeparata, Mulberry Leaf, Herba Ecliptae, Mouth-bitterness, throat-drying, soreness and weakness of waist and Fructus Ligustri Lucidi, Radix Paeoniae Alba, Rhizoma Polygonati, Radix knees, alopecia, poliothrix and angioneurotic headache, seborrheic aio- Glycyrrhizae. pecia and so on. Tian Ma Qu Feng Bu Pian Pill Rhizoma Gastrodiae, Angelica sinensis, Radix Aconiti praeparatae, Cortex Tonify kidney, nourish liver, dispel dampness and relieve pain, to treat the Zhongguo Yaodian Eucommiae, Radix Angelicae Pubescentis, Poria, Radix cyathulae, Radix Re- deficiency of liver and kidney caused by dizziness, tinnitus, muscle spasm, hmanniae, Cortex Cinnamomi, Rhizoma seu Radix Notopterygii, Radix arthralgia and the numbness of limbs. Scrophulariae

Approved by China Food and Drug Administration (CFDA) a –

Tian Ma Su Zhu She Ye Injection Gastrodin Used for neurasthenia, neurasthenia syndrome, angioneurotic headache CFDA 385 disorder, traumatic brain syndrome, vertigo meniere disease, medicinal with dizziness, vertigo, sudden deafness, vestibular neuronitis, vertebral Tian Ma Zhui Feng Gao Plaster Rhizoma Gastrodiae, Radix Aconiti Kusenzoffii, Radix aconite, Radix Aconiti Dispelbasilar wind artery and blood eliminate supply dampness, deficiency, promoteetc. blood circulation to remove CFDA a preparata, Radix Clematidis, Herba Ephedrae, Radix Saposhnikoviae, pine meridian obstruction, eliminate cold to stop pain. nodular branch, Ramulus mori, zaocys dhumnade, Flos Carthami, Resina Olibani. Borneol, etc. Tian Ma Zhuang Gu Wan Pill Rhizoma Gastrodiae, Radix Angelicae Dahuricae, Leopard bone, Ginseng, Dispel wind and eliminate dampness, promote blood circulation, reinforce CFDA a Herba Asari, Cornu cervi pantotrichum, Cortex Eucommiae, Cortex Acan- liver and kidney, strengthen the lumbus and knees, indicated for the thopanacis, Radix Gentianae Macrophyllae, Herba Siegesbeckiae, Radix Sa- rheumatism, headache, dizziness, rheumatism pain, lumbar debility, poshnikoviae, Radix angelica sinensis, Rhizoma Ligustici Chuanxiong, Radix numbness of limbs. Stephaniae Tetrandrae, Ramulus Mori, Radix Angelicae Dahuricae, Ligusti- cum sinense Oliv, Rhizoma seu Radix Notopterygii, Geranium wilfordii, He- dera helix. Tian Ma Xing Nao Jiao Capsule Rhizoma Gastrodiae, Pheretima, Rhizoma Acori Tatarinowii, Radix Polygala, Nourish liver and kidney, dredge the meridians and relieve pain, indicated CFDA a Nang Radix Rehmanniae Preparata, Herba Cistanche for headache, dizziness, memory loss, insomnia, unresponsive, tinnitus and lumbar acid caused by kidney deficiency. Qiang Li Tian Ma Du Pill, capsule Rhizoma Gastrodiae, Cortex Eucommiae, Radix angelica sinensis, Rhizoma Expel the wind and promote blood circulation, relieve swelling and pain, CFDA a Zhong Wan seu Radix Notopterygii, Radix Angelicae Dahuricae, Radix Rehmanniae, Ra- indicated for series of symptoms caused by stroke. dix Cyathulae, Viscum Coloratum, Radix aconiti kusnezoffi preparata, Radix H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 367

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 mechanisms. The phenolics constituents were reported to have

a a prominent neuroprotective, anti-inﬂammatory, anti-oxidant actions and many others (Lee et al., 2012a; Han et al., 2014; Sun et al., CFDA CFDA 2012).

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 (X. Chen et al., 2012; P.J. Chen et al., 2012). and promote blood circulation, relieve swelling and pain, in- Qi 3.3. Sterol and organic acids Tonify dicated for all kinds of joint pain, waist and leg pain, numbness of limbs. Nourish Yin and suppressbones, Yang, dispel indicated the for wind, stubbornterm strengthen headache, numbness muscles chronic in and lumbocrural the pain, hands long- and feet. 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., 1979a,b), palmitic acid (Wang et al., 2003), L-pyroglutamic acid, 6-methyl citrate, 1,5-dimethyl citrate (Hao et al., 2000), M-hydroxybenzoic acid, syringic acid, proto- catechuic 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., 2006a,b) 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.

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-(methox- ymenthyl) 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 (The website of China Food and Drug Administration). Dioscoreae Nipponicae, Flos Cartham. Aconiti preparata, Ligusticum sinense Oliv, Radix Scrophulariae. Rhizoma Gastrodiae, Radix AchyranthisRhizoma Bidentatae, Radix rehmanniae, Radix scrophulariae, AngelicaLigustici sinensis Chuanxiong, Cortex Viscum Eucommiae, Coloratum, Rhizoma Flosuncariae Chrysanthemi cum Indici, uncis. Ramulus 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 http://www.sda.com.cn Pill, capsule, chew- able tablet fungistatic activity against a broad spectrum of fungi (Hu et al., 1988; Hu et al., 1994,, 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 Cited from the website: Pian a control of diseases (Fan et al., 1991a,b; Li et al., 2015a,b). Some Ren Sen Tian Ma Yao Jiu Medicinal liquor Rhizoma Gastrodiae, Ginseng, Radix Astragali, Radix Cyathulae, Rhizoma Tian Ma Tou Feng Ling phenolic components are separated from the fresh G. elata as 368 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

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 BC Rhizome Lin et al. (1996) 4–5 Parishin DE Rhizome Yang et al. (2007) 6–7 Parishin FG Rhizome Wang et al. (2012a,b) 8–23 Parishin H Rhizome Li et al. (2015a,b) 24 Vanillin Rhizome Kim et al. (2007a,b) 25 Vanillyl alcohol Rhizome Kim et al. (2011) 26 Gastrodigenin Rhizome Choi et al. (2006) 27 4-hydroxybenzyl methyl ether Rhizome Taguchi et al. (1981) 28 (4-methoxyphenyl)methanol Rhizome Rohmann and Meisel (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. (2007) 34 4-(4′-hydroxybenzyl)phenol Rhizome Yang et al. (2007) 35 4-[4′-(4″-hydroxybenzyloxy)benzyloxy]benzyl methyl ether Rhizome Hye et al. (1998) 36 1-furan-2-yl-2-(4-hydroxyphenyl)-ethanone Rhizome Lee et al. (2007) 37 5-(4-hydroxybenzyloxymethyl)-furan-2-carbaldehyde Rhizome Lee et al. (2007) 38 2,4-Bis(4-hydroxybenzyl)phenol Rhizome Han et al. (2011) 39 5-[4′-(4″-hydroxybenzyl)-30-hydroxybenzyloxymethyl]-furan-2-carbaldehyde Rhizome Huang et al. (2014a,b) 40 4-butoxyphenylmethanol Rhizome Rohmann and Meisel (1961) 41 4,4′-methylenediphenol Rhizome Ma et al. (2015) 42 4,4′-sulfinylbis(methylene) diphenol Rhizome Yun-Choi 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) 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-Choi 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) 57 N6-(3-methoxyl-4-hydroxybenzyl) adenine riboside Rhizome Shi et al. (2014) 58 1-furan-2-yl-2-(4-hydroxy-phenyl)-ethane-1, 2-dione Rhizome Li et al. (2014) 59 4-hydroxy 3-4-hydroxybenzyl) benzyl methyl ether Rhizome Wang et al. (2012a,b) Polysaccharides 60 AGEW Rhizome Qiu et al. (2007) 61 WGEW Rhizome Qiu et al. (2007) 62 WSS25 Rhizome Chen et al. (2007) 63 WSS45 Rhizome Tong et al. (2010) 64 Adenosine glucoside Rhizome Wang et al. (2007a,b) 65 Gastrodin isomer Rhizome Wang et al. (2007a,b) 66 4-(methoxymethyl) phenyl-1-O-β-D-glucopyranoside Rhizome Wang et al. (2012a,b) 67 Trimethylcitryl-b-D-galactopyranoside Rhizome Choi et al. (2006) 68 5-(hydroxymethyl)-furfural Rhizome Ishida and Seri (1996) 69 5-(hydroxymethyl)-2-furaldehyde Rhizome Huang et al. (2014a,b) 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-Choi 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 components 77 Gastrodamine Rhizome Hao et al. (2000) 78 N2-(p-hydroxybenzyl) guanosine Rhizome Wang et al. (2009) 79 P-hydroxybenzyl guanosine Rhizome Wang et al. (2007a,b) 80 P-hydroxybenzyl adenosine Rhizome Wang et al. (2007a,b) 81 S-(4-hydroxybenzyl)glutathione Rhizome Andersson et al. (1995) well, such as, gastrodin, 4-hydroxybenzenemethanol, p-hydroxy 4. Pharmacological activities benzaldehyde, 4,4′-dihydroxy-Biphenyl methane, 4, 4′-dihydroxy-dibenzyl ether, 3,4-dihydroxy-benzaldehyde, 4-ethox- 4.1. Sedative and hypnotic activities ymethyl phenyl, 4′-hydroxy benzyl ether, 4-ethoxymethyl phenol 6 and parishin (Zhou et al., 1979b, 1980a,b, 1981). Among them, Up to date, only two active ingredients, N -(4-hydroxybenzyl) 6 gastrodin and 4-hydroxybenzenemethanol, can produce strong adenine riboside (NHBA, 0.2, 1 and 5 mg/kg i.p.) and its analog N - sedative and hypnotic effects (Deng and Mo, 1979; Deng and Mo, (3-methoxyl-4-hydroxybenzyl) adenine riboside (B2, 1 or 5 mg/kg, fi 1980). i.p.), isolated from G. elata, are reported to have signi cant H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 369

GRP78 (Lee et al., 2012a; Kim et al., 2007a, 2011a). Furthermore, 50% alcohol extract of G. elata has a protective effect against 1. Total phenolics (0.0485%) neuronal damage in kainic acid-treated rats by reducing neuronal 2. Total polysaccharides (21.6%) nitric oxide synthase, microglia activation and apoptosis (Hsieh 3. Total flavonoids (0.235%) et al., 2005). Not only organic solvent extracts but also the aqueous extracts of G. elata were shown to reduce the β-amyloid-induced 4. Total amino acids (1.92%˅ 5. Gastrodin (0.240%) neurotoxicity through inhibition of apoptosis and reduction of oxidative stress in both Drosophila and PC12 Cells (Ng et al., 2013). 6. β-sitosterol (0.113%) These results strongly suggest that G. elata could be further de- 7. Not determined (77.8%) veloped 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 Fig. 2. Contents of the chemical components from G. elata. induce heme oxygenase-1 (HO-1) expression through activation of p38 MAPK/Nrf2 signaling pathway, thus protecting human dopa- sedative and hypnotic effects. Further study showed that the minergic SH-SY5Y cells from 1-methyl-4-phenylpyridinium molecular mechanism of action for NHBA might be closely related þ MPP -induced oxidative cytotoxicity (Jiang et al., 2014) and up- to the activation of adenosine A /A receptors and stimulation to 1 2A regulating the decreased striatal dopamine (DA) content in IDPN- the sleep center in the ventrolateral preoptic area (VLPO) (Zhang induced rats and down-regulating the elevated striatal DA content et al., 2012), but the molecular mechanism of B2 remains to be in apo-induced rats (Zhang and Li, 2015). Moreover, gastrodin determined (Shi et al., 2014). could significantly and dose-dependently protect dopaminergic neurons against neurotoxicity to prevent dopamine depletion and 4.2. Antiepileptic and anticonvulsive activities reduce reactive astrogliosis, and is also effective in preventing neuronal apoptosis by attenuating antioxidant and antiapoptotic The aqueous extracts of G. elata can regulate the activator activities in these brain areas in experimental PD models (Kumar protein 1 (AP-1) expression, thus to further modulate the neuronal et al., 2013). These results suggest that it has the potential to be plasticity and apoptosis, via the JNK signaling pathway in KA-in- developed as a clinical drug to ameliorate PD symptoms of duced epilepsy (Hsieh et al., 2007). At the same time, the me- patients. thanol extract of G. elata was shown to inhibit the recovery time Other ingredients, such as vanillyl alcohol, was also found to and severity of PTZ-induced convulsion rats, and this action might protect dopaminergic MN9D cells against MPPþ -induced apopto- be realized by increasing the GABA content of brain (Hsieh et al., sis by relieving oxidative stress and modulating the apoptotic 2007). In addition, 4-hydroxybenzaldehyde (4-HBA), a kind of process (Kim et al., 2011b). Bis (4-hydroxybenzyl) sulfide (BIS) and active component of G. elata, demonstrated an anti-oxidative effect and positive modulation of GABA, which contributes to its NHBA demonstrated the ability to prevent serum deprivation-in- antiepileptic and anticonvulsive activity (Ha et al., 2000). duced apoptosis in PC12 cells, in a concentration-dependent manner, and the ability to bind the adenosine A2Areceptor (A2A- 4.3. Anti-anxiety and antidepressant activities R) gene that is highly expressed in GABA striatopallidal neurons (Huang et al., 2007). Oral administration of aqueous G. elata extract or injection of its phenolic constituents, 4-HA and 4-HBA, can significantly in- 4.4.2. Anti-oxidative activities crease the percentage of the time spent and arm entries into the It is found that methanol extracts from G. elata also possess a open arms of the elevated plus maze (EPM) in mice. This ob- potent neuroprotective effect against oxidative glutamate toxicity servation suggests that they possess the anxiolytic-like effects in HT22 cells through up-regulating the function of PI3K signaling (Jung et al., 2006). Furthermore, 75% ethanol extract of G. elata pathway in association with brain-derived neurotrophic factor exerted antidepressant-like effect comparable to that of fluoxetine (BDNF), indicating that it may be a useful therapeutic agent for the in an experimental animal model (Zhou et al., 2006); the treatment of oxidative neuronal death (Han et al., 2014). Further- SlitRobo pathway and neuronal cytoskeleton remodeling are more, gastrodin (100 or 200 mg/ml) can effectively resist hypoxia- possibly key players associated with the antidepressive-like effect induced neurotoxicity in cultured rat cortical neurons, and this of G. elata (Lin et al., 2014). At the same time, in a forced-swim- mechanism may involve a down-regulation of the extracellular ming test (FST), G. elata showed antidepressant-like effect; the glutamate level (Xu et al., 2007). In addition, vanillin, 4-hydro- possible mechanism might be via regulating both the serotonergic xybenzyl aldehyde (4-HBAL) and 4-HBA can significantly inhibit and dopaminergic systems (Chen et al., 2009) or modulating the oxidative stress and excitotoxicity, and suppress neuronal death in turnover of DA in rats (P.J. Chen et al., 2012; X. Chen et al., 2012). CA1 region (Kim et al., 2007b).

4.4. Neuroprotective activities 4.4.3. Protection of neuro-synaptic plasticity The solution of G. elata in deionized water may promote neuro- 4.4.1. Protection of neuronal cells and anti-apoptotic action activities regenerative processes via controlling chaperone/proteasomal Both in vitro and in vivo studies of G. elata extracts or its in- degradation pathways (such as CALR, FKBP3/4, HSP70/90) (Ra- gredients on the neuroprotective activities had been conducted in machandran et al., 2012). Moreover, it also exhibited a signiﬁcant the past few years. In an in vitro experiment, chloroform, methanol inhibition on stress-related proteins and neuroprotective genes or ethanol extracts of G. elata, as well as the pure compounds such as Nxn, Dbnl, Mobkl3, Clic4, Mki67 and Bax with various gastrodin and 4-HBA, were shown to protect against β-amyloid regenerative modalities and capacities related to neuro-synaptic insult, which is one of the major recognized causes for the onset of plasticity (Manavalan et al., 2012a) and protected against lead- AD. It was also reported that G. elata has a protective effect on induced impairments on synaptic plasticity in the hippocampal pheo-chromocytoma cells (PC12), primary neuronal cells and BV2 CA1 region, like LTP, PPF, and I/O functions (three electro- microglia cells; the protective mechanism to BV2 microglia cells is physiological parameters for evaluation of synaptic plasticity) suggested to be the induction of the chaperone ER stress protein (Yong et al., 2009). 370 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

O OH OH CH2 O O O C O OH CH2 O O OH OH H2C O C O OH OH OH H2C O OH OH HO C C O CH2 O O OH HO C C O CH2 O O OH OH H2C C O OH OH OH H2C COOH OH CH2 O O O OH OH OH 1 2

O OH O CH2 O O CH2 OH C O OH C O H C OH 2 H C OH 2 HO C COOH HO C COOH

H C 2 H C C O OH 2 C O CH2 O O O OH CH2 OH O OH 3 OH 4 O OH CH2 O O C O OH OH H2C OH HO C COOH

H2C COOH 5

O OH OH CH2 O O O C O OH OH H C O OH 2 OH OH O OH HO C C O CH2 O O OH OH H2C C O OH OH

CH2 O O O OH OH 6 OH COOH O OH H2C O CH2 O O OH C O OH OH O C C O CH2 O O H2C O H OH OH OH OH HO C O O H2C C CH2 O COOH OH OH OH H2C COOH OH OCH3 7 8

Fig. 3. The structures of phenolics from G. elata. H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 371

O OH CH2 O O C O OH OH H2C O OH OH OH HO C C O CH2 O O OH O O OH H2C C O OH OH COOH OH O 22

COOH H2C O CHO OH

HO C C O CH2 O O OH OH OH H2C C O OH HO OCH3 CH2 OH O OH OCH3 23 24 25

CH2OH OH CH2OH

OCH3

OCH3 OH 26 27 28 29

COOH CH2OCH2CH3

HO HO

OH O H3CO

OH OH H 30 31 32 33

HO H2C OH

HO CH2O CH2O CH2OCH3

Fig. 3. (continued) 372 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

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 CH2OH O O O OH HO OH HO O HO HO CH2OH OH 46 47 48

Fig. 3. (continued) H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 373

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 O O O OH

OH 53 54

Fig. 3. (continued)

4.5. Anti-cardio-cerebral-vascular diseases activities NO (Zeng et al., 2006). Meanwhile, 4-HA, the aglycone of gastrodin, can reduce cerebral infarct volumes in a murine model of focal G. elata also played an important role in the protection against brain ischemia/reperfusion (Elodie et al., 2009). It also ameliorated cerebral ischemia. The water extract of G. elata was found to ischemic injury induced by transient focal cerebral ischemia in contribute to the improvement of synaptic plasticity and neuror- rats, and this neuroprotective effect may partly relate to attenu- estorative processes by regulating the brain proteome (Manavalan ating apoptosis pathway (Yu et al., 2009). In addition, p-hydro- et al., 2012b), and thus might be beneficial to neurodegenerative xybenzyl alcohol (p-HBA) was found to protect against brain da- diseases. mage by modulating cytoprotective genes, for instance, protein As one of the main effective constituents of G. elata, gastrodin disulphide isomerase (PDI), nuclear factor-E2-related factor2 was demonstrated to markedly decrease the infarct volume and (Nrf2), and neurotrophic factors (Kam et al., 2011). edema volume, improve the neurological functions on cerebral ischemic injury in rats caused by transient middle cerebral arterial 4.6. Antipsychotic activities occlusion (MCAO) and also significantly inhibit oxygen/glucose deprivation (OGD) and glutamate-induced neuronal cell death and 5-HT1A receptor has been recently regarded as an important reduce the extracellular glutamate level following OGD. Moreover, therapeutic target of schizophrenia. GR extract was demonstrated it can significantly inhibit the increase of OGD-induced Ca2 þ and to affect phencyclidine (PCP)-induced abnormal behavior in mice, 374 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

OCH3 NH N HN OH HO O N NN N OH

N HO N O HO OH

55 OH OH 56

HO NH

N N

OH N O N HO O O

O HO OH

57 58

HO HO

Fig. 3. (continued)

which may be mediated via activation of 5-HT1A receptor (Shin 2006). Furthermore, polysaccharide 2-1 from G. elata has re- et al., 2011). As one of the main effective constituents of G. elata, markable effects of anticoagulation and antithrembosis (Ding ﬁ parishin C also showed high af nity with 5-HT1A receptor as a et al., 2007). This result suggested that it may be one of the main – 35 γ 5-HT1A-agonist in an 8-OH-DPAT stimulated [ S] GTP- S binding components from G. elata for antithrombosis. assay (Shin et al., 2010).

4.7. Anti-vertigo activities 4.8.2. Anti-atherosclerotic activities It was found that the ethanol extract of G. elata can suppress It was demonstrated that polysaccharides of G. elata could the endothelial extracellular matrix degradation induced by tumor improve food intake of vertiginous mice caused by machinery necrosis factor (TNF)-α, and decrease TNF-α-induced increase of rotation, and also obviously shorten the escaping time of electrical matrix metalloproteinase (MMP)-2/-9 activities (Jung et al., 2009). shock in maze experiment and jumping platform test (Lei et al., These observations provide new insights into the pathophysiolo- 2006). However, the exact molecular mechanisms of their actions gical mechanisms for the anti-atherosclerotic properties of G. elata still remain to be determined. in vascular diseases.

4.8. Effect on circulatory system 4.8.3. Antihypertensive activities 4.8.1. Anticoagulant and antithrombotic activities It was evidenced that acidic polysaccharides isolated from G. Gastrodin has anticoagulant activity and the mechanism elata could reduce hypertension and improve serum lipid levels in mainly involves its interference with the knob-to-hole interactions spontaneously hypertensive rats (SHR) produced by a high-fat diet between ﬁbrin molecules, thereby effectively inhibiting the for- (Lee et al., 2012b), but the mechanism of this effect still remains to mation of clots and decreasing the risk of thrombosis (Liu et al., be further studied. H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 375

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 O O O OH

OH 53 54

Fig. 3. (continued)

4.9. Anti-inflammatory and analgesic activities 2012). These results indicate that it may be effective in the treatment of painful diabetic neuropathy (PDN). Phenolic compounds are a kind of important component that can be extracted from G. elata and possess anti-inflammatory and 4.10. Improve memory and anti-aging activities analgesic properties via inhibiting COX activity. It was also demonstrated that both C-4 hydroxy and C-3 methoxy radicals of Oral administration of G. elata powder mixed with drinking benzyl aldehyde from G. elata play an important role in anti-in- water can effectively improve memory functions and normalize fl ammatory effects (Lee et al., 2006). Moreover, the ethanol extract GABA levels in rats exposed to AlCl3 suffering from deficits in of G. elata was found to inhibit NO production in vivo and in vitro learning and memory, accompanied by increase in GABA levels in as well as the mRNA expression of inducible nitric oxide synthase the neocortex (He et al., 2008). But, it might not decrease the (iNOS) and cyclooxygenase-2 (COX-2) upon stimulation by lipo- content of brain cortex aluminum of rats (Niu et al., 2004) though polysaccharide (LPS) in RAW264.7 macrophages (Ahn et al., 2007). could ameliorate the learning and memory deficits induced by At the same time, it could also suppress TNF-α-induced vascular forced swimming (Chen et al., 2011). In addition, gastrodin was inflammatory process via inhibition of oxidative stress and NF-κB found to improve memory impairments in the Morris water maze activation in HUVEC (Hwang et al., 2009), presenting anti-angio- test and probe test, and attenuate Aβ deposition and glial activa- genic, anti-inflammatory and analgesic activities. In addition, tion in brains of mice (Hu et al., 2014), suggesting that gastrodin gastrodin was shown to decrease sodium currents and enhance exerted neuroprotective activity via anti-inflammatory and anti- potassium currents in diabetic small DRG neurons (Sun et al., amyloidogenic effects. 376 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

OCH3 NH N HN OH HO O N NN N OH

N HO N O HO OH

55 OH OH 56

HO NH

N N

OH N O N HO O O

O HO OH

57 58

HO HO

Fig. 3. (continued)

It was evidenced that the antioxidant effect of G. elata extract in Another study demonstrated that gastrodin could promote NF-κB- the rat brain, another important biological function of the herb, may mediated gene transcription in CD4þ T cells that is implicated in result from the actions of p-HBA and other phenolic compounds such its anticancer immunomodulatory properties (Shu et al., 2013). as vanillin at the cellular and molecular level (Liu and Mori, 1993). However, further studies are required to determine its speciﬁc The order of antioxidation potency was as follows: hydroxybenzyl anticancer actions. alcohol4vanillyl alcohol4vanillin4hydroxybenzaldehyde (Jung et al., 2007). Thus G. elata and its main constituents may have a 4.12. Other pharmacological activities potential in treating neurological disease through the inhibition on lipid peroxidation in the brain. Besides above-mentioned activities, G. elata has been shown to exert other pharmacological effects. In a study on anti-huntingtin 4.11. Antivirus and antitumor activities aggregations, 70% methanol extracts of G. elata was demonstrated to prevent mutant huntingtin aggregations in PC12 cells in a Two glucans, WGEW and AGEW, isolated from G. elata and its model of Huntington’s disease (HD) and was demonstrated to sulfated derivatives (such as WSS25 and WSS45) were all shown to increase proteasomal activity by targeting the A2A-R through have strong anti-dengue virus bioactivities. However, the study on protein kinase A (PKA)-dependent pathway (Huang et al., 2011). structure-activity relationships (SAR) between the polysaccharides Studies on laboratory mice have shown that 30% methanol extract and their sulfated derivatives showed that the higher the degree of of G. elata protects the gastric mucosa against water immersion substitution is, the more potent the impact on the dengue virus restraint (WIR)-induced gastric damage, at least in part by de- infection would be (Qiu et al., 2007; Tong et al., 2010). Further- creasing NO levels via suppression of iNOS mRNA expression (Park more, G. elata extract may have the potential to alleviate tumor- et al., 2007). Gastrodin was also found to prevent steroid-induced igenesis by a GTP-Ras-dependent pathway (Heo et al., 2007); al- osteonecrosis of the femoral head in rats by anti-apoptosis and though the precise molecular mechanisms are still unclear. was found to protect against osteoporosis linking to a reduction in H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 377

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 O HO OH HO OH HO OH OH y n y n H(x+y=14) H(x+y=16) 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 OH HO OH OH OH y n y n R=SO or H(x+y=16) R=SO or H(x+y=16)

62 63

O O NH OH OH OH N O N O OH OH

N HO OH N O OH HOH C

OH OH 64 65 O HO O C O CH HO OH HO O OH O HO O OC C O CH O HO O

OH 66 67 C O CH O

O O CHO OH H HO

68 69

Fig. 4. The structures of polysaccharides from G. elata. 378 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

O H2C COOH O H2C C O CH3

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

O 70 71 72

O O

CH3CH2(CH2)17CH2CH2C 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. reactive oxygen species (Zheng et al., 2014; Huang et al., 2014). traditional use of it as a neuroprotective, sedative, hypnotic, anti- Another study found that gastrodin has a protective potential in epileptic, anti-convulsive, anti-anxiety, anti-depressant and blood targeting cardiac hypertrophy and ﬁbrosis through suppression of circulation regulating herbal medicine. Furthermore, besides its ERK1/2 signaling (Shu et al., 2012). Besides, BIS, isolated from G. traditional use for nervous system, modern pharmacological ex- elata was found possessing anti-melanogenesis ability (J.S. Chen periments have shown more other activities, such as anti-tumor, et al., 2015; W.C. Chen et al., 2015). Furthermore, the C-4 hydroxy anti-virus, memory-improving, anti-aging, etc. Although the me- and C-3 methoxy radicals in benzyl alcohols and aldehydes (such chanisms of some of these activities have not been fully clear, as 4-hydroxy-3-methoxybenzyl alcohol, 4-hydroxy-3-methox- there has already been a clue that the therapeutic effectiveness of ybenzoic acid, etc.) play important roles in mediating the anti- G. elata on a variety of disorders is somewhat based on its wide- asthmatic activities of phenolic compounds obtained from the reaching biological activities (Table 4). 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 5. Quality control a beneﬁcial therapeutic approach for metabolic syndrome (Kho et al., 2014; Teong et al., 2011). It was also found that the water G. elata can be found all over China and its broad distribution extract mainly reduced insulin resistance as a result of the action determines its quality variations among the different producing of 4-HBA and vanillin contained in G. elata (Park et al., 2011). areas. Up to date, there are almost ten representative national GAP All in all, the experimental results that G. elata has remarkable (Good Agricultural Practice) bases located in Yunnan, Sichuan, effects on nervous system, cardiocerebral vascular system and Guizhou, Shanxi and Hubei province. G. elata is one of the botanical blood circulation system have powerfully supported the drugs that is most prone to adulteration due to its high economic H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 379

HO CH2 N CH2 OH

OH 77

O O

N N HN N

N HO CH H N N H2N N 2 2 H3CO N O O HOH2C H2C HO

OH OH OH OH 78 79

HO CH2 NH2 25 N N

S N N O H O HOH C 2 H2N N COOH N

COOH H O OH OH

Fig. 6. The structures of other compounds from G. elata. value and there are many instances of fakes on the market. In the (Shu et al., 2013). But according to a recent report, intramuscular Pharmacopeia of Peoples Republic of China, qualitative identifi- injection of gastrodin could cause severe allergic reactions and cation by thin layer chromatography (TLC) and determination of even allergic shock (Hou and Fang, 2012). Subcutaneous injection content by high performance liquid chromatography (HPLC) are of Tianma Injection at the dose of 75 g/kg, mice were shown to be mainly used to evaluate the quality of G. elata. Gastrodin is chosen quiet without other behavioral changes. However, intravenous as the marker component to control the quality of G. elata, and it's injection of Tianma Injection, LD50 of the mice is 39.8 g/kg (36.5 g/ required that the content of gastrodin should be no less than 0.2% kg-43.5 g/kg), but intravenous injection of 1000 mg/kg glycosides with the specified methods (Chinese Pharmacopoeia Commission, from G. elata, no obvious toxic reaction was observed (Huang and 2015). However, using only one ingredient as the marker might Wang, 1985). BIS was found to be a strong competitive inhibitor not be sufficient to fully clarify the quality of G. elata due to its against mushroom tyrosinase, and an in vivo zebrafish assay re- complex constituents and multifarious pharmacological activities. veals that BIS can effectively reduce melanogenesis with no ser- In fact, more important bioactive constituents should be in- ious side effects. But in an acute oral toxicity study with mice, it tegrated into the quality control system of G. elata. Encouragingly, was shown to be free of discernable cytotoxicity (J.S. Chen et al., in recent years, the method of HPLC fingerprinting has been de- 2015; W.C. Chen et al., 2015). veloped 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). 7. Concluding remarks

A large number of investigations of G. elata have been carried 6. Toxicology out due to its wide use in the healthcare as well as in the clinical practice of TCM in both China and some Asian countries. To date, Clinical reports on the toxicity of G. elata are relatively few. It more than 81 compounds have been isolated from G. elata, pre- was found that gastrodin was capable of repressing transplanted dominantly phenolics and its glycosides, polysaccharides, sterols H22 ascitic hepatic tumor cell growth in vivo with low toxicity and organic acids. Among these ingredients, phenolics and their Table 4 380 Bioactivities of the extracts and compounds from G. elata.

Pharmacological Extract/Compound Types Testing subjects Dose Effects References activities

6 Sedative and hypnotic N -(3-methoxyl-4-hydroxybenzyl) ade- in vivo male ICR mice 1, 5 mg/kg i.p. Shortened the sleep latency, prolonged NREM Zhang et al., 2012 activities nine riboside (B2) sleep and shortened wakefulness N6-(4-hydroxybenzyl) adenine riboside in vivo adult male ICR mice-treated with so- 0.2, 1, 5 mg/kg i.p. Decreased wakefulness time and increased Shi et al., 2014 (NHBA) dium pentobarbital NREM sleep time Antiepileptic and antic- aqueous extracts of G. elata in vivo male SD rats –treated with kainic acid 0.5, 1.0 g/kg/day for Regulated the AP-1 expression via the JNK sig- Hsieh et al., 2007 onvulsive activities (KA) 2 weeks p.o. naling pathway 4-HBA in vivo male SD rats –treated with pentylene- 500 mg/kg p.o. Inhibited the recovery time and severity, in- Ha et al., 2000 tetrazole (PTZ) creased the brain GABA contents Anti-anxiety and anti- aqueous extracts of G. elata in vivo elevated plus maze (EPM) in male ICR 50, 100, 200, 400 mg/kg Increased the percentage of time spent and arm Jung et al., 2006 depressant activities mice p.o. entries into the open arms of the EPM 4-HA in vivo the same as above 5, 10, 25, 50, 100 mg/kg i. The same as above Jung et al., 2006

p. 361 (2016) 189 Ethnopharmacology of Journal / al. et Zhan H.-D. 4-HBA in vivo the same as above 5, 10, 25, 50, 100 mg/kg i. The same as above Jung et al., 2006 p. 75% ethanol extracts of G. elata in vivo behavioral models of male kunming 100, 200, 300 mg/kg p.o. Reduced the immobility duration in FST and Zhou et al., 2006 mice TST aqueous extracts of G. elata in vivo male SD rats 500 mg/kg p.o. Down-regulated Slit-Robo pathway mediating Lin et al., 2014 neuronal cytoskeletal remodeling processes aqueous extracts of G. elata in vivo using forced-swimming test as an 0.5, 1.0 g/kg p.o. Regulated serotonin and dopamine concentra- Chen et al., 2009 animal tion and their metabolism model of depression (6 weeks old male SD rats) water extracts of G. elata in vivo 6 weeks old male SD rats 1.0 g/kg p.o. Decreased the turnover of DA in striatum P.J. Chen et al., 2012; X. Chen et al., 2012 Neuroprotective activities Protection of neuronal cells chloroform, methanol or ethanol ex- in vitro BV2 mouse microglial cells- treated 1 mg/ml Against β-amyloid-induced cell death, possibly Lee et al., 2012a; KimKim et al., and anti-apoptotic tracts of G. elata, gastrodin, or 4-HBA with β-amyloid through the enhancement of protein folding et al., 2007a2011a; activities machinery of a representative protein, GRP78, and the regulation of CHOP in BV2 mouse mi- 50% alcohol extracts of G. elata in vivo adult male SD rats-treated with KA 0.5, 1.0 g/kg p.o.croglial Mediated cells the suppression of nNOS and micro- Hsieh et al., 2005 injection glia activation aqueous extracts of G. elata in vivo drosophila and PC12 cells- treated with 1, 5 mg/g 250–1000 mg/ Upregulated the enzymatic activities of cata- Ng et al., 2013 – and in β-amyloid ml lase, superoxide dismutase, and glutathione 385 vitro peroxidase 1, 5, 25 mM Up-regulated heme oxygenase-1 (HO-1) ex- Jiang et al., 2014 gastrodin in vitro þhuman dopaminergic cells-treated with MPP pression through activation of p38 MAPK/Nrf2 signaling pathway gastrodin in vivo Wistar rats (male, 4 weeks old)-treated 20 mg/kg/day in- Increased the down-regulated striatal DA con- Zhang and Li, 2015 with apomorphine (Apo) traperitoneal injection tent in IDPN-induced rats, decreased the upregulated striatal DA content in Apo-induced rats gastrodin in vitro six-week-old male C57BL/6 mice and 10, 30, 60 mg/kg 1, 5, and Prevented the ROS generation; augmented SOD Kumar et al., 2013 25 mM activity; regulated Bax/Bcl-2 mRNA, caspase-3, and human dopaminergicþ SH-SY5Y cells- in vivo treated with MPP and cleaved poly (ADP-ribose) polymerase (PARP) vanillyl alcohol in vitro MN9D dopaminergic cells-treated with 10, 100, 200 mg/m l Attenuated the elevation of ROS levels, de- Kim et al., 2011a,b þ MPP creased the Bax/Bcl-2 ratio and poly (ADP-ribose)polymerase proteolysis 10 5 BIS and NHBA in vitro PC12 cell ischemic/hypoxic model 1 10 to 1 10 M Prevent serum deprivation-induced apoptosis Huang et al., 2007 in PC12 cells and to bind A2A-R Anti-oxidative activities methanol extracts of G. elata in vitro HT22 hippocampal cells-treated with 0.1–30 g/ml Up-regulated the PI3K signaling pathway and Han et al., 2014 glutamate(5 mM) inhibited production of ROS gastrodin in vitro rat cortical neurons treated with 100, 200 mg/ml Inhibited the extracellular glutamate level Xu et al., 2007 hypoxia induced by NMDA insult Vanillin, 4-HBAL and 4-HBA in vivo hippocampal CA1 cell death following 40 mg/kg i.p. Suppressed neuronal death in CA1 region. after Kim et al., 2007b global ischemia global ischemia Protection of neuro-synap- supernatant of powdered Tianma in in vitro human neuronal SH-SY5Y cells 1 mg/ml per well Controlled chaperone/proteasomal degradation Ramachandran et al., tic plasticity water pathways (e.g. CALR, FKBP3/4, HSP70/90) and 2012 mobilized neuro-protective genes (such as AIP5) as well as modulated other proteins (RTN1/4, NCAM, PACSIN2, and PDLIM1/5) supernatant of G. elata powder in water in vivo mouse neuronal N2a cells 1 mg/ml per well Inhibited stress-related proteins and mobilized Manavalan et al., 2012a neuroprotective genes such as Nxn, Dbnl, Mobkl3, Clic4, Mki67 and Bax gastrodin in vitro wistar rats on postnatal day 22 50, 100, 200, 400 mg/kg/ Relieved LTP, PPF, and I/O functions were im- Yong et al., 2009 d intraperitoneally paired in lead-exposed rats injection Anti-cardio-cerebral-vas- supernatant of G. elata powder in water in vivo one-year-old male Wistar Kyoto rats 2.5 g/kg/day for Modulated the brain protein metabolism at the Manavalan et al., cular diseases activities brain tissue 3 months p.o. proteome level þ 2012b 2 and NO Zeng et al., 2006 phenolic glucoside gastrodin in vitro transient middle cerebral arterial oc- 50, 100 mg/kg (in- Inhibited the OGD-induced Ca increases

clusion (MCAO) model and rat hippo- traperitoneal injection) 361 (2016) 189 Ethnopharmacology of Journal / al. et Zhan H.-D. campal neurons injured byoxygen/glu- 15, 30 mg/ml cose deprivation (OGD) or glutamate 4-HBA in vivo C57 black J6 mice MCAO model 25 mg/kg i.e. Reduced total, cortical and sub-cortical infarct Elodie et al., 2009 volumes by 42%, 28% and 55% 4-HBA in vivo cerebral ischemic injury rats 25, 50 mg/kg p.o. Increased the expression of Bcl-2 and inhibited Yu et al., 2009 the activation of caspase-3 ultimately p-HBA in vitro female SD rats MCAO model 25 mg/kg p.o. Modulated cytoprotective genes, such as Nrf2 Kam et al., 2011 and and PDI, and neurotrophic factors in vivo in mice. Shin et al., 2011 Antipsychotic activities supernatant of G. elata in 0.5% carbox- in vivo male C57BL/6 J mice or male ICR mice- 500, 1000 mg/kg/day p.o. Mediated via activation of 5-HT1A ymethyl cellulose treated with Phencyclidine Parishin C in vivo male C57BL/6 J mice or male ICR mice 25, 50, 100 mg/kg /day i. Activated 5-HT1A receptors Shin et al., 2010 p. Anti-vertigo activities polysaccharides of G. elata in vivo male Kunming mice 50, 10, 200 mg/kg p.o. Obviously shortened the escaping time of Lei et al., 2006 electrical shock and increase food intake of mice Effect on circulatory system Anticoagulant and antith- gastrodin in vivo rats 7.5, 15, 30 mg /kg tail in- Interference with the knob-to-hole interactions Liu et al., 2006 rombotic activities travenous injection between ﬁbrin molecules polysaccharide 2-1 from G. elata in vitro male Kunming mice and Wistar rats 10, 20, 40 and 30, 60, Remarkably prolonged CT and BT, increased Ding et al., 2007 –

and 120 mg/kg in- bleeding capacity 385 in vivo traperitoneal injection Antihypertensive activities acidic polysaccharides in vivo spontaneously hypertensive rats model 6 mg/kg p.o. Decreased blood pressure and serum lipid Lee et al., 2012a,b levels Anti-inﬂammatory and an- phenolic compounds in vivo pathogen-free male SD rats- treated 12.5, 25, 50 mg/kg p.o. Had anti-inﬂammatory and analgesic proper- Lee et al., 2006 algesic activities with carrageenan ties and inhibited COX activity and silica-induced ROS generation in a dose-dependent manner ethanol extracts of G. elata in vivo male ICR mice-treated with 0.7% acetic 50, 100, 200 mg/kg p.o. 0, Inhibited NO production Ahn et al., 2007 and in acid and RAW264.7 macrophages trea- 0.25, 0.5, 1.0 mg/ml vitro ted with LPS 99.0%ethanol extracts of G. elata in vivo human umbilical vein endothelial cells 1, 10, 50 mg/ml Inhibited oxidative stress and NF-κB activation Hwang et al., 2009 gastrodin in vivo rats-treated with streptozotocin (STZ) 5, 10, 20 mg/kg in- Decreased transient sodium currents, increased Sun et al., 2012 traperitoneal injection potassium currents in diabetic small DRG neurons Improve memory and anti- G. elata powder mixed in the water in vivo adult male SD rats-treated with alumi- 0.4 g/kg p.o. Decreased Al concentrations in the neocortex He et al., 2008 aging activities num chloride (5 or 10 mg/kg/day (i.p.) and increased in cortical GABA levels

for 2 months) 381 water decoction of G. elata in vivo male Wistar rats- treated with lead 4 g/kg/d p.o. Increased the expression of c-fos mRNA in Hu et al., 2003 acetate(0.2 or 0.1 g/kg/d) hippocampus and cerebellum water extracts of G. elata in vivo four-week-old male SD rats learning 0.5, 1.0 g/kg p.o. Improved retention by shortening escape Chen et al., 2011 Table 4 (continued ) 382

Pharmacological Extract/Compound Types Testing subjects Dose Effects References activities

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. elata in vivo SD rats-treated with aluminum 0.4 g/kg p.o. Regulated the cholinergic system and the Niu et al., 2004 monoaminergic system. 0, 0.0025, 0.025, 0.25, a dose-dependent inhibition on Fe (Ⅱ)-H O - Liu and Mori, 1993 p-HBA, Vanillin in vitro rats brain tissue (8-week-old male SD 2 2 O ) 2.5% induced damage to benzoate, deoxyribose, rats-treated with Fe(Ⅱ)-H 2 2 glutamic acid, 2-aminobutyric acid and me- thionine, as well as benzoate hydroxylation ether fraction of the methanol extract in vivo male Mongolian gerbils-treated with 500 mg/kg/day for Inhibited auto-peroxidation and H 2O2- induced Jung et al., 2007 of G. elata, vanillin, vanillyl alcohol, 2O2H 2 weeks p.o. lipid peroxidation; the order of antioxidation hydroxybenzaldehyde and potency was as follows: hydroxybenzyl alcohol

hydroxybenzylalcohol 4vanillyl alcohol 4vanillin 361 (2016) 189 Ethnopharmacology of Journal / al. et Zhan H.-D. 4hydroxybenzaldehyde Antivirus and antitumor WSS45 in vitro BHK cells-treated with DV2 infection 0.1, 1, 10 mg/ml Inhibited DV2 infection in BHK cells with an Tong et al., 2010 7 m activities EC50 value of 0.68 0.17 g/ml, mainly inter- fered with virus adsorption WGEW and AGEW in vitro C6/36 cells 0.6 g WGEW, 1.8 g AGEW The higher the DS is, the more potent the im- Qiu et al., 2007 pact on the dengue virus infection would be 99.0% ethanol extract of G. elata in vitro primary cultured HUVEC and en- 30, 100 μg/ml Alleviated tumorigenesis, by a GTP-Ras-depen- Lee et al., 2009 dothelial cell-treated with necrosis dent pathway factor-alpha methanol extracts of G. elata in vitro murine melanoma cell line B16-F1 and 30, 100 μg/ml Alleviated tumorigenesis in a dose-dependent Heo et al., 2007 human umbilical vein endothelialcells manner, by a GTP-Ras-dependent pathway; but (HUVECs) the precise molecular mechanisms are still being examined cells 0 to 500 μg/ml Prevented mutant Htt aggregations targeting Huang et al., 2011 Other pharmacological 70% MeOH extracts of G. elata in vitro Ratl2 PC the A -R through PICA-dependent pathway. activities 2A 30% methanol extracts of G. elata in vivo mouse water immersion restraint 20 ml/kg p.o. 30 μg/ml Decreased in serum and gastric musica nitric Park et al., 2007 and in (WIR) stress-induced gastric lesion oxide (NO) levels to 50% and 28%, respectively vitro model gastrodin in vitro hBMMSCs and RAW264.7 cells-treated 0.1, 1, 10 μM Increased mRNA and protein expression of Bax, Zheng et al., 2014; with2O H2 Bcl-2, and Caspase-3, decreased the Bcl-2 Huang et al., 2014a,b mRNA and protein expression levels –

gastrodin in vivo adult male C57/B6 mice 100 mg/kg/day p.o. Attenuated fibrosis and collagen synthesis Shu et al., 2012 385 through abrogating ERK1/2 signaling pathway BIS in vivo zebrafish 5, 50 μM The molecular modeling demonstrates that the J.S. Chen et al., 2015; sulfur atom of BIS coordinating with the copper W.C. Chen et al., 2015 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-methoxybenzyl alcohol in vivo male dunkin hartley guinea pigs 12.5, 25, 50 mg/kg p.o. The C-4 hydroxy and C-3 methoxy radicals in Jang et al., 2010 benzyl alcohols and aldehydes play important roles in mediating the anti-asthmatic activities water extracts of G. elata in vivo male SD rats 0.3, 1.0 g/kg p.o. Reduced insulin resistance by decreasing fat Park et al., 2011 accumulation in adipocytes by activating fat oxidation and potentiating leptin signaling in diet-induced obese rats ethanol extracts of G. elata in vivo six-to-seven-week-old male SD rats 2.5 g/kg for 7 weeks p.o. Isoprenaline (IPNA)-induced relaxation re- Teong et al., 2011 mained unchanged in –UE strips after Tianma treatment, but the potency of IPNA was lower in Tianma-treated þUE strips in the longitudinal direction H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 383 glycosides have been proven to be closely linked to the pharma- newly recorded species of Gastrodia from Mainland, China. Acta Bot. Boreal. cological activities of G. elata. As one of the main active in- Occident. Sin 35, 1482–1484. Chen, P.J., Sheen, L.Y., 2011. Gastrodiae Rhizoma (tiān má): a review of biological gredients, gastrodin was shown to possess a variety of actions such activity and antidepressant mechanisms. J. Tradit. Complement Med. 1, 31–40. as protect ion of neuronal cells, anti-apoptotic, anti-oxidative, Chen, W.Q., Deng, B.W., Ding, R., Wu, S.Q., Li, X.S., 2005. Peroxidase isozyme in three anticoagulant and antithrombotic, anti-inflammatory, anti-aging Gastrodia elata variants. J. Acta Bot. Boreal.-Occident. Sin. 5, 1665–1668. Chen, P.J., Hsieh, C.L., Su, K.P., Hou, Y.C., Chiang, H.M., Sheen, L.Y., 2009. Rhizomes of and analgesic activities. Although the in vitro and in vivo studies Gastrodia elata BL. possess antidepressant-like effect via monoamine modula- have provided evidence strongly indicating that G. elata is useful in tion in subchronic animal model. Am. J. Chin. Med. 37, 1113–1124. many diseases, pharmacological research validating its traditional Chen, P.J., Hsieh, C.L., Su, K.P., Hou, Y.C., Chiang, H.M., Lin, I.H., Sheen, L.Y., 2012. The uses is still limited. antidepressant effect of Gastrodia elata BL. on the forced-swimming test in ratsAm. J. Chin. Med 36, 95–106. To date, most of the studies that have been performed on G. Chen, P.J., Liang, K.C., Lin, H.C., Hsieh, C.L., Su, K.P., Hung, M.C., Sheen, L.Y., 2011. elata were based on its total extracts (mostly poorly characterized), Gastrodia elata BL. attenuated learning deficits induced by forced-swimming more promising natural chemical compounds-especially the trace stress in the inhibitory avoidance task and Morris water maze. J. Med. Food 14, 610–617. amount but highly effective ingredients, should be extracted and Chen, X., Xiao, F., Wang, Y., Fang, J.P., Ding, K., 2012. Structure-activity relationship purified with the most advanced chemical technologies. In addi- study of WSS25 derivatives with anti-angiogenesis effects. Glycoconi J. 29, – tion, more studies regarding pharmacodynamics and pharmaco- 389 398. Chen, W.C., Tseng, T.S., Hsiao, N.W., Lin, Y.L., Wen, Z.H., Tsai, C.C., Leeb, Y.C., Lin, H.H., kinetics should be conducted using the key natural ingredients Tsai, K.C., 2015. Discovery of highly potent tyrosinase inhibitor, T1, with sig- derived from this plant in order to clarify the pharmacological nificant anti-melanogenesis ability by zebrafish in vivo assay and computa- mechanism of action and to search for the metabolites responsible tional molecular modeling. Sci. Rep. 5, 7995. Chen, S.J., 2010. Shuxuening injection with Banxia Baizhu Tianma Decoction for the activities of G. elata. Furthermore, the current study on the treatment Vertebral-Basilar insufficiency of 38 cases. J. Pract. Tradit. Chin. In- phytochemistry of this plant were mainly targeting on its tubers tern. Med. 24, 63–64. while studies on other parts, such as stem and leaves, are still Chik, S.C.C., Terry, C.T., Luo, D., Yang, C.L.H., Lau, A.S.Y., 2013. Pharmacological effects of active compounds on neurodegenerative disease with Gastrodia and Uncaria lacking. In Compendium of Materia Medica (Ben cao gang mu), Decoction, a commonly used Poststroke Decoction. Sci. World J. 10, 1155. both stem and leaves of G. elata are regarded as medicinal parts Chinese Academy of Sciences, 2004. Flora of China. Science Press, Beijing. entering liver meridian and also effective in treatment of the Chinese Pharmacopoeia Commission, 2015. Pharmacopoeia of the People’s Republic of China. Part Ⅰ. Chinese Medical Science And Technology Press, Beijing. diseases caused by invasion of the wind. Therefore, more in- Choi, J.H., Lee, D.U., 2006. A new citryl glycoside from Gastrodia elata and its investigations on the chemical composition and pharmacological hibitory activity on GABA transaminase. Chem. Pharm. Bull. 54, 1720–1721. actions of these medicinal parts should be encouraged. Chung, S.W., Hsu, T.C., 2006. Gastrodia shimizuana, a new record of Gastrodia (Orchidaceae) in Taiwan. Taiwania 51, 50–52. The current price for G. elata is becoming higher and higher due Deng, S.X., Mo, Y.Q., 1979. Pharmacological studies on Gastrodia elata Blume. I. The to its increasing demand in the herbal market, especially the wild sedative and anticonvulsant effects of synthetic gastrodin and its genin. Acta sources of G. elata are dwindling dramatically due to exhaustive Bot. Yunnanica 1, 66–73. exploitation. This thus raises concerns about the possible delib- Deng, S.X., Mo, Y.Q., 1980. Pharmacological studies on Gastrodia elata Blume. I. Effects of synthetic gastrodin and its genin on the heart and small intestine. erate confusion of this herbal drug with others, such as mirabills Acta Bot. Yunnanica 2, 230–234. jalapa L. (family nyctaginaceae), ahlia plnnata Cav. (family compo- Ding, C.S., Shen, Y.S., Li, G., Wei, Z., Wei, F., 2007. Study of a glycoprotein from sitae), canna edulis Ker.(family cannaceae), cacalia tangutica (Fr.) H. Gastrodia elata: its effects of anticoagulation and antithrombosis. China J. Chin. Mater. Med. 32, 1060–1064. M. (family composltae) and cacalla davidll (Fr.) H.M.(family com- Dong, M.H., 2012. The clinical application and progress of Banxia Baizhu Tianma positae). Though quite similar in appearance of dried roots or tu- decoction. Chin. J. Ethnomed. Ethnopharm. 3, 44–46. fi bers, their contents in the active ingredients and bioactivities vary Dressler, R.L., 1993. Phylogeny and Classi cation of the Orchid Family. Dioscorides Press, Oregon. greatly. Thus, how to exclusively and accurately monitor and Duan, X.H., Li, Z.L., Yang, D.S., Zhang, F.L., Lin, Q., Dai, R., 2013. Study on the chemical evaluate the quality of samples, by detection of multiple active constituents of Gastrodia elata. J. Chin. Med. Mater. 36, 1608–1611. ingredients instead of only one, to identify G. elata from its con- Elodie, D., Maud, P.L., Pierre, M., Nicole, P., Pierre, B., Regis, B., Joseph, V., 2009. fi Experimental stroke protection induced by 4-hydroxybenzyl alcohol is can- fusing herbs to ensure and maintain its clinical ef cacy and celled by bacitracin. Neurosci. Res. 64, 137–142. pharmaceutical stability, should be further studied. Fan, J.A., Yi, S.P., Li, S.R., Zhou, B.Z., 1991a. Preliminary research on the correlation between genuine medicinal materials and trace element in Sichuan. J. Chin. Med. Mater. 14, 3–5. Fan, J.A., Yi, S.P., Li, S.R., 1991b. Research on the correlation between genuine Acknowledgments medicinal materials and its trace element and geological background in Si- chuan. J. Chin. Med. Mater. 14, 3–6. Gao, X.P., 2012. Clinical examination of treating vertigo with the Tianmasu injec- This work was supported by grants from the National Natural tion. Clin. J. Chin. Med. 4, 86–87. Science Foundation of China (81274112; 81373986; 81473372; Gu, G.G., Yang, P.J., 2013. Shennong's Classic of Materia Medica. Academy Press, 81403322; 81403125), Beijing Municipal Natural Science Founda- Beijing. Ha, J.H., Lee, D.U., Lee, J.T., Kim, J.S., Yong, C.S., Kim, A., Ha, J.S., Huh, K., 2000. 4- tion (7152106), Inheritance Program of China Academy of Chinese Hydroxybenzaldehyde from Gastrodia elata BL. is active in the antioxidation Medical Sciences (CM2014GD3002) and Voluntary Program of and GABAergic neuromodulation of the rat brain. J. Ethnopharmacol. 73, China Academy of Chinese Medical Sciences (ZZ2014056). 329–333. Han, A.R., Shin, H.J., Jeon, H.R., Lee, J.H., Lee, D., Seo, E.K., 2011. Two New Phenolic Compounds from the Rhizomes of Gastrodia elata Blume. Helv. Chim. Acta 94, 1310–1314. References Han, Y.J., Je, J.H., Kim, S.Y., Ahn, S.M., Kim, H.N., Kim, Y.R., Choi, Y.W., Shin, H.K., Choi, B.T., 2014. Gastrodia elata shows neuroprotective effects via activation of PI3K signaling against oxidative glutamate toxicity in HT22 cells. Am. J. Chin. Med. 4, Ahn, E.K., Jeon, H.J., Lim, E.J., Jung, H.J., Park, E.H., 2007. Anti-inflammatory and anti- 1007–1019. angiogenic activities of Gastrodia elata Blume. J. Ethnopharmacol. 110, 476–482. Hao, X.Y., Tan, N.H., Zhou, J., 2000. Constituents of Gastrodia elata in Guizhou. Acta Andersson, M., Bergendorff, O., Nielsen, M., Sterner, O., Witt, R., Ai, J., Lu, A., Wang, Bot. Yunnanica 22, 81–84. A.M., 1995. Inhibition of kainic acid binding to glutamate receptors by extracts He, S.C., Niu, Q., Niu, P., He, M.W., Sun, X.S., Shao, F., Wang, S., Mark, O., 2008. of Gastrodia. Phytochemistry 38, 835–836. Protective effects of Gastrodia elata on aluminium-chloride-induced learning Aoyama, M., Yokota, M., 2012. Chromosome number of Gastrodia javanica (Blume) impairments and alterations of amino acid neurotransmitter release in adult Lindl., a myco-heterotrophic orchid. Chromosome Sci. 14, 39–40. rats. Restor. Neurol. Neurosci. 6, 467–473. Baek, N.I., Choi, S.Y., Jin, K.P., Cho, S.W., Ahn, E.M., Jeon, S.G., Lee, B.R., Bahn, J.H., Kim, He, K.L., Zhang, P., Liu, X., 2014. Tianma injection in the treatment of vertebral Y.K., 1999. Isolation and identification of succinic semialdehyde dehydrogenase basilar artery insufficiency randomized parallel group study. J. Pract. Tradit. inhibitory compound from the rhizome of Gastrodia elata, blume. Arch. Phar- Chin. Intern. Med. 5, 44–46. macal Res. 22, 219–224. Heo, J.C., Woo, S.U., Son, M., Park, J.Y., Choi, W.S., Chang, K.T., Kim, S.U., Yoon, E.K., Chen, J.S., Hou, Z.Q., Wen, G.Y., Wang, M., Ye, D.P., Du, F., 2015. Gastrodia gracilis, a Shin, S.H., Lee, S.H., 2007. Anti-tumor activity of Gastrodia elata Blume is closely 384 H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385

associated with a GTP-Ras-dependent pathway. Oncol. Rep. 18, 849–853. Gastrodia elata Blume through suppression of oxidative stress and anti-apop- Hong, Q.M., Shan, S.S., Wang, C., Wang, S.C., Li, X.L., Wu, X.J., 2010. Structural totic activity in toxin-induced dopaminergic MN9D cells. Molecules 16, characterization of a glucan isolated from Gastrodia elata. J. Chin. Med. Mater. 5349–5361. 33, 726–729. Kumar, H., Kim, I.S., More, S.V., Kim, B.W., Bahk, Y.Y., Choi, D.K., 2013. Gastrodin Hou, J.Y., Fang, T.H., 2012. Pharmacology of Chinese Materia Medica. China Tradi- protects apoptotic dopaminergic neurons in a toxin-induced Parkinson’s dis- tional Chinese Medicine Press, Beijing. ease model. Evid.-based Complement. Altern. Med. 514095, 1–13. Hsieh, C.L., Chen, C.L., Tang, N.Y., Chuang, C.M., Hsieh, C.T., Chiang, S.Y., Lin, J.G., Hsu, Lai, H.Y., 2012. Asymbiotic seed germination of Gastrodia flabilabella and in vitro S.F., 2005. Gastrodia elata BL mediates the suppression of nNOS and microglia rhizome propagation of G. pubilabiata. D. Department Of Agronomy National activation to protect against neuronal damage in kainic acid-treated rats. Am. J. Chung-Hsing Univerity, Taiwan. Chin. Med. 33, 599–611. Lee, J.Y., Jang, Y.W., Kang, H.S., Moon, H., Sim, S.S., Kim, C.J., 2006. Anti-inflammatory Hsieh, C.L., Lin, J.J., Chiang, S.Y., Su, S.Y., Tang, N.Y., Lin, G.G., Lin, I.H., Liu, C.H., action of phenolic compounds from Gastrodia elata root. J. Arch. Pharm. Res. 29, Hsiang, C.Y., Chen, J.C., Ho, T.Y., 2007. Gastrodia elata modulated activator 849–858. protein 1 via c-Jun N-terminal kinase signaling pathway in kainic acid-induced Lee, Y.K., Woo, M.H., Kim, C.H., Kim, Y., Lee, S.H., Jeong, B.S., Chang, H.W., Son, J.K., epilepsy in rat. J. Ethnopharmacol. 109, 241–247. 2007. Two new benzofurans from Gastrodia elata and their DNA topoisome- Hu, Z., Huang, Q., 1994. Induction and accumulation of the antifungal protein in rases I and II inhibitory activities. Planta Med. 73, 1287–1291. Gastrodia elata. Acta Bot. Yunnanica 16, 169–177. Lee, Y.J., Huang, M.S., Kang, D.G., Kim, S.J., Lee, H.S., 2009. Effect of Gastrodia elata on Hu, Z., Yang, Z., Wang, J., 1988. Isolation and partial characterization of an antifungal tumor necrosis factor-alpha-induced matrix metalloproteinase activity in en- protein from Gastrodia elata corm. Acta Bot. Yunnanica 10, 373–380. dothelial cells. J. Nat. Med. 63 (4), 463–467. Hu, Z., Huang, Q., Liu, X., Yang, J., 1999. Primary structure and cDNA cloning of the Lee, G.H., Kim, H.R., Han, S.Y., Bhaandary, B., Kim, D.S., Kim, M.G., So, B.O., Kim, S.Y., antifungal protein GAFP-1 from Gastrodia elata. Acta Bot. Yunnanica 21, Jo, K.S., Lee, B.H., Seos, H.N., Chae, S.W., Chae, H.J., 2012a. Gastrodia elata Blume 131–138. and its pure compounds protect BV-2 microglial-derived cell lines against β- Hu, Y.H., Li, C.Y., Shen, W., 2014. Gastrodin alleviates memory deficits and reduces amyloid: the involvement of Gastrodia elata P78 and CHOP. Biol. Res. 45, neuropathology in a mouse model of Alzheimer’s disease. Neuropathology 34, 403–410. 370–377. Lee, O.H., Kim, K.I., Han, C.K., Kim, Y.C., Hong, H.D., 2012b. Effects of acidic poly- Huang, J., Wang, G., 1985. Studies on some pharmacological effects of gastrodia saccharides from Gastrodia Rhizome on systolic blood pressure and serum lipid injection and gastrodin. Acta Acad. Med. Sin. 7, 399–402. concentrations in spontaneously hypertensive rats fed a high-fat diet. Int. J. Huang, Z.B., Wu, Z., Chen, F.K., Zou, L.B., 2006. The protective effects of phenolic Mol. Sci. 13, 698–709. constituents from Gastrodia elata on the cytotoxicity induced by KCI and glu- Lee, D.K., Lim, D.K., Um, J.,A., Lim, C.J., Hong, J.Y., Yoon, Y.A., Ryu, Y., Kim, H.J., Cho, H. tamate. Arch. Pharmacal Res. 29, 963–968. J., Park, J.H., Seo, Y.B., Kim, K., Lim, J., Kwon, S.W., Lee, J., 2014. Evaluation of four Huang, N.K., Chern, Y., Fang, J.M., Lin, C.I., Chen, W.P., Lin, Y.L., 2007. Neuroprotective different analytical tools to determine the regional origin of Gastrodia elata and principles from Gastrodia elata. J. Nat. Prod. 70, 571–574. Rehmannia glutinosa on the basis of metabolomics study. Molecules 19, Huang, C.L., Yang, J.M., Wang, K.C., Lee, Y.C., Lin, Y.L., Yang, Y.C., Huang, N.K., 2011. 6294–6308. Gastrodia elata prevents huntingtin aggregations through activation of the Lei, Y.U., Shen, Y.S., Miao, H.C., 2006. Study on the Anti-vertigo Function of Poly-

adenosine A2A receptor and ubiquitin proteasome system. J. Ethnopharmacol. saccharides of Gastrodia elata and Polysaccharides of Armillaria Mellea. Chin. J. 138, 162–168. Inf. Tradit. Chin. Med. 13, 29. Huang, L.Q., Li, Z.F., Wang, Q., Cui, Y.R., Ou, Y.H., Xiong, S.S., Huang, W.P., Feng, Y.L., Lei, Y.C., Li, J.R., Xiao, J.J., Yue, Y., Zhang, X.G., Zhang, M., Lv, G.H., 2015. Correlation Yang, S.L., 2014a. Two new furaldehyde compounds from the rhizomes of between contents of gastrodin and polysaccharides with grade of Gastrodia Gastrodia elata. J. Asian Nat. Prod. Res. 17, 352–356. Tuber. Chin. Tradit. Herb. Drugs 46, 418–423. Huang, Q., Shi, J., Gao, B., Zhang, H.Y., Fan, J., Li, X.J., et al., 2014b. Gastrodin: an Li, H.B., Hou, J.P., Shao, K.Z., Fu, Y.T., 2002. Identification the gastrodin of compound ancient Chinese herbal medicine as a source for anti-osteoporosis agents via Tianma Shouwu wine. Anhui Tradit. Chin. Med. Coll. 21, 54. reducing reactive oxygen species. Bone 73, 132–144. Li, N., Wang, K.J., Chen, J.J., Zhou, J., 2007. Phenolic compounds from the rhizomes of Hwang, S.M., Lee, Y.J., Kang, D.G., Lee, H.S., 2009. Anti-inflammatory effect of Gas- Gastrodia elata. J. Asian Nat. Prod. Res. 9, 373–377. trodia elata rhizome in human umbilical vein endothelial cells. Am. J. Chin. Med. Li, Z.F., Wang, Y.W., Wang, Q., Huang, L.Q., Meng, T., Feng, Y.L., Yang, S.L., 2014. 37, 395–406. Chemical constituents from Gastrodia elata(Ⅱ). Chin. Trad. Herb. Drugs 45, Ishida, H., Seri, K.I., 1996. Catalytic activity of lanthanoideions for dehydration of 1976–1979. d-glucose to 5-(hydroxymethyl) furfural. J. Mol. Catal. A: Chem 112, 163–165. Li, Y., Ke, Y., Jiang, J.Y., Li, X.J., Jiang, Y.B., 2015. Effect of Tianma gouteng decoction on Jang, Y.W., Lee, J.Y., Kim, C.J., 2010. Anti-asthmatic activity of phenolic compounds the endothelial function and the renal protein expression in spontaneously from the roots of Gastrodia elata BL. Int. Immunopharmacol. 10, 147–154. hypertensive rats. Chin. J. Integr. Tradit. West. Med. 35, 481–487. Jang, J.H., Son, Y., Kang, S.S., Bae, C.S., Kim, J.C., Kim, S.H., Shin, T., Moon, C., 2015. Li, J.L., Zhao, Z., Liu, H.C., Luo, C.L., Huang, M.J., Luo, F.L., Wang, H.L., 2015a. Content Neuropharmacological potential of Gastrodia elata Blume and its components. of mineral elements of Gastrodia elata by principal components analysis. China Evid. Based Complement Altern. Med., 309261. J. Chin. Mater. Med. 40, 1123–1128. Jiang, L., Wan, S., Wang, S., Yu, C., 2001. Isozyme analysis of Gastrodia elata f. elata Li, Z.F., Wang, Y.W., Ouyang, H., Lu, Y., Qiu, Y., Feng, Y.L., Jiang, H.L., Zhou, X., Yang, S. and G. elata f. glaucca and their hybrid. J. Chin. Med. Mater. 24, 547–548. L., 2015b. A novel dereplication strategy for the identification of two new trace Jiang, J.H., Wang, X.Z., Luo, S.S., Wang, Y., Lu, J.F., Bian, K., Ke, Y., 2011. Effect of compounds in the extract of Gastrodia elata, using UHPLC/Q-TOF-MS/MS. J. Banxia baizhu tianma decoction on the vascular endothelial function of spon- Chromatogr. B 988, 45–52. taneous hypertensive rats. Chin. J. Integr. Tradit. West. Med. 31, 811–815. Li, S.Z., 2011. Compendium of Materia Medica. Jiangshu People’s Press, Nanjing. Jiang, G.L., Hu, Y.Q., Liu, L.L., Cai, J.L., Peng, C., Li, Q.L., 2014. Gastrodin protects Lin, J.H., Liu, Y.C., Hau, J.P., Wen, K.C., 1996. Parishins B and C from rhizomes of against MPP(þ)-induced oxidative stress by up regulates heme oxygenase-1 Gastrodia elata. Phytochemistry 42, 549–551. expression through p38 MAPK/Nrf2 pathway in human dopaminergic cells. Lin, S.H., Chen, W.C., Lu, K.H., Chen, P.J., Hsieh, S.C., Pan, T.M., Chen, S.T., Sheen, L.Y., Neurochem. Int. 75, 79–88. 2014. Down-regulation of slit-robo pathway mediating neuronal cytoskeletal Jones, D.L., 1991. New taxa of Australian Orchidaceae. Aust. Orchid Res 2, 62–65. remodeling processes facilitates the antidepressive-like activity of Gastrodia Jung, W., Yoon, B.H., Oh, H.R., Ahn, J.H., Kim, S.Y., Park, S.Y., Ryu, J.H., 2006. An- elata Blume. J. Agric. Food Chem. 62, 10493–10503. xiolytic-like effects of Gastrodia elata and its phenolic constituents in mice. Biol. Liu, J.K., Mori, A., 1993. Antioxidant and pro-oxidant activities of p-hydroxybenzyl Pharm. Bull. 29, 261–265. alcohol and vanillin: effects on free radicals, brain peroxidation and degrada- Jung, T.Y., Suh, S., Lee, H., Kim, I.S., Kim, H.J., Yoo, H.S., Lee, S.R., 2007. Protective tion of benzoate, deoxyribose, amino acids and DNA. Neuropharmacology 32, effects of several components of Gastrodia elata on lipid peroxidation in gerbil 659–669. brain homogenates. Phytother. Res. 21, 960–964. Liu, X.Q., Baek, W.S., Kyun, A.D., Choi, H.Y., Yook, C.S., 2002. The constituents of the Kam, K.Y., Yu, S.J., Jeong, N., Hong, J.H., Jalin, A.A., Lee, S., Choi, Y.W., Lees, C.K., Kang, aerial part of Gastrodia elata blume. Nat. Prod. Sci. 8, 137–140. S.G., 2011. p-Hydroxybenzyl alcohol prevents brain injury and behavioral im- Lok, A., Ang, W., Tan, H., 2009. The status of Gastrodia javanica (BL.) lindl. Singap. J. pairment by activating Nrf2, PDI, and neurotrophic factor genes in a rat model 2, 415–419. of brain ischemia. Mol. cells 31, 209–215. Luo, S.S., Jiang, J.Y., Li, Y., Lu, J.F., Ke, Y., 2012. The effect of Banxia Baizhu Tianma Kho, M.C., Lee, Y.J., Cha, J.D., Choi, K.M., Kan, D.G., Lee, H.S., 2014. Gastrodia elata decoction on renal protein expression in spontaneously hypertensive rats. Ameliorates high-fructose diet-induced lipid metabolism and endothelial dys- J. Chin. Med. Mater. 35, 935–939. function. Evid.-Based Complement. Altern. Med. 10, 57–66. Ma, Q.Y., Wan, Q.L., Huang, S.Z., Dai, H.F., Wu, Y.R., Zhou, J., Luo, H.R., Zhao, Y.X., Kim, D.S., Kim, J.Y., Han, Y.S., 2007a. Alzheimer’s disease drug discovery from herbs: 2015. Phenolic Constituents with Inhibitory Activities on Acetylcholinesterase neuroprotectivity from beta-amyloid (1-42) insult. J. Altern. Complement. Med. from the Rhizomes of Gastrodia elata. Chem. Nat. Compd. 51, 158–160. 13, 403–410. Manavalan, A., Ramachandran, U., Sundaramurthi, H., Manisha, M., Sze, S.K., Hu, J., Kim, H.J., Hwang, I.K., Won, M.H., 2007b. Vanillin, 4-hydroxybenzyl aldehyde and Feng, Z.W., Heese, K., 2012a. Gastrodia elata Blume (tian ma) mobilizes neuro- 4-hydroxybenzyl alcohol prevent hippocampal CA1 cell death following global protective capacities. Int. J. Biochem Mol. Biol. 3, 219–241. ischemia. Brain Res. 1181, 130–141. Manavalan, A., Feng, L., Sze, S.K., Hu, J.M., Heese, K., 2012b. New insights into the Kim, S.Y., Back, H.I., Park, S.H., Park, E.O., Oh, M.R., Kim, M.G., So, B.O., Chae, S.W., brain protein metabolism of Gastrodia elata-treated rats by quantitative pro- Lee, G.H., Kim, D.S., Kim, H.R., Han, S.Y., Han, J.C., Chae, S.W., 2011a. Neuro- teomics. J. Proteom. 75, 2468–2479. protective effect of Gastrodia elata Blume ethanol extracts (GEB) against beta- Meng, Q., Song, X., Luo, Y., 2007. A new species of Gastrodia (Orchidaceae) from amyloid-induced BV2 cell death: Gastrodin and 4-hydroxybenzaldehyde (4- Hainan Island, China and its conservation status. Nord. J. Bot. 25, 23–26. HBA) are the bio active candidates. FASEB J. 25, ib298. Mi, K.P., Jing, L.J., Koo, Y.K., Yun-Choi, H.S., 2004. Phenolic and furan type com- Kim, I.S., Choi, D.K., Jung, H.J., 2011b. Neuroprotective effects of vanillyl alcohol in pounds isolated from Gastrodia elata and their anti-platelet effects. Arch. H.-D. Zhan et al. / Journal of Ethnopharmacology 189 (2016) 361–385 385

Pharmacal Res. 27, 381–385. Wang, L., Xiao, H.B., Liang, X.M., 2009. Chemical constituents from Gastrodia elata Ng, C.F., Ko, C.H., Koon, C.M., Xian, J.W., Leung, P.C., Fung, K.P., Chan, H.Y.E., Lau, C.B. (Ⅲ). Chin. Tradit. Herb. Drugs 40, 1186–1189. S., 2013. The Aqueous Extract of Rhizome of Gastrodia elata Protected Droso- Wang, L., Xiao, H.B., Yang, L., Wang, Z.T., 2012a. Two new phenolic glycosides from phila and PC12 Cells against Beta-Amyloid-Induced Neurotoxicity. Evid.-based the rhizome of Gastrodia elata. J. Asian Nat. Prod. Res. 14, 457–462. Complement. Altern. Med. 516741, 1–12. Wang, Y., Lin, S., Chen, M.H., Jiang, B.Y., Guo, Q.L., Zhou, C.G., Wang, S.J., Yang, Y.C., Niu, Q., Niu, P., He, S.C., 2004. Effect of Gastrodia elata on learning and memory Shi, J.G., 2012b. Chemical constituents from aqueous extract of Gastrodia elata. impairment induced by aluminum in rats. J. Hyg. Res. 33, 45–48. China J. Chin. Mater. Med. 37, 1775–1781. Noda, N., Kobayashi, Y., Miyahara, K., Fukahori, S., 1995. 2, 4-Bis(4-hydroxybenzyl) Wang, Y.W., Li, Z.F., He, M.Z., Feng, Y.L., Wang, Q., Li, X., Yang, S.L., 2013. Chemical phenol from Gastrodia elata. Phytochemistry 39, 1247–1248. constituents of Gastrodia elata. Chin. Tradit. Herb. Drugs 44, 2974–2976. Ojemann, L.M., Nelson, W.L., Shin, D.S., Rowe, A.O., Buchanan, R., 2006. Tian ma, an Wei, Y.L., Cui, X.F., 2012. Clinical observation on patients with diabetic neuropathy ancient Chinese herb, offers new options for the treatment of epilepsy and treated with combination of Kudiezi injection and Tianmasu injection. Chin. other conditions. Epilepsy Behav. 8, 376–383. Med. Mod. Distance Educ. China 10, 12–13. Park, S., Da, S.K., Kang, S., 2011. Gastrodia elata Blume water extracts improve in- Wu, G.B., 2013. Chemical constituents from Gastrodia elata. Chin. J. Ethnomed. sulin resistance by decreasing body fat in diet-induced obese rats: vanillin and Ethnopharm. 5, 28. 4-hydroxybenzaldehyde are the bioactive candidates. Eur. J. Nutr. 50, 107–118. Xiao, R., Tian, Y., Liu, L.G., Xu, K.L., 2009. Action of silky chicken-Gastrodia elata Qiu, H., Tang, W., Tong, X., Ding, K., Zuo, J.P., 2007. Structure elucidation and sulfated Blume nutrient solution on immunoregulatory function in mice. J. Hyg. Res. 38, derivatives preparation of two α-D-glucans from Gastrodia elata BL. and their 283–286. anti-dengue virus bioactivities. Carbohydr. Res. 342, 2230–2236. Xie, X.T., Li, H.Y., Wang, Q., Zheng, P., 2004. The study of chemical constituents in Ramachandran, U., Manavalan, A., Sundaramurthi, H., Sze, S.K., Feng, Z.W., Hu, J.M., Gastrodia elata blume. J. Yunnan Norm. Univ. 24, 22–25. Heese, K., 2012. Tian ma modulates proteins with various neuro-regenerative Xu, X., Lu, Y., Bie, X., 2007. Protective effects of gastrodin on hypoxia-induced modalities in differentiated human neuronal SH-SY5Y cells. Neurochem. Int. 60, toxicity in primary cultures of rat cortical neurons. J. Planta Med. 73, 650–654. 827–836. Yang, Z.M., Hu, Z., 1990. A preliminary study on the chitinase and β-1, 3-glucanase Rohmann, C., Meisel, D., 1961. Über die Darstellung pharmakologisch interessanter in corms of Gastrodia elata. Acta Bot. Yunnanica 12, 421–426. Aminoäther. Arch. Pharm. 294, 538–549. Yang, X.D., Zhu, J., Yang, R., Liu, J.P., Li, L., Zhang, H.B., 2007. Phenolic constituents Shen, X., Wang, G.D., Zhao, Y.B., 2006. Evaluation of the clinical effect in the from the rhizomes of Gastrodia elata. Nat. Prod. Res. 21, 180–186. treatment of 42 patients with acute cerebral infarctions with Qiangli Tianma Yang, H.P., Yu, D.L., Yang, Z.B., Liu, Q., 2013. New records of Orchids from Yunnan. Duzhong Capsule. Chin. Tradit. Pat. Med. 28, 1602–1604. China J. 42, 350–352. Shi, Y., Dong, J.W., Tang, L.N., Kang, R.X., Shi, J.G., Zhang, J.J., 2014. N(6)-(3-methoxyl- Yeh, C.L., Leou, C.S., Hsu, T.C., Yeh, C.R., 2011. Gastrodia sui sp. nov. (Orchidaceae) 4-hydroxybenzyl) adenine riboside induces sedative and hypnotic effects via from Taiwan. Nord. J. Bot. 29, 417–419. GAD enzyme activation in mice. Pharmacol. Biochem. Behav. 126, 146–151. Yokota, M., 1998. A new form of Gastrodia javanica (Orchidaceae) from the Ryukyus. Shin, E.J., Whang, W.K., Kim, S., Bach, J.H., Kim, J.M., Nguyen, X.K., Nguyen, T.T., Jung, Acta Phytotaxon. Et. Geobot. 49, 147–150. B.D., Yamada, K.F., Nabeshima, T., Kim, H.C., 2010. Parishin C Attenuates Phen- Yong, W., Xing, T.R., Wan, S., Chen, L., Hu, P., Li, C.C., Wang, H.L., Wang, M., Chen, J.T., cyclidine-induced Schizophrenia-Like Psychosis in mice: involvements of 5-HT Ruan, D.Y., 2009. Protective effects of gastrodin on lead-induced synaptic receptor. J. Pharmacol. Sci. 113, 404–408. plasticity deficits in rat hippocampus. J. Planta Med. 75, 1112–1117. Shin, E.J., Kim, J.M., Nguyen, X.K., Nguyen, T.T., Lee, S.Y., Jung, J.H., Kim, M.J., Wang, Yu, F., Shi, T., Moriya, J., Kawaura, K., Yamakawa, J., Kusaka, K., Itoh, T., Morimoto, S., W.K., Yamada, K., Nabeshima, T., Kim, H.C., 2011. Effects of Gastrodia elata BL on Yamaguchi, N., Kanda, T., 2006. Traditional Chinese medicine and kampo: a phencyclidine-induced schizophrenia-like psychosis in mice. J. Curr. Neuro- review from the distant past for the future. J. Int. Med. Res. 34, 231–239. pharm. 9, 247–250. Yu, S.S., Zhao, J., Zheng, W.P., Zhao, Y., 2009. Neuroprotective effect of 4-hydro- Shu, C., Chen, C.G., Zhan, D.P., Guo, H.P., Zhou, P., Zong, J., et al., 2012. Gastrodin xybenzyl alcohol against transient focal cerebral ischemia via anti-apoptosis in protects against cardiac hypertrophy and fibrosis. J. Mol. Cell Biochem. 59, 9–16. rats. J. Brain Res. 1308, 167–175. Shu, G.W., Yang, T.M., Wang, C.Y., Su, H.W., Xiang, M.X., 2013. Gastrodin stimulates Yun-Choi, H.S., Pyo, M.K., Park, K.M., 1997. Isolation of 4,4′-dihydroxybenzyl sulf- anticancer immune response and represses transplanted H22 hepatic ascitic oxide from Gastrodia elata. Arch. Pharmacal Res. 20, 91–92. tumor cell growth: involvement of NF-κB signaling activation in CD4þ T cells. Yun-Choi, H.S., Pyo, M.K., Park, K.M., 1998. Isolation of 3-O-(4′-Hydroxybenzyl)-β- Toxicol. Appl. Pharmacol. 269, 270–279. sitostero and 4-[4′-(4″-Hydroxybenzyloxy) benzyloxy] benzyl methyl ether Shuan, C., Chen, S., 1983. Notes on Chinese Gastrodia. Acta Bot. Yunnanica 5, from fresh tubers of Gastrodia elata. Arch. Pharmacal Res. 21, 357–360. 361–368. Zeng, X.A., 2006. Study of the neuroprotective effect of the phenolic glucoside State Administration of Traditional Chinese Medicine, 1999. Chinese Materia Gastrodin during cerebral ischemia in vivo and in vitro. J. Planta Med. 72, Medica. 24. Shanghai Scientific And Technical Press, Shanghai, pp. 716–722. 1359–1365. Sun, W., Miao, B., Wang, X.C., Duan, J.H., Ye, X., Han, W.J., Wang, W.T., Luo, C., Hu, S.J., Zhang, Y.J., Ji, J.Y., 2010. Gastrodia elata Bl.var.obovata, a new variety of the Orchi- 2012. Gastrodin inhibits allodynia and hyperalgesia in painful diabetic neuro- daceae from Shaanxi. China J. Acta Bot. Boreal.-Occident. Sin. 30, 1277–1278. pathy rats by decreasing excitability of nociceptive primary sensory neurons. Zhang, F., Li, A., 2015. Dual restoring effects of gastrodin on dopamine in rat models PLoS One 7, e39647. of Tourette’s syndrome. J. Neurosci. Lett. 588, 62–66. Taguchi, H., Yosioka, I., Yamasaki, K., Kim, I., 1981. Studies on the constituents of Zhang, Y., Li, M., Kang, R.X., Shi, J.S., Liu, G.T., Zhang, J.J., 2012. NHBA isolated from Gastrodia elata Blume. Chem. Pharm. Bull. 29, 55–62. Gastrodia elata exerts sedative and hypnotic effects in sodium pentobarbital- Tang, K.M., 2013. DNA (barcoding research and medicinal compositions analysis of) treated mice. J. Pharmacol. Biochem. Behav. 102, 450–457. Gastrodia elata (Orchidaceae). D. Yunnan Traditional Chinese Medicine College, Zhang, Z.C., Su, G., Li, J., Wu, H., Xie, X.D., 2013. Two new neuroprotective phenolic Yunnan. compounds from Gastrodia elata. J. Asian Nat. Prod. Res. 15, 619–623. Teong, I.W., Ko, A.A., Li, M., Heese, K., Liang, W., 2011. Gastrodia elata decreases Zhang, B.H., Liu, W., Zhao, Z., Luo, F.L., Liu, H.C., Huang, M.J., Wang, H.L., Li, J.L., Luo, isoprenaline potency and enhances spontaneous phasic activity in the rat de- C.L., Wen, P., Chen, W.Y., 2014. Research on life history and phenological period trusor. Int. J. Physiol. Pathophysiol. Pharm. 3, 29–37. of wild-stimulated cultivated Gastrodia elata f. elata in Guizhou. China J. Chin. The Plant List, 2013. Version 1.1. Published on the Internet. 〈http://www.theplant Mater. Med. 39, 4311–4316. list.org〉 (accessed 12.12.15). Zhang, Z.C., Su, G., Li, J., Wu, H., Xie, X.D., 2013. Two new neuroprotective phenolic Tian, H.Z., Li, H.Q., Yang, C.K., 2010. Gastrodia R. Br., a newly recorded genus of compounds from Gastrodia elata. J. Asian Nat. Prod. Res. 15, 619-623. Zhao, Y., Orchidaceae in Guangdong Province. J. Trop. Subtrop. Bot. 18, 488–490. Kang, Z.J., Zhou, X., Yang, S.L., 2013. An edible medicinal plant-Gastrodia elata Bl. Tong, X.K., Qiu, H., Zhang, X., Shi, L.P., Wang, G.F., Ji, F.H., Ding, H.Y., Tang, W., Ding, J. Guizhou Norm. Univ. 31, 9–12. K., Zuo, J.P., 2010. WSS45, a sulfated α-D-glucan, strongly interferes with Dengue Zheng, H.F., Yang, E.P., Peng, H., Li, J.P., Chen, S., Zhou, J.L., Fang, H.S., Bo, L., Wang, Z., 2 virus infection in vitro. Acta Pharmacol. Sin. 31, 585–592. 2014. Gastrodin prevents steroid-induced osteonecrosis of the femoral head in Tsi, Z.H., Chen, S.C., 1994. New taxa of orchidaceae from Xishuangbanna of south rats by anti-apoptosis. Chin. Med J. 127, 3926–3931. Yunna, China. Acta Phytotaxon. Sin. 32, 553–562. Zhou, J., Yang, Y.B., Yang, C.R., 1979a. The isolation and identification of chemical Tuyama, T., 1982. A new Gastrodia from the Ryukyus. Acta Phytotaxon. Et. Geobot. constituents of Gastrodia elata BL. Acta Chim. Sin. 37, 183–189. 33, 380–382. Zhou, J., Yang, Y.B., Yang, C.R., 1979b. The chemistry of Gastrodia elata BL. I. The Wang, L., Xiao, H.B., Liang, X.M., 2003. Studies on chemical constituents of Gastrodia isolation and identification of chemical constituents of Gastrodia elata BL. Acta elata (Ⅰ). Chin. Tradit. Herb. Drugs 34, 584–585. Chim. Sin. 37, 183–189. Wang, L., Xiao, H.B., Liang, X.M., 2006a. Chemical constituents from Gastrodia elata Zhou, J., Yang, Y.B., Yang, C.R., 1980a. Chemical study on Gastrodin elata BL. Ⅱ The (Ⅱ). Chin. Tradit. Herb. Drugs 37, 1635–1637. synthesis of gastrodin and released compounds. Acta Chim. Sin. 38, 162–166. Wang, L., Cheng, M.C., Xiao, H.B., Liang, X.M., 2006b. HPLC fingerprint of Gastrodia Zhou, J., Yang, Y.B., Pu, X.Y., 1980b. The phenolic compounds of fresh. Gastrodia elata elata. Chin. Tradit. Herb. Drugs 37, 1402–1405. Blume. Acta Bot. Yunnanica 2, 370. Wang, H.X., Yang, T., Zeng, Y., Hu, Z., 2007a. Expression analysis of the gastrodianin Zhou, J., Pu, X.Y., Yang, Y.B., 1981. The nine kinds of phenolic compounds of fresh gene ga4B in an achlorophyllous plant Gastrodia elata Bl. J. Plant Cell Rep. 26, rhizoma gastrodiae. Chin. Sci. Bull. 18, 1118–1120. 253–259. Zhou, X., Yang, X.H., Liang, H.X., Liu, C.Y., 1987. Tian-Ma (Gastrodia) Morphology. Wang, L., Xiao, H.B., Liang, X., Wei, L., 2007b. Identification of phenolics and nu- Science Press, Beijing. cleoside derivatives in Gastrodia elata by HPLC-UV-MS. J. Sep. Sci. 30, Zhou, B.H., Li, X.J., Liu, M., Wu, Z.H., Hu, X.M., 2006. Antidepressant-like activity of 1488–1495. the Gastrodia elata ethanol extract in mice. J. Fitoter. 77, 592–594. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP 图书馆。图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具