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Epilepsy & Behavior 8 (2006) 376–383

Review

Tian ma, an ancient Chinese herb, offers new optionsfor the treatment of epilepsy and other conditions

Linda Moretti Ojemann a,*, Wendel L. Nelson b, Donella S. Shin c,Ann Ojemann Rowe d, Robert A. Buchanan e

a Department of Neurological Surgery, Regional Epilepsy Center, University of Washington School of Medicine, Seattle, WA, USAb University of Washington, Seattle, WA, USA

c Western University School of Health Sciences, Pomona, CA, USAd Cascade Medical Center, Leavenworth, WA, USA

e Dainippon Pharmaceutical USA Corporation, Teaneck, NJ, USA

Received 14 September 2005; accepted 10 December 2005

Abstract

Our purpose is to bring attention to the antiepileptic properties of the Chinese herb tian ma and its constituents, as well as to suggest thepotential for the development of new antiepileptic drugs (AEDs) related to this herb. All available literature regarding the chemistry, phar-macology, animal data, and clinical use of tian ma and its constituents are reviewed, showing that tian ma, its constituents, and its sym-biotic fungus Armillaria mellea have antiepileptic properties in in vitro and in vivo models. One clinical study reportedly demonstrated theAED effects of a component of tian ma, vanillin. Thus, tian ma, its constituent vanillin, and its symbiotic fungus armillaria hold promise ascost-effective and less toxic alternatives to standard AEDs. In addition, similar chemical compounds may be developed as AEDs.� 2006 Elsevier Inc. All rights reserved.

Keywords: Epilepsy; Seizures; Tien ma; Tian ma; Gastrodia elata; Armillaria mellea; Drugs; Chinese herbal; Antiepileptic drugs; Gastrodin; Vanillin;c-aminobutyric acid

1. Introduction

Tian ma (literal translation: ‘‘heavenly hemp’’), the tuberof the orchid, Gastrodia elata Blume, has been used sinceancient times in China for the treatment of a variety of con-ditions including epilepsy [1]. The Chinese pharmacopoeialists it as an anticonvulsant, analgesic, and sedative effec-tive against vertigo, general paralysis, epilepsy, and tetanus[2]. However, its use has not been reported in Western med-ical reviews of herbal medications for epilepsy [3], and onlyone study in humans with epilepsy is referenced in theavailable Chinese medical literature [4]. Because the activecomponents have been identified and many have been syn-thesized, there has been further investigation of the mech-

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doi:10.1016/j.yebeh.2005.12.009

* Corresponding author. Fax: +1 206 731 4409.E-mail address: lojemann@u.washington.edu (L.M. Ojemann).

anism by which tian ma exerts anticonvulsant propertiesin in vitro assays and in in vivo animal models. Isolationof the specific chemical constituents of gastrodia has pro-vided new information on its usefulness as an antiepilepticand its potential as a novel agent for the treatment ofepilepsy.

Gastrodia elata is found primarily in eastern Asia, spe-cifically in the mountainous ranges of China and Korea.The orchid grows in a tenuous and complex relationshipwith two fungi: Mycena osmundicola, which providesnutrients to the seed during germination, and Armillaria

mellea (Chinese name, mihuanjuan), which invades thesprouted tuber and provides nutrients and energy. Theabsence of these fungi prevents the germination and growthof the orchid gastrodia. However, the fungus A. mellea is acommon cause of root rot in other plants, and itscultivation is not encouraged. Wild G. elata has become

L.M. Ojemann et al. / Epilepsy & Behavior 8 (2006) 376–383 377

increasingly difficult to find due to its rare habitat and itsdesirability as a medicinal agent [5].

To provide a reliable supply of gastrodia, research in the1960s focused on the interdependence of the tuber of theorchid and its symbiotic fungi, allowing for larger-scalecultivation [5]. Attempts to isolate the active ingredientshave focused on the tuber of the orchid G. elata and thefungus A. mellea. Numerous compounds have been identi-fied and their effects on neurotransmission and smoothmuscle and as antioxidants have been described. The pri-mary active ingredient isolated from G. elata has beentermed gastrodin and is available in oral formulations. Inaddition to oral administration, gastrodin has been report-ed to have been used intravenously and intramuscularly inclinical trials of a number of conditions in China [6–9]. It isa simple glycoside consisting of glucose and 4-hydroxyben-zyl alcohol. Additionally, other compounds from gastrodiashow potential anticonvulsant activity, specifically 4-hydroxybenzaldehyde, vanillyl alcohol, and vanillin(3-methoxy-4-hydroxybenzaldehyde).

Multiple in vitro and in vivo animal studies indicate thatG. elata and its constituents have antiepileptic drug proper-ties [10–16]. One of the isolated constituents has antiepilep-tic properties and is perhaps more potent than valproicacid or vigabatrin [12,17]. Gastrodia or its constituentsappear to act via the c-aminobutyric acid (GABA) path-way, either through inhibition of degradative enzymes ofGABA or by an effect on the GABAA/benzodiazepine(BZD) receptor [12,17–22].

Following is a review of the available literature on theuse of G. elata, A. mellea, or their constituents as an anti-epileptic or anticonvulsant. Although much of the litera-ture is difficult to interpret due to language barriers,incomplete study design descriptions, discrepancies, andinconsistencies among preparations of gastrodia andarmillaria, it appears worthwhile to further study these

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HOHO

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2 3

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CH2OCH3

OCH2 OH

CH2

OH OR

H2CO

R = H

R = g

89

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compounds for use in our current armamentarium ofagents for the treatment of epilepsy.

2. Methods

Available literature was reviewed from Pub Med, Medscape, Sci-Finder, and Internet searches using the following search terms: Gastro-dia elata, Armillaria mellea, Armellaria mellea, tienma, tien ma, tianma,and tian ma. Abstracts and full texts were evaluated for their clarityand scientific merit. Unfortunately, some did not give a thoroughdescription of methods, and some conclusions were referenced despiteincomplete information. We have attempted to indicate these problemsin our results. Many of the articles were printed in Chinese, and despitetranslation by native speakers, some of the information is difficult toassess due to language vagaries.

3. Results

3.1. Chemistry and method of determination

The rhizome of Gastrodia elata Blume (tien ma) containsa variety of constituents that have previously been charac-terized. Most published accounts report results of structureidentificationwork on constituents either found inmethano-lic or aqueous methanolic extracts of rhizome that has beensteamed and dried (including products from commercialsources) or directly extracted from the fresh rhizome, fol-lowed by chromatographic separation. Recent studies haveconfirmed the presence of the phenolic glucoside gastrodin(1) and its aglycone gastrodigenin (4-hydroxybenzyl alco-hol) (2) as primary constituents. Many structurally relatedconstituents that are present in smaller amounts continueto be identified; see Zhao et al. [23]. Biological and biochem-ical activities of several of the constituents of G. elata arereported in a variety of assays. Gastrodin is the phenolic glu-coside of 4-hydroxybenzyl alcohol. Closely related constitu-ents, including 4-hydroxybenzaldehyde (3), vanillyl alcohol(4), vanillin (5), and 4-hydroxybenzyl methyl ether (6), have

654

CH2OCH3

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OHOCH3

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_OCH2R =

lucose1112

HOCH 2

HOHO

OH

OO

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CH2COOR3

C

CH2COOR1

CH2COOR2

R1 = R2 = R3 = RR1 = R2 = R R3 = HR1 = R3 = R R2 = H

10

378 L.M. Ojemann et al. / Epilepsy & Behavior 8 (2006) 376–383

been reported [24]. Compounds containing two or more 4-hydroxylbenzyl alcohol moieties (7–9) and the structurallyrelated citric acid tricarboxylic acid ester parishin (10) anddicarboxylic acid esters parishin B and C (11 and 12) havebeen reported [25].

Previously known variants of 4-hydroxybenzyl alcoholstructures (13–19) and a new related trimeric structure(20) were reported by Hayashi et al. [26]. A structurally-re-lated unusual glutathione congener (21) has also beenreported [27]. Additional minor components are apparentlycarbohydrate-derived furan aldehydes (22) and (23) (cir-siumaldehyde), as reported by Pyo et al. [28], and the wide-ly distributed constituents b-sitosterol, palmitic acid,succinic acid, and sucrose have also been observed [29].

3.2. Pharmacology

Mechanisms of action of gastrodia or its active constit-uents include increasing GABA by inhibition of its break-down by degradative enzymes. Various in vitro and in vivostudies suggest that the active components of G. elata actby inhibiting GABA breakdown, through inhibition ofeither GABA transaminase (GABA-T), succinic semialde-hyde dehydrogenase (SSADH), or succinic semialdehydereductase (SSR). Some studies suggest that the active com-pounds enhance the effects of GABA through modulationof the GABAA/BZD receptor complex.

Three studies specifically attempted to isolate the effectof gastrodia on the GABA pathway. One in vitro studylooked specifically at gastrodin and SSADH [18]. An in vi-vo study with gerbils evaluated GABA synthesis, transport,and degradation in the presence of gastrodin [19], andanother in vivo study in rats evaluated the effect of theether fraction of the methanol extract of G. elata onGABA–T and the GABAA/BZD receptor [17]. One studyemployed a rat model of epilepsy to evaluate multiple com-

21

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H19

16

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OC-OOCCH 2NH

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ponents of G. elata in relation to its effects on seizure sever-ity, brain GABA levels, and lipid peroxidation comparedwith valproic acid [12]. Four in vitro studies indicate poten-tial binding sites of gastrodin at the glutamate andGABAA/BZD receptors [20–22,29].

Baek et al., through multiple fractions of methanolextract of G. elata, isolated two compounds, gastrodin(1) and parishin (10) [18], and determined the effectsof these compounds on SSADH. Parishin undergoesalkaline hydrolysis to produce gastrodin. The authorsrefer to previous studies showing no effect of gastrodinon GABA-T, but no data are given. They conclude thatgastrodin is the active anticonvulsant compound inG. elata and that its mechanism of action is irreversibleinhibition of SSADH and prevention of GABA degrada-tion [18].

An et al. [19] evaluated the location of action of gastro-din in the GABA pathway in the in vivo gerbil model ofepilepsy. Seizure-sensitive Mongolian gerbils pretreatedwith gastrodin (60 mg/kg/day) orally for 1 week were com-pared with a non-pretreated control group. Brains werethen evaluated by immunoreactivity for GABA synthesisvia glutamic acid decarboxylase, GABA transport via spe-cific sodium-dependent transporters, or GABA degrada-tion via GABA-T, SSADH or SSR. They observed thatthe gastrodin-treated animals had fewer seizures of lessseverity (seizure score dropped from 4–5 to 2.3, whichwas improved compared with the control group). Theimmunoreactivity studies showed no difference in syntheticand transport enzymes between the two groups, with thegastrodin-treated group having significantly decreaseduptake of GABA-T, SSADH, and SSR. In contrast toBaek et al. [18], An et al. demonstrated an in vivo effectof inhibition of GABA-T by gastrodin. They suggest theanticonvulsant effect of gastrodin lies in its inhibition ofGABA degradation [19].

O

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CH2O CH2O

OR

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O CHO OOHC CH2OH2C O CHO

L.M. Ojemann et al. / Epilepsy & Behavior 8 (2006) 376–383 379

Ha et al. found that the ether fraction of the methanolextract (EFME) of G. elata contained the most potent anti-convulsant compounds [17]. Isolation of the various chemi-cals in this fraction showed varying effects on GABAtransmission and on theGABAA-BZD receptor; 4-hydroxy-benzaldehyde (3) potently inhibited GABA-Tmore stronglythan did vigabatrin, and 4-hydroxy-3-methoxybenzalde-hyde (vanillin) (5) increased the binding of radiolabeled flu-nitrazepam to the GABAA-BZD receptor in the presence ofGABA in the brains of Sprague–Dawley rats [17].

Comparison of 4-hydroxybenzaldehyde (3) and 4-hydroxybenzyl alcohol (2), major and minor components,respectively, showed that aldehyde potently inhibitedGABA-T activity to a greater extent than did vigabatrin,whereas the alcohol had very weak activity. This largedifference led them to test other analogs. Ten relatedderivatives were selected, and their inhibitory effects onGABA-T were described. The aldehyde-substituted com-pounds had significantly greater inhibitory activity thanother functional groups such as cyanomethyl, carboxyl,and hydroxyl groups. Shifting the hydroxyl group of 4-hydroxybenzaldehyde (3) to other sites led to reduction ininhibitory activity. Similar tests of the compounds on theGABAA/BZD receptor complexes in rat brains showedthat most compounds did not have agonistic activity atthese receptors. Vanillin (5) appears to enhance GABAbinding at the GABAA/BZD receptor using flunitrazepam.Small changes in chemical structure lead to varying degreesof inhibition of GABA degradation or agonistic activity atthe GABAA/BZD receptor. Further investigation into thebioactivity of these compounds could lead to more specificand effective drugs.

A previous study by Ha et al. [12] looked at the effects ofthe ether extract of G. elata to increase brain GABA levelsin pentylenetetrazole (PTZ)-treated rats, decrease seizureseverity and recovery time, and decrease lipid peroxidase.The effect of 4-hydroxybenzaldehyde (3), a constituent ofG. elata, on inhibiting GABA-T was examined. In the firsttest, Sprague–Dawley rats received convulsive doses ofPTZ and this ether extract of G. elata. Compared withthe control, the G. elata-treated rats had seizures of lessseverity and recovered faster. In the second test, comparedwith controls, Sprague–Dawley rats pretreated with G. ela-

ta had significantly higher brain GABA levels after receiv-ing subconvulsive doses of PTZ. Pretreatment with G. elata

returned brain GABA levels almost to the baseline controllevel, a statistically significant increase in brain GABA lev-els compared with the PTZ-treated rats that did not receiveG. elata.

Lipid peroxidation in rat brain tissue after 4-hydroxy-benzaldehyde (3) administration to PTZ-treated rats wasalso determined, and was significantly higher in the PTZ-treated rats. Thus, 4-hydroxybenzaldehyde (3) had a pro-tective effect, decreasing the level of lipid peroxidation.Lastly, the effect of 4-hydroxybenzaldehyde (3) onGABA-T activity in untreated rat brain was evaluated. 4-Hydroxybenzaldehyde (3) had an inhibitory effect on

GABA-T and was more potent than valproic acid. Takentogether, these results suggest that G. elata exerts its anti-convulsant effects by increasing brain GABA levels, possi-bly through inhibition of GABA-T, by actions on theGABAA/BZD receptor, and that these constituents of gas-trodia have antioxidant effects [12].

Andersson et al. described the isolation and structuralcharacterization of S-(4-hydroxybenxyl)-glutathione (21)from an aqueous extract of G. elata [27]. This compounddisplaced [3H]kainic acid in the cerebral cortex homogenatefrom male Wistar rats with about one-tenth the affinity ofglutamate and between one-third and one-half the affinityof glutathione. Data from functional assays are not avail-able to determine whether it is an agonist or antagonistat these glutamate receptors.

A study describing the use of gastrodigenin derivativesas potential central nervous system BZD receptor imagingagents is reported [21]. Radiolabeled gastrodigenin deriva-tives were found to bind to BZD receptor on rat brainmembranes. Interestingly, gastrodin itself did not binddirectly to BZD receptors. The authors postulated that gas-trodin may be metabolized in vivo to gastrodigenin, whichhas affinity for BZD receptor [20–22].

3.3. Pharmacokinetics

Two reports refer to the pharmacokinetics of gastrodinand its components in animal models. Single intravenousbolus doses of vanillin and 4-hydroxybenzaldehyde (3) inrats indicate short half-lives: 4 and 2.3 minutes, respectively[30]. In another study, tissue extracts were analyzed bythin-layer chromatography after intravenous injection of[3H]gastrodin in mice. Gastrodin crossed the blood–brainbarrier and was rapidly metabolized to the glycone gastro-digenin (3) in brain, liver, and blood. Most of the dose wasexcreted as gastrodin and gastrodigenin in the urine [31].

3.4. AED effects of G. elata

Numerous studies have evaluated the in vitro and in vivocharacteristics of G. elata and its components in relation toits anticonvulsant properties. Multiple models have beenemployed to simulate epileptic conditions including the fer-ric chloride model in Sprague–Dawley rats, kainic acid(KA) injection, PTZ injection, and amygdala-kindled rats.Multiple preparations of G. elata were used, as were specif-ic components including vanillin (5), vanillyl alcohol (4),4-hydroxybenzaldehyde (3), and ether extracts. Endpointsvaried widely between studies, with most relying on obser-vational data on the onset, duration, severity, and frequen-cy of the seizure, electrophysiology, and biochemicalanalysis of markers of cell injury. As no standardizedmethod exists between these studies, it is impossible tocompare data from them.

Hsieh et al. described the anticonvulsant efficacy of van-illyl alcohol (4) in the ferric chloride Sprague–Dawley ratmodel [10]. In this model, intracortical injection of ferric

380 L.M. Ojemann et al. / Epilepsy & Behavior 8 (2006) 376–383

chloride resulted in wet dog shakes (WDSs), whereas ani-mals injected with phosphate-buffered saline (PBS) didnot develop WDSs. WDSs were verified by clinical obser-vation, electroencephalography (EEG), and electromyog-raphy (EMG). Pretreatment with phenytoin (PHT)10 mg/kg intraperitoneally or vanillin 100 or 200 mg/kgintraperitoneally reduced the number of WDSs, whereaspretreatment with PBS did not. Free radical scavengingactivity of vanillin was demonstrated in this model as wellas in vitro. Hsieh et al. suggest the anticonvulsant effect ofvanillin may be due to free radical scavenging propertiesand that the anticonvulsant effect of G. elata may be due,in part, to vanillin [10].

A similar article by Hseih et al. reports the anticonvul-sant effects of varying concentrations of G. elata as com-pared with PHT in KA-treated rats [32]. The in vitroportion of the study showed that G. elata decreased KAlevels and had antioxidant properties. The in vivo portionconsisted of five groups of Sprague–Dawley rats. One con-trol group received PBS only; the other four received KA12 mg/kg intraperitoneally with the following treatments:(1) nothing, (2) G. elata 0.5 mg/kg orally 30 minutes beforeKA, (3) G. elata 1.0 mg/kg orally 30 minutes before KA, or(4) PHT 20 mg/kg orally 30 minutes before KA. The high-er-dose G. elata- and PHT-treated groups had significantlyfewer WDSs, paw tremor, and facial myoclonus than thelower-dose G. elata-treated and control groups [32].

Kim et al. [11] demonstrated anticonvulsant effects ofG. elata in KA-treated mice. Administration of the etherextract of G. elata 200 or 500 mg/kg/day orally for 14 daysprior to KA injection (45 mg/kg ip) delayed the time ofonset of neurobehavioral change (P < 0.01) and reducedthe severity of convulsions (P < 0.05). Those treated withG. elata had a decrease in damage to neurons in the CA1and CA3 regions of the hippocampus [11].

Huh et al. [13] demonstrated that convulsions inducedby PTZ in rats were significantly inhibited by treatmentwith the methanol extract of G. elata (500 mg/kg orally).Multiple extracts of G. elata also reduced the level of lipidperoxidase in the brain. Huh et al. suggest the anticonvul-sive effect of G. elata is possibly due to the antioxidativeeffects of the active components in G. elata [13]. The greaterAED effect of 4-hydroxybenzaldehyde (3) compared withvalproic acid, as reported by Ha [12], was discussed earlier(see Pharmacology).

Wu et al. [14] used both vanillin and PHT to suppress ful-ly kindled seizures produced by electrical stimulation of thebasolateral amygdala in rats. Pretreatment with vanillinintraperitoneally 1 hour before stimulation (ED50 = 286 mg/kg) suppressed clinically observed stage 5 seizures, whichwere verified by EEG recordings. Phenytoin 50 mg/kg intra-peritoneally also reduced stage 5 seizures. Vanillin signifi-cantly shortened the epileptic afterdischarge duration [14].

The results of a study on the anticonvulsant activity andfree radical scavenging effects of oral doses of the mixtureof components obtained from the 50% aqueous ethanolextract of G. elata, in combination with those from a meth-

anol extract of another Chinese herb, Uncaria rhynchophy-

lla, are also reported by Hseih et al. [15]. Effects of theextract from U. rhynchophylla in the presence and absenceof the extract from G. elata on lipid peroxidation in vitrowere determined. Behavioral observation and EEG andEMG recordings were determined in vivo, and in vivoeffects on production of free radicals were also determined.However, because effects of the extract from U. rhyncho-

phylla were very highly significant, mostly reductions of80% from control values, no additional effects of the addedG. elata extract were measurable within the limits of theassays, with the exception that a further delay in the onsetof WDSs in rats treated with intraperitoneal KA wasobserved. These studies are closely related to other workon the extract from G. elata alone and on vanillyl alcohol(4), one of the components [10,32].

3.5. Use in epilepsy in humans

Human studies of G. elata or its constituents for epilepsyare lacking in quantity and quality of scientific rigor. Onereport in a review was identified as being potentially rele-vant to the use of one of gastrodia’s components in thetreatment of human epilepsy [4]. Unfortunately, the pub-lished methods and outcome measures are not specificenough to allow any firm conclusions. Cited in this review[4] was the study sponsored by the pharmaceutical compa-ny of the Nanjing College of Pharmacy, reporting on 291patients from seven hospitals in the Jiangsu province treat-ed with vanillin for various types of epilepsy. Patients (184individuals) were treated with vanillin monotherapy 0.1 to0.2 mg orally three times a day for 3 months, with claimedeffective rates of 86% in petit mal seizures and 75% in grandmal seizures. In 107 cases that were previously unrespon-sive to AED therapy, vanillin was added to the regimen.Of a total of 291 cases including monotherapy and poly-therapy, 216 patients were considered to have had ‘‘effec-tive therapy.’’ Mild vertigo was the prominent side effect.

3.6. Use in conditions other than epilepsy

Multiple studies in humans and animals have reportedon the use of gastrodia for other conditions. Studies sug-gest that gastrodia and its constituents affect smooth mus-cle tone, protect against oxidative damage in neuronal andmyocardial cells, and may have anticoagulant effects.

Three trials in humans evaluated gastrodia in multipledisease states. One study described its effects in senile vas-cular dementia. Tian ma cuzhi granules 0.5 g were given to30 patients with senile vascular dementia three times a dayfor 2 months. The authors stated that it improved scores onthe Mini-Mental State Examination and Hamilton depres-sion scales as compared with baseline [33]. In a randomizedcontrolled clinical trial in the treatment of diabetic periph-eral neuropathy, 36 patients were treated with reinforcedtian ma duzhong capsules, containing gastrodia andeucommia, and another 26 patients in the control group

L.M. Ojemann et al. / Epilepsy & Behavior 8 (2006) 376–383 381

were treated with 40 mg of aspirin daily. Both symptomsand electromyographic changes were significantlyimproved in the tian ma-treated group [34]. Tian ma hasbeen investigated for use in Parkinson’s disease [35].

Animal studies with gastrodia have shown effects on thecentral nervous system, vascular system, coagulation sys-tem, and myocardium and smooth muscle. In the centralnervous system, gastrodia has been found to amelioratethe symptoms of motion sickness in mice induced by rota-tion [36]. Memory consolidation and retrieval in a rat mod-el were improved with gastrodin and 4-hydroxybenzylalcohol (2) [37].

Vanillin (5) and 4-hydroxybenzaldehyde inhibited gluta-mate-induced cellular apoptosis and the associated increasein intracellular calcium in human neuronal cells [38]. Invitro assays of the effects of various fractions of the meth-anol extract of gastrodia on amyloid b peptide-inducedneuronal cell death showed that the ethyl ether fractionhas the greatest neuroprotective effect. The chloroformand butanol fractions had protective effects as well, butto a lesser extent. The authors wistfully suggest a possiblebeneficial effect in the treatment of Alzheimer’s disease [39].

Administration of oral gastrodin to rats pretreated withintraperitoneal aluminum injections protected againstincreased cortical aluminum levels and had positive effectson memory impairment induced by aluminum, possibly viathe acetylcholine and monoamine oxidase systems [40]. Theether fraction of the methanol extract of G. elata protectsagainst KA-induced neuronal damage in the CA1 andCA3 regions of the mouse hippocampus [11] and in theCA1 region of gerbil hippocampus [41] after transient glob-al ischemia. The ethyl ether fraction dramatically reducedneuronal cell death induced by amyloid b peptide inIMR-32 neuroblastoma cells [39].

The effects of gastrodia on the myocardium and smoothmuscle have been described in multiple in vitro experimentsand animal models. G. elata, administered intravenously torabbits after ligation of the coronary artery, has been foundto be protective inminimizing the effects ofmyocardial ische-mia and lipid peroxidation [42]. In goat models, tian ma hasbeen shown to be synergistic with intraaortic balloon pumpsin limiting the size of infarcts [43]. Injection of tian ma, butnot gastrodin, inhibited the proliferation of cultured vascu-lar smooth muscle cells, suggesting a potential benefit inthe treatment of hypertension [44].

To further characterize the muscle relaxant effects ofG. elata on smooth muscle, Hayashi et al. [26] isolated 11phenolic compounds from G. elata via methanol extractionand subsequent fractionation. The pure methanol extractof gastrodia did not affect smooth muscle in the restingphase, but inhibited electrically induced contractions in aconcentration-dependent manner. To determine if its effectwas onpostsynaptic parasympathetic nerves or smoothmus-cle, various fractions were tested with either serotonin-in-duced contractions (acting on 5-HT3 and 5-HT4 receptorson parasympathetic postsynaptic nerves to elicit acetylcho-line release) or with acetylcholine-induced contractions (act-

ing on muscarinic M3 receptors in smooth muscle). Theresults showed that methanol extract inhibited smooth mus-cle contractions induced by serotonin, but not those inducedby acetylcholine. The ether fraction markedly inhibited con-traction with serotonin, even when compared with theunfractionated methanol extract. The water, n-hexane, andn-butanol fractions had no effect on 5-HT- or acetylcho-line-induced smooth muscle contraction. This suggests theactive ingredient in G. elata that prevents smooth musclecontraction is present in the ether fraction of the methanolextract and works on postsynaptic parasympathic nerves.Further testing of the ether fraction of the methanol extractofG. elata in neurogenic contractions of ileal smoothmuscleinduced by serotonin, nicotine, and capsaicin showed inhibi-tion in a concentration-dependent manner. Similar testingwith acetylcholine and histamine, which work directly onsmooth muscle, did not show inhibition. The authors con-clude that gastrodia’s effects cannot be explained by the pres-ence of gastrodin alone, and that it may have an inhibitoryeffect on neurotransmitter release by stimulation of nicotine,serotonin, and vanilloid receptors. There may be mild directacetylcholine effects from a specific compound found in theether fraction of the methanol extract ofG. elata. These find-ings may account for the reported use of gastrodia in head-aches, migraines, and dizziness [26].

The potential anticoagulant properties of gastrodia wereaddressed in one study [28]. A phenolic compound, 4,4 0-dihydroxybenzyl sulfone (18), derived from the methanolextract of G. elata inhibited platelet aggregation about 4times more potently than aspirin. Another compound,4,4 0-dihydroxybenzylether (8), inhibited collagen- and epi-nephrine-induced platelet aggregation 10–80 times morepotently than aspirin [28]. Mesenchymal stem cells frombone marrow of rats were induced by gastrodia to differen-tiate into neuronlike cells [45].

3.7. Other considerations

The clinical and pharmacological effects of armillariaare similar to those of gastrodia. The fungus armillariahas also been shown to have anticonvulsant properties.Glucose, fructose, and sucrose fermentation extracts ofarmillaria raised the seizure threshold in PTZ-induced sei-zures in mice, as did the aqueous extract of gastrodia [46].Recently, the compound, N6-substituted adenosine, isolat-ed from armillaria, has been shown to have cerebrum-pro-tective effects in ischemic mice [47]. Armillaria has beenused in place of gastrodia to treat various neurological con-ditions [48,49]. Although they are pharmacologically simi-lar, the chemical constituents of armillaria are differentfrom those of gastrodia.

None of the components of armillaria—sesquiterpenoidaromatic esters [50] and N6-substituted adenosine [49]—ap-pear to be constituents isolated from tian ma. Conversely,there is no indication that compounds noted as parts oftian ma, listed above, are found in extracts of armillaria.One possibility is that the active components of gastrodia

382 L.M. Ojemann et al. / Epilepsy & Behavior 8 (2006) 376–383

are metabolites from the absorbed nutrients of the armil-laria mushroom.

3.8. Toxicity/side effects

The toxicity of gastrodia in humans is low [1]. Sideeffects included skin rash [8], vertigo [4], and leukopeniain one study [49], but not others. In a review by Benskyand Gamble [1], reports of allergic reactions including ana-phylaxis were rare. Acute toxicity in animals is low; theLD50 in adult mice injected intraperitoneally with crudetian ma extract was 51.4–61.4 g/kg [51].

4. Discussion

The modern management of epilepsy commenced withthe introduction of phenytoin (diphenylhydantoin, Dilan-tin) in 1938 by Merritt and Putnam [52]. Following a burstof progress, no new antiepileptic drugswere introduced from1978 to 1993. Progress again accelerated in the last decade ofthe 20th century [53]. But if progress is to continue, newsources of chemical entities with antiepileptic activity arerequired.Many therapeutic agents have been identified fromnatural sources, the classic examples being penicillin andstreptomycin. Therefore, turning to herbal compounds inthe search for antiepileptics seems a logical approach.

Although gastrodia has been used for thousands ofyears in China, the lack of standardization and of safetyand efficacy studies restricts its utilization in Western med-icine. A review of the available literature indicates gastro-dia and its components have AED properties in in vitroand in vivo models; one AED clinical trial in China sug-gests that gastrodia and its components may be efficaciousin the treatment of epilepsy and that it holds promise as acost-effective and less toxic alternative to many standardAED regimens.

An important advantage of gastrodia and its analogs isthat the chemical structures are known, as shown earlier.This means that the medicinal chemist can synthesize thecompound for larger-scale production by the manufactur-ing chemist. In addition, and perhaps more importantly,armillaria or vanillin (synthesized or from the plant Vanillaplanifolia), which are more readily available, can be substi-tuted for gastrodia. Our intention is that this review mayencourage the development of a large-scale Western studyto evaluate the potential of tian ma, gastrodia, Armillariamellea, or their specific components as a novel antiepileptic.

Acknowledgments

This study was supported in part by the Drueding Foun-dation. The authors thank Dr. Subhuti Dharmananda forreferences; Ms. Guoying Tai, Dr. Yixing Lin, Dr. YounongXu, Dr. Dorna Chu, Mr. Spencer Cohen, and Ms. ManWan for translation; and Mr. Matthew Jung and Ms.Rosemary Kimmel for preparation of the article.

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