YEBEH-04347; No of Pages 9 Epilepsy & Behavior xxx (2015) xxx–xxx

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Review

Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine Fenglai Xiao 1, Bo Yan 1, Lei Chen, Dong Zhou ⁎ Department of Neurology, West China Hospital, Sichuan University, 610041 Chengdu, People's Republic of China

a r t i c l e

i n f o

Article history: Revised 19 April 2015 Accepted 20 April 2015 Available online xxxx Keywords: Botanicals Traditional Chinese medicine Epilepsy

a b s t r a c t In traditional Chinese medicine, botanical remedies have been used for centuries to treat seizures. This review aimed to summarize the botanicals that have been used in traditional Chinese medicine to treat epilepsy. We searched Chinese online databases to determine the botanicals used for epilepsy in traditional Chinese medicine and identified articles using a preset search syntax and inclusion criteria of each botanical in the PubMed database to explore their potential mechanisms. Twenty-three botanicals were identified to treat epilepsy in traditional Chinese medicine. The pharmacological mechanisms of each botanical related to antiepileptic activity, which were mainly examined in animal models, were reviewed. We discuss the use and current trends of botanical treatments in China and highlight the limitations of botanical epilepsy treatments. A substantial number of these types of botanicals would be good candidates for the development of novel AEDs. More rigorous clinical trials of botanicals in traditional Chinese medicine for epilepsy treatment are encouraged in the future. This article is part of a Special Issue entitled “Botanicals for Epilepsy”. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Epilepsy is a serious and complex set of neurological conditions, which affects 65 million individuals worldwide, and more than 85% of these patients live in developing countries [1]. Although the majority of patients with epilepsy will achieve remission, seizures in up to 30% will become drug-resistant despite treatment with adequate doses of appropriate antiepileptic drugs (AEDs) [2]. Furthermore, approximately 30–40% of patients with epilepsy suffer from numerous side effects from the standard AEDs. In the context of this predicament, there is a constant search for novel modes of treatment [3]. Over thousands of years, individuals with epilepsy have used a variety of botanicals and herbs, which are considered natural and are generally regarded as safe in many instances. Botanical therapies may potentially yield new treatment options for patients whose seizures are uncontrolled despite available AEDs and may also represent inexpensive, culturally acceptable treatments for the millions of individuals worldwide with untreated epilepsy [4]. China has had rich traditions regarding botanical therapies for epilepsy for thousands of years. The first known document regarding epilepsy in China appeared in the Yellow Emperor's classic of internal

⁎ Corresponding author at: Department of Neurology, West China Hospital, Sichuan University, Guoxue Road 37#, 610041 Chengdu, Sichuan Province, People's Republic of China. Tel./fax: +86 2885422548. E-mail address: [email protected] (D. Zhou). 1 These authors contributed to this work equally.

medicine, Huang Di Nei Ching, written by a group of physicians between 770 and 221 B.C. The description of epilepsy in this book, and in many other subsequent publications, was confined to generalized convulsive seizures. No documentation of absence or simple partial seizures was noted. The first classification of epilepsy, likely by Cao Yuan Fang in 610 A.D., listed five types of epilepsy: ‘Yang Dian’, ‘Yin Dian’, ‘Feng (Wind) Dian’, ‘Shih (Wet) Dian’, and ‘Ma (Horse) Dian’. Nevertheless, these five ancient classifications have no relation with the modern classification. From a traditional Chinese medicine (TCM) perspective, seizures are directly caused by Liver Yang Rising. Liver Yang Rising generates Heat, which flares up and disturbs the brain and Shen (Mind), and thus, leads to Internal Wind (seizures). Liver Yang Rising can be caused by Liver Yin Deficiency, Liver Blood Deficiency, Phlegm, Blood Stagnation and Liver Fire. Liver Qi Stagnation can also trigger Liver Yang Rising. In addition, ‘Yin Dian’, ‘Feng (Wind) Dian’, ‘Shih (Wet) Dian’, and ‘Ma (Horse) Dian’ indicate the different causes of seizures [5]. The treatment of epilepsy based on the principles of ‘Yin Yang Wu Xing’ consisted of herbs, acupuncture, massage, food therapy, and therapeutic exercise [6]. Traditional Chinese botanical medicine, which is often considered to be a gentle and safe alternative to synthetically manufactured drugs, is the most widely practiced form of herbalism worldwide. Traditional Chinese botanical medicines are obtained or synthesized from natural plants. Typical traditional Chinese botanical treatment uses one type of botanical as the basic drug to treat the major disease problem. This botanical is subsequently mixed with other botanicals to treat additional symptoms, which creates a multifunction formula for the disease. However, botanical medicine is an area of TCM that is readily amenable

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Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050

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to empirical research. Most botanicals have only been examined in animal models for antiepileptic effects without adequate evidence from controlled clinical trials. Few articles have focused on a single botanical used by traditional Chinese medical practitioners, which may possess the antiepileptic/anticonvulsant effects. In this review, we investigated botanicals that were used in TCM as treatments for epilepsy. We listed the most frequently used botanicals by traditional Chinese medical practitioners and discussed the potential mechanisms of their antiepileptic/anticonvulsant activities.

2. Methods We searched online Chinese databases, including Wanfang, Weipu, and CNKI, using the Chinese characters “中药”, “草药”, “中草药”, “癫痫”, which represent the botanicals used for the treatment of epilepsy. We hand searched the Journal of Chinese Integrative Medicine, Chinese Medical Journal, Chinese Journal of Internal Medicine, Chinese Journal of Integrated Traditional and Western Medicine, Chinese Journal of Integrative Medicine, and other traditional Chinese medicine journals for the botanicals used solely or in a formula to treat epilepsy. We subsequently searched the PubMed online database using terms that included “botanical”, “herbal”, “epilepsy”, “seizure”, “TCM”, and “traditional Chinese medicine” and identified articles that used the preset search syntax of each botanical and inclusion criteria. We searched the reference lists of all relevant papers for additional studies. In addition, we contacted colleagues and experts in the field to identify unpublished or ongoing studies. There was no language restriction in the search or inclusion of studies.

3. Results The sources consulted in this work noted that 23 botanicals were used in Chinese traditional medicine to treat epilepsy. We reviewed the latest Chinese pharmacopeia [7] to determine whether there is a monograph for these Chinese medicines. Table 1 presents their names, Chinese names, and main active components. In the following sections, the results of tests performed on 23 botanicals have been summarized; attention was focused on their anticonvulsant activity.

3.1. Cynanchum otophyllum (qingyangshen) Qingyangshen is a traditional Chinese medicine that consists of the root of C. otophyllum, which is one of the most important medicinal plants used in southwest China to treat epilepsy. Two C-21 steroidal saponins, otophylloside A and B, were identified as its main active constituents that exhibit anticonvulsant activities [8]. Recently, five additional polyhydroxypregnane glycosides were isolated from the roots of C. otophyllum and exhibited neuroprotective activity against homocysteic acid-induced cell death in a dose-dependent manner [9]. Previous studies have demonstrated that qingyangshen has antiepileptic properties and a therapeutic effect on kainic acid (KA)-induced experimental seizures [10,11]. In addition, its modulatory effect in the cotreatment with diphenylhydantoin sodium (DPH) inhibits hippocampal c-fos expression in rats during seizures, which was suggested to be associated with KA-induced seizures [11]. It has been postulated that qingyangshen, when used in combination with PHT, may reduce the early production of fos protein, which thereby inhibits the secondary gene transcription that would contribute to the intracellular responses that lead to acute seizures [11]. A product based on C. otophyllum extract has previously been developed by the Yunnan Baiyao Group together with the Kunming Institute of Botany, Chinese Academy of Sciences. 3.2. Scutellaria baicalensis (huangqin) Scutellaria baicalensis or huangqin is a famous botanical medicine in the Shanxi Province, which is in the northwest of China. Baicalin, the major flavonoid in the S. baicalensis, possesses anticonvulsant effects. The pharmacological profile of baicalin was explored in mice in recent studies [12–14], and it has been discovered to possess remarkable anticonvulsant and neuroprotective effects on pilocarpine-evoked status epilepticus (SE) in adult SD rats [14]. Furthermore, the anticonvulsant effect may be ascribed to the protection of endogenous enzyme levels, an increase in the GABA level in the brain, and inhibition of oxidative injury [12]. 3.3. Gastrodia elata (tianma) Gastrodia elata or tianma is primarily found in the mountainous ranges of China. The Chinese pharmacopeia lists this compound as an anticonvulsant, analgesic, and sedative effective against vertigo, general

Table 1 Botanicals in traditional Chinese medicine used in epilepsy therapy. Generic name

Scientific name

Pinyin/Chinese name

Main active components

Cynanchum otophyllum Radix scutellariae Rhizoma gastrodiae Radix bupleuri chinensis Rhizoma coptidis Nandina Piper Ramulus uncariae cum uncis Herba centellae Saffron Ginkgo biloba Rhizoma acori tatarinowii Radix salviae miltiorrhizae Ginger Matricaria recutita Licorice root Turmeric Radix paeoniae rubra Semen ziziphi spinosae Radix astragali Radix ginseng All-grass of Snakefoot clubmoss Rhizoma pinelliae

Cynanchum otophyllum Scutellaria baicalensis Gastrodia elata Bupleurum chinense Coptis chinensis Nandina domestica Piper nigrum Uncaria rhynchophylla Centella asiatica Crocus sativus Ginkgo biloba Acorus tatarinowii Salvia miltiorrhiza Zingiber officinale Matricaria chamomilla Glycyrrhiza glabra Curcuma longa Paeonia lactiflora Ziziphus jujuba Astragalus mongholicus Panax ginseng Huperzia serrata Pinellia ternata

Qingyangshen/青阳参 Huangqin/黄芩 Tianma/天麻 Chaihu/柴胡 Huanglian/黄连 Nantianzu/南天竹 Hujiao/胡椒碱 Gouteng/钩藤 Jixuecao/积雪草 Zanghonghua/藏红花 Yinxingye/银杏叶 Shichangpu/石菖蒲 Danshen/丹参 Jiang/姜 Muju/母菊 Gancao/甘草 Jianghuang/姜黄 Chishao/赤芍 Hongzao/红枣 Huangqi/黄芪 Renshen/人参 Shezhushishan/蛇足石杉 Banxia/半夏

Otophylloside A and B (C-21 steroidal saponin) Baicalin Vanillin Saikosaponin A Berberine Nantenine Piperine Rhynchophylline, isorhynchophylline N-hexane, ethyl acetate, n-butanol Safranal Bilobalide Asarone Hydrophobic tanshinone Zingerone Apigenin Licorice flavonoid Curcumol Paeoniflorin Sanjoinine A Saponin Ginsenoside Huperzine A Pinelliae alkaloids

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paralysis, epilepsy, and tetanus [15]. Multiple in vitro and in vivo animal studies indicate that G. elata and its constituents have antiepileptic drug properties [15]. Gastrodia elata or its constituents appear to act via the ɣ-aminobutyric acid (GABA) pathway, either through the inhibition of degradative enzymes of GABA or via an effect on the GABAA/ benzodiazepine (BZD) receptor [16–19]. Although tianma has been used for thousands of years in China and tested in animal trials, the lack of standardization and safety and efficacy studies restricts its utilization in modern medicine. However, several AED clinical trials in China suggest that G. elata and its components may be efficacious in the treatment of epilepsy, and it holds promise as a cost-effective and less toxic alternative to many standard AED regimens [20].

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uterine bleeding, according to the traditional Chinese medical book Ben Cao Gang Mu [5]. Phytochemical investigation of this plant resulted in the isolation and identification of alkaloids [31], mainly nantenine, which is the major active component that exhibits anticonvulsant effects. Recent data indicate nantenine has a dose-dependent inverse effect on the Na+- and K+-ATPase of synaptosomal membranes [32]. At lower doses, nantenine reduced pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures and increased the hypnotic–sedative effects of phenobarbital and diazepam, which were most likely attributed to nantenine's direct inhibitory effect on Ca2 + influx [33]. 3.7. Piper nigrum (hujiao)

3.4. Bupleurum chinense (chaihu) Bupleurum chinense or chaihu, which grows in large parts of mainland China, is a major ingredient in many TCM formulas. Saikosaponin is the primary active constituent derived from B. chinense [21]. One recent study in rat epilepsy models demonstrated that the inhibition of the N-methyl-D-aspartate (NMDA) receptor current and INaP may be the underlying mechanisms of saikosaponin's anticonvulsant properties [21]. Furthermore, the authors also demonstrated that saikosaponin enhances transient inactivating potassium currents in rat hippocampal CA1 neurons [22]. Chaihu longgu muli tang (TW-001) is based on chaihu and mixed with 12 other botanicals [23]. It has been used as a sedative and an anticonvulsant drug from ancient times according to the description in the Chinese medicine book Shang Han Lun [24]. In experimental seizure models in rats, it exerts an anticonvulsant activity through the inhibition of sodium and calcium channels, which stabilizes the neuronal membrane excitability and inhibits glutamate release [25]. One clinical trial of Chaihu longgu muli tang in 20 patients with refractory epilepsy has suggested that before treatment with this botanical, patients exhibited disturbances in lipid peroxidation and antioxidant activities, including serum Cu, Zn-SOD, and GSH. Chaihu longgu muli tang can reduce the seizure frequency [23] via the correction of disturbances in lipid peroxidation via an increase in the activities of antioxidants, including serum Cu, Zn-SOD, and GSH. Although the study results appear to indicate that it is a relatively safe treatment modality, we cannot be assured of the safety of this formula for patients with epilepsy because the small sample sizes may have limited power to identify rare adverse effects. 3.5. Coptis chinensis (huanglian) Coptis chinensis grows in the mountainous districts of Southwest China. Berberine is an alkaloid derived from C. chinensis, which is the major active constituent that exhibits antiseizure properties. It has multiple pharmacological effects, including anticholinergic, antihypotensive, antiarrhythmic, antiosteoporotic, cardioprotective, antitumor, and antimalarial effects [26]. Berberine exhibited anticonvulsant activity via the modulation of neurotransmitter systems. It protected mice against KAinduced clonic convulsions, decreased mortality, and protected against NMDA-induced turning behavior [27]. Moreover, berberine has been reported to exhibit antidepressant-like effects and ameliorate memory dysfunction in experimental animals [28,29]. Depression and cognitive impairments are the most common psychiatric comorbidities in epilepsy, which severely affect patients' quality of life [30]. Thus, C. chinensis has great potential for clinical applications in the treatment of epilepsy and its comorbidities.

Piper nigrum was used to treat epilepsy in China approximately 1400 years ago according to the traditional Chinese book Tang Xin Xiu Ben Cao in the Tang Dynasty [34]. Piperine, a piperidine alkaloid derived from Piper, exhibited effects on inhibitory amino acids and the GABAergic system, which significantly increased the latencies to first convulsion and death, as well as the percentage of survival in pilocarpine-induced convulsive mice [35]. Benzoyl ester may be an important active center for its anticonvulsant effects [36]. One medication mainly derived from piperine, Kangxianning (Ilepcimide Tablets), has been developed by Peking University Pharmaceutical Company Limited. 3.8. Uncaria rhynchophylla (gouteng) Uncaria rhynchophylla is a traditional Chinese botanical that has been used to treat epileptic seizures for centuries. According to the legendary recording of Ben Cao Gang Mu [5], U. rhynchophylla can treat vertigo and epileptic seizures. Uncaria rhynchophylla has traditionally been used for the suppression of liver hyperfunction, relief of dizziness, and the treatment of tremor and convulsion. Recently, the anticonvulsant effect of this herb was demonstrated in kainic acid-induced epileptic rats [37]. Furthermore, whether the alkaloid fraction of U. rhynchophylla has a protective effect against excitotoxicity induced by NMDA and the relation of this effect on apoptosis has also been investigated [38]. The U. rhynchophylla alkaloid is composed of five main components: rhynchophylline, isorhynchophylline, corynoxeine, hirsutine, and hirsuteine. Rhynchophylline is one of the major oxindole alkaloids and strongly protects against NMDA-mediated cytotoxicity [39]. In addition, one recent study investigated the anticonvulsant mechanisms of U. rhynchophylla and its rhynchophylline component during acute seizures; this study demonstrated that they were involved in the initiation of c-jun N-terminal kinase phosphorylation of the MAPK signal pathways in acute seizures of KA-induced rats [40]. 3.9. Centella asiatica (jixuecao) Centella asiatica is widely used and promoted in TCM as a miracle plant for longevity. It has been used for mental fatigue and anxiety [41]. One recent finding reported that its anticonvulsant properties are related to cholinergic neurotransmission in a PTZ-induced rat seizure model [41]. The changes in ACh content and AChE activity were maximal with n-hexane, ethyl acetate, and n-butanol. Thus, it may be concluded that these three extracts of C. asiatica have antiseizure activity and cause perceptible changes in the cholinergic system, at least as part of their antiepileptic effects. 3.10. Crocus sativus (zanghonghua)

3.6. Nandina (nantianzu) Nandina grows wild in East Asia. In China, different parts of the plant, including the fruits, stems, roots, and leaves, have been used in the indigenous system of medicine for the treatment of various human ailments, such as asthma, whooping cough, pharyngeal tumors, and

According to the recording of Ben Cao Gang Mu [5], C. sativus is mainly planted in Tibet and West China. Crocus sativus, which is commonly known as safranal, has traditionally been used in Chinese traditional medicine as an antispasmodic, eupeptic, gingival sedative, anticatarrhal, nerve sedative, carminative, diaphoretic, expectorant, stimulant,

Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050

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stomachic, aphrodisiac, and emmenagogue [42]. Furthermore, recent research has demonstrated that the C. sativus extract or its active constituents have antidepressant [43], anti-inflammatory, and antitumor effects [42]. Safranal, an active monoterpene aldehyde in C. sativus, had beneficial effects on PTZ-induced convulsions in mice via interactions with the GABAA–benzodiazepine receptor complex [44–46]. Safranal (0.15 and 0.35 ml/kg, i.p.) reduced the seizure duration, delayed the onset of tonic convulsions, and protected mice from death. 3.11. Ginkgo biloba (yinxingye) Ginkgo is mainly rooted in the southwestern region of China. Ginkgo biloba comprises a variety of biologically active chemical constituents, including components that induce [47,48] and inhibit [49–52] seizure activity. The principal antiepileptic compounds in the ginkgo plant are ginkgolides and bilobalide. Three mechanisms of action may explain the seizure-protective characteristics of ginkgo: both ginkgolides and bilobalide found in ginkgo leaves are known to antagonize plateletactivating factor, which thus reduces the incidence of ischemic injury that could lead to seizures [53]; Gingko has been demonstrated to inhibit the excitatory actions of one type of glutamate receptor, the NMDA receptor [52]. Glutamate receptors play a principal role in excitatory neurotransmission [54]. Components of the ginkgo leaf, bilobalide in particular, may enhance the metabolism of the ginkgotoxin responsible for seizure induction [55]. Ginkgotoxin (4-O-methylpyridoxine or MPN) is present in ginkgo seeds and other plant parts [49]. The exact mechanism of action by which increased ginkgotoxin metabolism occurs is unknown; however, it is hypothesized to be the induction of a hepatic drug. Therefore, commercial products produced solely from stem and leaf parts are less likely to induce seizures, unless they have been adulterated with ginkgo seeds. 3.12. Acorus tatarinowii (shichangpu) Rhizomes of A. tatarinowii (shichangpu) have been used in Chinese herbal medicine for the treatment of various ailments, such as epilepsy, headache, eye disorders, insomnia, and loss of memory [56,57]. Modern pharmacological studies have also demonstrated that some extracts of A. tatarinowii may induce sedation, decrease spontaneous activity, and potentiate pentobarbital-induced sleeping time, as well as possess anticonvulsant and spasmolytic actions [58–63]. In one recent study [60], increased amounts of GABA-IR neurons and the density of immunohistochemical reactions in the hippocampus were identified in prolonged PTZ kindling models after treatment with both the decoction and volatile oil of A. tatarinowii. These changes correlate with decreased seizure severity, which suggests that the GABA content may be one factor involved in the mechanism of the anticonvulsant effect. 3.13. Salvia miltiorrhiza (danshen) Salvia miltiorrhiza (Chinese red sage) or danshen is used by TCM practitioners to treat neurological, cardiovascular, and cerebrovascular disorders [64,65]. It is commonly prescribed by TCM practitioners to stroke patients and is included in a TCM drug formulation ding xian wan to control epileptic seizures [65,66]. One recent epilepsy model study demonstrated that the acetone crude extract of danshen can significantly decrease convulsions induced in the larval zebrafish-PTZ assay, and a number of its hydrophobic tanshinones are responsible for this activity. Tanshinone IIA, which is used as a prescription drug in China to treat cerebral ischemia in patients [64], has anticonvulsant activity in both the zebrafish-PTZ and mouse 6-Hz psychomotor seizure models; furthermore, it has a complex profile in the mouse-PTZ infusion model [67]. Readily available pharmacokinetic properties [68,69], including enhanced solubility, bioavailability, and multitarget effects, make tanshinones a potential source of novel anticonvulsants.

3.14. Zingiber officinale (jiang) Ginger, Z. officinale, has long been widely used in China as a spice. China has traditionally produced ginger as a tonic root for over 3000 years to treat many ailments, and this plant is now cultivated throughout the humid tropics, mainly in Shandong province, in China [70]. Glutamate has been recognized as the key excitatory transmitter in the central nervous system that underlies the expression of seizure discharges [71,72]. The expression of glutamate receptors known as mGluRI is strongly implicated in the initiation of an epileptogenic process, in which normal neuronal cortex is converted to a persistently hyperexcitable state with a decreased threshold for seizure discharge production [72]. Ginger has neuroprotective and inhibitory effects on glutamate receptors, which may be responsible for the anticonvulsant activity and the prevention of seizure discharges [71]. In addition, several investigators have previously demonstrated that the extract of ginger and its fractions have anti-5-HT-3-receptor effects [73,74]. Also, 5-HT3receptor antagonists have been suggested to possess anticonvulsant activity [75]. Ginger extract, with its modulatory effect on the 5-HT-3receptor, may alter PTZ-induced seizures and increase the seizure threshold. One recent study in mouse seizure model demonstrated that the acute administration of ginger extract had anticonvulsant effects on a timed intravenous PTZ-induced seizure and suggested that the anticonvulsant effect of ginger may have been mediated by antioxidant mechanisms, oxidative stress inhibition, and a simultaneous influence on different types of calcium channels, as well as both excitatory and inhibitory systems of neurotransmission [76]. 3.15. Matricaria chamomilla (muju) The dried M. chamomilla flower has been used in TCM to prepare a spasmolytic and sedative tea for a gentle sleep aid, as well as a sore stomach and irritable bowel syndrome. Research with animals supports the antispasmodic, anxiolytic, anti-inflammatory, antimutagenic, and cholesterol-lowering effects of chamomile [77]. Its anticonvulsant effects are mainly related, in part, to linoleic acid and/or flavonoid compounds present in the extract [78]. Apigenin, a flavonoid isolated from M. chamomilla, is the potential active ingredient for the anticonvulsant effect, which could reduce the latency in the onset of PTZ-induced convulsions [79]. 3.16. Glycyrrhiza glabra (gancao) Glycyrrhiza glabra (licorice) or gancao is widely used in China as a food and botanical medicine. Licorice flavonoids, the major bioactive components of licorice root, have demonstrated various antioxidant, antitumor, and antiviral biochemical activities [80–82]. One recent study demonstrated that the licorice flavonoid extract has protective effects on seizure-induced neuronal cell death and cognitive impairment through its antioxidative effects [83]. This finding may suggest a potential use in the prevention and treatment of seizure-induced brain injury. 3.17. Curcuma longa (jianghuang) Curcuma longa has been used as a condiment and home remedy in South Asia and China for thousands of years. As the main extract, Rhizoma Curcumae oil not only dominates the traditional use of this medicinal plant, but also has been increasingly recognized to possess multiple therapeutic activities for the treatment of viral infection, tumor, and inflammation, as well as substantial pharmacological properties, such as cognitive enhancement [84]. Turmeric, obtained from the rhizomes of C. longa, is used in Asia as a traditional medicine for the treatment of epilepsy [85]. Curcumol has been cited as the principal component responsible for the antiseizure activity of turmeric [85]. It has been demonstrated that curcumol may suppress epileptic seizures

Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050

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by significantly facilitating GABAA receptors in a zebrafish seizure model [85].

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combination of ginsenosides. All ginseng products also had significant neuroprotective activity in addition to the reduction in seizure severity and duration [108,109].

3.18. Paeonia lactiflora (Chishao) 3.22. All-grass of snakefoot clubmoss (qiancengta) Paeonia radix, obtained from the dry root of the common plant of P. lactiflora (Ranunculaceae), has been widely used to treat inflammatory conditions according to the Traditional Chinese Medical System [86]. Paeoniflorin, a major bioactive component of Paeonia radix, has been used for neuromuscular blocking, cognitive enhancement, and immune regulatory function [87–89]. A previous study demonstrated the inhibitory effect of paeoniflorin extract on PTZ-induced EEG power spectrum changes and suggested that paeoniflorin had anticonvulsant activity [90]. The anticonvulsant effects of paeoniflorin may primarily be associated with the inhibitory effects of peony root extract on the large conductance calcium-activated potassium current essential in the production of bursting activity [91,92] and its protective effects on neuron damage in the hippocampus induced by the cobalt focus epilepsy model [90]. One recent study demonstrated the anticonvulsant effect of paeoniflorin on experimental febrile seizures in immature rats and suggested the potential application for febrile seizures in children [93]. 3.19. Jujube (hongzao) Jujube is the fruit of Ziziphus jujuba (Rhamnaceae), which is commonly referred to as a Chinese date or red date. According to Huang Di Nei Ching, the fruit of Z. jujuba was considered one of the five most valuable fruits in China. Shen Nong Ben Cao Jing (300 B.C.–200 A.D.) cited jujube as one of the superior herbal medicines. The daily intake of a jujube decoction is thought to increase the “Qi” (the vital energy), which thus prolongs the life span. Today, nutrition data have indicated that jujube contained a variety of nutrients, including carbohydrates, minerals, vitamins, sugars, and amino acids [94]. Studies have demonstrated its sedative [95], tranquilizing, and hypnotic effects in rats [96]. One recent finding suggested that sanjoinine A, a component of the alkaloid fraction of Z. jujuba, protects against NMDA-induced seizures via the inhibition of intracellular calcium influx [97]. Another author demonstrated the anticonvulsant effect of the hydroalcoholic extract of Z. jujuba, as well as the amelioration of cognitive impairment induced by seizures in rats [98]. Furthermore, the hydroalcoholic extract of Z. jujuba potentiated the anticonvulsant effect of phenytoin and phenobarbital without altering the serum levels of these drugs [99]. 3.20. Astragalus mongholicus (huangqi) Astragalus mongholicus is a traditional Chinese herb used as a neuroprotective agent for its anxiolytic, antidepressant, antiamnesic, and antiaggressive effects [100–102]. The anticonvulsant effects of the saponin fraction obtained from A. mongholicus on acute PTZ-induced seizures has been reported in recent studies [103,104]. These findings suggested that the anticonvulsant effects of A. mongholicus extract may be mediated by its protective actions against oxidative damage and the amelioration of mitochondrial dysfunction [104].

All-grass of Snakefoot clubmoss or qiancengta is a Chinese folk medicine derived from Huperzia serrata, a Chinese club moss, which mainly grows in the northern region of China. Huperzine A is the main active component of All-grass of Snakefoot clubmoss, which is thought to act as a noncompetitive NMDA receptor antagonist and is a sesquiterpene lycopodium alkaloid isolated from H. serrata. Huperzine A has traditionally been used in China for the treatment of swelling, fever, inflammation, blood disorders, schizophrenia, and Alzheimer's disease [110]. Huperzine A has been demonstrated to be potently active against NMDA-induced seizures/status epilepticus [111]. It requires further evaluation in animal epilepsy models as a potential anticonvulsant. 3.23. Pinellia ternata (banxia) Pinelliae ternata is a TCM herb that is distributed in areas along the Yangtze River in China. Pinelliae ternata has been used by Chinese traditional medical practitioners for the treatment of cough, vomiting, infection, and inflammation since ancient times [112]. It has been reported that a combination of Pinelliae total alkaloids and Uncarial total alkaloids could inhibit electroshock-induced seizures via decreased excitability of glutamatergic neurons and increased inhibition of GABAergic neurons [113]. Thus, extracts from Rhizoma Pinelliae exhibit anticonvulsant activities, and these activities may be related to the GABAergic system. 4. Discussion The oldest, most commonly practiced, and important form of therapy in TCM is pharmacotherapy using drugs derived from botanicals [6]. In folk Chinese traditions, botanical therapies are widely used for general health maintenance or chronic conditions, such as pain or epilepsy, that respond poorly or incompletely to standard treatments [65]. Drugs derived from botanicals have been regarded as a therapy for seizures with few significant side effects [114]. Recent research regarding botanicals in animal epilepsy models suggests that medicinal plants have the potential to be a rich source for the identification of safer and more effective antiepileptic agents. For patients with pharmacoresistant seizures, botanical treatments may provide significant benefits in terms of reduced adverse effects and an improved quality of life [115]. In resource-poor regions, botanical therapies may yield low-cost antiepileptic agents and culturally acceptable treatments for epilepsy. Based on the limited literature regarding a single botanical or botanical extracts with anticonvulsant activities, the present work summarized 23 types of Chinese traditional botanicals that may possess antiepileptic properties. The plant species, geographical origin, and potential mechanisms that underlie the anticonvulsant or antiepileptic effects have been reviewed. Next, the status and use of botanicals in TCM are discussed.

3.21. Panax ginseng (renshen) 4.1. Status of TCM for epilepsy in China Panax ginseng has been considered a valuable tonic, prophylactic, and restorative medicine in traditional Chinese botanicals [105]. The ginsenosides have been identified as the main bioactive component in ginseng [106]. The pharmacological effects attributed to ginsenosides have been demonstrated in the central nervous, cardiovascular, endocrine, and immune systems. Ginsenosides are thought to have antineoplastic, antistress, and antioxidant properties. One study suggested anticonvulsant effects in a rat model using a mixture of ginsenosides, including the panaxadiols and panaxatriols [107], whereas another study demonstrated that the most effective anticonvulsant product is a

The term “Dian Xian” for epilepsy is derived from TCM and implies both insanity and convulsion [6]. Chinese culture and folk traditions have previously regarded it as punishment from ghosts and, thus, viewed epilepsy as a feared and incurable disease [6]. In the previous two decades, the understanding and treatment of epilepsy has remarkably advanced in China [116]. Currently, in west China where our center is based, there is a requirement for physicians to receive neurology training, including epilepsy care [117]. Physicians are required to prescribe antiepileptic medications according to evidence-based guidelines

Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050

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[118]. Compared with a survey from China in 1988 in which nearly 40% of individuals would seek a doctor for traditional herbal or botanical medicine [119], substantially fewer (6.3%) patients in urban areas used Chinese traditional medicine as antiepileptic drugs [120]. We believe that the standardization of physician training for epilepsy care [117] may be responsible for this difference. Nevertheless, according to our recent study [121], in the rural areas of west China, 23.0% of patients choose botanical or herbal medicine for epilepsy treatment from private pharmacies. The majority of these patients consulted a doctor but failed to receive or adhere to an antiepileptic treatment program mostly because of economic and cultural reasons. The course and outcomes of epilepsy in these patients are now under investigation.

4.2. Use of and concerns regarding traditional Chinese botanicals in epilepsy treatment Our review has listed the single or purified botanicals that have been reported to exhibit anticonvulsant or antiepileptic effects. Most of these botanicals have not been used solely for seizure control but were mixed with other herbs to create a formula for this disease. Combination therapy is a fundamental principle of Chinese medicine [6]. The combination of multiple drugs in complex formulations is thought, by traditional Chinese medical practitioners, to maximize the therapeutic efficacy via the facilitation of synergistic drug actions and amelioration of potential adverse effects while simultaneously targeting one or several pathophysiological mechanisms. In clinical practice, botanical formulas have comprised fixed combinations of weighed botanicals with no consideration of an individualized dose titration or dosing regimens. For example, the modified formula of the Chinese medicine “Chaihu longu muli tang”, which is based on a mixture of extracts from 13 types of botanicals, including bupleuri radix, fossilia ossis mastodi, scutellariae radix, zingiberis rhizoma, codonopsitis radix, cinnamomi ramulus, hoelen, pinelliae tuber, ostrease testa, gastrodiae rhizoma, rhei rhizoma, zizyphi fructus, and uncaria thorn, can reduce the seizure frequency in patients with refractory epilepsy [23]. Shitei-To, a mixture of extracts from three medicinal herbs — kaki calyx, the rhizome of Z. officinale, and the flowerbud of Syzygium aromaticum — protects against the development of convulsions and has therapeutic effects in the prevention of

Table 2 Two TCM formulas for treatment of epilepsy. Name (Pinyin) Dianxianning Matixiang马蹄香 Qianniuzi牵牛子 Gouteng钩藤 Shichangpu Qianjinzi千金子 Gansong甘松 Bohe薄荷 Zhenxian pill Niuhuang牛黄 Guangyujin广郁金 Tiannanxing天南星 Fuling茯苓 Gancao甘草 Shichangpu石菖蒲 Suanzaoren酸枣仁 Hongshen红参 Maidong麦冬 Yuanzhi远志 Lianzixin莲子心

Generic name

Weight (g) for formula

Saruma henryi Pharbitisnil choisy Uncaria rhynchophylla Acorus tatarinowii Euphorbialathyris Nardostachys jatamansi Mentha haplocalyx

5.0 g 2.0 g 2.0 g

Bos taurus domesticus Curcuma longa Arisaema erubescens Poria cocos Glycyrrhiza uralensis Acorus tatarinowii Ziziphus jujuba Radix ginseng rubra Ophiopogon japonicus Polygala tenuifolia Plumula nelambinis

3.0 g

5.0 g 1.5 g 2.0 g 0.3 g

5.0 g 5.0 g 7.0 g 1.0 g 5.0 g 10.0 g 5.0 g 7.0 g 5.0 g 5.0 g

secondarily generalized seizures [122]. Zheng Tai instant powder is a complex prescription of Chinese botanical medicines, which is indicated for generalized tonic–clonic seizure [123]. However, the most popular formulas in China are Dianxianning tablets and Zhenxian pill (Table 2), despite the lack of high quality clinical trials and the limited number of patients who use them. The ingredients of these traditional Chinese formulas are complex. Notwithstanding the belief that a combined botanical formula could increase efficacy, the mechanisms with respect to the antiepileptic activities have mainly been related to the natural compounds from medicinal botanicals. One recent article reviewed several natural components with anticonvulsant or antiepileptic activities in botanical treatments. The authors summarized alkaloids, flavonoids, terpenoids, saponins, and coumarins as the main active compounds responsible for antiepileptic activities [36]. One recent Cochrane review by our group [124] identified five, short-term randomized controlled trials of TCM for epilepsy that comprised 1125 participants. Although these Chinese botanical formulas have been reported to have impressive clinical results, there were underlying methodological problems in these studies that resulted in poor methodological quality regarding randomization, allocation concealment, and blinding. Furthermore, there is a lack of information regarding quality standards for the development of herbal preparations and the manufacture of botanical products [124]. Two recent clinical trials of “Chaihu longu muli tang” [23] and “Dianxianning” [125] have reported that the add-on treatment of these formulas could decrease the seizure frequency in refractory epilepsy, which suggests that the role of botanicals in TCM could be used as an adjunctive therapy in refractory epilepsy. Furthermore, the Chinese botanical treatments are not based on evidence regarding the effectiveness and efficacy for an individual's seizure type. The botanicals and formulas have mainly been indicated for generalized tonic–clonic seizures [124]. The clinical utility and combination of botanicals in Chinese traditional medicine for epilepsy have not been influenced by patient-specific features, including age, sex (childbearing potential), and comorbidities. Safety is another crucial issue that deserves consideration. Similar to other antiepileptic pharmaceuticals, botanicals may cause serious or life-threatening adverse effects despite being regarded as natural and, therefore, safe by the public [126]. None of the clinical trials of botanical therapies in TCM have reported side effects, and the follow-ups were included [124]. Thus, the long-term safety profile of these botanicals remains unclear. Furthermore, no studies strictly investigated the adverse effects of botanicals for epilepsy treatment [124]. Botanical medications, especially the formularized prescriptions, should be subjected to more rigorous clinical trials in the hope of identifying more effective and safer treatments. All botanicals reviewed in this study were only examined in animal seizure models. Nevertheless, it is interesting to note that plants, such as qingyangshen (C. otophyllum), hujiaojian (P. nigrum L), and gouteng (U. rhynchophylla), are present in Chinese botanical modular treatments for epilepsy. Thus, these plants are of particular interest for further scientific investigations and would be good candidates for future evaluation as antiepileptic treatment.

4.3. Limitations In this study, we reviewed the most important journals and books in Chinese traditional medicine, explored antiepileptic treatments, identified the plant species, and discussed what is known regarding their potential effectiveness. Although we conducted comprehensive searches, animal experiment publications were predominately identified and included, and no multicenter, large-scale randomized controlled trial (RCT) was identified. We conducted extensive searches for unpublished material, and few of the identified studies qualified for inclusion; however, we cannot disregard the fact that studies with negative findings may remain unpublished.

Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050

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5. Conclusion The current evidence is insufficient to support botanicals in TCM as a treatment for epilepsy despite the widespread use of botanical therapies by patients with epilepsy. However, the centuries old traditions of botanical use in TCM for epilepsy provide a reasonable basis for systematically proceeding with preclinical assessments using modern scientific methods [4]. Future studies should improve the description of the botanicals that are prepared, processed, and tested. Substantially larger, high quality, randomized clinical trials are needed to evaluate the effectiveness and safety of the traditional Chinese botanicals previously described for the treatment of epilepsy. Rigorous clinical trials are encouraged to help the legacy of botanicals in TCM gain more impact and recognition. Acknowledgments This study was supported by the Sichuan Provincial Administration of Traditional Chinese Medicine (No. 2014k162). Disclosure None of the authors have any conflict of interest to disclose. References [1] Newton CR, Garcia HH. Epilepsy in poor regions of the world. Lancet 2012; 380(9848):1193–201. [2] Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med 2011; 365(10):919–26. [3] Sørensen AT, Kokaia M. Novel approaches to epilepsy treatment. Epilepsia 2012; 54(1):1–10. [4] Schachter SC. Herbs and botanicals. In: Rho JM, Sankar R, Strafstrom CE, editors. Epilepsy: mechanisms, models, and translational perspectives. Boca Raton, FL: CRC Press; 2010. p. 403–11. [5] Chen G, Li S. Ben cao gang mu tong shi = General explanation of Compendium of Materia Medica. Beijing Shi: Xue yuan chu ban she 1992;2. [6] Lai CW, Lai YH. History of epilepsy in Chinese traditional medicine. Epilepsia 1991; 32(3):299–302. [7] Chinese pharmacopoeia. 2005;328:547. [8] Mu QZ, Lu JR, Zhou QL. Two new antiepilepsy compounds — otophyllosides A and B. Sci Sin, Ser B, Chem Biol Agric Med Earth Sci 1986;29(3):295–301. [9] Zhao Z-M, Sun Z-H, Chen M-H, Liao Q, Tan M, Zhang X-W, et al. Neuroprotective polyhydroxypregnane glycosides from Cynanchum otophyllum. Steroids 2013; 78(10):1015–20. [10] Guo Q, Kuang P. Studies of qingyangshen (I): differential expression of hippocampal c-fos proto-oncogene during kainic acid induced acute and chronic seizures. J Tradit Chin Med 1995;15(4):292–6. [11] Guo Q, Kuang P. Studies of qingyangshen (II): modulatory effect of co-treatment with qingyangshen and diphenylhydantoin sodium on rat hippocampal c-fos expression during seizures. J Tradit Chin Med 1996;16(1):48–50. [12] Wang F, Xu Z, Ren L, Tsang SY, Xue H. Neuropharmacology. Neuropharmacology 2008;55(7):1231–7. [13] de Carvalho RSM, Duarte FS, de Lima TCM. Involvement of GABAergic nonbenzodiazepine sites in the anxiolytic-like and sedative effects of the flavonoid baicalein in mice. Behav Brain Res 2011;221(1):75–82. [14] Liu Y-F, Gao F, Li X-W, Jia R-H, Meng X-D, Zhao R, et al. The anticonvulsant and neuroprotective effects of baicalin on pilocarpine-induced epileptic model in rats. Neurochem Res 2012;37(8):1670–80. [15] Ojemann LM, Nelson WL, Shin DS, Rowe AO, Buchanan RA. Tian ma, an ancient Chinese herb, offers new options for the treatment of epilepsy and other conditions. Epilepsy Behav 2006;8(2):376–83. [16] Ha JH, Lee DU, Lee JT, Kim JS, Yong CS, Kim JA, et al. 4-Hydroxybenzaldehyde from Gastrodia elata B1 is active in the antioxidation and GABAergic neuromodulation of the rat brain. J Ethnopharmacol 2000;73(1–2):329–33. [17] Ha JH, Shin SM, Lee SK, Kim JS, Shin US, Huh K, et al. In vitro effects of hydroxybenzaldehydes from Gastrodia elata and their analogues on GABAergic neurotransmission, and a structure–activity correlation. Planta Med 2001;67(9): 877–80. [18] Baek NI, Choi SY, Park JK, Cho SW, Ahn EM, Jeon SG, et al. Isolation and identification of succinic semialdehyde dehydrogenase inhibitory compound from the rhizome of Gastrodia elata Blume. Arch Pharm Res 1999;22(2):219–24. [19] Guo Z, Tan T, Zhong Y, Wu C. Study of the mechanism of gastrodin and derivatives of gastrodigenin. Hua Xi Yi Ke Da Xue Xue Bao 1991;22(1):79–82. [20] Xu J, Guo S. Retrospect on the research of the cultivation of Gastrodia elata Bl, a rare traditional Chinese medicine. Chin Med J 2000;113(8):686–92. [21] Yu Y-H, Xie W, Bao Y, Li H-M, Hu S-J, Xing J-L. Saikosaponin a mediates the anticonvulsant properties in the HNC models of AE and SE by inhibiting NMDA receptor current and persistent sodium current. PLoS One 2012;7(11):e50694.

7

[22] Xie W, Yu Y-H, Du YP, Zhao YY, Li CZ, Yu L, et al. Saikosaponin A enhances transient inactivating potassium current in rat hippocampal ca1 neurons. Evid Based Complement Alternat Med 2013;2013:413092. [23] Hung-Ming W, Liu C-S, Tsai J-J, Ko L-Y, Wei Y-H. Antioxidant and anticonvulsant effect of a modified formula of chaihu-longu-muli-tang. Am J Chin Med 2002; 30(2–3):339–46. [24] Chen F-P, Chen F-J, Jong M-S, Tsai H-L, Wang J-R, Hwang S-J. Modern use of Chinese herbal formulae from Shang-Han Lun. Chin Med J 2009;122:1889–94. [25] Wu HM, Huang CC, Li LH, Tsai JJ, Hsu KS. The Chinese herbal medicine Chai-HuLong-Ku-Mu-Li-Tan (TW-001) exerts anticonvulsant effects against different experimental models of seizure in rats. Jpn J Pharmacol 2000;82(3):247–60. [26] Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res 2008;22(8): 999–1012. [27] Bhutada P, Mundhada Y, Bansod K, Dixit P, Umathe S, Mundhada D. Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. Epilepsy Behav 2010;18(3): 207–10. [28] Zhu F, Qian C. Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer's disease. BMC Neurosci 2006;7:78. [29] Kulkarni SK, Dhir A. On the mechanism of antidepressant-like action of berberine chloride. Eur J Pharmacol 2008;589(1–3):163–72. [30] Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. The Lancet 2012;380(9848):1180–92. [31] Peng C-Y, Liu J-Q, Zhang R, Shu J-C. A new alkaloid from the fruit of Nandina domestica Thunb. Nat Pro Res 2014;28(15):1159–64. [32] Ribeiro RA, Rodríguez de Lores Arnaiz G. In vitro dose dependent inverse effect of nantenine on synaptosomal membrane K+-p-NPPase activity. Eur J Integr Med 2001;8(2):107–11. [33] Ribeiro RA, Leite JR. Nantenine alkaloid presents anticonvulsant effect on two classical animal models. Eur J of Integr Med 2003;10(6–7):563–8. [34] Pei YQ. A review of pharmacology and clinical use of piperine and its derivatives. Epilepsia 1983;24(2):177–82. [35] da Cruz GMP, Felipe CFB, Scorza FA, da Costa MAC, Tavares AF, Menezes MLF, et al. Piperine decreases pilocarpine-induced convulsions by GABAergic mechanisms. Pharmacol Biochem Behav 2013;104:144–53. [36] Zhu H-L, Wan J-B, Wang Y-T, Li B-C, Xiang C, He J, et al. Medicinal compounds with antiepileptic/anticonvulsant activities. Epilepsia 2014;55(1):3–16. [37] Hsieh CL, Tang NY, Chiang SY, Hsieh CT, Lin JG. Anticonvulsive and free radical scavenging actions of two herbs, Uncaria rhynchophylla (MIQ) Jack and Gastrodia elata Bl., in kainic acid-treated rats. Life Sci 1999;65(20):2071–82. [38] Lee J, Son D, Lee P, Kim S-Y, Kim H, Kim C-J, et al. Alkaloid fraction of Uncaria rhynchophylla protects against N-methyl-D-aspartate-induced apoptosis in rat hippocampal slices. Neurosc Lett 2003;348(1):51–5. [39] Shimada Y, Goto H, Itoh T, Sakakibara I, Kubo M, Sasaki H, et al. Evaluation of the protective effects of alkaloids isolated from the hooks and stems of Uncaria sinensis on glutamate-induced neuronal death in cultured cerebellar granule cells from rats. J Pharm Pharmacol 1999;51(6):715–22. [40] Hsu H-C, Tang N-Y, Liu C-H, Hsieh C-L. Antiepileptic effect of Uncaria rhynchophylla and rhynchophylline involved in the initiation of c-jun N-terminal kinase phosphorylation of MAPK signal pathways in acute seizures of kainic acid-treated rats. Evid Based Complement Alternati Med 2013;2013(3):1–9. [41] Visweswari G, Prasad KS, Chetan PS, Lokanatha V, Rajendra W. Evaluation of the anticonvulsant effect of Centella asiatica (gotu kola) in pentylenetetrazol-induced seizures with respect to cholinergic neurotransmission. Epilepsy Behav 2010; 17(3):332–5. [42] Srivastava R, Ahmed H, Dixit RK, Dharamveer, Saraf SA. Crocus sativus L.: a comprehensive review. Pharmacogn Rev 2010;4(8):200–8. [43] Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol Clin Exp 2014;29(6):517–27. [44] Hosseinzadeh H, Talebzadeh F. Anticonvulsant evaluation of safranal and crocin from Crocus sativus in mice. Fitoterapia 2005;76(7–8):722–4. [45] Hosseinzadeh H, Sadeghnia HR. Protective effect of safranal on pentylenetetrazolinduced seizures in the rat: involvement of GABAergic and opioids systems. Phytomedicine 2007;14(4):256–62. [46] Sadeghnia HR, Cortez MA, Liu D, Hosseinzadeh H, Snead OC. Antiabsence effects of safranal in acute experimental seizure models: EEG and autoradiography. J Pharm Pharm Sci 2008;11(3):1–14. [47] Miwa H, Iijima M, Tanaka S, Mizuno Y. Generalized convulsions after consuming a large amount of gingko nuts. Epilepsia 2001;42(2):280–1. [48] Kajiyama Y, Fujii K, Takeuchi H, Manabe Y. Ginkgo seed poisoning. Pediatrics 2002; 109(2):325–7. [49] Arenz A, Klein M, Fiehe K, Groß J, Drewke C. Occurrence of neurotoxic 4′-0methylpyridoxine in Ginkgo biloba leaves, ginkgo medications, and Japanese ginkgo food. Planta Med 1996;62:548–51. [50] Sasaki K, Hatta S, Haga M, Ohshika H. Effects of bilobalide on gamma-aminobutyric acid levels and glutamic acid decarboxylase in mouse brain. Eur J Pharmacol 1999; 367(2–3):165–73. [51] Sasaki K, Hatta S, Wada K, Ohshika H, Haga M. Bilobalide prevents reduction of gamma-aminobutyric acid levels and glutamic acid decarboxylase activity induced by 4-O-methylpyridoxine in mouse hippocampus. Life Sci 2000;67(6):709–15. [52] Weichel O, Hilgert M, Chatterjee SS, Lehr M, Klein J. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus. Naunyn Schmiedebergs Arch Pharmacol 1999;360(6):609–15.

Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050

8

F. Xiao et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

[53] Smith PF, Maclennan K, Darlington CL. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). J Ethnopharmacol 1996;50(3):131–9. [54] Harms SL, Garrard J, Schwinghammer P, Eberly LE. Ginkgo biloba use in nursing home elderly with epilepsy or seizure disorder. Epilepsia 2006;47(2):323–9. [55] Sasaki K, Wada K, Hatta S, Ohshika H, Haga M. Bilobalide, a constituent of Ginkgo biloba L., potentiates drug-metabolizing enzyme activities in mice: possible mechanism for anticonvulsant activity against 4-O-methylpyridoxine-induced convulsions. Res Commun Mol Pathol Pharmacol 1997;96(1):45–56. [56] Dong Y, Shi R, Liu B. Study on chemical compositions of Acorus tatarinowii Schott (I)[J]. J Beijing Univ Tradit Med 2007;1:018. [57] Tian S, Ma Y, Sun L, Tan L, Liu J, Li G, et al. Effects of different fractions of Acori graminei rhizoma extracts on learning and memory abilities in Aβ-induced Alzheimer disease mice. Chinese J Pathophysiol 2012;1:037. [58] Liu GQ, Sun JN, He ZZ, Jiang Y. Spasmolytic actions of active principals of volatile oil of Acorus gramineus. Zhongguo Yao Li Xue Bao 1983;4(2):95–7. [59] Liao JF, Huang SY, Jan YM, Yu LL, Chen CF. Central inhibitory effects of water extract of Acori graminei rhizoma in mice. J Ethnopharmacol 1998;61(3):185–93. [60] Liao W-P, Chen L, Yi Y-H, Sun W-W, Gao M-M, Su T, et al. Study of antiepileptic effect of extracts from Acorus tatarinowii Schott. Epilepsia 2005;46(Suppl. 1): 21–4. [61] Cho J, Kong JY, Jeong DY, Lee KD, Lee DU, Kang BS. NMDA recepter-mediated neuroprotection by essential oils from the rhizomes of Acorus gramineus. Life Sci 2001; 68(13):1567–73. [62] Cho J, Kim YH, Kong J-Y, Yang CH, Park CG. Protection of cultured rat cortical neurons from excitotoxicity by asarone, a major essential oil component in the rhizomes of Acorus gramineus. Life Sci 2002;71(5):591–9. [63] Ono J, Vieth RF, Walson PD. Electrocorticographical observation of seizures induced by pentylenetetrazol (PTZ) injection in rats. Funct Neurol 1990;5(4):345–52. [64] Zhou L, Zuo Z, Chow MSS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 2005;45(12):1345–59. [65] Sucher NJ. Insights from molecular investigations of traditional Chinese herbal stroke medicines: implications for neuroprotective epilepsy therapy. Epilepsy Behav 2006;8(2):350–62. [66] Sun X, Chan LN, Sucher NJ. Magnesium as NMDA receptor blocker in the traditional Chinese medicine Danshen. Euro J Integrae Med 2005;12(3):173–7. [67] Buenafe OE, Orellana-Paucar A, Maes J, Huang H, Ying X, De Borggraeve W, et al. Tanshinone IIA exhibits anticonvulsant activity in zebrafish and mouse seizure models. ACS Chem Neurosci 2013;4(11):1479–87. [68] Xu S, Liu P. Tanshinone II-A: new perspectives for old remedies. Expert Opin Ther Patents 2013;23(2):149–53. [69] Tian X-H, Wu JH. Tanshinone derivatives: a patent review (January 2006–September 2012). Expert Opin Ther Patents 2013;23(1):19–29. [70] Benzie IFF, Wachtel-Galor S. Herbal medicine: biomolecular and clinical aspects. 2nd ed. Boca Raton (FL): CRC Press; 2011. [71] Yeh H-Y, Chuang C-H, Chen H-C, Wan C-J, Chen T-L, Lin L-Y. LWT-Food Sci Technol 2014;55(1):329–34. [72] Anwyl R. Metabotropic glutamate receptor-dependent long-term potentiation. Neuropharmacology 2009;56(4):735–40. [73] Abdel-Aziz H, Windeck T, Ploch M, Verspohl EJ. Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum. Eur J Pharmacol 2006; 530(1–2):136–43. [74] Riyazi A, Hensel A, Bauer K, Geissler N, Schaaf S, Verspohl EJ. The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum. Planta Med 2007;73(4):355–62. [75] Vishwakarma SL, Pal SC, Kasture VS, Kasture SB. Anxiolytic and antiemetic activity of Zingiber officinale. Phytother Res 2002;16(7):621–6. [76] Hosseini A, Mirazi N. Acute administration of ginger. Epilepsy Res 2014;108(3): 411–9. [77] McKay DL, Blumberg JB. A review of the bioactivity and potential health benefits of chamomile tea (Matricaria recutita L.). Phytother Res 2006;20(7):519–30. [78] Heidari MR, Dadollahi Z, Mehrabani M, Mehrabi H, Pourzadeh-Hosseini M, Behravan E, et al. Study of antiseizure effects of Matricaria recutita extract in mice. Ann N Y Acad Sci 2009;1171(1):300–4. [79] Avallone R, Zanoli P, Puia G, Kleinschnitz M, Schreier P, Baraldi M. Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla. Biochem Pharmacol 2000;59(11):1387–94. [80] Sun Y-X, Tang Y, Wu A-L, Liu T, Dai X-L, Zheng Q-S, et al. Neuroprotective effect of liquiritin against focal cerebral ischemia/reperfusion in mice via its antioxidant and antiapoptosis properties. J Asian Nat Prod Res 2010;12(12):1051–60. [81] Asha MK, Debraj D, Prashanth D, Edwin JR, Srikanth HS, Muruganantham N, et al. In vitro anti-Helicobacter pylori activity of a flavonoid rich extract of Glycyrrhiza glabra and its probable mechanisms of action. J Ethnopharmacol 2013;145(2):581–6. [82] Wang K-L, Hsia S-M, Chan C-J, Chang F-Y, Huang C-Y, Bau D-T, et al. Inhibitory effects of isoliquiritigenin on the migration and invasion of human breast cancer cells. Expert Opin Ther Targets 2013;17(4):337–49. [83] Zeng L-H, Zhang H-D, Xu C-J, Bian Y-J, Xu X-J, Xie Q-M, et al. Neuroprotective effects of flavonoids extracted from licorice on kainate-induced seizure in mice through their antioxidant properties. J Zhejiang Univ Sci B 2013;14(11):1004–12. [84] Sun C-Y, Hu W, Qi S-S, Dai K-Y, Hu S-W, Lou X-F. Effect of Rhizoma curcumae oil on the learning and memory in rats exposed to chronic hypoxia and the possible mechanisms. Sheng Li Xue Bao 2008;60(2):228–34. [85] Ding J, Wang J-J, Huang C, Wang L, Deng S, Xu T-L, et al. Neuropharmacology 2014; 81(c):244–55.

[86] Wang C-H, Wang R, Cheng X-M, He Y-Q, Wang Z-T, Wu C, et al. Comparative pharmacokinetic study of paeoniflorin after oral administration of decoction of Radix Paeoniae Rubra and Radix Paeoniae Alba in rats. J Ethnopharmacol 2008;117(3): 467–72. [87] Dezaki K, Kimura I, Miyahara K, Kimura M. Complementary effects of paeoniflorin and glycyrrhizin on intracellular Ca2+ mobilization in the nerve-stimulated skeletal muscle of mice. Jpn J Pharmacol 1995;69(3):281–4. [88] Watanabe H. Candidates for cognitive enhancer extracted from medicinal plants: paeoniflorin and tetramethylpyrazine. Behav Brain Res 1997;83(1–2): 135–41. [89] Tang N-Y, Liu C-H, Hsieh C-T, Hsieh C-L. The anti-inflammatory effect of paeoniflorin on cerebral infarction induced by ischemia-reperfusion injury in Sprague–Dawley rats. Am J Chin Med 2010;38(1):51–64. [90] Tsuda T, Sugaya A, Ohguchi H, Kishida N, Sugaya E. Protective effects of peony root extract and its components on neuron damage in the hippocampus induced by the cobalt focus epilepsy model. Exp Neurol 1997;146(2):518–25. [91] Sugaya E, Jin W, Sugaya A, Sunaga K, Tsuda T. Inhibitory effects of peony root extract on the large conductance calcium-activated potassium current essential in production of bursting activity. J Herb Pharmacother 2006;6(2):65–77. [92] Sugaya A, Suzuki T, Sugaya E, Yuyama N, Yasuda K, Tsuda T. Inhibitory effect of peony root extract on pentylenetetrazol-induced EEG power spectrum changes and extracellular calcium concentration changes in rat cerebral cortex. J Ethnopharmacol 1991;33(1–2):159–67. [93] Hino H, Takahashi H, Suzuki Y, Tanaka J, Ishii E, Fukuda M. Anticonvulsive effect of paeoniflorin on experimental febrile seizures in immature rats: possible application for febrile seizures in children. In: Kline AE, editor. PLoS One, 7(8); 2012. p. e42920. [94] Chen J, Du CYQ, Lam KYC, Zhang WL, Lam CTW, Yan AL, et al. The standardized extract of Ziziphus jujuba Fruit (jujube) regulates pro-inflammatory cytokine expression in cultured murine macrophages: suppression of lipopolysaccharidestimulated NF-κB activity. Phytother Res 2014;28(10):1527–32. [95] Ma Y, Han H, Eun JS, Kim HC, Kim H-C, Hong J-T, et al. Sanjoinine A isolated from Zizyphi Spinosi Semen augments pentobarbital-induced sleeping behaviors through the modification of GABA-ergic systems. Biol Pharm Bull 2007;30(9): 1748–53. [96] Peng WH, Hsieh MT, Lee YS, Lin YC, Liao J. Anxiolytic effect of seed of Ziziphus jujuba in mouse models of anxiety. J Ethnopharmacol 2000;72(3):435–41. [97] Ma Y, Yun S-R, Nam S-Y, Kim Y-B, Hong J-T, Kim Y, et al. Protective effects of sanjoinine A against N-methyl-D-aspartate-induced seizure. Biol Pharm Bull 2008;31(9):1749–54. [98] Pahuja M, Mehla J, Reeta KH, Joshi S, Gupta YK. Epilepsy Behav 2011;21(4):356–63. [99] Pahuja M, Kleekal T, Reeta KH, Tripathi M, Gupta YK. Epilepsy Behav 2012;25(3): 368–73. [100] Xie X, Zhang H-D, Chen Y-Z, Cao Y, Wang L, Xu Z. Chemical constituents and activities of total flavonoids from Yushen Tang. Zhongguo Zhong Yao Za Zhi 2012;37(23):3585–90. [101] Yang X-J, Hong Y-L, Wu F, Ruan K-F, Feng Y. Determination of rhynchophylline and isorhynchophylline in Uncaria rhynchophylla by HPLC. Zhongguo Zhong Yao Za Zhi 2013;38(5):720–4. [102] Wang D, Zhuang Y, Tian Y, Thomas GN, Ying M, Tomlinson B. Study of the effects of total flavonoids of Astragalus on atherosclerosis formation and potential mechanisms. Oxid Med Cell Longev 2012;2012:282383. [103] Jalsrai A, Grecksch G, Becker A. Evaluation of the effects of Astragalus mongholicus Bunge saponin extract on central nervous system functions. J Ethnopharmacol 2010;131(3):544–9. [104] Aldarmaa J, Liu Z, Long J, Mo X, Ma J, Liu J. Anti-convulsant effect and mechanism of Astragalus mongholicus extract in vitro and in vivo: protection against oxidative damage and mitochondrial dysfunction. Neurochem Res 2010;35(1):33–41. [105] Liu CX, Xiao PG. Recent advances on ginseng research in China. J Ethnopharmacol 1992;36(1):27–38. [106] Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58(11):1685–93. [107] Lee J-H, Kim S-R, Bae C-S, Kim D, Hong HN, Nah SY. Protective effect of ginsenosides, active ingredients of Panax ginseng, on kainic acid-induced neurotoxicity in rat hippocampus. Neurosci Lett 2002;325(2):129–33. [108] Lian X-Y, Zhang Z-Z, Stringer JL. Anticonvulsant activity of ginseng on seizures induced by chemical convulsants. Epilepsia 2005;46(1):15–22. [109] Lian X-Y, Zhang Z, Stringer JL. Anticonvulsant and neuroprotective effects of ginsenosides in rats. Epilepsy Res 2006;70(2–3):244–56. [110] Zangara A. The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease. Pharmacol Biochem Behav 2003;75(3):675–86. [111] Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, et al. [+]Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/ status epilepticus in rats. Chem Biol Interact 2008;175(1–3):387–95. [112] Mao SJ, Wu LY, Cheng LP. Sedative and anticonvulsive effects of differently processed rhizoma Pinelliae. Zhongguo Zhong Yao Za Zhi 1994;19(4):21820-256. [113] Mao S, Cheng L, Wu L. Study on anticonvulsive effect of rhizoma Pinelliae. Zhong Yao Cai 2001;24(11):813–4. [114] Fong SYK, Wong YC, Zuo Z. Alterations in the CNS effects of anti-epileptic drugs by Chinese herbal medicines. Expert Opin Drug Metab Toxicol 2014;10(2):249–67. [115] Schachter SC. Botanicals and herbs: a traditional approach to treating epilepsy. Neurotherapeutics 2009;6(2):415–20. [116] Li S, Wu J, Wang W, Jacoby A, de Boer H, Sander JW. Stigma and epilepsy: the Chinese perspective. Epilepsy Behav 2010;17(2):242–5.

Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050

F. Xiao et al. / Epilepsy & Behavior xxx (2015) xxx–xxx [117] Li J, Si Y, Hu J, Liu L, Deng Y, He J, et al. Enhancing medical compliance of patients with convulsive epilepsy in rural community: a randomized intervention trial. Epilepsia 2013;54(11):1988–96. [118] Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kalviainen R, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54(3):551–63. [119] Lai CW, Huang XS, Lai YH, Zhang ZQ, Liu GJ, Yang MZ. Survey of public awareness, understanding, and attitudes toward epilepsy in Henan Province, China. Epilepsia 1990;31(2):182–7. [120] Hong Z, Qu B, Wu X-T, Yang T-H, Zhang Q, Zhou D. Economic burden of epilepsy in a developing country: a retrospective cost analysis in China. Epilepsia 2009;50(10): 2192–8. [121] Hu J, Si Y, Zhou D, Mu J, Li J, Liu L, et al. Prevalence and treatment gap of active convulsive epilepsy: a large community-based survey in rural West China. Seizure 2014;23(5):333–7.

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[122] Minami E, Shibata H, Nomoto M, Fukuda T. A traditional Chinese medicine formulation. Euro J Integra 2000;7(1):69–72. [123] Hu H, Zhou Y, Sui Y, Qi M. An experimental study of effect of Zheng Tai instant powder on grand mal epilepsy. J Tradit Chin Med 2000;20(3):210–5. [124] Li Q, Chen X, He L, Zhou D. Traditional Chinese medicine for epilepsy. Cochrane Database Syst Rev 2009;3:CD006454. [125] He L, Wen T, Yan S, Li R, Liu Z, Ren H, et al. Reevaluation of the effect of Dianxianning on seizure rate of refractory epilepsy as additive treatment in clinical practice. Front Med 2011;5(2):229–34. [126] Pearl PL, Drillings IM, Conry JA. Herbs in epilepsy: evidence for efficacy, toxicity, and interactions. YSPEN 2011;18(3):203–8.

Please cite this article as: Xiao F, et al, Review of the use of botanicals for epilepsy in complementary medical systems — Traditional Chinese Medicine, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.050