Epilepsy in the Renaissance: A survey of remedies from 16th and 17th century German herbals

Journal of Ethnopharmacology 143 (2012) 1–13

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Review

Epilepsy in the Renaissance: A survey of remedies from 16th and 17th century German herbals Michael Adams a,n, Sarah-Vanessa Schneider a, Martin Kluge b, Michael Kessler b, Matthias Hamburger a a b

Department of Pharmaceutical Sciences, Division of Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland Swiss Pharmaceutical Museum, University of Basel, Toteng¨ asslein 3, CH-4051 Basel, Switzerland

a r t i c l e i n f o

abstract

Article history: Received 5 March 2012 Received in revised form 7 June 2012 Accepted 7 June 2012 Available online 16 June 2012

Ethnopharmacological relevance: Before modern anticonvulsive drugs were developed people in central Europe used herbal remedies to treat epilepsy. Hundreds of different plants for this indication can be found in German herbals of the 16th and 17th centuries. Here we compile these plants and discuss their use from a pharmacological perspective. Materials and methods: Nine of the most important European herbals of the 16th and 17th century including Bock (1577), Fuchs (1543), Mattioli (1590), Lonicerus (1660, 1770), Brunfels (1532), Zwinger (1696), and Tabernaemontanus (1591, 1678) were searched for terms related to epilepsy, and plants and recipes described for its treatment were documented. We then searched scientific literature for pharmacological evidence of their effectiveness. Additionally the overlapping of these remedies with those in De Materia Medica by the Greek physician Dioscorides was studied. Results: Two hundred twenty one plants were identified in the herbals to be used in the context of epilepsy. In vitro and/or in vivo pharmacological data somehow related to the indication epilepsy was found for less than 5% of these plants. Less than 7% of epilepsy remedies are in common with De Materia Medica. Conclusions: Numerous plants were used to treat epilepsy in the 16th and 17th centuries. However, few of these plants have been investigated with respect to pharmacological activity on epilepsy related targets. & 2012 Elsevier Ireland Ltd. All rights reserved.

Keywords: European herbals Renaissance Epilepsy Medicinal plants Pharmacological activity Anti-epileptic

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Experimental methods in antiepileptic Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BAC, Baclofen; BMC, Bicucullin; CA1-neurons, Neurones from the CA1 region of the hippocampus; CC(T), Computer tomography; [3H]5,7-DCKA, 5,7-dichlor kynurenic acid; EBOB, 40 -ethynyl-4-n-[2,3-(3)H(2)]propylbicycloorthobenzoate; EEG, Electroencephalography; FCS, Fluorescence-correlation-spectroscopy; [3H]FNT, [3H]Flunitrazepam; GABA, Gamma amino butyric acid; GABA-T, GABA-transaminase; GAD, Glutamate decarboxylase; GBL, g-butyrolacton; GBZ, The vehicle registration code of Gibraltar; GH4C1-cells, Rat hypophyse cell line; I.m., Intramuscularly; INH, Isoniazid; I.p., Intraperitoneally; KA, Kainic acid; MAO, Monoamine oxidase; MES, Maximal electroshock seizure threshold model; MRS, Magnetic resonance spectroscopy; MRT, Magnetic resonance tomography; NMDA, N-methyl D-aspartate; NMRI-mice, Mouse strain from the Naval Medical Research Institute; MTT, 3-(4,5-Dimethylthiazol-2-yl)2,5, Diphenyltetrazoliumbromid; PET, Positron emission tomography; PTZ, Pentylenetetrazole; PTX, Picrotoxin; PTZ, Pentylenetetrazole; [35S]TBPS, [35S]T, Butylbicyclophosphorothionate; SPECT, Single-photon-emission-computer tomography n Corresponding author. Tel.: þ41 61 267 15 64; fax: þ 41 61 267 14 74. E-mail address: [email protected] (M. Adams). 0378-8741/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2012.06.010

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M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13

1. Introduction ‘‘Behind everyone alive today stand 30 ghosts, for that is the ratio by which the dead outnumber the living’’ Clarke, (1968) wrote in the foreword to ‘‘2001: A Space Odyssey’’. The exact number of people who ever lived is a matter of some speculation (Haub, 2011), but it is indisputable that most of them used plants as medicines. It is very wise to study peoples’ herbal medicines because they have been a prolific source of drugs, and continue to inspire drug discovery to this day (Rates, 2001). Epilepsy affects 50 million people worldwide. Eighty percent of them live in developing countries, of which 90% do not receive appropriate treatment (Scott et al., 2001). It is not a single disorder, but rather a number of divergent symptoms all of which involve episodic seizures (Baumgartner, 2001). Epilepsy is not curable but can commonly be controlled with modern anticonvulsants which prevent the seizures or lessen their intensity enabling a less restricted life. However, over 30% of people with epilepsy have uncontrolled seizures even with the best available drugs (Engel, 1996). Throughout history epilepsy has been viewed with bewilderment and the uncontrollable seizures were often atributed to the influence of spirits. Stone aged people are thought to have performed trepanations (drilling holes into the skull) to dispell the spirits (see Tajerbashi and Friedrich, 2007). The ancient Greek hippocratic thinking was that the seizures were a sign of a person having prophetic abilities (Temkin, 1994). Early christian and mideaval belief was that epilepsy was a punishment from god, and in the early modern times epilepsy was viewed accordinig to the concepts of humural pathalogy—as an imbalance of the four bodily fluids or humors-blood, phlegm, black bile, and yellow bile (Temkin, 1994). The first synthetic anticonvulsant, paraldehyde, was introduced in 1882. Later, phenobarbital (1921) became the main drug prescribed for epilepsy, followed in 1938 by diphenylhydantoin (dilantin, phenytoin) (Baumgartner, 2001). Before that people in central Europe just like anywhere else in the world depended mainly on plants to treat epileptic seizures. Because epilepsy always was a relatively common neurological disorder one could reasonably anticipate finding herbal drugs and recipes for its treatment in major medical works from past times such as the 16th and 17th century German language Renaissance herbals we deal with in this study. We have here documented and discussed herbal remedies to treat epilepsy reported in these herbals with the aim of presenting them to a wider scientific community and to discuss what is known about their pharmacological effects on drug targets relevant to pharmacotherapy of epileptic diseases. This is the fourth in a series of surveys we have done on German Renaissance herbals. Previously we reported remedies used to treat dementia (Adams and Hamburger, 2007), rheumatism (Adams et al., 2009a), and malaria (Adams et al., 2011a). These studies form the basis for the focused selection of plants to be screened against targets relevant to each of the indications to identify their active constituents (Adams et al., 2009b,c, 2011b ; Zimmermann et al., 2012a,b).

2. Methodology We accessed nine original herbals kept at the Swiss Pharmaceutical Museum in Basel, including (Bock, 1577; Fuchs, 1543; Mattioli, 1590; Lonicerus (1660, 1770); Brunfels, 1532; Zwinger, 1696 and Tabernaemontanus, 1591, 1678). The herbal by Matthioli is the only herbal which was not originally in German but in Italian. The later edition of Tabernaemontanus is an expanded version, which allowed some insight into the development of an herbal over time.

These books were amongst the most important European herbals of the 16th and 17th century (see Adams et al., 2011a). The herbals were then searched systematically using the following scheme: First, we searched Deutsches Krankheitsnamen-Buch‘‘ by Max ¨ Hofler (1970) (the dictionary of German disease names‘‘) for the terminology used for epilepsy in those times and identified: ¨ Fallend Sucht‘‘, ‘‘Fallend’’, ‘‘Fallendweh’’, ‘‘Fallubel’’, (which translate roughly to ‘‘the falling sickness’’; ‘‘obere Begreifung’’ (‘‘upper seizing’’), ‘‘St. Veits-Arbeit’’ or ‘‘St. Valentinskrankheit’’ (Saint Valentines sickness), ‘‘Kindliweh/Kindleinweh’’ (‘‘children’s ¨ sickness’’), ‘‘boses Wesen’’ (‘‘evil being’’ or ‘‘evil character’’), ‘‘Hinfallend’’, ‘‘(hin)fallender Siechtag/Siechtum’’ (‘‘falling infirmity’’), ‘‘heilige or schwere Krankheit’’ (‘‘holy or severe sickness’’), ¨ Bose Seuch‘‘ (‘‘evil epidemic‘‘), hinfallend Weh‘‘ (‘‘falling down sickness’’), hohe Krankheit‘‘ (‘‘high sickness’’), schwere Not(h)‘‘ (‘‘the great distress’’), grosse Krankheit (‘‘the great disease’’). Second, we searched for these terms in the herbals’ indices and studied the corresponding text. Third, we identified the plants by checking up the old names in lists of old plant names, and/or by identifying them on the basis of the illustration. Comprehensive listings of historic or regional ¨ plant names can be found in ‘‘Worterbuch der Deutschen Pflanzennamen’’ by Marzell (2000). Illustrations in these herbals resemble those in modern day plant guides quite well (see for ¨ example: Jager and Werner, 2005; Lauber and Wagner, 2007; Spohn et al., 2008) and can be identified by a trained botanist. All possible effort was taken to assign the correct scientific plant names, but absolute taxonomic certainty cannot be guaranteed when dealing with texts from times before the introduction of the concepts of Linnaean taxonomy. Finally, we did an extensive search of the scientific data bank SciFinders (2010, CAS, American Chemical Society) to find recent results concerning the phytochemistry and possible anticonvulsive activities of the plants. First of all we searched for in vivo anticonvulsive effects by searching the plant genus names in combination with the terms ’’epilepsy’’, ‘‘seizures’’, and ‘‘anticonvulsive’’. We then also documented in vitro effects: Most in vitro inticonvulsive effects described in the literature concerned ion channel modulating effects. The most important ion channel involved in epilepsy is the GABA receptor which is the ionotropic receptor ligand gated ion channel for the endogenous ligand gaminobutyric acid (GABA). GABA is thus the most important central nervous system inhibitory neurotransmitter. The most important excitatory neurotransmitter is glutamate, acting through several receptor subtypes (Bromfield et al., 2006). Our literature search therefore included the terms ‘‘GABA’’, ‘‘aspartate’’, ‘‘glutamate’’, ‘‘NMDA’’ and ‘‘AMPA’’. If hits were found, the search was refined at species level. Other ion channels which may also play an important role in epilepsy (Bromfield et al., 2006) but are less well studied in terms of their interaction with plant extracts and phytochemicals are not discussed here in detail. Because our literature sources are not available to most readers we have listed all the recipes referred to here as supporting information unaltered in the original wording. We have also included photographs of the plant illustrations (see Supporting Information). 2.1. Experimental methods in antiepileptic drug discovery Numerous in vivo models and in vitro assays have been developed to model different aspects of epilepsy and to perform drug discovery targeted at specific molecular targets implicated in the disease. An extensive overview of these is not within the scope of this paper, since several excellent reviews are available

M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13

(Nsour et al., 2000; Jefferys,1994; Meldrum,1997). We just focus on some basic principles of anticonvulsant assays. The first main type of in vitro assay used are the competitive binding assays with radio tagged ligands, which specifically bind to certain convulsion related receptors in isolated cells or membrane homogenates. Targets commonly studied are distinct GABAA receptor ligand binding sites like the GABA/muscimol, the benzodiazepine, and the butylbicyclophosphorothionate (TBPS)/picrotoxin binding site, and NMDA receptors (Sieghart, 1995). Second, allosteric interactions of substances with ligand gated ion channels such as GABAA and NMDA receptors are investigated with electrophysiological methods which directly measure substance induced ion currents across membranes. Patch clamps or voltage clamp techniques are used. Receptors are expressed in Xenopus oocytes or in mammalian cell lines such as HEK 293 (Barnard et al., 1987; Wisden and Seeburg, 1992; Tierney, 2011). In vivo anticonvulsive test systems measure the mitigating effects of a test compound on seizures which are induced by administering proconvulsive compounds like PTZ (pentylenetetrazole), strychnine, KA (kainic acid), INH (isoniazid), PTX (picrotoxin), GBL (g-butyrolacton), BAC (baclofen), BMC (bicucullin), pilocarpine, or metrazol to the test animals which are usually mice or rats. In microelectrode seizure models (MES) convulsions are induced by using electrodes implanted in the brain or clipped to the ears of rodents.

3. Results In the nine herbals we identified 221 plants from 53 plant families that were described for their use as remedies for treating epilepsy. In Table 1 plants are listed alphabetically by family, and within these, by genus and species with botanical authority. Column two lists the herbals that reported on them, and the third column provides information on way of administration (internal or external use). After completion of this list we did a systematic literature search to find recent results concerning the phytochemistry and possible experimental antiepileptic effects of the plants. We found recent in vitro or in vivo studies for just 49 species from this list (22%). This data included both pro and anticonvulsant results, obtained from very heterogeneous tests. In the following section the plants for which pharmacological data was available are presented with a brief description of how they were used, and possible effects are discussed judging from published literature. The order of plants follows the sequence in Table 1. The largest single in vitro study on anticonvulsive European plants done so far ¨ was by Jager et al. (2006), who screened aqueous and ethanolic extracts from 51 plants used traditionally in Danish folk medicine to treat epilepsy and convulsions or as sedative, for affinity to the benzodiazepine binding site of the GABAA receptor in a radioligand displacement assay. Since 24 of the plants from that study can be found in this survey too, it alone greatly increases the number of ‘‘studied’’ plant we could present here. The plants in common were: Pimpinella anisum L., Hedera helix L., Hieracium pilosella L., Buxus sempervirens L., Stellaria media Vill., Bryonia alba L., Betonica officinalis L., Melissa officinalis L., Origanum vulgare L., Rosmarinus officinalis L., Thymus vulgaris L., Convallaria majalis L., Viscum album L., Malva sylvestris L., Paeonia sp. L., Primula elatior (L.) Hill, Primula veris L., Helleborus sp. L., Ruta graveolens L., Tilia europaea L., Valeriana officinalis L., Verbena officinalis L., Viola odorata L., and Viola tricolor L.. Furthermore this study contained aqueous and ethanolic extracts of Apium graveolens L., Carum carvi L., Arnica montana L., Tanacetum parthenium Sch. Bip., Borago officinalis L., Cynoglossum officinale L., Cheiranthus cheiri L.,

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Nasturtium microphyllum Boenn. ex Rchb., Humulus lupulus L., Sedum acre L., Sempervivum tectorum L., Calluna vulgaris (L.) Hull, Euphorbia peplus L., Trigonella foenum graecum L., Glechoma hederacea L., Nuphar lutea Sibth. & Sm., Euphrasia nemorosa Pers., and Datura stramonium L.. Instead of discussing all the plants in that study we have restricted ourselves to presenting just the three most active extracts from Primula elatior, Primula veris, and from Tanacetum parthenium in the section below. That is why we shall discuss just 26 plants here and not all 49 for which some data would be available. For all other results please refer to the ¨ original study (Jager et al., 2006). Drinking a schnaps, (an alcoholic destillate) made from the roots of Angelica archangelica was recommended by Tabernaemontanus to treat epileptic fits. A chloroform extract from the roots of A. archangelica was tested in vitro in GH4C1-cells from rat hypophysae, where it inhibited Ca2 þ uptake. Subsequently, fifteen furocoumarins were isolated and tested. The most potent ¨ al ¨ a¨ et al., calcium uptake antagonist was archangelicin (Harm 1992). The anticonvulsive activity of imperatorin from the fruits of A. archangelica was tested in mice, where the threshold of MES induced seizures was measured after 15, 30, 60 and 120 min. Thirty minutes after the injection (50–100 mg/kg i.p.) the elevation of the threshold reached a maximum of 38–68% (Luszczki et al., 2007). Zaugg et al. (2011a) identified the furocoumarins imperatorin, cnidilin, osthol, and columbianedin from the related species Angelica pubescens as GABAA receptor modulators in a functional two-microelectrode voltage clamp assay with Xenopus oocytes which expressed recombinant g-aminobutyric acid type A (GABAA) receptors of the subtype a1b2g2S. Osthol and cnidilin, at 300 mM, showed maximal potentiation of the GABA induced chloride current (274% and 205%, respectively). Bisabolangelone only showed minor activity at the GABAA receptor. From a therapeutic point of view these compounds may be problematic because of the phototoxicity of linear furanocoumarins. Tabernaemontanus recommended that epileptics were to eat coriander (Coriandrum sativum) with every meal. Coriander essential oil actually enhanced the effects of GABA in Xenopus oocytes expressing GABAA- receptors. Pentobarbital-induced sleeping time in mice was studied after both i.p. and inhalational administration of coriander oil prior to i.p. administration of pentobarbital. This co-administration prolonged the sleeping time. Therefore, it was presumed that coriander oil activated GABAA receptors and thus potentiated the effects of barbiturates (Mubassara et al., 2008). Mattioli, Tabernaemontanus and Fuchs recommended anise (Pimpinella anisum) seeds against epilepsy, and Lonicerus advised drinking anise oil in wine. The oil from the fruits contains mainly eugenol, anethol, methyl chavicol, anis aldehyde and estragol, and showed anticonvulsive effects in a study with male NMRI mice. Anise oil not only suppressed MES (ED50 ¼0.2 ml/kg) and PTZ (ED50 ¼0.52 ml/kg) induced seizures, but also increased the threshold for PTZ-induced seizures (Pourgholami et al., 1999). However, in PTZ treated neurons from Helix aspera (garden snail) anise oil (0.01% and 0.05%) caused stronger paraxomal depolarisation and enhancement of nerve impulses, elevated the triggering of action potentials, decreased the following hyperpolarisation, and enhanced the proepileptic effects of PTZ. Therefore it was concluded that anise oil may cause neuronal overexcitement by increasing Ca2 þ activity and by inhibiting current dependant and Ca2 þ dependant sodium channels (Janahmadi et al., 2008). Chamomile (Matricaria chamomilla) flowers soaked in vinegar and honey were consumed to treat epilepsy (Bock, Lonicerus, Matthioli and Tabernaemontanus). Viola et al. (1995) showed that aqueous chamomile extract had GABAA receptor affinity in a flunitrazepam binding assay. Consequently they isolated the flavone apigenin, which was active in the binding assay at

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M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13

Table 1 Plants found in the nine Renaissance herbals, Bock (1577) (Bo.) Brunfels (1532) (Br.), Fuchs (1543) (Fu.), Mattioli (1590) (Ma.), Lonicerus (1560, 1770) (Lo.), Tabernaemontanus (1591), (1687) (Ta.1), (Ta. 2), and Zwinger (1696) (Zw.) to treat epilepsy are sorted by family, genus and species with the botanical authority. The application was internal (i) or external (e). Species names given in bold indicate those plants discussed in the text. Family

Plant

Use

Herbal author

Allium sativum L. Allium schoenoprasum L.

i þe e

Bo,Ma and Ta2 Ma

Angelica archangelica L. Angelica sylvestris L. Anthriscus sylvestris (L.) Hoffm. Astrantia major L. Bupleurum fruticosum L. Coriandrum sativum L. Dorema ammoniacum D. Don Eryngium campestre L. Eryngium maritimum L. Eryngium planum L. Ferula assa-foetida L. Ferula galbaniflua Boiss. & Buhse Ferula persica Willd. Heracleum austriacum L. Heracleum sphondylium L. Laserpitium gallicum L. Laserpitium halleri Crantz Laserpitium latifolium L. Laserpitium siler L. Opopanax chironium Koch Pastinaca sativa L. Peucedanum cervaria Lapeyr. Peucedanum officinale L. Peucedanum ostruthium (L.) Koch Pimpinella anisum L. Seseli gummiferum Boiss. Seseli libanotis (L.) Koch Seseli tortuosum L.

i i i i i i i i i i i i þe i i i i i i i i i i e i i þe i i i

Ta2 Ta2 Ma Zw, Ma and Ta2 Zw Ta2 Ma and Ta2 Lo, Bo, Ta, Ma, Zw and Fu Zw and Ma Zw and Ma Lo and Ma Ta2 and Ma Ta2 and Ma Ta2 Bo,Ma and Ta2 Ta2 and Ma Ta2 Fu and Ta2 Ma, Ta2, Zw Zw and Ta2 Ma and Ta2 Fu Fu and Ta2 Ma, Zw and Bo Ma, Fu, Lo2 and Ta2 Zw Ma and Ta2 Zw

Hedera helix L.

i

Ma

Aristolochia clematitis L. Aristolochia longa L. Aristolochia pistolochia L. Aristolochia rotunda L. Asarum europaeum L.

i i i i þe i

Fu, Ta, Ta2 and Ma Fu, Ma, Zw and Lo Ma Ma, Lo and Lo2 Ma and Ta2

Achillea clavennae L. Achillea filipendulina Lam. Achillea millefolium L. Achillea tomentosa L. Anacyclus officinarum Hayne Anacyclus pyrethrum (L.) Link Anthemis arvensis L. Anthemis nobilis L. Chamaemelum nobile (L.) All. Anthemis nobilis var. Plena L. Anthemis tinctoria L. Artemisia absinthium L. Artemisia pontica L. Artemisia umbelliformis L. Aster alpinus L. Aster amellus L. Aster linosyris Bernh. Aster tripolium L. Centaurea benedicta L. Cichorium intybus L. Cichorium intybus var.foliosum L. Cichorium spinosum L. Doronicum grandiflorum Lam. Doronicum pardalianches L. Erigeron acris L. Hieracium caesium Fr. Hieracium lactucella Wallr. Hieracium murorum L. Hieracium pilosella L. Hieracium staticifolium L. Inula conyza DC.

i i i i i þe i þe i i i i i i i i i i i i i i i i i i i i i I I I I

Ta2 Ta2 Ta2 Ta2 Lo2 and Ta2 Zw, Bo, Ta2 and Lo2 Lo Ta2 Lo and Bo Ta2 and Ma Ta2 Ta2 and Zw Zw Zw and Ta2 Ma Ta and Ma Ma Ma Lo Zw Zw Zw Zw Zw Ta and Ma Lo2 Ta2 Ta2 Zw, Lo2 and Ta2 Zw and Lo2 Bo, Ta, Ma and Lo2

Alliaceae

Apiaceae

Araliaceae Aristolochiaceae

Asteraceae

M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13

Table 1 (continued ) Family

Plant

Use

Herbal author

Inula germanica L. Inula hirta L. Matricaria chamomilla L. Picris hieracioides L. Pulicaria dysenterica (L.) Bernh. Pulicaria vulgaris Gaertn. Scorzonera hispanica L. Scorzonera sp. L. Taraxacum officinale (L.) Weber Xanthium strumarium L.

I I I I I I I I I i þe

Ma Ma Lo, Bo, Ma and Ta2 Zw Lo2 and Ma Lo2 Zw and Lo2 Ta Ta2 Ma

Corylus avellana L.

I

Zw

Alliaria officinalis Andrz. ex DC. Alliaria petiolata (M.Bieb.) Cavara & Grande Barbarea vulgaris W.T.Aiton Brassica nigra (L.) Koch Brassica oleracea L. Descurainia sophia (L.) Prantl Eruca sativa Mill. Sinapis alba L. Sinapis arvensis L. Sisymbrium sophia L. Thlaspi arvense L.

I i þe I E I I e i þe e I e

Lo2 Bo and Ma Bo Ma, Ta and Ta2 Ta Zw Ta Ma, Ta2 and Bo Ta2 and Ma Zw Bo

Commiphora gileadensis (L.) M.R.Almeida

I

Lo and Lo2

Buxus sempervirens L.

I

Zw

Sambucus nigra L.

i þe

Zw

Dianthus caryophyllus L. Dianthus sp. L. Holosteum umbellatum L. Stellaria media (L.) Vill.

I I I

Zw Bo, Ta, Fu and Ta2 Ta2 Ma

Convallaria majalis L.

i þe

Bo, Ta, Ma, Zw and Fu

Ipomoea batatas (L.) Lam.

i

Ta

Bryonia alba L. Bryonia dioica Jacq.

i þe i

Bo, Ta, Zw, Fu, Lo2 and Ta2 Fu, Ta2, Ta, Zw and Bo

Cupressus sempervirens L. Juniperus communis L.

i i þe

Zw Lo, Ta and Ma

Dioscorea communis (L.) Caddick & Wilkin

i

Zw

Succisa pratensis Moench

i

Zw and Ta2

Bituminaria bituminosa (L.) C.H.Stirt. Galega officinalis L. Ononis arvensis L. Ononis natrix L. Ononis spinosa L. Trigonella melilotus-coerulea (L.) Ser.

i i i i i i

Ma Ma and Lo2 Ta Ta Ta Bo

Quercus ilex L.

i

Ma

Urginea maritima Baker

i

Ta, Ma, Zw and Ta2

Hypericum androsaemum L. Hypericum hypericoides Crantz Hypericum perforatum L. Hypericum tomentosum L.

i i i i

Lo2 Lo2 Bo, Ta, Ma and Lo2 Ta

Crocus sativus L.

e

Bo and Ma

Ajuga chamaepitys (L.) Schreb. Colutea arborescens L. Dracocephalum moldavica L. Hyssopus officinalis L. Lavandula angustifolia var. alba Mill. Lavandula latifolia Medik. Lavandula officinalis Chaix Lavandula stoechas L.

i i i i i i i i

Zw and Ta Fu Ta Ta, Ma and Bo Ta2 Ta2 and Ma Ta2 and Ma Zw, Ta2 and Ta

Betulaceae Brassicaceae

Burseraceae Buxaceae Caprifoliaceae Caryopyllaceae

Convallariaceae Convolvulaceae Cucurbitaceae

Cupressaceae

Dioscoreaceae Dipsacaceae Fabaceae

Fagaceae Hyacinthaceae Hypericaceae

Iridaceae Lamiaceae

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Table 1 (continued ) Family

Plant

Use

Herbal author

Leonurus cardiaca L. Melissa officinalis L. Mentha pulegium L. Origanum dictamnus L. Origanum heracleoticum L. Origanum majorana L. Origanum vulgare L. Rosmarinus officinalis L. Salvia hispanica L. Salvia horminum L. Salvia nemorosa L. Salvia officinalis L. Salvia pratensis L. Salvia sclarea L. Salvia sclarea var.turkestanica alba L. Salvia viridis L. Stachys alpina L. Stachys betonica Scop. Stachys officinalis var. alba (L.) Trev. Stachys recta L. Thymus serpyllum L. Thymus vulgaris L.

i i i i þe i i þe i þe i i i i i þe i þe i i i i þe i i i i i þe

Fu and Ma Lo, Ta and Bo Fu Lo2 and Bo Zw and Ta2 Bo, Ma, Zw, Ta2, Ta and Lo Lo and Bo Ma, Zw, Ta2, Lo2 and Bo Ta2 Ta2 Ta2 Zw and Lo Lo Ta2 and Bo Ta2 Zw Lo Bo, Lo, Fu, Ta, Zw and Lo2 Zw Ta Zw Ma, Bo, Ta, Ta2 and Fu

Cinnamomum camphora L. Cinnamomum cassia D.Don Cinnamomum verum J.Presl

i i i

Zw Ma and Zw Ma and Zw

Erythronium dens-canis L. Lilium martagon L.

i i

Ma Zw

Loranthus europaeus Jacq. Viscum album L.

i þe i þe

Bo, Ta, Ma and Zw Lo2, Bo and Zw

Malope trifida Cav. Malva crispa L. Malva neglecta Wallr. Malva rotundifolia L. Malva sylvestris L.

i i i i i

Ta Ta Lo2 and Bo Ta and Ma Bo and Lo2

Veratrum album L.

i

Ta, Ta2, Fu and Lo2

Ficus carica L.

i

Lo, Bo, Ma and Fu

Anagallis arvensis L. Anagallis foemina Mill.

i i

Ma Ma

Lathraea squamaria L.

i

Ma

Paeonia officinalis L.

i þe

Lo, Bo, Ta, Ma, Zw, Fu, Lo2 and Ta2

Corydalis cava Schweigg. & Kort.

i þe

Bo, Fu and Lo2

Piper cubeba L.f.

I

Lo and Ta

Plantago lanceolata L. Plantago major L. Plantago psyllium L.

I I

Fu Fu and Lo2 Bo

Polygala vulgaris L.

I

Ma and Fu

Primula elatior (L.) Hill Primula veris L.

I I

Ma Ma

Adonis autumnalis L. Aquilegia vulgaris L. Aquilegia vulgaris var.plena L. Clematis vitalba L. Helleborus cyclophyllus Boiss. Helleborus niger L. Thalictrum minus L.

I I I I I I I

Ta2 Zw Zw Fu Ma and Ta Bo, Ta, Ma and Fu Ta2

Alchemilla alpigena Buser Alchemilla vulgaris L. Filipendula vulgaris Moench Geum montanum L. Geum rivale L.

I I I E E

Ma Lo2, Ta2, Bo and Ma Zw, Fu and Lo2 Ma Ma

Lauraceae

Liliaceae

Loranthaceae

Malvaceae

Melanthiaceae Moraceae Myrsinaceae

Orobanchaceae Paeoniaceae Papaveraceae Piperaceae Plantaginaceae

Polygalaceae Primulaceae

Ranunculuceae

Rosaceae

M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13

7

Table 1 (continued ) Family

Plant

Use

Herbal author

Geum urbanum L. Potentilla alba L. Potentilla argentea L. Potentilla atrosanguinea Raf. Potentilla erecta Hampe Potentilla reptans L. Potentilla sp. L. Potentilla verna L.

E I I I I I I I

Ma Fu and Ma Ma Ma Ta2 and Zw Ma and Fu Lo2 and Ta2 Fu

Dictamnus albus L. Ruta graveolens L. Ruta montana Mill.

i þe i þe I

Bo, Ta2 and Zw Zw, Lo2 and Ta2 Ta2

Populus nigra L.

i þe

Ma and Ta2

Saxifraga aquatica Lapeyr. Saxifraga oppositifolia L.

i i

Zw Zw

Asarina procumbens Mill. (Syn. Antirhinum asarina L.) Digitalis purpurea L.

i

Ma

i

Zw

Smilax china L.

i

Zw

Nicotiana rustica L.

i

Ma

Tilia platyphyllos Scop Tilia sp.

i i

Ma Bo, Ma, Ta, Zw and Fu

Paris quadrifolia L.

i

Zw

Centranthus ruber (L.) DC. Valeriana dioica L. Valeriana montana L. Valeriana officinalis L. Valeriana phu L. Valeriana saxatilis L. Valeriana wallichii DC.

i i i i i i i

Zw Zw Zw Zw Zw Zw Zw

Verbena officinalis L.

i

Bo, Ma, Fu and Ta2

Viola odorata L. Viola suavis Fisch. ex Ging. Viola tricolor L.

i i i

Bo, Lo2, Ta, Ma and Fu Lo2 Ma

Vitis vinifera L.

i

Ta

Elettaria cardamomum (L.) Maton

i

Bo and Ta

Guaiacum officinale L. Peganum harmala L.

i i þe

Zw Ma, Lo2 and Ta2

Rutaceae

Salicaceae Saxifragaceae

Scrophulariaceae

Smilacaceae Solanaceae Tiliaceae

Trilliaceae Valerianaceae

Verbenaceae Violaceae

Vitaceae Zingiberaceae Zygophyllaceae

0.2–10 nM. In a PTZ mouse model apigenin was only slightly anticonvulsive. In doses of 20–80 mg/kg i.p. it did, however, significantly delay the onset of the seizures. Avallone et al. (2000) studied a methanolic extract of M. chamomilla flowers and also isolated apigenin. In electrophysiological measurements using a patch clamp technique, apigenin had weak in vitro affinity to GABAA receptors (IC50 ¼2.5  10  4 M). In vivo effects of apigenin were determined in rats with picrotoxin induced convulsions. At 25 and 50 mg/kg i.p. apigenin significantly shortened the latency period of the picrotoxin induced fit, but did not reduce the incidence of seizures. One can thus conclude that apigenin interacts in vitro with the GABAA-receptor but shows low in vivo activity. St. John’s wort Hypericum perforatum was used to treat epilepsy, alone (Bock, Mattioli, Tabernaemontanus, and Lonicerus) or in combination with peonies (Lonicerus and Tabernaemontanus). Ivetic et al. (2002) administered the water, butanol and ether fractions of an 80% ethanolic H. perforatum extract

(100 mg/kg i.m.) to rabbits and, with implanted electrodes, studied epileptic activities in the brain before and after application. The aqueous fraction caused a clear antiepileptic effect. The activity of the butanol was weaker, whereas the ether fraction was proepileptic. Hosseinzadeh et al. (2005a) examined aqueous and ethanolic extracts of the aerial parts of H. perforatum in PTZand MES-models in mice at 0.1–1 g/kg i.p.. The control group received 1 mg/kg diazepam i.p. In the PTZ group both extracts delayed the onset of tonic fits and lowered mortality. In the MES model, however, no anticonvulsive effects were seen at this dose. In a third, Radhika et al. (2009) studied a sample they referred to as ‘‘powder of a H. perforatum extract’’ using INH- PTZ- and MESmodels on male Wistar rats H. perforatum extract i.p. was given at concentration of 81, 162 and 324 mg i.p. either alone or in combination with clonazepam (0.2 mg/kg) and phenytoin (18 mg/kg). The sample alone showed no anticonvulsant activity, yet it significantly reduced the antiepileptic effects of phenytoin at 324 mg in the MES model. In the PTZ model at doses of 81 and

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162 mg there were a higher number of epileptic fits and a longer duration of the seizures. At 324 mg there was also a shortened latency period. In the INH-model 81 mg of extract increased the number of seizures but not their duration. At 162 mg both number and duration increased, and at 324 mg there was also a shortened latency time. In combination with clonazepam the extracts lessened the antiepileptic effects of clonazepam significantly, and the ethanolic H. perforatum extracts was thus proconvulsive (Radhika et al., 2009). Another study focussed on pure constituents of H. perforatum, namely hypericin, pseudohypericin and hyperforin. In rat hippocampus slices hyperforin was an in vitro NMDA- and AMPA-receptor antagonist. The IC50-value on the NMDA- and AMPA-receptors was 3.2 and 4.6 mM, respectively (Kumar et al., 2006; Kaehler et al., 1999). In electrophysiological tests hypericin (10 mM) lowered NMDA-activated ion currents by 30%, as well as GABA-induced chloride currents by 43%. Pseudohypericin at 10 mM reduced NMDA-induced ion currents by 20% and GABA-induced chloride currents by 57% (Vandenbogaerde et al., 2000). In summary, extracts and purified compounds from H. perforatum purified compounds have shown both antiepileptic and proepileptic characteristics. Mattioli and Bock recommended saffron, the stamens of Crocus sativus, mixed with vinegar and castoreum (an exudate from the castor sacks of male beavers) and placed in ones nose. Safranal, a main constituent of saffron, reduced the effects of GBZ, BAC, PTZ-, PTX- or BMC-induced convulsions in mice in a dose dependant manner. The effects of safranal on GABAA- and GABABreceptors in mouse brains were studied using flunitrazepam, and the GABAB-receptor antagonist CGP54626A. Safranal (291 mg/kg, i.p.) displaced 33% of the flunitrazepam from the cortex, 27% from the hippocampus and 30% from the thalamus, whilst CGP54626A was not displaced (Sadeghnia et al., 2008). Safranal administered intracerebroventricularly in a PTZ model (90 mg/kg) had no effects, yet when applied i.p. at 73, 146 and 291 mg/kg it inhibited tonic-clonic and tonic seizures and prolonged the delay of the seizures (Hosseinzadeh and Sadeghnia, 2007). Crocin, a further major constituent of saffron, when administered (200 mg/kg i.p.) in a PTZ model in mice, had no anticonvulsive effect (Hosseinzadeh and Talebzadeh, 2005b). Pills made of hyssop (Hyssopus officinalis) were used to treat epileptic seizures (Bock and Mattioli), and both Mattioli and Tabernaemontanus recommended hyssop together with peony roots. Tabernaemontanus also reported the use of hyssop wine. The essential oil of H. officinalis was shown to be proconvulsive at 1.6 and 4 ml/kg i.p.. Neurotoxic effects were also described, which were caused by the monoterpene ketones pinocamphon and isopinocamphon (Burkhard et al., 1999; Steinmetz et al., 1980). Starting at 0.13 g/kg (i.p.) hyssop essential oil caused seizures in rats, and 1.25 g/kg (i.p.) were lethal (Millet et al., 1981). In another study hyssop oil and cis- and trans-3-pinanon were given to mice i.p. and their brains were used for a binding assay using EBOB. The IC50-values were 64 mM for hyssop oil, 36 mM for cis-3pinanon, and 35 mM for trans-3-pinanon. The LD50 of the two ¨ isomers cis- and trans-3-pinanon were 175– 4250 mg/kg (Hold et al., 2002). The aerial part of lavender (Lavandula officinalis and L. angustifolia) flowers were soaked in water or wine and this was drunk against epilepsy. A schnaps was also used (Tabernaemontanus and Mattioli). Huang et al. (2008) used an electrophysiological method as well as in binding assays with TBPS, muscimol, flunitrazepam, AMPA and MK-801 to study the relaxant effects of L. officinalis essential oil. The oil prevented the binding of the radio tagged ligand TBPS to the GABAA-receptor in rat brains (IC50 ¼30 mg/ml), yet showed no affinity to the AMPA- and NMDA-receptors. Also in muscimol- and flunitrazepam binding assays it did not affect the binding of the ligands. The subsequent

electrophysiological patch clamp study with Wistar rat cortical cells showed that lavender oil at 0.1–1 mg/ml reversibly inhibited the GABAA-receptor. The oil suppressed both inhibitory and excitatory impulses and therefore inhibits signal transmission between neurons. Stoechas lavender (Lavandula stoechas) was used alone or in combination with other herbs soaked in alcoholic beverages (Tabernaemontanus and Zwinger). Tabernaemontanus also described syrup. An aqueous/methanolic extract from the flowers of L. stoechas was tested for its anticonvulsive effects in a PTZ induced mouse model at 400 and 600 mg/kg i.p.. Whilst 400 mg/kg caused no significant anticonvulsive effect, 600 mg/kg delayed the onset of the seizures by 3.4 min and lengthened survival time by 18.2 min. Further tests showed that the extract had a calciumblocking effect (Gilani et al., 2000). A schnaps distilled from lemon balm (Melissa officinalis) was used by those suffering from seizures (Mattioli). Bock and Tabernaemontanus, on the other hand, recommend a decoction of the herb in white wine. According to Awad et al. (2007) an aqueous M. officinalis extract had GABA-transaminase modulating effects in two different assays on rat brain homogenates( IC50 0.35 mg/ml). The essential oil of M. officinalis showed similar effects as the oil of Lavandula officinalis in the study by Huang et al. (2008). It inhibited the binding of TBPS with an IC50 of 0.04 mg/ml but showed no effects on AMPA- and NMDA-receptors. In electrophysiological measurements the oil (0.01–1 mg/ml) inhibited GABAA-receptors in a concentration dependant manner (Abuhamdah et al., 2008). Fuchs recommended taking Mentha pulegium in vinegar against epilepsy. M. pulegium essential oil was amongst the proconvulsive essential oils discussed by Burkhard et al. (1999). The flowers of sage (Salvia officinalis) were recommended for epilepsy by Lonicerus and Zwinger to be taken with schnaps (alcoholic distillate), or wine, and sugar. Millet et al. (1981) whose work is discussed above under Hyssopus officinalis also studied the essential oil from S. officinalis and showed them to be toxic and to cause tonic clonic seizures. The seizures started at 0.50 g/kg i.p. At 3.2 g/kg i.p. the oil was lethal. Burkhard et al. (1999) also showed the essential oil S. officinalis to be proconvulsive in some case studies. Most herbals recommend treating epileptics by rubbing thyme (Thymus vulgaris) under their noses (Mattioli, Bock, Tabernaemontanus, and Fuchs). Fuchs and Mattioli advised that epileptics were to spice their foods with thyme. There are two major thyme chemotypes, namely the geraniol and the linalool chemotype. Linalool showed anticonvulsive activity in rats (Sakurada et al., 2009). A schnaps distilled from cinnamon, the bark of Cinnamomum cassia, was used by Mattioli and Zwinger. An aqueous extract (0.1–1 mg/ml) from C. cassia bark was studied in cultivated granule cells from rat brains, where at 1 mg/ml a 75% reduction of the glutamate activated Ca2 þ -influx was seen (Shimada et al., 2000). Lonicerus wrote that wearing mistletoe (Viscum album) around the neck and boiling it in wine to drink would ward off epilepsy. Bock described the use of pulverized mistletoe from hazelnut Corylus avellana L. (Betulaceae) or from pear trees Pyrus communis L. (Rosaceae), and Zwinger recommended mistletoe from lime (linden, Tilia sp., Malvaceae) taken in wine. Three lectins from V. album were tested for activity on the NMDAreceptor in a binding assay in synaptic plasma membranes from rat hippocampuses, where the galactose specific lectins had an in vitro inhibitory effect on various binding sites of the NMDAreceptor at a concentration of 10 mg/ml, whereas the acetyl galactose amine specific lectin had no such effects (Machaidze and Mikeladze, 2001). All herbals authors report on the use of peonies Paeonia officinalis against epilepsy, and more than 25 different recipes

M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13

are listed (see discussion). Ethanolic extracts of Paeonia rubra, a related species used in traditional Chinese medicine (TCM), were studied for their neuroprotective effects on CA1 neurons from rat hippocampi using a patch-clamp technique. The extract (0.8 mg/ml) lowered sodium currents in the neurons in a time and dose dependant manner but did not interact directly with sodium channels. Furthermore, the extract lengthened the duration the Na þ channels needed to recover from blocking. It was concluded that the P. rubra moved the inhibition curve towards hyperpolarisation (Dong and Xu, 2002). Masatoshi and Atsuko (1969) described the sedative effects of paeonol from P. moutan in vivo. After i.p. and oral administration, paeonol decreased motor activity and caffeine-induced hyper reactivity in mice. Mi et al. (2005) compared the anxiolytic-like effect of paeonol with diazepam in mice in the elevated plus maze and the light/dark boxtest. The comparison was also with regard to locomotor activity (open-field test) and myorelaxant potential (inclined plane test). Just like with 2 mg/kg of diazepam, paeonol (at 17.5 mg/kg) increased the percentage of time spent on open arms in the elevated plus maze and increased the time spent in the light area of the light/dark box (at 8.75 and 17.5 mg/kg). The side-effect profile was considered as superior to the benzodiazepine. The roots of Corydalis cava were soaked with castoreum in olive oil and rubbed on the skin to treat epilepsy (Bock, Lonicerus). Fuchs recommended boiling the roots of Corydalis cava in water and drinking this. The rhizomes of C. cava contain protoberberine alkaloids. With a radioligand assay using BCM and FNT, Halbsguth et al. (2003) studied the effects of these protoberberines on the GABAA-receptor binding pockets. Palmatine, dehydroapocavidine, dehydrocorydaline, and coptisine showed no activity from 1 nM/10 mM, whilst tetrahydropalmatine, scoulerine, isocorypalmine, isoapocavidine and corydaline showed an increase of BCM-binding, with the strongest effects from 0.1 to 0.01 mM. None of the alkaloids affected the benzodiazepine binding site. Fluorescence-correlation-spectroscopy (FCS) using rat hippocampi and 7.5 nM fluorescing muscimol-alexa (AlexaFluor) as a ligand showed that scoulerin decreased the specific binding by 27% at 7.5 nM (Halbsguth et al., 2003). Therefore, some protoberberine alkaloids from water—ethanol extracts of C. cava have a positive modulating effect on the GABAA-receptor in vitro. Mattioli described the use of Primula elatior in sugar for epilepsy, but others described it as an additive to other remedies (Zwinger and Tabernaemontanus). Aqueous and ethanolic extracts of the roots, flowers, and leaves P. elatior were tested in a binding assay for affinity to the benzodiazepine binding site on the GABAA receptor. The ethanolic extract from the leaves ¨ displaced up to 90% of the ligand (IC50 ¼0.41 mg/ml) (Jager et al., 2006). Alongside Primula elatior Mattioli also recommended using cowslip (Primula veris) to treat epilepsy. In the same study as described above, the ethanolic P. elatior extracts also showed effects with inhibition of flumazenil binding by 68% for the flower extract, 77% for leaf extract, and 74% inhibition by the root extract at the lowest test concentration of 0.01 mg/ml. The leaf extract ¨ had an IC50 of 0.48 mg/ml (Jager et al., 2006). Pulverized seeds of the common columbine (Aquilegia vulgaris) were recommended against epilepsy by Zwinger. An aqueous A. vulgaris extract showed in vitro GABAA-receptor modulating effects, and myo-inositol and oleamide were identified as the main constituents in the extracts with HPLC and GCMS. Myo-inositol prevented the binding of the specific GABAA-ligand muscimol and stimulated the binding of NMDA-ligand MK801 (Solomonia et al., 2004). The anticonvulsive effects of myoinositol were also shown in vivo in mice which received myoinositol (20 mg/kg i.p.), and PTZ to induce convulsions. 40% of the treated animals had no seizures compared to 10% in the control group. In a kainic acid model there was no significant difference

9

in the incidence of convulsions, but the severity of the seizures was reduced. (Solomonia et al., 2007). Valerian (Valeriana officinalis) was not widely used to treat epilepsy. Only Zwinger mentions taking the roots which had been soaked in an alcoholic beverage. The in vivo effect of an aqueous and a petrol ether extract from the roots of V. officinalis were studied by Rezvani et al. (2010) in a microelectrode model of induced temporal lobe epilepsy. The aqueous extract, administered at 500 and 800 mg/kg i.p. increased the time between convulsions. The petrol ether extract, on the other hand, was proconvulsive, lengthening the after discharge duration in the brain and the duration of the seizures. Ortiz et al. (1999) studied the effects of an ethanolic extract of V. officinalis roots on GABAAreceptors from rat plasma membranes. At their highest concentrations the extract inhibited flunitrazepam binding (IC50 ¼ 4.82  10  1 mg/ml). Together with guvacin, valerian extracts inhibited GABA uptake in a concentration range of 0.1–3.3 mg/ ml. At higher concentrations the extract increased the release of GABA in hippocampus slices (Ortiz et al., 1999). A further study explored the effects of V. officinalis root extracts on GABA release of rat synaptosomes. The aqueous and ethanolic/aqueous extracts, which both themselves contained GABA, increased the release of GABA, whereas the ethanolic, which did not contain GABA, showed no effects. It was concluded that the intrinsic GABA content of the extracts was responsible for the observed GABA release (Ferreira et al., 1996). Mennini et al. (1993) tested the effects of aqueous and ethanolic extracts from the roots of V. officinalis, and dihydrovaltrate and dihydroxyvalerenic acid isolated from this plant. The aqueous and the aqueous/alcoholic extracts showed affinity to the GABAA receptor. Dihydrovaltrate and the lipophilic fraction affected the barbiturate binding site and to a lesser extent the benzodiazepine binding site. Yuan et al. (2004) studied the effects a V. officinalis extract and pure valerenic acid, on the neuronal activity in the nucleus solitarius from murine brainstems. Valerian extract and valerenic acid inhibited the neuronal activity with IC50s of 240 mg/ml and 23 mM, respectively (Yuan et al. 2004). Aqueous, DMSO and ethanolic extracts from valerian roots were tested with 20 nM glutamate in synaptic plasma membranes. The aqueous extract was inactive on NMDA whereas, DMSO and ethanolic showed significant effects at 1 mg/ ml (Torres-Hernanadez et al., 2007). Ortiz et al. (2006) studied different commercial valerian root extracts and valerenic acid in cortical membranes from rat brains usingbinding assays with flunitrazepam and MK-801 (10 nM). From 0.05 to 1 mg/ml of extract there were no effects on the binding of MK-801, but at 2– 5 mg/ml an inhibition of MK-801 binding to the NMDA-receptor was seen. Both valerian extracts inhibited glutamate decarboxylase activity by 40% at a dose of 1 mg/ml (Awad et al., 2007). Isovaleramide when administered at 100 mg/kg p.o., showed 90% protection against the maximal electroshock seizure in mice (MES), comparable to sodium phenytoin at 20 mg/kg, p.o. (100% protection)(Giraldo, 2010). Khom et al. (2007) identified the sesquiterpene valerenic acid as a potent subunit specific modulator of GABAA receptors. Only channels containing b2 or b3 subunits were activated by the compound, while the b1 subunit drastically reduced the sensitivity. Trauner et al. (2008) studied different extracts of V. officinalis with varying contents of sesquiterpenic acids (valerenic acid, acetoxyvalerenic acid) and the in vitro GABAA modulating effects and showed that the effects were linked to the content of valerenic acid. Zwinger used Valeriana wallichii in the same way that V. officinalis. Wasowski et al. (2002) showed in a competitive binding assay that 6-methylapigenin from the rhizomes of V. wallichii bound to the benzodiazepine-binding site of GABAA (KI ¼495 nM).

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A latwerg (a thick jam) from the grape vine (Vitis vinifera) berries was recommended by Tabernaemontanus as a remedy to treat epilepsy. Wines and grape juices contain up to 25 mg/l of resveratrol, which has been shown to have anticonvulsive effects in various in vitro and in vivo models. In dorsal ganglion cells resveratrol was anticonvulsive by enhancing the inactive state of voltage dependant Na þ -channels (Rocha-Gonzalez et al., 2008). Male Wistar rats received a daily dose of about 8 mg/kg of resveratrol in their drinking water for 43–45 day and were studied for kainic acid (10 mg/kg) induced seizures. Resveratrol showed a neuroprotective effect by reduced inhibition of GAD activity in the olfactory region of the brain and in the hippocampus (Virgili and Contestabile, 2000). Drenska et al. (1989) induced seizures in mice with PTZ and administered 200–400 mg/kg anthocyanin from grapes either alone, in combination with vitamin E, or in combination with 200 mg/kg of the nootropic drug piracetam. In all three cases anticonvulsive effects were observed. Cardamom (Elettaria cardamomum) schnaps was used to treat the falling sickness (Bock and Tabernaemontanus). A 70% methanolic extract from the fruits of cardamom lengthened the diazepam induced sleeping duration in mice at 30–300 mg/kg i.p. so that an interaction with GABA receptors seemed probable (Gilani et al., 2008). Lonicerus used a schnaps distilled from harmel (Peganum harmala) to treat epilepsy, and Tabernaemontanus (1678) administered it with honey and sesame oil. Especially in Mattioli there are many preparations made from P. harmala, such as the juice with vinegar from Scilla maritima, the seeds with water, in sesame oil or plant soaked in vinegar. P. harmala contains harmaline and harmine, indole alkaloids, which are hallucinogenic, convulsant and tremorgenic (Pranzatelli and Snodgrass, 1987).

4. Discussion In this study we systematically explored antiepileptic remedies from nine German Renaissance herbals, identified the plant species, compiled them (Table 1) and discussed what is known about their potential effectiveness. In the following sections we shall draw some conclusions about this survey: About half the plant species were from just three plant families, namely the Asteraceae with 41 species (19%), Lamiaceae with 38 species (17%) and Apiaceae with 28 species (13%). All other families were represented with five or less species, and half the plant families (26) only had one species in the list. Species rich plant families of the central European flora which are underrepresented in this list are the Solanaceae, Fabaceae and Ranunculaceae. Noticeably overrepresented families are the Valerianaceae. In the case of Rutaceae all three species native to Central Europe were used. There are no native Lauraceae in central Europe so the three plants from that family (Cinnamomum camphora. C. cassia, C. verum) represent imported herbs. Most applications of the plants found in the herbals were internal; only 40 plants (17.8%) were applied externally. This may make a rational use of the plants more likely from a pharmacological perspective. A systematic search for relevant biomedical/ pharmacological studies on these plants afforded data for just 26 of them. None of the plants had been studied in larger clinical trials, and anticonvulsive activity in animal models and receptor binding properties of extracts and compounds are of obviously limited predictive value concerning clinical effectiveness in humans. Also, many in vivo studies used test concentrations so excessively high that is not possible to draw conclusions on the efficacy in humans. Lavandula stoechas extract, for example, was tested in a PTZ induced mouse model at 400 and 600 mg/kg i.p. (Gilani et al., 2000). For these reasons, and also due to the fact that

most plants have never been studied at all, we cannot draw generalized conclusions about the predictive value of Renaissance herbals for the discovery of anticonvulsive compounds. Yet some examples shall be highlighted and discussed in the following section: Amongst the 26 pharmacological studies discussed here Lamiaceae account for 7. Accumulation of essential oil is a characteristic feature of this family, and interestingly half of the in vivo tested samples reported here were done with essential oils. These studies, however, produced quite contradictory results. Various authors reported in vitro anticonvulsive effects (exam¨ ples: Pourgholami et al., 1999; Huang et al., 2008; Hold et al., 2002), whereas numerous other studies including clinical case reports indicate that essential oils can be pro-convulsive as well. Burkhard et al. (1999) reported on 3 patients with isolated generalized tonic-clonic seizure related to the uptake of essential oils and reviewed clinical evidence of the essential oils of Hyssopus officinalis, Mentha pulegium, Rosmarinus officinalis, and Salvia officinalis, as well as from the AsteraceaeTanacetum vulgare, and Artemisia absinthium which are proconvulsive in humans. This was reportedly due to their content of highly reactive monoterpene ketones, such as camphor, pinocamphone, thujone, cineole, pulegone, sabinylacetate, and fenchone. It should therefore be concluded that there is evidence that numerous essential oils bear the risk of severe convulsive complications. Four of the pharmacological studies presented here are from Apiaceae (4) which, apart from essential oils contain a number of linear and angular furocoumarins. It is for this substance class, typical for Apiaceae and Rutaceae (Adams et al., 2006), that probably have the best characterised anticonvulsive effects both in vitro and in vivo. In the cases shown here for Angelica archangelica, Pimpinella anisum, there is substantial evidence of effectiveness, although their potency and efficiency as positive GABAA ¨ al ¨ a¨ receptor modulators is moderate (Luszczki et al., 2007; Harm et al., 1992, Zaugg et al., 2011a). For valerian Valeriana officinalis there is a strong body of in vitro (Yuan et al., 2004; Ortiz et al., 2006; Torres-Hernanadez et al., 2007) and in vivo (Giraldo, 2010) experimental evidence which suggests that some efficacy might be expected. Khom et al. (2007) identified the active constituent as valerenic acid. The pharmacokinetic properties of valerenic acid have been studied in detail. In rats, the extent of absorption after oral administration was 33.70% with a half-life of 2.7–5 h. Dose proportionality was observed in terms of dose and AUCs suggesting linear pharmacokinetics at the dose levels studied (Sampath et al., in press). A lot of pharmacological data suggest that resveratrol from grape vines may have anticonvulsive effects. Considering the very low oral bioavalability of resveratrol (Walle et al., 2004), however, the in vivo efficacy is questionable, or may be due to pharmacologically active metabolites. The experimental data for Hypericum perforatum extracts is contradictory, with in vivo results showing it to be pro- and anticonvulsant (Ivetic et al., 2002; Hosseinzadeh et al., 2005a; Radhika et al., 2009; Vandenbogaerde et al., 2000). A confounding factor with these conflicting studies is the fact that different and phytochemically poorly or uncharacterized extracts were used. The use of peonies is interesting, because all authors reported this use with a total of 25 different recipes. Two applications appear in all herbals: The first was supposedly based on Galenus and was the practice of hanging peony roots around ones neck. Tabernaemontanus and Zwinger report to have gotten the citation from Mattioli, who in turn wrote that he got his information from an unspecified trustworthy person. Paeonia officinalis is listed in ’’De Materia Medica’’ by Dioscorides, but not against epilepsy (Berendes, 1902). There are also numerous reports of its antiepileptic use in TCM and Ayurveda.The herbal drug is therefore

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well studied, and in vivo and in vitro, suggest it to be antiepileptic (Dong and Xu, 2002; Masatoshi and Atsuko, 1969; Mi et al., 2005). Saslis-Lagoudakis et al. (2011) recently discussed the predictive value of cross-cultural comparison of medicinal floras in drug discovery, and hypothesised that plant families by several cultures for the same indication would display ‘‘exceptional potential for discovery of previously overlooked or new medicinal plants and should be placed in high priority in bio screening studies’’. While we would not generally subscribe to that on a family level, plants with the same active principle like paeonol in different peonies have been utilized by different cultures for epilepsy. Most plants were mentioned by several authors and few only by one. Especially Zwinger and Tabernaemontanus commonly described plants that the other authors did not mention in the context of epilepsy, which shows these authors relative independence from the other German herbals (see Table 1). The question of origin and influence of Renaissance remedies has been discussed recently, and some authors see substantial influences from classical Greek/Roman physicians in the selection of plants (Leonti et al., 2009; De Vos, 2010, 2010). We did not find this to be the case for antimalarial remedies from German Renaissance herbals (Adams et al., 2011a), and we checked the plants described in this study (at a species level) with plants indentified in De Materia Medica (translation by Berendes (1902)). About one third (n¼75, 34%) of the plants described in the nine Renaissance herbals for the treatment of epilepsy can also be found in De Materia Medica for various indications, yet only 17 of these were used for epilepsy. Thus, only 6.6% of epilepsy remedies are in common with De Materia Medica. We identified in this study a large number of plants which were traditionally used in European Renaissance as antiepileptics. A majority of these plants have not been investigated pharmacologically with respect to potential antiepileptic activity. For some of the plants discussed in more detail available pharmacological evidence is, in part, in support of, in part in cotrast to the traditional use. Only 5% of the plant species presented in Table 1 have shown ’’in vitro and/or in vivo pharmacological data somehow related to the indication epilepsy. A systematic screening of the uninvestigated plants for activity in disease-relevant targets (e.g., GABAA and NMDA receptors) would be of interest. We have characterized a broad spectrum of GABAA receptor modulators from herbal drugs traditionally used in TCM as sedative, anxiolytics and antiepileptics (Yang et al., 2011; Zaugg et al., 2011a,b,c; Kim et al., 2012). Also, our previous study of malaria remedies from Renaissance herbals resulted in a focused screen of these plants and the identification of active constituents (Adams et al., 2010, 2011b; Hata et al., 2011; Julianti et al., 2011; S´lusarczyk et al., 2011; Zimmermann et al., 2012a). Hence, we anticipate that potentially useful molecules could be discovered from some of the plants listed in this publication.

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