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Journal of Ethnopharmacology 143 (2012) 1–13
Contents lists available at SciVerse ScienceDirect
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
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, Totengässlein 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . .2
. . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . .2
drug discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
. . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . . . . .. . . . . .3
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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: michael.adams@unibas.ch (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
Author's personal copy
2
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
Höfler (1970) (the dictionary of German disease names‘‘) for the
terminology used for epilepsy in those times and identified:
Fallend Sucht‘‘, ‘‘Fallend’’, ‘‘Fallendweh’’, ‘‘Fallübel’’, (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’’), ‘‘böses Wesen’’ (‘‘evil being’’ or ‘‘evil character’’),
‘‘Hinfallend’’, ‘‘(hin)fallender Siechtag/Siechtum’’ (‘‘falling infirmity’’), ‘‘heilige or schwere Krankheit’’ (‘‘holy or severe sickness’’),
Böse 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 ‘‘Wörterbuch der Deutschen Pflanzennamen’’ by Marzell (2000). Illustrations in these herbals
resemble those in modern day plant guides quite well (see for
example: Jäger 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
Author's personal copy
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 Jäger 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.,
3
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 (Jäger 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
calcium uptake antagonist was archangelicin (Härmälä et al.,
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
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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
5
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M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13
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
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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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M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13
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 (Höld
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
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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) (Jäger
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 (Jäger 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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M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13
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 (examples: Pourgholami et al., 1999; Huang et al., 2008; Höld 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
receptor modulators is moderate (Luszczki et al., 2007; Härmälä
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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M. Adams et al. / Journal of Ethnopharmacology 143 (2012) 1–13
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;
Ślusarczyk 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.
Acknowledgements
Part of the study was carried out as MSc thesis of S.V. Schneider.
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