Volume 143, Issue 1, 30 August 2012, Pages 1–13
Review
Epilepsy in the Renaissance: A survey of remedies from 16th and 17th century German herbals
Abstract
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 and Lonicerus, 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.
Graphical abstract
Abbreviations
- AMPA, α-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, 4′-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, γ-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
Keywords
- European herbals;
- Renaissance;
- Epilepsy;
- Medicinal plants;
- Pharmacological activity;
- Anti-epileptic
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, Adams et al., 2009c, Adams et al., 2011b, Zimmermann et al., 2012a and Zimmermann et al., 2012b).
2. Methodology
We accessed nine original herbals kept at the Swiss Pharmaceutical Museum in Basel, including (Bock, 1577; Fuchs, 1543; Mattioli, 1590; Lonicerus, 1660 and Lonicerus, 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 et al., 2006, Kumar et al., 2006 and 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 SciFinder®
(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 γ-aminobutyric 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 (
Nsour et al., 2000, Janahmadi et al., 2008 and 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 ( Baumgartner, 2001, Wisden and Seeburg, 1992 and Tierney, 2011).
In vivoanticonvulsive 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 (γ-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).
- 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 and Tabernaemontanus, 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 Alliaceae Allium sativum L. i+e Bo,Ma and Ta2 Allium schoenoprasum L. e Ma Apiaceae Angelica archangelica L. i Ta2 Angelica sylvestris L. i Ta2 Anthriscus sylvestris (L.) Hoffm. i Ma Astrantia major L. i Zw, Ma and Ta2 Bupleurum fruticosum L. i Zw Coriandrum sativum L. i Ta2 Dorema ammoniacum D. Don i Ma and Ta2 Eryngium campestre L. i Lo, Bo, Ta, Ma, Zw and Fu Eryngium maritimum L. i Zw and Ma Eryngium planum L. i Zw and Ma Ferula assa-foetida L. i Lo and Ma Ferula galbaniflua Boiss. & Buhse i+e Ta2 and Ma Ferula persica Willd. i Ta2 and Ma Heracleum austriacum L. i Ta2 Heracleum sphondylium L. i Bo,Ma and Ta2 Laserpitium gallicum L. i Ta2 and Ma Laserpitium halleri Crantz i Ta2 Laserpitium latifolium L. i Fu and Ta2 Laserpitium siler L. i Ma, Ta2, Zw Opopanax chironium Koch i Zw and Ta2 Pastinaca sativa L. i Ma and Ta2 Peucedanum cervaria Lapeyr. i Fu Peucedanum officinale L. e Fu and Ta2 Peucedanum ostruthium (L.) Koch i Ma, Zw and Bo Pimpinella anisum L. i+e Ma, Fu, Lo2 and Ta2 Seseli gummiferum Boiss. i Zw Seseli libanotis (L.) Koch i Ma and Ta2 Seseli tortuosum L. i Zw Araliaceae Hedera helix L. i Ma Aristolochiaceae Aristolochia clematitis L. i Fu, Ta, Ta2 and Ma Aristolochia longa L. i Fu, Ma, Zw and Lo Aristolochia pistolochia L. i Ma Aristolochia rotunda L. i+e Ma, Lo and Lo2 Asarum europaeum L. i Ma and Ta2 Asteraceae Achillea clavennae L. i Ta2 Achillea filipendulina Lam. i Ta2 Achillea millefolium L. i Ta2 Achillea tomentosa L. i Ta2 Anacyclus officinarum Hayne i+e Lo2 and Ta2 Anacyclus pyrethrum (L.) Link i+e Zw, Bo, Ta2 and Lo2 Anthemis arvensis L. i Lo Anthemis nobilis L. i Ta2 Chamaemelum nobile (L.) All. i Lo and Bo Anthemis nobilis var. Plena L. i Ta2 and Ma Anthemis tinctoria L. i Ta2 Artemisia absinthium L. i Ta2 and Zw Artemisia pontica L. i Zw Artemisia umbelliformis L. i Zw and Ta2 Aster alpinus L. i Ma Aster amellus L. i Ta and Ma Aster linosyris Bernh. i Ma Aster tripolium L. i Ma Centaurea benedicta L. i Lo Cichorium intybus L. i Zw Cichorium intybus var.foliosum L. i Zw Cichorium spinosum L. i Zw Doronicum grandiflorum Lam. i Zw Doronicum pardalianches L. i Zw Erigeron acris L. i Ta and Ma Hieracium caesium Fr. i Lo2 Hieracium lactucella Wallr. i Ta2 Hieracium murorum L. I Ta2 Hieracium pilosella L. I Zw, Lo2 and Ta2 Hieracium staticifolium L. I Zw and Lo2 Inula conyza DC. I Bo, Ta, Ma and Lo2 Inula germanica L. I Ma Inula hirta L. I Ma Matricaria chamomilla L. I Lo, Bo, Ma and Ta2 Picris hieracioides L. I Zw Pulicaria dysenterica (L.) Bernh. I Lo2 and Ma Pulicaria vulgaris Gaertn. I Lo2 Scorzonera hispanica L. I Zw and Lo2 Scorzonera sp. L. I Ta Taraxacum officinale (L.) Weber I Ta2 Xanthium strumarium L. i+e Ma Betulaceae Corylus avellana L. I Zw Brassicaceae Alliaria officinalis Andrz. ex DC. I Lo2 Alliaria petiolata (M.Bieb.) Cavara & Grande i+e Bo and Ma Barbarea vulgaris W.T.Aiton I Bo Brassica nigra (L.) Koch E Ma, Ta and Ta2 Brassica oleracea L. I Ta Descurainia sophia (L.) Prantl I Zw Eruca sativa Mill. e Ta Sinapis alba L. i+e Ma, Ta2 and Bo Sinapis arvensis L. e Ta2 and Ma Sisymbrium sophia L. I Zw Thlaspi arvense L. e Bo Burseraceae Commiphora gileadensis (L.) M.R.Almeida I Lo and Lo2 Buxaceae Buxus sempervirens L. I Zw Caprifoliaceae Sambucus nigra L. i+e Zw Caryopyllaceae Dianthus caryophyllus L. - Zw Dianthus sp. L. I Bo, Ta, Fu and Ta2 Holosteum umbellatum L. I Ta2 Stellaria media (L.) Vill. I Ma Convallariaceae Convallaria majalis L. i+e Bo, Ta, Ma, Zw and Fu Convolvulaceae Ipomoea batatas (L.) Lam. i Ta Cucurbitaceae Bryonia alba L. i+e Bo, Ta, Zw, Fu, Lo2 and Ta2 Bryonia dioica Jacq. i Fu, Ta2, Ta, Zw and Bo Cupressaceae Cupressus sempervirens L. i Zw Juniperus communis L. i+e Lo, Ta and Ma Dioscoreaceae Dioscorea communis (L.) Caddick & Wilkin i Zw Dipsacaceae Succisa pratensis Moench i Zw and Ta2 Fabaceae Bituminaria bituminosa (L.) C.H.Stirt. i Ma Galega officinalis L. i Ma and Lo2 Ononis arvensis L. i Ta Ononis natrix L. i Ta Ononis spinosa L. i Ta Trigonella melilotus-coerulea (L.) Ser. i Bo Fagaceae Quercus ilex L. i Ma Hyacinthaceae Urginea maritima Baker i Ta, Ma, Zw and Ta2 Hypericaceae Hypericum androsaemum L. i Lo2 Hypericum hypericoides Crantz i Lo2 Hypericum perforatum L. i Bo, Ta, Ma and Lo2 Hypericum tomentosum L. i Ta Iridaceae Crocus sativus L. e Bo and Ma Lamiaceae Ajuga chamaepitys (L.) Schreb. i Zw and Ta Colutea arborescens L. i Fu Dracocephalum moldavica L. i Ta Hyssopus officinalis L. i Ta, Ma and Bo Lavandula angustifolia var. alba Mill. i Ta2 Lavandula latifolia Medik. i Ta2 and Ma Lavandula officinalis Chaix i Ta2 and Ma Lavandula stoechas L. i Zw, Ta2 and Ta Leonurus cardiaca L. i Fu and Ma Melissa officinalis L. i Lo, Ta and Bo Mentha pulegium L. i Fu Origanum dictamnus L. i+e Lo2 and Bo Origanum heracleoticum L. i Zw and Ta2 Origanum majorana L. i+e Bo, Ma, Zw, Ta2, Ta and Lo Origanum vulgare L. i+e Lo and Bo Rosmarinus officinalis L. i Ma, Zw, Ta2, Lo2 and Bo Salvia hispanica L. i Ta2 Salvia horminum L. i Ta2 Salvia nemorosa L. i Ta2 Salvia officinalis L. i+e Zw and Lo Salvia pratensis L. i+e Lo Salvia sclarea L. i Ta2 and Bo Salvia sclarea var.turkestanica alba L. i Ta2 Salvia viridis L. i Zw Stachys alpina L. i+e Lo Stachys betonica Scop. i Bo, Lo, Fu, Ta, Zw and Lo2 Stachys officinalis var. alba (L.) Trev. i Zw Stachys recta L. i Ta Thymus serpyllum L. i Zw Thymus vulgaris L. i+e Ma, Bo, Ta, Ta2 and Fu Lauraceae Cinnamomum camphora L. i Zw Cinnamomum cassia D.Don i Ma and Zw Cinnamomum verum J.Presl i Ma and Zw Liliaceae Erythronium dens-canis L. i Ma Lilium martagon L. i Zw Loranthaceae Loranthus europaeus Jacq. i+e Bo, Ta, Ma and Zw Viscum album L. i+e Lo2, Bo and Zw Malvaceae Malope trifida Cav. i Ta Malva crispa L. i Ta Malva neglecta Wallr. i Lo2 and Bo Malva rotundifolia L. i Ta and Ma Malva sylvestris L. i Bo and Lo2 Melanthiaceae Veratrum album L. i Ta, Ta2, Fu and Lo2 Moraceae Ficus carica L. i Lo, Bo, Ma and Fu Myrsinaceae Anagallis arvensis L. i Ma Anagallis foemina Mill. i Ma Orobanchaceae Lathraea squamaria L. i Ma Paeoniaceae Paeonia officinalis L. i+e Lo, Bo, Ta, Ma, Zw, Fu, Lo2 and Ta2 Papaveraceae Corydalis cava Schweigg. & Kort. i+e Bo, Fu and Lo2 Piperaceae Piper cubeba L.f. I Lo and Ta Plantaginaceae Plantago lanceolata L. - Fu Plantago major L. I Fu and Lo2 Plantago psyllium L. I Bo Polygalaceae Polygala vulgaris L. I Ma and Fu Primulaceae Primula elatior (L.) Hill I Ma Primula veris L. I Ma Ranunculuceae Adonis autumnalis L. I Ta2 Aquilegia vulgaris L. I Zw Aquilegia vulgaris var.plena L. I Zw Clematis vitalba L. I Fu Helleborus cyclophyllus Boiss. I Ma and Ta Helleborus niger L. I Bo, Ta, Ma and Fu Thalictrum minus L. I Ta2 Rosaceae Alchemilla alpigena Buser I Ma Alchemilla vulgaris L. I Lo2, Ta2, Bo and Ma Filipendula vulgaris Moench I Zw, Fu and Lo2 Geum montanum L. E Ma Geum rivale L. E Ma Geum urbanum L. E Ma Potentilla alba L. I Fu and Ma Potentilla argentea L. I Ma Potentilla atrosanguinea Raf. I Ma Potentilla erecta Hampe I Ta2 and Zw Potentilla reptans L. I Ma and Fu Potentilla sp. L. I Lo2 and Ta2 Potentilla verna L. I Fu Rutaceae Dictamnus albus L. i+e Bo, Ta2 and Zw Ruta graveolens L. i+e Zw, Lo2 and Ta2 Ruta montana Mill. I Ta2 Salicaceae Populus nigra L. i+e Ma and Ta2 Saxifragaceae Saxifraga aquatica Lapeyr. i Zw Saxifraga oppositifolia L. i Zw Scrophulariaceae Asarina procumbens Mill. (Syn. Antirhinum asarina L.) i Ma Digitalis purpurea L. i Zw Smilacaceae Smilax china L. i Zw Solanaceae Nicotiana rustica L. i Ma Tiliaceae Tilia platyphyllos Scop i Ma Tilia sp. i Bo, Ma, Ta, Zw and Fu Trilliaceae Paris quadrifolia L. i Zw Valerianaceae Centranthus ruber (L.) DC. i Zw Valeriana dioica L. i Zw Valeriana montana L. i Zw Valeriana officinalis L. i Zw Valeriana phu L. i Zw Valeriana saxatilis L. i Zw Valeriana wallichii DC. i Zw Verbenaceae Verbena officinalis L. i Bo, Ma, Fu and Ta2 Violaceae Viola odorata L. i Bo, Lo2, Ta, Ma and Fu Viola suavis Fisch. ex Ging. i Lo2 Viola tricolor L. i Ma Vitaceae Vitis vinifera L. i Ta Zingiberaceae Elettaria cardamomum (L.) Maton i Bo and Ta Zygophyllaceae Guaiacum officinale L. i Zw Peganum harmala L. i+e Ma, Lo2 and Ta2
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., 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+
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 γ-aminobutyric acid type A (GABAA) receptors of the subtype α1β2γ2S.
Osthol and cnidilin, at 300 μM, 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=0.2 ml/kg) and PTZ (ED50=0.52 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+ activity and by inhibiting current dependant and Ca2+ 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
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=2.5×10−4 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 PTZ- and 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 MES-models 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 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 μM, respectively ( Kim et al., 2012 and Julianti et al., 2011).
In electrophysiological tests hypericin (10 μM) lowered NMDA-activated
ion currents by 30%, as well as GABA-induced chloride currents by 43%.
Pseudohypericin at 10 μM 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 GABAB-receptors 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 and 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 μM for hyssop oil, 36 μM for cis-3-pinanon, and 35 μM for trans-3-pinanon. The LD50 of the two isomers cis- and trans-3-pinanon were 175–>250 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=30 μg/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 calcium-blocking 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+-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 NMDA-receptor 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 NMDA-receptor at a concentration of 10 μg/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 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+ 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 box-test. 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 μM, whilst
tetrahydropalmatine, scoulerine, isocorypalmine, isoapocavidine and
corydaline showed an increase of BCM-binding, with the strongest effects
from 0.1 to 0.01 μM. None of the alkaloids affected the benzodiazepine
binding site. Fluorescence-correlation-spectroscopy (FCS) using rat
hippocampi and 7.5 nM fluorescing muscimol-alexa (Alexa-Fluor) 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=0.41 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 myo-inositol were also shown in vivo
in mice which received myo-inositol (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 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 GABAA-receptors from rat plasma membranes. At their highest concentrations the extract inhibited flunitrazepam binding (IC50=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 μg/ml and 23 μM, 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 β2 or β3 subunits were activated by
the compound, while the β1 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=495 nM).
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+-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, Hosseinzadeh and Sadeghnia, 2007 and Höfler, 1970), 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 ( Leonti et al., 2009, Haub, and Zaugg et al., 2011a).
For valerian Valeriana officinalis there is a strong body of in vitro ( Yuan et al., 2004, Ortiz et al., 2006 and 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 ( Huang et al., 2008, Höld et al., 2002, Radhika et al., 2009 and 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 well studied, and in vivo and in vitro, suggest it to be antiepileptic ( De Vos, 2010, Marzell, 2000 and 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., 2010, Clarke, 1968 and Lauber and Wagner, 2007). 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 (n=75,
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, Zaugg et al., 2011b, Zaugg et al., 2011c and Khom et al., 2007).
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, Adams et al., 2011b, Halbsguth et al., 2003, Jefferys, 1994, Ślusarczyk et al., 2011 and 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.
References
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