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Plants traditionally used in age related brain disorders—A surveyof ethnobotanical literature

Michael Adams, Francine Gmunder, Matthias Hamburger ∗Institute of Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland

bstract

In traditional herbal medicine, numerous plants have been used to treat age related cognitive disorders. In this review we compiled availableiterature from four Swiss university libraries, scientific journals and online database query’s on plants and remedies used in traditional medicinalystems for such diseases. Over 150 plant species in various preparations and mixtures were found. European herbals from the 16th and 17th

entury alongside traditional Chinese and Indian medicinal works were the most prolific sources. The information is organised into geographicegions and when available the findings are discussed in the light of more recent scientific findings concerning their secondary metabolites andn vitro and in vivo activities relevant to dementia and Alzheimer’s disease.

eywords: Ethnomedicine; Traditional medicine; Herbal remedies; Alzheimer’s disease; Senile dementia

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3632. Literature search and organisation of information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3643. Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3644. The Americas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3665. Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3696. Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

6.1. Traditional Chinese medicine (TCM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3706.2. Korea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3726.3. Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3726.4. Ayurveda. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372

7. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; APP,myloid precursor protein; BuChE, butyrylcholinesterase; ChAT, choline acetyl-ransferase; GABA, gamma aminobutyric acid; NMDA, N-methyl-d-aspartate;KC, protein kinase C; TCM, traditional Chinese medicine.∗ Corresponding author. Tel.: +41 61 267 14 25; fax: +41 61 267 14 74.

E-mail address: matthias.hamburger@unibas.ch (M. Hamburger).

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

. Introduction

The occurrence of dementia and age related brain disorderss dramatically on the rise as life expectancy likewise increases.

lzheimer’s disease (AD), a complex, multifactoral, progres-

ive, neurodegenerative disease primarily affecting the elderlyopulation is estimated to account for 50–60% of dementiaases in persons over 65 years of age. According to the World

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ealth Organisation (WHO, 2006), around 35 million peoplen industrialized countries will suffer from AD by 2010. Theisease is characterized by loss of memory and impairment ofultiple cognitive and emotional functions (Frank and Gupta,

005). The pathological features identified in the central ner-ous system (CNS) in AD are amyloid plaques, neurofibrillaryangles, inflammatory processes and disturbance of neurotrans-

itters (Selkoe, 2001; Bossy-Wetzel et al., 2004). Basicallyrain cells wither away and die, causing disorientation, demen-ia and severe changes in personality and social interactions.here is currently no cure for most forms of dementia includingD. Pharmacotherapy is focussed on symptomatic benefit and

lowing disease progression (Desai and Grossberg, 2005), butnumber of possible disease modifying and preventive strate-

ies based on current understanding of AD pathophysiology arender investigation (Citron, 2004; Selkoe, 2005).

Before the development of modern medicine people reliedn a large arsenal of natural remedies for the treatment of CNSelated maladies. In western societies, here has been increas-ng interest in herbal medicines, which are often perceived as

more ‘natural’ and ‘soft’ treatments compared to syntheticrugs. Successful treatments for dementia have been devel-ped from herbal drugs. Extracts from Ginkgo biloba (mainlyGb 761—a standardised extract marketed by Wilmar SchwabembH) have been proven effective in clinical trials as a treat-ent for Alzheimer type dementia and vascular dementia (Gertz

nd Kiefer, 2004). Ginkgo extracts also has a favourable safetyrofile (Andrieu et al., 2003; Stromgaard et al., 2005). Galan-amine, an alkaloid obtained from the bulbs and flowers of theaucasian snowdrop Galanthus woronowii (Amaryllidaceae)

Heinrich and Teoh, 2004), is a fine example of a plant sec-ndary compound successfully used for the treatment of mildo moderate AD (Bullock and Dengiz, 2005; Marco-Contellest al., 2006). Several milestones in the history of drug therapyave been discovered from ethnomedical knowledge, such astropine, pilocarpine, cardiac glycosides, curare, and reserpine.ourcing in ethnomedical information may also be useful as atarting point for the discovery of new drugs for the treatment ofD and cognitive disorders. Here we have compiled literature

vailable from seven libraries and recent literature of scientificournals from online database searches.

. Literature search and organisation of information

The four main Swiss university libraries in Berne, Basel,urich, and Geneva were searched for relevant ethnobotanical

iterature. Furthermore, the Library of the Museum of Cultures‘Museum der Kulturen’), of a third world project, “Mission 21”nd the Swiss Pharmaceutical Museum, all three in Basel, werelso at our disposal. Suitable books of potential literature sourcesere identified in online databases of the particular libraries by

earching for the terms ethno medicine, traditional medicine,olk medicine, indigenous medicine, herbs, traditional herbs,

lants, indigenous plants, ethno botany and botanical medicine.he search was further refined by checking the titles of retrievedooks. Finally, a total of 192 books were consulted. Informationas searched for by scanning the indices of books for keywords

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elated to the topic. For books lacking an index, the tables ofontents and list of plants were scanned through. Of these 192ooks, 140 contained no specific listings for certain plants usedn the treatment of age related brain disorders. They are nev-rtheless listed separately as Supplementary information. Theelevant remainder of this collection was carefully viewed, infor-ation extracted and corroborated with data from other sources

o compile this survey.Two electronic sources, the online databases PubMed and

cifinder, were used to search for additional information in jour-als. Linguistic constraints limited us to literature in English,talian, French, German and Spanish. The terms ethno medicine,raditional medicine, folk medicine, indigenous medicine, herbs,raditional herbs, plants, indigenous plants, ethno botany andotanical medicine were combined with terms like Alzheimer,lzheimer’s disease, used to treat Alzheimer’s disease, demen-

ia, senile dementia, and memory loss. Plants and herbalombinations traditionally used for the treatment of age relatedrain diseases are listed according to geographic regions.

. Europe

Europe is the birthplace of modern western rational medicine.ith the industrialization came the development of modern

ynthetic drugs, medicinal equipment and health care institu-ions such as hospitals or nursing homes. Yet the continent hasong traditions of phytotherapy dating back thousands of years.specially in the German speaking world herbal remedies stilllay an important role and any pharmacy will provide and pro-uce a large number of plant based medicines (Reuter, 1991).oday, many traditional medical practices in Europe are sum-arized by the popular terms ‘alternative’ or ‘complementary’edicine. In widespread understanding these terms also includeore recent techniques such as homeopathy, ‘spagyrik’, dance

r music therapy, acupuncture, etc.Tabernaemontanus (1687) recommended sage, Salvia sp.,

rom various regional provenances for the treatment of a ‘weakrain’. Flowers should be crushed and mixed with sugar. Orhe plant can be extracted in strong wine in the sun for a dayefore distilling. The remedies help those who shiver and suf-er the effects stroke and strengthen weak minds and memories.

ost pharmacological research on Salvia has been done withhe essential oils of Salvia officinalis and Salvia lavendulifolia,nd a number of promising pharmacological results have beenublished. Since Perry et al. (2000, 2003) recently provided aeview, summarizing available literature on the use of Salviapecies in dementia therapy, this plant will only be treated briefly.avelev et al. (2004) examined the inhibition of the butyryl-holinesterase (BuChE) by essential oils from Salvia fruticosa,alvia officinalis var. purpurea, Salvia officinalis and Salviaavendulaefolia. The IC50 values measured after 5 min of incu-ation were 0.05, 0.4, 0.03, 0.07 and 0.0.3 mg/ml, respectively.dditionally pure compounds from the oil were tested, none of

hich could fully account for the activity of the essential oils.alvia lavandulaefolia and Salvia officinalis purpurea oils hadpparent dual cholinergic activity, as they were active on both,ChE and BuChE (Savelev et al., 2004). Besides the choliner-

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ic activity, there has already been a wider range of activitieseported for the genus Salvia, which may be relevant for CNSisorders. These include nicotinic activity (Wake et al., 2000),nti-inflammatory properties (Moretti et al., 1997), antioxidantZupko et al., 2001), estrogenic (Bartram, 1995) and glutamergicctivities (Kuang and Xiang, 1994). In a double blind, random-zed, placebo-controlled trial, with 39 patients, Akhondzadeh etl. (2003) assessed the efficacy and safety of Salvia officinalisxtract in patients with mild to moderate AD. The participantsxperienced statistically significant benefits in cognition after 16eeks of treatment. Despite the limitations of this study, a smallumber of patients and a relatively short period of follow-up, thisnitial clinical data suggests that Salvia lavandulaefolia essen-ial oil and extracts, may have potential for treatment of ADnd memory related disorders. Salvia spp. leaves contain tan-ins, tannosetonins and essential oil. The essential oil content of–2% varies within the plant and location. The components ofhe essential oil vary in the different Salvia species (Savelev etl., 2004). The oil of Salvia officinalis is rich in �-caryophyllene23.2%), camphor (11.0%) and borneol (8.7%), while, cam-hor, 1,8-cineole and 2-carene are abundant in the oil of Salviaavendulaefolia (Sfikas, 1980).

“Aerial parts of lemon balm, Melissa officinalis (Lamiaceae)re finely cut and covered in good wine over night in a clean dish,efore being distilled. Taken on an empty stomach a spoonfuluickens the senses, brightens the mind and improves memory.t aides shaking limbs caused by stroke, and helps retrieve theost ability to speak” (Lonicerus, 1679). The remainder of thisistoric citation is a romantic description of clever bees suckingt the flowers. Essential oil of Melissa officinalis, which containsonoterpenes such as citral and citronellal (Mills, 1993), showsdose-dependent inhibitory effect on the enzyme AChE, with

C50 values of less than 0.1 �l/ml (Perry et al., 1996).Lonicerus (1679) reports that dried parsley roots (Pet-

oselinum crispum, Apiaceae) soaked in good wine canmprove brain function and memory, alongside their then moreidespread uses as an abortifacient, aiding birth labour andeaning.Galbanum, a resin from the roots of Ferula gummosa (Api-

ceae) and its subspecies and varieties should be crushed, hotater added and left overnight. Then essential oil is distilled here

rom. The oil can be applied to the neck or drunk for improvingemory, hearing and sense of smell (Tabernaemontanus, 1687).he use of this plant, native to Syria and grown in herb gardensy European practitioners might have biblical roots, as it wasart of incense in the tabernacle (Exodus 30, 34–36).

The flowers of Caryophyllus species (Caryophyllaceae) arerushed with sugar so create a candy – Confecta florumaryophyllum – which is consumed to treat fever, strengthen

he brain and the memory. Cloves, the highly revered fruits ofyzygium aromaticum (Myrtaceae) were regarded as a similarlant and served as a remedy against ‘weakness of the brain’,troke and loss of memory (Tabernaemontanus, 1687). Another

on-native plant used in a confectum was the fruit of Anacardiumrientale (Anacardiaceae). It was processed to a ‘Confectioapientum’ a ‘wisdom candy’. Flowers of German chamomile,atricaria recutita (Asteraceae) are soaked in water. A person

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ho drinks this at least 2–3 times a week and washes his feet int should retain good memory (Tabernaemontanus, 1687).

There are numerous recipes for various types of aqua-it. Aquavits, literally ‘water of life’, are strong alcoholiceverages with very complex modes of preparation. Numer-us such drinks, are still widely sold today for medical orecreational purposes. Only one such comprehensive recipeill exemplarily be described here, as further listings would

xceed the scale of this review. Tabernaemontanus (1687) listsn aquavit which was claimed to be particularly useful inreating forgetful old people. Arial parts of Achillea mille-olium (Asteraceae), Adiantum capillus-veneris (Pteridaceae),orminum sp. (Lamiaceae), Eryngium caeruleum (Apiaceae),oeniculum vulgare (Apiaceae), Petroselinum crispum (Api-ceae) and roots of Asparagus officinalis (Asparagaceae) andichorium endivia (Asteraceae) are extracted with good wine.his concoction is then distilled before cinnamon (Cinnamo-um verum, Lauraceae), caraway (Carum carvi, Apiaceae),

ither lavender (Lavandula angustifolia, Lamiaceae) or valerianValeriana celtica, Valerianaceae), ginger (Zingiber officinale,ingiberaceae) and pepper (Piper nigrum, Piperaceae) are addedlongside more good red wine. Then the roots of greateralangal (Alpinia galanga, Zingiberaceae), lovage seeds (Levis-icum officinale, Apiaceae), Caryophyllus sp. (Caryophyllaceae)eeds, nutmeg (Myristica fragrans, Myristicaceae) and finallyiper cubeba (Piperaceae) are placed in the concoction before

t is left for 8 days and then again distilled. Finally, to com-lete the aquavit recipe musk and amber are added. This remedyhould be mixed with wine and consumed regularly by oldeople to strengthen the head, brain and memory according toabernaemontanus (1687), who made a strong emphasis on theuality of wine used for its preparation.

Half a spoonful of coriander, Coriandrum sativum (Apiaceae)eeds covered in a little sugar can be taken to strengthen head,rain and memory. If so much sugar was used to coat the seedshat they were as large as peas, then the remedy helped patientsall asleep (Tabernaemontanus, 1687).

The flowers of the Lilly of the Valley, Convallaria majalisConvallariaceae) should be crushed with sugar to make a candyo treat fever and strengthen the brain, senses and memoryTabernaemontanus, 1687). Actually two forms of the herbre described, of which one fits the description of Conval-aria majalis, and the other one is said to be identical but forhe fact that it blooms red. Herba Convalariae contains toxicardenolides like convallatoxin, convallatoxol, lokundjosid andonvallosid, as well as flavanoids and saponins (Krenn et al.,996). It has been used for heart insufficiency, and was officiallyisted in the German pharmacopoeia.

Herb from Euphrasia officinalis complex (Orobanchaceae,ormerly included amongst the Scrophulariaceae) is tradition-lly used in many parts of Europe for ailments of the eyes.abernaemontanus (1687) states that the powdered herb, when

aken in wine may cure a ‘stupid’ brain and strengthens the

ead. It contains various iridoid glycosides, such as aucubin,atalpol and euphrosid, the lignan dehydrodiconiferylalcohol-�-d-glucoside, tannins and flavanoids (Sticher and Salama,981).

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To sharpen senses and memory wine containing marjo-am, Origanum majorana (Lamiaceae) should be consumed. Ittrengthens the head and the inner organs (Tabernaemontanus,687). Powdered marjoram can be spread on the tongue to returnost speech and strengthen brain and memory. Snuffed it makesou sneeze and thereby cleanses the brain. In salt and vine-ar it is said to help against scorpion bites and in wine it isdiuretic (Fuchs, 1543). Origanum majorana contains large

mounts of essential oil consisting mainly of monoterpenes andome sesquiterpenes (Raghavan et al., 1997). Basil, Ocimumasilicum (Lamiaceae) ‘strengthens the heart and head’ anddispels darkness from the eyes’ (Fuchs, 1543).

Fuchs (1543) recommended smelling the very aromaticowers of Lavandula stoechas (Lamiaceae) in its variouseographic forms to strengthen a ‘stupid’ and dizzy brain.abernaemontanus (1687) cites Plinius in warning that ivy (Hed-ra helix, Araliaceae) should not be consumed because it ‘makesne wrong in ones head’ and weakens the nerves.

In 1978 Brøndegaard reported on the traditional use of plantsn Denmark, from the Middle Ages through to present times.ased on this, the genus Corydalis (Papaveraceae) was selected

or the isolation of compounds and in vitro examinations, as itad been used in the treatment of memory dysfunction. Adsersent al. (2005) showed that protoberberine and protopine-typelkaloids, common compounds in Corydalis species, are potentChE inhibitors. The inhibition of the enzyme was examined,ith methanolic and aqueous extracts of Corydalis species. Inhi-ition by methanolic extracts was generally higher than by theater extracts. Tuber- and herb-extracts were assayed at concen-

rations of 0.1, 0.05 and 0.025 mg/ml. With 92%, 83% and 77%or the methanolic tuber extract of Corydalis cava showed theest results compared to Corydalis intermedia, Corydalis sol-da and Corydalis solida ssp. slivenensis. Pure protopine had anC50 value of 50 �M (Adsersen et al., 2005). In a passive avoid-nce task test mice treated with protopine exhibited diminishedcopolamine-induced dementia (Kim et al., 1999).

Galanthamine is an alkaloid from Galanthus spp. and othermaryllidaceae, such as Narcissus and Leucojum species. It is a

elective and competitive AChE inhibitor. It has been approvednd is successfully used as a treatment for AD in numorousountries. Wether or not galanthamine containing plants wereraditionally used in Europe to treat dementia is not really clearHeinrich and Teoh, 2004). It is appellative that a drug for thereatment of the most severe form of dementia was developedrom the little snowdrop – the first sign of spring – a symbol ofegeneration in nature (Heinrich, 2005).

Consistent with current aroma therapeutic applications ofosemary Rosmarinus officinalis (Lamiaceae) to improve mem-ry, the ancient Greeks considered this herb a stimulator of theind, in particular the memory. Indeed many early Europeanritings refrain to rosemary to be a memory enhancer (see Perry

t al., 1999, and citations therein).In a handwritten folk-medicinal document from the Diemtig-

al valley in the Berner Oberland in Switzerland Artemisiabsinthium L. (Asteraceae) together and chervil (Anthriscuserefolium, Apiaceae) ‘water’ – a distilled beverage – is rec-mmended to improve memory (Personal communication M.

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luge, Swiss Pharmaceutical Museum). Artemisia absinthiumas a record of use against declining cognitive function (seeake et al., 2000). An alcohol extract displaced nicotine from

icotine binding receptors (Perry et al., 1996; Wake et al., 2000).odl et al. (2000) showed �-thujon to have GABAA receptor

ntagonist activity. These reports should be viewed with cau-ion, considering the toxicity of absinthe, a strong alcoholicrink, which when abused, leads to hallucinations, sleeplessness,remors, and convulsions, a syndrome known as absinthism. The

onoterpene thujon is responsible for these effects (Olsen, 2000;achenmeier et al., 2006) (Table 1).

. The Americas

The meaning of the term ‘medicine’ to Native Americansas quite different from that of Western societies. Illness was

egarded as a disharmony or imbalance that may be directlyelated to spiritual causes, which may have natural, human orupernatural origins. A person’s equilibrium can be lost as aesult of grief, sadness, hatred or personal wrongdoing (Kavaschnd Baar, 1999). The concept of healing is to determine whatas to be rectified and to bring the person back into balance.ractices to draw people back into equilibrium, include rituals,weat lodge rites of purification, spirit feasts, fumigation andmoke therapy, massage, prayers, blessings, incantations anderbals (Vogel, 1970).

Despite the vast number of books and references on Amer-can Indian medicine and related topics, we only found a feweferences of plants used in the treatment of AD and relatedymptoms affecting the memory.

One remedy, unknown from which tribe it originated,ncludes eight different plants: Clematis sp. (Ranunculaceae),arrea tridentate (Zygophyllaceae), Oplopanax horridusAraliaceae), Capsicum annuum (Solanaceae), Ginkgo bilobaGinkgoaceae), Centella asiatica (Apiaceae), Chrysanthemump. (Asteraceae) and Rosmarinus officinalis (Lamiaceae). Alend of these herbs was administered to assist memory as wells for eczema, emphysema and asthma. It must be remarkedhat Centella asiatica and Ginkgo biloba are not native to Northmerica but to Asia (Kavasch and Baar, 1999).A tincture of the roots of Lachnanthes tinctoria (Haemodor-

ceae) was prepared against typhus, pneumonia, various andevere forms of brain diseases, rheumatic wry–neck and laryn-eal cough. Unfortunately there was no specification given abouthe ‘various and severe forms of brain diseases’. Constituentsf Lachnanthes tinctoria are glycosides, chelidonic acid andaphthalene derivatives, as well as phenylphenalenone pigmentsMillspaugh, 1974). Nowadays, Lachnanthes tinctoria is a rem-dy known in homeopathy, amongst others, for pains for in theoints.

Mexico is famous for the pre-Columbian Aztecs, whoseophisticated empire came to a dire end with the arrival of Span-sh invaders. In 1571 King Philipp II of Spain commissioned a

hysician to document medicinal remedies used by the Aztecs.

Tagetes lucida (Asteraceae) known to the Aztecs as ‘yauhtli’as a remedy for ailments such as fever, fear, dementia, lighten-

ng stroke and was also used as a diuretic (Ortiz de Montellano,

Table 1Plants used in Europe in the context of age related CNS disorders

Plant Family Traditional use References

Anacardium orientale auct. exSteud.

Anacardiaceae A ‘Confectio Sapientum’—a ‘wisdom candy’ Tabernaemontanus (1687)

Artemisia absinthium L. Asteraceae Traditionally for lost or declining cognitive function Howes et al. (2003)Caryophyllus spp. Caryophyllaceae Strengthen the brain and the memory Tabernaemontanus (1687)Convallaria majalis L. Convallariaceae A candy to treat fever and strengthen the brain, senses and

memoryTabernaemontanus (1687)

Coriandrum sativum L. Apiaceae Covered in a little sugar can be taken to strengthen head, brainand memory

Tabernaemontanus (1687)

Corydalis sp. Papaveraceae Several species used in folk medicine for treatment of memorydysfunction

Adsersen et al. (2005)

Euphrasia officinalis complexHayne

Orobanchaceae Powdered herb when taken in wine may cure a ‘stupid’ brainand strengthens the brain

Tabernaemontanus (1687)

Ferula gummosa Boiss. Apiaceae Oil can be applied to the neck or drunk for improving memory Tabernaemontanus (1687)Matricaria recutita L. Asteraceae Flowers soaked in water. Drunk and used to wash feet to retain

good memoryTabernaemontanus (1687)

Melissa officinalis L. Lamiaceae To sharpen the senses and improve memory, strenghtens thebrain, clears the head

Lonicerus (1679), Perry et al.(1998) and Mills (1993)

Lavendula stoechas L. Lamiaceae To strengthen a ‘stupid’ and dizzy brain. Tabernaemontanus (1687)Ocimum basilicum L. Lamiaceae for abdominal cramps, upset stomach, nervous migraine,

memory, ‘strengthens the heart and head’ loss and forgetfulnessFuchs (1543) and Sfikas (1980)

Origanum majorana Moench Lamiaceae To return lost speech and strengthen brain and memory,cleanses the brain

Fuchs (1543)

Peroselinum vulgare (Mill.)Nym. and A.W. Hill

Apiaceae Soaked in good wine can improve brain function and memory Lonicerus (1679)

Rosmarinus officinalis L. Lamiaceae As a circulatory stimulant for improving concentration andmemory. To stimulate the mind, in particular the memory. Usedby herbalists and aromatherapists for memory problems

Chevallier (1996), Perry et al.(1998) and Price and Price(1995)

Salvia officinalis L. Lamiaceae Remedies help those who shiver and suffer the effects strokeand strengthen weak minds and memories, for a sensitivestomach, general debility, irregular menstruation and dementia

Tabernaemontanus (1687),Sfikas (1980), Savelev et al.(2004), Akhondzadeh et al.(2003) and Perry et al. (2003)

Syzygium aromaticum (L.)Merrill and Perry

Myrtaceae Remedy against ‘weakness of the brain’, stroke and loss ofmemory

Tabernaemontanus (1687)

Achillea millefolium L. Asteraceae This complex ‘aqua vit’ is prepared stepwise by extraction anddistillation of a large number of plants. The remedy should bemixed with wine and consumed regularly by old people tostrengthen the head, brain and memory

Tabernaemontanus(1687)Adiantum capillus-veneris L. Pteridaceae

Asparagus officinalis L. AsparagaceaeCarum carvi L. ApiaceaeCaryophyllus sp. CaryophyllaceaeCichorium endivia L. AsteraceaeCinnamomum verum J. S. Presl LauraceaeEryngium caeruleum M. Bieb. ApiaceaeFoeniculum vulgare Mill. ApiaceaeHorminum sp. LamiaceaeLavandula angustifolia Mill. LamiaceaeLevisticum officinale Koch ApiaceaeMyristica fragrans Houtt. MyristicaceaePetroselinum crispum (Mill.)

Nym. and A.W. HillApiaceae

PV

1stqna(

o

u(wpc

iper cubeba L. Piperaceaealeriana celtica L. musk and

amber are addedValerianaceae

990). Originally, Tagetes lucida is native to Mexico, but wasoon introduced to Europe as a decorative plant and a substi-ute for French tarragon. Campherole, tagetiin, tagetone anduercetagritin, flavonol-gylcosides, quercetagenin, glucopyra-oside, phenolic acids, propanoic acids, flavonols, aromatic

cids, methoxycoumarin were found to be present in the plantAquino et al., 2002).

Nowadays cocoa is of great global significance as good dealf the 3,000,000 tonnes produced each year (WHO, 2007) are

sabo

sed to meet our craving desire for chocolate. Theobroma cacaoSterculiaceae), however, was used by the Aztecs as medicine,here potions of ground bark and roots were used to treat stu-or (Roeder, 1988). The chemical constituents of Theobromaacao include sterols, coumarins, catechins, catechol, glyco-

ides, galactosides, tannins, polyphenols, triglycerides, linoleiccids, and alkaloids including caffeine, theophylline, and theo-romine, rutin, vitexin. The stimulating effects are most likelynly due to caffeine, theophylline, and theobromine.

Table 2Plants used in North America in the context of age related CNS disorders

Plant Family Traditional use References

Erythroxylum catuaba A.J. Silva Erythroxylaceae It is used as aphrodisiac, stimulant of the CNS, for sexual impotence,general exhaustion, fatigue, poor memory and insomnia related tohypertension

Taylor (1998)

Capsicum annuum L. Solanaceae Native healers blend these herbs assisting memory, as well as foreczema, emphysema, asthma and other ailments of aging

Kavasch and Baar(1999)Centella asiatica (L.) Urban Apiaceae

Chrysanthemum sp. AsteraceaeClematis sp. RanunculaceaeGinkgo biloba L. GinkoaceaeLarrea tridentata (Sesse et Moc.) Coville ZygophyllaceaeOplopanax horridus Sm. Mic. AraliaceaeRosmarinus officinalis L. Lamiaceae

L the roariou

d lary

atca1

vtMcBs

(idIpLA

ttawni

pwrotk

RdIoCCdh(h1

oadtE

TP

P

BL

M

TT

achnanthes tinctoria Ell. Haemodoraceae A tincture ofpneumonia, vwry–neck an

Today, in the United States, Medicago sativa (Fabaceae),lfalfa, is considered an invasive plant. In Mexico, it was believedo improve the memory, cure skin eruptions, kidney pain,ough, sore muscles and inflammation. Triterpenes, saponinsnd sapogenins were identified in Medicago sativa (Finkler,985) (Table 2).

Brugmansia candida (Solanaceae) was used by native El Sal-adorian peoples in various cases of memory problems. Fiveo ten flowers were used to make a decoction for one bottle.

ore than one cup had to be drunk, because the first couple ofups would not be effective (Gonzalez Ayala, 1994). The genusrugmansia is known for toxic tropane alkaloids, so the remedyhould be treated with necessary caution.

A remedy reported from Guadeloupe was Lantana camaraVerbenaceae), used to medicate memory weakness and enhancentellect and cognition. Tea brewed from the leaves should berunk before going to bed (Muller-Ebeling and Ratsch, 1989).t is remarkable that this use of a globally spread toxic invasivelant should have an activity known merely in tiny Guadalupe.antana camara contains triterpenes such as the toxins lantadenand B, essential oil, and sesquiterpenes.Ananas comosus, pineapple (Bromeliaceae) originally cul-

ivated in Central and South America, is used for ailments ofhe CNS in South American traditional folk medicine. It was

lso administered for neurasthenia, melancholy, sadness and foreakness of memory (Wolters, 1994). Unfortunately, there waso detailed description about the exact region or tribes wheret was used for this purpose. The best known bioactive com-

medw

able 3lants used in Central America and the Caribbean Islands in the context of age relate

lant Family Traditional use

rugmansia candida Pers. Solanaceae Tea or decoction is used forantana camara L. Verbenaceae Tea of the leaves is believed

and enhances intellect and cedicago sativa L. Fabaceae To improve the memory, cur

cough, sore muscles and inflagetes lucida Cav. Asteraceae To treat fever, fear, dementiaheobroma cacao L. Sterculiaceae In a potion for stupor

ots was used against typhus and typhoid fevers,s and severe forms of brain diseases, rheumaticngeal cough

Millspaugh (1974)

onent of the Ananas sp. is the proteolytic enzyme bromelaine,hich is responsible for the positive effects on digestion and has

ecently been advertised for rapid weight-loss. Highest contentsf bromelaine occur in the stem and in the fruit. Consideringhe wide use and popularity of pineapple, astonishingly little isnown about the phytochemistry of pineapple plants (Table 3).

As in Europe, in Ecuadorian traditional medicine rosemaryosmarinus officinalis is used in connection with AD andementia, for general symptoms of old age, debility and fatigue.t was also applied for neuralgia, indigestion, pain of nervousrigin, circulatory disorders and hypertension (CESA, 1992).ESA (1993), and De Barradas (1957), listed the leaves ofhenopodium ambrosioides (Chenopodiaceae) in the context ofementia symptoms. Its traditional indications include uses foreadache, caries, toothache and memory. Lactuca sativa, lettuceAsteraceae) is, according to Ecuadorian natives, supposed toelp with insomnia and weak memory (Schweitzer de Palacios,994).

In Brazil catuaba has traditionally been used as a stimulantf the CNS with aphrodisiac properties. The source of catu-ba is said to be the elusive Erythroxylum catuaba, a poorlyefined botanical entity, lacking both proper description and aype specimen. The botanically correct identity the drug may berythroxylum vacciniifolium (Erythroxylaceae), Anemopaegma

irandum (Bignoniaceae), Trichilia catigua (Meliaceae) or oth-

rs (see Kletter et al., 2004). One to three cups of a barkecoction are to be consumed daily against sexual impotence andeakness, agitation, nervousness, neurasthenia, poor memory,

d brain disorders

References

memory problems Gonzalez Ayala (1994)to prevent weakness of memoryognition

Muller-Ebeling and Ratsch (1989)

e skin eruptions, kidney pain,ammation

Finkler (1985)

, lightning stroke and as a diuretic Ortiz de Montellano (1990)Roeder (1988)

fc

cag(tamboaiisd

imrEoA

df(aibtaGwot(Aftm(T1smcSrirvaeta

TorpppGS1

5

isSetgfcoattp

(ti

amrp2

pmrlpaoSmgeHat

(

orgetfulness and insomnia. Erythroxylum vaciniifolium barkontains a number of tropane alkaloids (Zanolari et al., 2005).

Paullinia cupana (Sapindaceae), guarana, has been used forenturies as an effective tonic, heart tonic, to thin the bloodnd for mental acuity and to benefit long-term memory. Todayuarana is used word-wide as a tonifying drink against fatigueTaylor, 1998). Due to its caffeine content guarana is a substi-ute for coffee. Other phytochemicals are adenine, catechutanniccid, choline, d-catechin, guanine, guaranine, hypoxanthine,ucilage, saponin, tannins, theobromine, theophylline, tim-

onin and xanthine. An in vivo study with an interesting outcomen mental insufficiency was conducted in 1997. Guarana wasdministered in single and chronic doses to rats. Physical activ-ty, physical endurance under stress and memory effort increasedn both of the doses administered. It is interesting that the wholeeed extract of guarana showed better results than a comparableose of caffeine (Espinola et al., 1997).

Colombia hosts a vast diversity of plants and numerousndigenous tribes. The Colombian Indians reputably treat aged

embers of the clan with care, patience and honour. Over twentyemedies for afflictions of old age were described by Richardvans Schultes (1993a,b), the “father of ethnobotany”, a mostutstanding botanist who spent many years in the North Westernmazone.The Puinave Indians living along the Rio Vaupe mixed the

ried leaves of Unonopsis veneficiorum (Annonaceae) into theood of elderly patients suffering from not knowing how to talkWolters, 1994). Pulverised leaves of Unonopsis stipitata, aredded to the food of elderly people who have difficulty speak-ng. The genus Unonopsis has interesting azafluorenones andisaporphinoids (Laprevote et al., 1987, 1988). Warm decoc-ions of the whole plant of Justicia ideogenes (Acanthaceae)re poured over the lower limbs to treat trembling. Latex fromalactophora crassifolia (Apocynaceae) is used for childrenith ‘uncontrollable shaking of the head’. A root decoctionf Mandevilla steyermarkii (Apocynaceae) is administered tohe ‘aged and the weak’. The latex of Parahamcornia amapaApocynaceae) is used against general debility in the Brasilianmazonas. Vismia tomentosa (Clusiaceae) provides a remedy

or the aged who have difficulty in understanding instructions,alking and suffering of physical degeneration. Tukano medicine

en prepared tea of the leaves of Tabernaemontana heterophyllaApocynaceae) to give to elderly who were slow and forgetful.he tree contains a number of indole alkaloids (Wolter et al.,983). Leaves of Lundia erionema (Bignoniaceae) or Memorachomburgkii (Bignoniaceae) are crushed by Vaupes medicineen and mixed with a palm oil to treat elderly ‘who speak

razily without making sense’. Tikuna Indians make a tea fromchlegelia macrophylla (Bignoniaceae) leaves for those whoefuse to eat and lose appetite. The Muinane Indians, who liven the area of the Rıo Caqueta, knew about the properties of theather unknown plant called Pagaea recurva (Gentianaceae). Aery bitter decoction, made of the whole plant, was prepared

nd indicated in cases of debilitating forgetfulness among thelderly (Schultes, 1993a,b). Practically nothing is known abouthe chemistry of this plant. For patients with mental problems,recipe of the seeds of Barbieria pinnata (Fabaceae) was used.

sm

b

he seeds are soaked in a fermented drink made of maniocr maize before being administered. Cassia lucens (Fabaceae)epresents another remedy with a rather vague indication. Thislant’s most known use is as an insect repellent. Some Kubeoeople administer a drink from the dried and powdered leaves toeople with poor memory (Schultes, 1993a,b). The gymnospermnetum nodiflorum (Gnetaceae) is used by the Wyana tribe inuriname for cases of physical and mental weakness (Schultes,993a,b) (Table 4).

. Africa

The relative numbers of traditional practitioners and doctorsn proportion to the population in most African countries demon-trate the importance of traditional medicine. In the Venda area ofouth Africa, for example, there is one traditional practitioner forvery 700–1200 people, compared to one university-trained doc-or for almost 18,000 people. Drugs used are considered a divineift, valued as much for its symbolic and spiritual significance asor its medicinal effect. In addition to plants, healers may employharms, incantations and casting of spells in their healing meth-ds (Tella, 1979; Helwig, 2006; Kale, 1995). African healing isn inextricable part of African religion (Kale, 1995). This needso be considered when cures for mental diseases involve prac-ices such as wrapping plants around a persons head or similarharmacologically less plausible forms of administration.

In East Africa, the roots of water lettuce, Pistia stratiotesAraceae), a perennial floating plant, are wrapped in a rag andied around a demented persons head. At the same time annfusion of the leaves is poured over the head (Kokwaro, 1976).

In South Africa leaves, stems and roots of Asparagusfricanus (Asparagaceae) are pounded and soaked in water toake an infusion. Drunken two to three times a day, it should

elieve problems of mental disturbance (Kokwaro, 1976). Thelant contains steroidal saponins and lignans (Debella et al.,000).

The following three recipes refer to the Yoruba speakingart of West Africa. They are a large linguistic group of 40illion individuals mostly in Nigeria, Benin and Togo. One

ecipe consists of the leaves of Hydrolea glabra (Hydrophi-aceae), the leaves of Digitaria species (Poaceae) and a guineaig. The ingredients are eaten together with Indian cornmealnd are believed to enhance memory (Fatumbi, 1995). A blendf leaves of Pleiocarpa pycnantha (Apocynaceae), leaves ofpondias mombin (Anacardiaceae) and a fruit of Aframomumelegueta (Zingiberaceae) are administered to gain and retainood memory (Fatumbi, 1995). According to traditional heal-rs a formula consisting of Symphonia globulifera (Clusiaceae),ydrolea glabra (Hydrophilaceae), and Glyphaea brevis (Tili-

ceae) was also given to aid memory. A snake was also addedo the concoction (Fatumbi, 1995).

In Senegal a maceration of the roots of Ximenia americanaOlacaceae) – native to Africa not the Americas, as the name

uggests – is used to cure leprosy and is applied externally forental sickness (Sofowora, 1982).Crinum glaucum and Crinum jagus (Amaryllidaceae) have

een used in Southwest Nigeria by traditional healers for mem-

Table 4Plants used in South America in the context of age related CNS disorders

Plant Family Traditional use References

Ananas comosus (L.) Merill Bromeliaceae Against neurasthenia, melancholy, sadness, weakness of memoryand stupidity

Wolters (1994)

Barbieria pinnata (Pers.) Baill. Fabaceae The Kubeos prepared a tea of the seeds for elderly men withvarious mental problems

Schultes (1993a,b)

Cassia lucens Vog. Fabaceae A drink prepared from powdered leaves for people with badmemory

Schultes (1993a,b)

Chenopodium ambrosioides L. Chenopodiaceae For headache, memory, caries and toothache CESA (1993)Preparations of the leaves are used to ameliorate the memory CESA (1992)The Indios believe that the plant has potential to increase thememory

De Barradas (1957)

Erythroxylum catuaba A.J.SilvaJuniperus brasiliensis

Erythroxylaceae;Cupressaceae

In Brazil, a decoction is used for sexual impotency, agitation,nervousness, neurasthenia, poor memory, forgetfulness and sexualweakness

Taylor (1998)

Gnetum nodiflorum Brongn. Gnetaceae Wyana Indians administered the plant in the treatment of physicaland mental weakness

Schultes, 1993a,b

Justicia ideogenes Leonard Acanthaceae Kofan Indians pour warm decoction over lower limbs for palsy-liketrembling

Schultes (1993a,b)

Lactuca sativa L. Asteraceae Lactuca is used for insomnia and believed to help a weak memory Schweitzer de Palacios(1994)

Lundia erionema De Candolle Aristolochiaceae Crushed leaves mixed with Jessenis oil are given to elderly ‘whospeak crazily without making sense’

Schultes (1993a,b)

Mandevilla steyermarkii Woodson Apocynaceae Given to the aged and the sickPagaea recurva Benth. Bentham et

Hooker filGentianaceae Amongst the Muinane Indians a decoction of the whole plant was

prepared for debiliating forgetfulness in the elderlySchultes, 1993a,b

Parahamcornia amapa (Hub.) Ducke Apocynaceae Is used against general debility in the Brasilian Amazonas Schultes (1993a,b)Paullinia cupana KUNTH ex. H. B. K Sapindaceae Indians used guarana as a heart tonic, energy tonic, to thin the

blood, for mental acuity and long-term memoryTaylor (1998)

Rosmarinus officinalis L. Lamiaceae For circulatory disorders, hypertension, pain of nervous origin,indigestion, neuralgia, general debility and fatigue, and for generalsymptoms of old age

CESA (1993)

Schlegia macrophylla Ducke Bignoniaceae Leaves given to people who refuse to eat and lose appetite Schultes (1993a,b)Tabernaemontana heterophylla Vahl. Apocynaceae Tukano Indians prepared a tea of the leaves for the old folks who

are slow and forgetfulSchultes (1993a,b)

Unonopsis veneficiorum (Mart.) R.E.Fries

Annonaceae Puinave Indians at Rio Vaupe mixed dried leaves in the food ofelderly people who forgot how to talk

Schultes (1993a,b)

Unonopsis stipitata Diels Annonaceae Added to the food of elderly people who have difficulty speaking Schultes (1993a,b)Vismia tomentosa Ruiz and Pav. Clusiaceae Yukuna and Makuna Indians prepared the plant for the elderly who

suffer difficulty in understanding instructions and have physicaland

Schultes (1993a,b)

oHa2i0(apei

6

awm

6

isTsepcUhhe

degeneration

ry loss and other mental ailments associated with aging.oughton et al. (2004) isolated alkaloids from the plants

nd tested their AChE inhibitory properties. Hamayne (IC5050 �M) and lycorine (IC50 450 �M) showed only slight activ-ties compared to the positive control physostigmine (IC50 of.25 �M). A preparation of macerated roots of Opilia celtidifoliaOpiliaceae) is believed to help with mental illness when takens a beverage for about 1 week (Assi and Guinko, 1991). Triter-enoid saponins were found to be present in the plant (Crespint al., 1993). The mark of Canthium glabriflorum (Rubiaceae)s used for cough and mental diseases (Bep, 1960) (Table 5).

. Asia

Asia is the largest and, with 60% of the world’s populationlso the most populous continent of the world. It is home to theorld’s oldest documented medical systems, traditional Chineseedicine (TCM) and Ayurveda.

mtot

difficulty in talking

.1. Traditional Chinese medicine (TCM)

Chinese herbal medicine is an interesting subject for medic-nal plant research. According to But et al. (1980), from 26,092pecies listed in Flora Sinica, 4941 (19%) are used medicinally.CM concepts such as yin, yang and qi are used to describepecific medical states but are difficult to translate into west-rn medical terms. Despite the entirely different underlyinghilosophical frameworks, there has been a great amount ofooperation between TCM and western medicine in recent years.sing western methods and techniques traditional remediesave been pharmacologically and clinically validated, and manyave been shown to have therapeutic value in terms of west-rn medical understanding. Besides herbal therapy acupuncture,

oxibustion, massage, hydrotherapy, dietetics and exercise are

herapeutic forms in TCM treatment. For detailed informationn the spiritual and philosophical aspects of TCM please refero specialised literature (such as Jiang, 2005).

Tabl

e5

Plan

tsus

edin

Afr

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inth

eco

ntex

tof

age

rela

ted

CN

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dro

ots

are

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day

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tald

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rban

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aro

(197

6)an

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al.(

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ceae

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tis

used

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enta

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num

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lier

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The club moss Huperzia serrata (Lycopodiaceae) is used inCM to alleviate problems of memory loss, promote circulation,

or fever and inflammation (Houghton and Howes, 2005). Qianeng Ta is a formula prepared from Huperzia serrata, used inCM to treat memory loss (Howes et al., 2003). It is reported

o be a cognition enhancer that facilitates memory and motorctivity in aged persons and was recommended in the treatmentf senile dementia, including AD and multi-infarct dementiaKee, 1999).

Huperzine A, an alkaloid from Huperzia serrata, was foundo be a reversible AChE inhibitor and is neuroprotectiveSkolnick, 1997; Chiu and Zhang, 2000; Yaniv and Bachrach,005). It was shown that huperzine A has a neuroprotectiveffect against �-amyloid peptide fragment 25–53, oxygen glu-ose deprivation and against free radical-induced cytotoxicity. Itlso attenuates apoptosis by inhibiting the mitochondria-caspaseathway. In cortex or synaptic plasma membranes it counter-cted N-methyl-d-aspartate-induced toxicity (NMDA) This maye due to the fact that huperzine A facilitates cholinergic neuro-ransmission by increasing the concentration of acetylcholine inhe CNS about 100 times more effectively than tacrine, a drugsed for AD (Anekonda and Reddy, 2005). In cell culture stud-es huperzine A decreased neuronal cell death caused by toxicevels of glutamate (Bores et al., 1996).

In rats huperzine A reversed �-amyloid-(1–40) inducedeficit in learning in a water maze task, and reduced the lossf choline acetyltransferase activity in cerebral cortex, and theeuronal degeneration induced by �-amyloid protein-(1–40). Iteversed the down-regulation of anti-apoptotic Bcl-2 and thep-regulation of pro-apoptotic Bax and P53 proteins as wells reducing apoptosis caused by �-amyloid injection. The ben-ficial effects are not confined to the cholinergic system, butlso include favourable changes in the expression of apoptosis-elated proteins and in the extent of apoptosis in other regionsf the brain (Wang et al., 2001).

Huperzine A (400 �g) was given daily to 100 patients for2 weeks. It was reported to be more selective for AChE thanuChE and was less toxic than the synthetic AChE inhibitorsonepezil and tacrine (Frank and Gupta, 2005). Possible sideffects are nausea, vomiting, diarrhoea and muscle cramps haveeen observed. Cholinergic effects may also worsen pulmonarynd peptic ulcer disease and cardiac arrhythmia (Ott and Owens,998).

Qingkailing, a traditional Chinese formulation, does notave a direct indication in traditional medicine for dementiar AD therapy. Some recent data, however, indicates a cer-ain potential to be used as such. The herbs Scutellaria spp.Lamiaceae), Lonicera spp. (Caprifoliaceae), Pittosporum spp.Pittosporaceae) and Isatis tinctoria (Brassicaceae) are com-ined with cow-bezoar (Jinzhoun, 1998). It is a remedy usedor re-establishing the energy balance and to remove the causesf heat and phlegm, which in TCM are symptoms, associ-ted with dementia. Clinical studies report beneficial effects

f qingkailing: Patients with dementia following a stroke,eceived qingkailing intravenous daily, for 30 days. At the sameime, a tea was given twice daily. It contained Pinellia ter-ata (Araceae) tubers, Acorus gramineus (Acoraceae), Angelica

darpTrwqTpgcbt

Jepoa

6

dgbrioetpSdA

omoC(A((C(jcaovaTeta

6

msojtasrttpi

aswraratesra2eam

6

pteAiRidgogRtultc

ahurica (Apiaceae) roots, Atractylodes macrocephala (Aster-ceae), and Pseudostellaria heterophylla (Caryophyllaceae)oot. An improvement of intellect by increasing the score 10oints on Hasegawa Dementia Scale was stated by five patients.hree patients improved 5 or less points, while two patients

emained without benefit. In a randomized double blind study,ith 15 participants with syndromes of vascular dementia,ingkailing was administered i.v. to 10 patients daily for 14 days.he control group (n = 5), received an infusion of chuanxiongiperazine (Ligusticum chuanxiong, Apiacae). The qingkailingroup improved their score by 10.4, whereas the score of theontrol group increased only by 4.9. These studies have, atest, a pilot character and need to be followed up by largerrials.

Polygala tenuifolia (Polygalaceae) is used in TCM andapanese formulas for the treatment of psychoneurological dis-ases. It is thought to have an effect on the will and mentalowers, improving understanding and strengthening the mem-ry. It is also indicated as a cerebrotonic, cardiotonic, sedativend tranquillizer (Howes and Houghton, 2003).

.2. Korea

Oh et al. (2004) lists seven plants in Korea’s history of tra-itional medicine, including Acorus calamus rhizome, Acorusramineus rhizome, Bupleurum falcatum root, Dioscoreaatatas rhizome, Epimedium koreanum herb, Poria cocos scle-otium and Zizyphus jujuba fruit, which are used for the generalndication for improvement of cognition and memory function inld age. They were all tested for cholin esterase inhibitory prop-rties using the Ellman colorimetric method. The data revealedhat extracts of Acorus gramineus, Dioscorea batatas and Zizy-hus jujuba did not show any inhibitory effects on AChE.ignificant dose-dependent inhibition of the enzyme at the highose of 200 �g/ml was observed for methanolic extracts fromcorus calamus and Epimedium koreanum.

Paeng-Jo-Yeon-Nyeon-Baek-Ja-In-Hwan (PJBH) is a decoctf 18 dried herbs including the whole plant of Dendrobiumoniliforme, seeds of Thuja orientalis (Cupressacae), fruitsf Torilis japonica (Apiaceae), Rubus coreanus (Rosaceae),ornus officinalis (Cornaceae) and Schizandra chinensis

Schisandraceae), roots of Morinda officinalis (Rubiaceae),sparagus cochinchinensis (Asparagaceae), Polygala tenuifolia

Polygalaceae), Phlomis umbrosa (Lamiaceae), Panax ginsengAraliaceae) and Rehmannia glutinosa (Gesneriaceae), stems ofinnamomum cassia (Lauraceae), rhizome of Acorus calamus

Araceae), Alisma canaliculatum (Alismataceae) and Dioscoreaaponica (Dioscuraceae) and leaves of Cistanche salsa (Oroban-haceae). PJBH has an extensive history in Korea, and islso used in TCM to activate brain function, promote mem-ry and lengthen life span. The herbal medicine has shownarious activities including immune modulation, anti-infarct,nti-inflammatory and anti-allergic effects (Koo et al., 2004).

he effects of PJBH on H2O2 induced injury in PC12 cells wasxamined and revealed an elevating effect on catalase and glu-athione peroxidase activities as well as on cell survival (Koo etl., 2004).

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.3. Japan

Choto-San, a remedy from Kampo – Japanese traditionaledicine adapted from TCM – consists of 10 herbs and a

ulphate mineral. The formula is composed of the fruit shellf Citrus aurantium (Rutaceae), the tubers of Ophiopogonaponicus (Convallariaceae) and Pinellia ternate (Araceae),he stem including the hooks of Uncaria tomentosa (Rubi-ceae), the roots of Panax ginseng (Araliaceae), Ledebouriellaeseloides (Apiaceae) and Glyzyrrhiza glabra (Fabaceae), thehizome of Zingiber officinalis (Zingiberaceae), the flowers ofhe Chrysanthemum species and parts of Poria cocos. The tradi-ional indication does not relate to age related brain disorders inarticular, but recent data reveals the possible use of Choto-Sann the therapy of cognitive disorders (Murakami et al., 2005).

Murakami et al. (2005) tried to clarify the mechanisms ofction of the Choto-san formula in mice with induced hypoperfu-ion by permanent occlusion of both the common carotid arterieshich induces spatial memory deficits and neuronal damage in

odents. Choto-san extract was given orally to mice for 5 daysn hour prior to the start of each experiment. Tacrine was used aseference. Choto-san and Choto-san Uncaria-free extract weredministered. Choto-san raised the level of ACh, comparedo that in the control group, whereas Choto-san Uncaria-freextract had no effect. Choto-san also improved 2VO-inducedpatial learning deficits, via the stimulation of muscarinic M1eceptor, while Choto-san Uncaria-free extract did not showny improvement. Choto-san extract ameliorated the effect ofVO in the Morris water maze task whereas the Uncaria-freextract showed no effect. The results suggest that Uncaria playskey role in the beneficial effect of Choto-san on learning andemory impairment caused by chronic hypoperfusion.

.4. Ayurveda

The history of medicine in India can be traced to the remoteast. The earliest mention of medicinal use of plants is found inhe Rigveda, probably the oldest repositories of human knowl-dge written between 4500 and 1600 b.c. (Kapoor, 1990).yurveda encompasses philosophy, science and religion and

s a very complex system of knowledge applied to daily life.asayana tantra – geriatrics including rejuvenation therapy –

s one of eight major disciplines in Ayurveda. Caraka Samhitaefined rasayana as a treatment to attain longevity, intelli-ence, freedom from age related disorders, youthful appearance,ptimum strength of physique and sense organs, maintain lan-uage ability and improve memory (Bala and Manyam, 1999).asayana is not merely a drug therapy but a regimen covering

he general mode of life, social conduct, behaviour, diet and these of specific restorative remedies. This process should begin inate adult life or midlife, and may not be effective when startedoo late as many of the approaches are preventive rather thanurative. Some rasayana recipes directly refer to dementia. It is

uite remarkable that an ancient medical system includes suchwell-elaborated medical theory and treatment for age relatedroblems like dementia, whilst contemporary systems attributednexplicable phenomena to the spiritual realm.

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One preparation is called Aindrarasayana (Bala and Manyam,999). Aindri or Brahmi are names for Bacopa monniera, one ofix plants in the formula. The other five are Alternanthera ses-ilis (Amaranthaceae), Acorus calamus (Araceae), Piper longumPiperaceae), Convolvulus pluricaulis (Convolvulaceae) and onelant with the Sanskrit name Brahmasuvarcala, which was notdentified. Three parts of Aindrarasayana including the salt andwo parts of gold oxide are mixed with Aconitum chasmanthumRanunculaceae). The mixture is consumed on an empty stom-ch. Several hours later, when the preparation is digested, honeynd a generous amount of butterfat (ghee) should be consumed.

Another Ayurvedic formula consists of the juice of Cen-ella asiatica (Apiaceae), the powder of Glycyrrhiza glabraFabaceae) mixed with milk, the juice of the stem of Tinosporaordifolia (Menispermaceae) and a paste made of the rootsnd flowers of Convolvulus pluricaulis (Convolvulaceae) mixedogether and taken to prevent dementia, retard age and to improveomplexion and digestion (Bala and Manyam, 1999).

Emblica officinalis (Euphorbiaceae) is a native plant withasayana properties and the main ingredient in this preparationor a disease-free life with long lasting youth, great vigour ando dementia. Terminalia officinalis, Acorus calamus, Embeliaibes, Sida spinosa, Semecarpus anacardium, Bacopa monnieri,ternanthera sessilis, Coelogyne evalis, Boerhaavia diffusa,esmodium gangeticum, Baliospermum montanum and Polyg-natum verticillatum are also added to the mixture. Six plantsith Sanskrit names are not identified but also part of the formula

Bala and Manyam, 1999).Another traditional recipe made is prepared with 1000 fruits

f Emblica officinalis (Euphorbiaceae) and 1000 fruits of Piperongum (Piperaceae). They are dipped in alkaline water preparedrom a Butea monosperma (Fabaceae) tree, and then powdered.he powder is mixed four times its weight with honey and ghee,nd one-fourth of sugar and stored underground for 6 months.he preparation should be taken life-long from new moon to

ull moon starting later in youth or middle age. The dose isased on the person’s individual digestive ability. This remedys optimistically recommended for a lifespan of 100 years withull vigour, cognitive function and to preserve youth (Bala and

anyam, 1999).Withania somnifera (Solanaceae) roots are one of the most

ighly regarded herbs in Ayurvedic medicine and of similar sta-us of ginseng in TCM. They are classed among the Rasayanasejuvenating tonics used for treating age associated decline inognitive function (Parrotta, 2001).

Steroid lactones such as withanolides A-Y, glycowithano-ides, dehydrowithanolide-R, withasomniferin-A, withasomi-ienone, withasomniferols A-C, withaferin A, withanoneave been isolated from the root and leaf (Williamson,002). The phytosterols, sitoindosides VII–X and perpetual �-itosterol were found, alongside the alkaloids ashwagandhine,shwaghandhinine, cuscohygrine, anahygrine, tropine, pseu-otropine, anaferine, isopelletierine, withasomine, visamine,

omniferine, somniferinine, withanine, withaninine, pseu-owithaninine and solasodine.

There have been numerous studies regarding the cognitivenhancing activities of Withania somnifera. Withanoside IV or

stTo

I produced dendritic outgrowth in normal cortical neurons ofsolated rat cells, whereas axonal outgrowth was observed inhe treatment with withanolide A in normal cortical neuronsTohda et al., 2005). Neuritic regeneration or synaptic recon-truction was induced by withanolide A, withanoside IV andI in amyloid-� (25–35)-induced damaged cortical neurons. In

ddition, these components also facilitated the reconstruction ofost-synaptic and pre-synaptic regions in neurons, where severeynaptic loss had already occurred.

Withania somnifera extract, containing the steroidal sub-tances sitoinodosides VII–X and withaferin A augmentedearning acquisition and memory in both young and old ratsGhosal et al., 1989). It enhanced AChE activity in the lateraleptum and globus pallidus and decreased it in the vertical diag-nal band. Receptor binding on the muscarinic M1 receptor wasnhanced in the lateral and medium septum and in the frontal cor-ices. M2 receptor binding increased in cortical regions but dideither affect �-aminobutyric acid (GABAA), benzodiazepine,or NMDA receptor binding. The extract reversed ibotenic acidnduced cognitive deficit and reversed the reduction in choliner-ic markers, such as acetylcholine (Schliebs et al., 1997).

Acorus calamus is originally native to Europe, but has beenultivated and naturalized throughout India and Sri Lanka.ala et al. (1993) list the plant with traditional uses as an

ntellect-promoting agent against depression, mental disordersnd general debility. Acorus calamus is also combined witholygala root to help maintain mental and intellectual healthf the elderly (Hou and Jin, 2005). When powdered, it can be ofvail for depressed psychosis and dementia. Further indicationsnclude the loss of consciousness, confusion of the mind, for-etfulness, anorexia and epilepsy and as a traditional Ayurvedicedicine to treat memory loss (Howes and Houghton, 2003).Acorus calamus contains essential oil with the main com-

onents �-asarone and �-asarone. Other components found inhe plant are caryophyllene, �-humulene and sekishone (Hound Jin, 2005). Methanolic extracts of the roots, which containssential oil which the toxin �-asarone showed inhibitory effectn AChE with an IC50 value of 188 �g/ml (Oh et al., 2004).n vitro and in vivo studies have shown Acorus calamus oil tonduce malignant tumours, due to �-asarone. In view of toxicity,roducts should contain no or a negligible amount of �-asarone,uch as that from the Acorus calamus var. americanus (Singht al., 2001). In mice, the root extract of Acorus calamus pro-ected against acrylamide-induced neurotoxicity and reducedhe incidence of paralysis (Shukla et al., 2002). Acorus cala-us is registered in the Pakistani Materia Medica where both

he roots and rhizomes are used for nervous diseases and dis-rders, whereas the rhizome is especially indicated in cases ofeurological symptoms of the brain (Said and Ahmad, 1986).

The seeds of Celastrus paniculatus (Celastraceae) are cred-ted with emetic, diaphoretic, febrifugal and nerve benefitingroperties and are used in traditional Indian medicine to sharpenhe memory, to cure ulcers, gout, sores and rheumatism. The

eeds and the seed oil are used as a brain tonic, for diseases ofhe CNS, epilepsy, oedema, stomach disorders and psychosis.he leaves, roots and bark do not have indications related to ADr dementia, so most in vivo and in vitro pharmacological stud-

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es have focused on seeds and the seed oil (Parrotta, 2001). Inats the oil helped improve learning and memory, and decreasedoradrenalin, dopamine and serotonin in the brain (Nalini et al.,995). It reversed scopolamine induced task deficit but this wasot associated with an AChE inhibition (Gattu et al., 1997). Forore pharmacological information see Howes and Houghton

2003).Traditional indications were found for Convolvulus pluri-

aulis (Convolvulaceae), a plant common in southern India,here the whole plant is used in various formulae as a nervine

onic for improvement of memory and intellect. The leaves andowers possess hypotensive properties used for treating anxietyeurosis. Furthermore, it is also recommended as a brain tonico promote intellect and memory, eliminate nervous disordersnd to treat hypertension (Bala and Manyam, 1999).

The bark, leaves, flowers, fruits and pods of Sesbania gran-iflora (Fabaceae) are used in Ayurvedic medicine. The podsre considered useful for promoting memory power and foresolving glandular tumours or enlargements (Parrotta, 2001).anscora decusata (Gentianaceae) is a notable Ayurvedic drug

or improving memory and intellect. A paste is made of thehole plant, including the flowers, to be taken with milk asnervine tonic and to alleviate memory problems (Parrotta,

001). Gmelina arborea (Verbenaceae) is used in Ayurvedicedicine to improve digestion, strengthen memory, to overcome

iddiness and to treat fever, thirst, emaciation, heart diseasesnd nervous disorders (Parrotta, 2001). The ripe fruit of Ter-inalia chebula (Combretaceae) is considered to possess the

bility to promote memory, intellect and to prolong life. Its also believed to improve eyesight and has the ability toelay aging. It is suggested that one ripe fruit should be eatenvery morning to achieve the listed effects (Vohra and Gupta,005).

Nardostachys jatamansi (Valerianaceae) is a reputed medhya,n intellect-promoting herb, with various medicinal properties,specially on the nervous system (Joshi and Parle, 2006). Aecent study was undertaken to determine the effect of Nar-ostachys jatamansi as a memory enhancer in mice. An elevatedlus maze and a passive avoidance task were employed to eval-ate learning and memory parameters. An ethanolic extract ofhe plant was administered orally for at doses of 50, 100 and00 mg/kg. Furthermore, diazepam and scopolamine inducedmnesia as well as aging induced amnesia was examined. Theigh dose of 200 mg/kg dose significantly improved learning andemory in young mice and also reversed amnesia induced by

copolamine and diazepam. It was also claimed to have reversedmnesia due to natural aging of mice (Joshi and Parle, 2006).

Bacopa monnieri L. (syn.: B. monniera) (Scrophulariaceae)ccupies a predominant position in ayurvedic medicine ands recommended for the management of a range of mentalonditions including anxiety, poor cognition and a lack of con-entration (Russo and Borelli, 2005), as a nerve tonic, foremory and intelligence improvement (Parrotta, 2001) for an

ntellect promoting effect and helpful in cases of general debilitySala et al., 1993). Russo and Borelli (2005) recently providedn update of current knowledge of nootropic effects of Bacopaonnieri.

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The effects Bacopa monnieri (40 mg/kg) on learning per-ormance in rats were studied in shock-motivated brightnessiscrimination reaction and in conditioned fight reaction. Inoth schedules the treated groups showed a shorter reaction timehan the control group. In addition, the rats improved learningapability confirmed by a maze-learning experimental methodWilliamson, 2002).

Major chemical constituents found in Bacopa monnieri areaponins, triterpenes and dammaranes, such as bacosides A,, C, bacosaponines D, E and F (Williamson, 2002; Russond Borelli, 2005). The alkaloids brahmine and herpestine,avonoids such as glucuronyl-7-apigenin and glucuronyl--luteolin, luteolin-7-glucoside and luteolin, phenylethanoidlycosides, monnierasides I–III and plantainoside B have beensolated.

The saponins bacoside A and B have been claimed to behe active principles regarding enhancement of cognitive func-ion (Singh and Dhawan, 1992; Russo and Borelli, 2005). They,part from facilitating learning and memory in normal rats,nhibited the amnesic effects of scopolamine, electroshock andmmobilization stress. Furthermore, Bacopa monnieri has beenhown to enhance protein kinase activity in the hippocam-us, which could also contribute to its nootropic action. Whenacopa monnieri was administered along with phenytoin for 2eeks, it significantly reversed phenytoin-induced impairment

n rats (Williamson, 2002). Bacopa monnieri, administered forweeks, reversed the depletion of acetylcholine. Further, it

educed the choline acetylase activity and decreased muscarinic,holinergic receptor binding in the frontal cortex and hippocam-us, induced by neurotoxins, such as colchicine (Russo andorelli, 2005).

In a double blind placebo-controlled trial 76 participants,ged 40–65, received capsules of Bacopa monnieri extractquivalent to 6–9 g of dried rhizome. Effects on anxiety andemory functions were tested. The results did not show any

ignificant effect on measures of short-term memory, workingemory, attention, or the retrieval of information from long-termemory acquired pre-experimentally. No effects on subjec-

ive measures of psychological state as depression, anxiety andtress, or everyday memory were observed. There was, how-ver, an activity measured in a task requiring the retention ofew information, recalling unrelated word pairs after a shortelay (Roodenrys et al., 2002).

The medicinal value of Centella asiatica (Apiaceae) ishought to be similar to that of Bacopa monnieri. The wholelant is used as a nervine tonic in various brain diseases andiven to children as syrup to increase the memory. It is thoughto be effective for memory disorders, impaired intelligence ands a rejuvenator and blood purifier. It is used in various skiniseases. In parts of India it is given with milk to improveemory against dementia and aging (Ahuja, 1965). Con-

tituents in Centella asiatica include essential oil, triterpenoidaponins, such as asiaticocide, brahmoside and thankuniside,

lkaloids (hydrocotyline) and some bitter principles (Chevallier,996).

Mook-Jung et al. (1999) tested articoside and 28 deriva-ives for protective effects against A �-induced cell death in

Table 6Plants used in Asia in the context of age related CNS disorders

Origin Plant Family Traditional use References

China Qingkailing (QKL)Isatis tinctoria L. Brassicaceae QKL is not mentioned as ‘traditional’: Studies suggest that the most

frequent causes of dementia associated with stroke are heat, phlegm andblood stasis syndromes. Treatment should re-establish the energybalance and remove the causes. QKL resolves phlegm and clears the heat

Jinzhoun (1998)Lonicera sp. CaprifoliaceaePittosporum sp. PittosporaceaeScutellaria sp. cow-bezoar LamiaceaeCoptis chinensis Franch. Ranunculaceae For several conditions including age related

cognitive and memory declineHoughton and Howes (2005)

Huperzia serrata Thunb. Lycopodiaceae Huperzine A is found to be an active cognitionenhancer that faciliates memory and motoractivity in aged persons

Kee (1999)

Qian Ceng Ta is a traditional Chinese formulato alleviate problems of memory loss. Theformula is prepared from Huperzia serrata

Howes et al. (2003)

Huperzia serrata has been used and is still acomponent of various formulae in traditionalChinese medicine to alleviate problems ofmemory loss, fever, inflammation and forsymtomps of aging

Ott and Owens (1998),Chiu and Zhang (2000),Anekonda and Reddy (2005),Houghton and Howes (2005),Frank and Gupta (2005) andHoughton et al. (2006)

Polygala tenuifolia Willd. Polygalaceae Effect upon the will and mental powers,improving understanding and strengthening thememory

Howes and Houghton (2003)

Korea Paeng-Jo-Yeon-Nyeon- Baek-Ja-In-Hwa (PJBH)Acorus calamus L. Acoraceae According to ancient Chinese medicinal

literature PJBH supplies and nourishes thekidney and consolidates essence, thusactivating brain function, promoting memoryand lengthening life span. PJBH has anextensive history as a medicinal herb inKorea, and it is possible that widespreadPJBH use may contribute to the reducedage-adjusted prevalence of AD in Korea

Koo et al. (2004)Alisma canaliculatum A.Br. and Bouche AlismataceaeAsparagus cochinchinensis (Lour.) Merr. AsparagaceaeCinnamomum cassia Blum. LauraceaeCornus officinalis L. CornaceaeCistanche salsa C. A. Mey. OrobanchaceaeDioscorea japonica Thunb. DioscoraceaeDendrobium moniliforme (L.) Sw. OrchidaceaeEucommia ulmoides Oliv. EucommiaceaeMorinda officinalis How. RubiaceaePanax ginseng C. A. Mey. AraliaceaePhlomis umbrosa Turc. Bull LamiaceaePolygala tenuifolia Willd. PolygalaceaeRehmannia glutinosa Gaertn. GesneriaceaeRubus coreanus Miq. RosaceaeSchizandra chinensis L. SchisandraceaeThuja orientalis (L.) Franco

Torilis japonica (Houtt.)Cupressaceae;Apiaceae

Table 6 ( Continued )

Origin Plant Family Traditional use References

Japan (Kampo) Choto-sanGypsum fibrosum Sulphate mineral The Choto-san formula is usually prescribed

to middle-age patients of considerable buildwith a weak physical constitution as well asfor chronic headache, painful tension of theshoulders and cervical muscle, vertigo,morning headaches, a heavy feeling of thehead, feelings of uprising heat, tinnitus andinsomnia

Murakami et al. (2005)Chrysanthmum sp. AsteraceaeCitrus aurantium L. RutaceaeGlycyrrhiza glabbra L. FabaceaLedebouriella seseloides (Hoffm.) Wolff. ApiaceaeOphiopogon japonicus Thunb. ConvallariaceaePanax ginseng C. A. Mey. AraliaceaePinellia ternata Thunb. AraceaePoria cocos (Schw.) Wolff PolyporaceaeUncaria tomentosa Willd. RubiaceaeZingiberis officinalis L. Zingiberaceae

India (ayurveda) AindrarasayanaAcorus calamus L. Araceae This preparation is considered to alleviate

dementiaBala and Manyam, 1999

Alternanthera sessilis (L.) R. Br. AmaranthaceaeBacopa monnieri (L). Pennell ScrophulariaceaeConvolvulus pluricaulis Choisy ConvolvulaceaePiper longum L. PiperaceaeCentella asiatica (L.) Urban Apiaceae This recipe is believed to prevent dementia,

improve digestion and complexionBala and Manyam (1999)

Convolvulus pluricaulis Choisy ConvolvulaceaeGlycyrrhiza glabra L. Fabaceae;

MenispermaceaeTinospora cordifolia Miers

BrahmarasayanaAcorus calamus L. Araceae The fruits of Embilica officinalis are

steamend to remove the seeds, dried andpowdered. The powder is mixed with thejuice of fresh Embilica fruit and mixed withthe other 17 plants. It is then mixed with thejuice of the fruits of Sida spinosa, dried, andghee and honey are added. It is stored inboluses in a vessel underground surroundedby hemp ashes for 2 weeks. Beforeadministration, oxide of gold, silver, copperand iron are added. Brahmarasayana isthought to create a disease-free, youthfulstate and significant vigor and no dementia

Bala and Manyam (1999)Alternanthera sessilis (L.) R. Br. AmaranthaceaeBacopa monnieri (L.) Pennell SchrophulariaceaeBaliospermum montanum (Willd.) EuphorbiaceaeBoerhavia diffusa L. NyctaginaceaeCoelogyne evalis Lindl. OrchidaceaeEmblica officinalis Gaertn. EuphorbiaceaeDesmodium gangeticum (L.) DC. FabaceaeEmbelia ribes (Roxb. ex. Willd.) DC. MyrsinaceaePolygonatum verticillatum (L.) All. LiliaceaeTerminalia chebula Retz. CombretaceaeSida spinosa L. MalvaceaeSemecarpus anacardium L. fil. AnacardiaceaeButea monosperma (Lam.) Taub Fabaceae The formula is recommended for a life span

of 100 years, to preserve youth, full vigorand cognitive function

Bala and Manyam (1999)Emblica officinalis Gaertn. EuphorbiaceaePiper longum L. PiperaceaeAcorus calamus L. Araceae The plant is said to be capable of improving

memory and intellect, treats various diseasesincluding epilepsy and mental ailments

Parrotta (2001)

Withania somnifera (L.) Dun. Solanaceae Withania somnifera is used in cases of debilityfrom old age

Ahuja (1965)

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103 cells. Hereby asiatic acid showed the strongest protec-ive effect reducing H2O2-induced cell death and loweringntracellular free radical concentration. The triterpene asi-tic acid and its derivatives have been also been shown torotect cortical neurons from glutamate-induced excitotoxic-ty in vitro. Glutamate can induce neuronal degeneration byver-stimulation of NMDA receptors. Some NMDA receptorntagonists like memantine (NamendaTM), have been approvedy the U.S. Food and Drug Administration (FDA) for the treat-ent of moderate to severe AD (Farlow, 2004). Rao et al.

2005) showed that treatment of mice during postnatal devel-pment with Centella asiatica extracts influences the neuronalorphology and promotes higher brain function later on in

ife.Centella asiatica extract (100, 200 and 300 mg/kg) showed a

ose-dependent protective effect against cognitive deficits andxidative stress in rats. The results indicated improved acqui-ition and retention of memory. No significant changes werebserved in the locomotive activity. The rats were sacrificed onay 21 for estimation of oxidative stress parameters as malondi-ldehyde (MDA), a marker of lipid peroxidation, SOD, GSH-Pxnd CAT. A decrease in MDA and an increase in GSH-Px levelsere observed in rats treated with the rather high doses of 200r 300 mg/kg extract (Kumar and Gupta, 2003).

In Thailand the leaves of Michelia champaca (Magno-iaceae), a tree valued for its strongly fragrant yellow orhite flowers, are used in the treatment of brain disorders

Clayton et al., 1994). Michelia champaca contains essential oil,arthenolide and other sesquiterpene lactones (Jacobsson et al.,995).

Two plants were mentioned in the viewed literature on Viet-amese medicine for treating age related dementia (Agence deooperation Culturelle et Technique, 1990a,b). Acanthopanax

rifoliatus (Araliaceae) is used as a stimulant and tonic ands believed to ameliorate the memory. Some of the chemi-al constituents of the leaves of Acanthopanax trifoliatus havere kaur-16-en-19-oic acid, taraxerol, taraxerol acetate (Du andao, 1992), lupane-triterpene carboxylic acids, called acantri-

oic acid and acantrifoside (Kiem et al., 2004). Dimocarpusongan (Sapindaceae), the source of the delicious longan fruits,s used as a tonic and administered in the treatment for men-al deficiency, neurasthenia, insomnia and amnesia (Agence deooperation Culturelle et Technique, 1990a,b). It could not beetermined what part of this widespread plant is used.

In Malaysia Casuarina equisetifolia (Casuarinaceae) aidespread shrub or tree which somewhat resembles pine trees,

s used as a sedative for the demented and to treat memoryroblems (Woodley, 1991).

In Tibet Iris germanica (Iridaceae) is believed to be a pro-oter of intellect and also useful in the treatment of insanity,

pilepsy and against evil spirits (Dash, 1994). Centella asiaticalready listed in the part on India is also used in Tibet as a pro-oter of memory and voice and is believed to be rejuvenating

n general. Another remedy, believed to prevent aging is ghee, aorm of melted butterfat which is said to promote complexion,eauty, voice, intellect, memory and give strength, virility andongevity (Dash, 1994) (Table 6).

7

lagtTd(oatsaatirtdssgaaaoao

Easa1ptmTwac1tp

cb(a

otbMm

stgSvwM(smwrt

Fmoasdahaoclitp

A

GDB

A

i

R

A

A

A

. Conclusions and perspectives

Despite the access to a large ethnobotanic florilegium inibraries and databases, the yield in numbers of herbs used forge related dementia turned out to be rather limited for most geo-raphic regions. Various reasons may be responsible for that: Onhe one side, it can be due to cultural reasons. Both Ayurveda andCM have clear millennia-old concepts of age related cognitiveisorders and corresponding treatments with specific remediesYan et al., 2000), whereas folk medicines mostly lack this kindf foundation. Memory loss, confusion and forgetfulness in oldge are fatalistically accepted as inevitable part of life, or often-imes dementia is attributed to madness caused by spiritual andupernatural causes. Also, dementias are diseases which occurt an advanced age which was rarely reached in countries withlow life expectancy. On the other hand, there may also be

he difficulty of gathering and reporting data, i.e. in translat-ng traditional concepts into scientific terminology. Also, dataecording may not have been optimal from today’s perspec-ive. Indeed, the interest of Western medicine in Alzheimer’sisease is a relatively recent phenomenon. Our awareness hasubstantially increased over the past 20 years, due to significantcientific progress in the understanding of the disease and therowing socioeconomic issue for our ageing societies. Before,ge-related loss of cognitive function was largely considered asnatural phenomenon. Thus, the literature may possibly be neg-tively biased in the sense that many of the ethnobotanical booksriginate from a period where ethnobotanists probably paid lessttention to information concerning treatments for cognitive dis-rders.

Quite a number of traditionally used medicines were found inuropean herbals from the 16th and 17th Century, despite the rel-tively small number of available references. These herbals wereometimes printed in a number of languages, many of whichre even available as reprints nowadays (Fuchs, 1543; Pomet,717). They formed the basis for what evolved into modern dayharmacopoeias. However, a major part of what was known tohe antique and medieval world probably was lost in the early

iddle ages or has not yet been analyzed by modern science.his can be concluded from some documents long thought lost,hich have only recently resurfaced. For example, a medieval

ccount of 412 plants from the late 14th Century was redis-overed in the university library in Basel, Switzerland (Pfister,961). Unfortunately, these treasures still await their transla-ion and scientific analysis due to lack of funding and qualifiedhilologists.

Quite a number remedies for the treatment of age relatedognitive disorders were recorded for the Amazonian regiony the father of modern ethnobotany, Richard Evans SchultesSchultes, 1993a,b), who spent many years living with nativesnd studying their medicinal herbs.

A small selection of herbs traditionally used for CNS dis-rders have been evaluated pharmacologically and regarding

heir active constituents in terms our modern understanding ofrain functions, but so far very little clinical data is available.any prescriptions that claim to prevent or restore cognitive andemory deficits have not shown any actions in established test

A

A

ystems. Research for new potential drugs, however, is restrictedo the pathways known or assumed to be included in the pro-ression of AD, which are frequently based on AChE inhibition.everal traditional remedies have demonstrated interesting initro and in vivo activities and provided promising componentsith potential as therapeutics for neurodegenerative disorders.ost in vitro studies have focussed on inhibition of AChE

Houghton et al., 2006; Mukherjee et al., 2007), because this haso far been the most promising clinical approach for the treat-ent of AD. For some compounds, clinical data is very limitedhile others such as galanthamine and huperzine A have already

eached widespread clinical use and contribute a great effort inhe combat of AD.

To date the pathophysiology of AD is not yet nearly clarified.urther research will provide better understanding of theolecular pathways involved and hereby lead to the devel-

pment of additional pharmacological test systems, in whichctivities may yet be observed. Also, some traditional medicalystems such as Ayurveda emphasize health maintenance andisease prevention over curative treatments. Hence, preclinicalnd clinical research into protective and preventive effects oferbals drugs should be carried out in the future. Interestingly,large study conducted with Ginkgo extract EGb761 in Francever 7 years suggested a preventive effect in an aged populationohort (Andrieu et al., 2003). On the basis of this study, twoarge interventional studies have been initiated in the USA andn France (Christen, 2004). The outcome of these long-termrials will be important in defining a possible role of naturalroduct based preventive therapy in AD.

cknowledgements

Thanks are due to Prof. K. Hostettmann, University ofeneva, for providing access to ethnobotanical literature, and tor. M. Kessler and M. Kluge, Swiss Pharmaceutical Museum,asel, for assistance, valuable information and access to herbals.

ppendix A. Supplementary data

Supplementary data associated with this article can be found,n the online version, at doi:10.1016/j.jep.2007.07.016.

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