Plants traditionally used in age related brain disordersA survey of ethnobotanical literature

Michael Adams, Francine Gm nder, Matthias Hamburger u

Institute of Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland

Abstract In traditional herbal medicine, numerous plants have been used to treat age related cognitive disorders. In this review we compiled available literature from four Swiss university libraries, scientic journals and online database querys on plants and remedies used in traditional medicinal systems for such diseases. Over 150 plant species in various preparations and mixtures were found. European herbals from the 16th and 17th century alongside traditional Chinese and Indian medicinal works were the most prolic sources. The information is organised into geographic regions and when available the ndings are discussed in the light of more recent scientic ndings concerning their secondary metabolites and in vitro and in vivo activities relevant to dementia and Alzheimers disease.
Keywords: Ethnomedicine; Traditional medicine; Herbal remedies; Alzheimers disease; Senile dementia

Contents
1. 2. 3. 4. 5. 6. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Literature search and organisation of information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Americas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Traditional Chinese medicine (TCM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Korea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Ayurveda. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 364 364 366 369 370 370 372 372 372 378 378 378 378

7.

1. Introduction The occurrence of dementia and age related brain disorders is dramatically on the rise as life expectancy likewise increases. Alzheimers disease (AD), a complex, multifactoral, progressive, neurodegenerative disease primarily affecting the elderly population is estimated to account for 5060% of dementia cases in persons over 65 years of age. According to the World

Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; APP, amyloid precursor protein; BuChE, butyrylcholinesterase; ChAT, choline acetyltransferase; GABA, gamma aminobutyric acid; NMDA, N-methyl-d-aspartate; PKC, 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).

Health Organisation (WHO, 2006), around 35 million people in industrialized countries will suffer from AD by 2010. The disease is characterized by loss of memory and impairment of multiple cognitive and emotional functions (Frank and Gupta, 2005). The pathological features identied in the central nervous system (CNS) in AD are amyloid plaques, neurobrillary tangles, inammatory processes and disturbance of neurotransmitters (Selkoe, 2001; Bossy-Wetzel et al., 2004). Basically brain cells wither away and die, causing disorientation, dementia and severe changes in personality and social interactions. There is currently no cure for most forms of dementia including AD. Pharmacotherapy is focussed on symptomatic benet and slowing disease progression (Desai and Grossberg, 2005), but a number of possible disease modifying and preventive strategies based on current understanding of AD pathophysiology are under investigation (Citron, 2004; Selkoe, 2005). Before the development of modern medicine people relied on a large arsenal of natural remedies for the treatment of CNS related maladies. In western societies, here has been increasing interest in herbal medicines, which are often perceived as a more natural and soft treatments compared to synthetic drugs. Successful treatments for dementia have been developed from herbal drugs. Extracts from Ginkgo biloba (mainly EGb 761a standardised extract marketed by Wilmar Schwabe GmbH) have been proven effective in clinical trials as a treatment for Alzheimer type dementia and vascular dementia (Gertz and Kiefer, 2004). Ginkgo extracts also has a favourable safety prole (Andrieu et al., 2003; Stromgaard et al., 2005). Galantamine, an alkaloid obtained from the bulbs and owers of the Caucasian snowdrop Galanthus woronowii (Amaryllidaceae) (Heinrich and Teoh, 2004), is a ne example of a plant secondary compound successfully used for the treatment of mild to moderate AD (Bullock and Dengiz, 2005; Marco-Contelles et al., 2006). Several milestones in the history of drug therapy have been discovered from ethnomedical knowledge, such as atropine, pilocarpine, cardiac glycosides, curare, and reserpine. Sourcing in ethnomedical information may also be useful as a starting point for the discovery of new drugs for the treatment of AD and cognitive disorders. Here we have compiled literature available from seven libraries and recent literature of scientic journals from online database searches. 2. Literature search and organisation of information The four main Swiss university libraries in Berne, Basel, Zurich, and Geneva were searched for relevant ethnobotanical literature. Furthermore, the Library of the Museum of Cultures (Museum der Kulturen), of a third world project, Mission 21 and the Swiss Pharmaceutical Museum, all three in Basel, were also at our disposal. Suitable books of potential literature sources were identied in online databases of the particular libraries by searching for the terms ethno medicine, traditional medicine, folk medicine, indigenous medicine, herbs, traditional herbs, plants, indigenous plants, ethno botany and botanical medicine. The search was further rened by checking the titles of retrieved books. Finally, a total of 192 books were consulted. Information was searched for by scanning the indices of books for keywords

related to the topic. For books lacking an index, the tables of contents and list of plants were scanned through. Of these 192 books, 140 contained no specic listings for certain plants used in the treatment of age related brain disorders. They are nevertheless listed separately as Supplementary information. The relevant remainder of this collection was carefully viewed, information extracted and corroborated with data from other sources to compile this survey. Two electronic sources, the online databases PubMed and Scinder, were used to search for additional information in journals. Linguistic constraints limited us to literature in English, Italian, French, German and Spanish. The terms ethno medicine, traditional medicine, folk medicine, indigenous medicine, herbs, traditional herbs, plants, indigenous plants, ethno botany and botanical medicine were combined with terms like Alzheimer, Alzheimers disease, used to treat Alzheimers disease, dementia, senile dementia, and memory loss. Plants and herbal combinations traditionally used for the treatment of age related brain diseases are listed according to geographic regions. 3. Europe Europe is the birthplace of modern western rational medicine. With the industrialization came the development of modern synthetic drugs, medicinal equipment and health care institutions such as hospitals or nursing homes. Yet the continent has long traditions of phytotherapy dating back thousands of years. Especially in the German speaking world herbal remedies still play an important role and any pharmacy will provide and produce a large number of plant based medicines (Reuter, 1991). Today, many traditional medical practices in Europe are summarized by the popular terms alternative or complementary medicine. In widespread understanding these terms also include more recent techniques such as homeopathy, spagyrik, dance or music therapy, acupuncture, etc. Tabernaemontanus (1687) recommended sage, Salvia sp., from various regional provenances for the treatment of a weak brain. Flowers should be crushed and mixed with sugar. Or the plant can be extracted in strong wine in the sun for a day before distilling. The remedies help those who shiver and suffer the effects stroke and strengthen weak minds and memories. Most pharmacological research on Salvia has been done with the essential oils of Salvia ofcinalis and Salvia lavendulifolia, and a number of promising pharmacological results have been published. Since Perry et al. (2000, 2003) recently provided a review, summarizing available literature on the use of Salvia species in dementia therapy, this plant will only be treated briey. Savelev et al. (2004) examined the inhibition of the butyrylcholinesterase (BuChE) by essential oils from Salvia fruticosa, Salvia ofcinalis var. purpurea, Salvia ofcinalis and Salvia lavendulaefolia. The IC50 values measured after 5 min of incubation were 0.05, 0.4, 0.03, 0.07 and 0.0.3 mg/ml, respectively. Additionally pure compounds from the oil were tested, none of which could fully account for the activity of the essential oils. Salvia lavandulaefolia and Salvia ofcinalis purpurea oils had apparent dual cholinergic activity, as they were active on both, AChE and BuChE (Savelev et al., 2004). Besides the choliner-

gic activity, there has already been a wider range of activities reported for the genus Salvia, which may be relevant for CNS disorders. These include nicotinic activity (Wake et al., 2000), anti-inammatory properties (Moretti et al., 1997), antioxidant (Zupko et al., 2001), estrogenic (Bartram, 1995) and glutamergic activities (Kuang and Xiang, 1994). In a double blind, randomized, placebo-controlled trial, with 39 patients, Akhondzadeh et al. (2003) assessed the efcacy and safety of Salvia ofcinalis extract in patients with mild to moderate AD. The participants experienced statistically signicant benets in cognition after 16 weeks of treatment. Despite the limitations of this study, a small number of patients and a relatively short period of follow-up, this initial clinical data suggests that Salvia lavandulaefolia essential oil and extracts, may have potential for treatment of AD and memory related disorders. Salvia spp. leaves contain tannins, tannosetonins and essential oil. The essential oil content of 12% varies within the plant and location. The components of the essential oil vary in the different Salvia species (Savelev et al., 2004). The oil of Salvia ofcinalis is rich in -caryophyllene (23.2%), camphor (11.0%) and borneol (8.7%), while, camphor, 1,8-cineole and 2-carene are abundant in the oil of Salvia lavendulaefolia (Skas, 1980). Aerial parts of lemon balm, Melissa ofcinalis (Lamiaceae) are nely cut and covered in good wine over night in a clean dish, before being distilled. Taken on an empty stomach a spoonful quickens the senses, brightens the mind and improves memory. It aides shaking limbs caused by stroke, and helps retrieve the lost ability to speak (Lonicerus, 1679). The remainder of this historic citation is a romantic description of clever bees sucking at the owers. Essential oil of Melissa ofcinalis, which contains monoterpenes such as citral and citronellal (Mills, 1993), shows a dose-dependent inhibitory effect on the enzyme AChE, with IC50 values of less than 0.1 l/ml (Perry et al., 1996). Lonicerus (1679) reports that dried parsley roots (Petroselinum crispum, Apiaceae) soaked in good wine can improve brain function and memory, alongside their then more widespread uses as an abortifacient, aiding birth labour and weaning. Galbanum, a resin from the roots of Ferula gummosa (Apiaceae) and its subspecies and varieties should be crushed, hot water added and left overnight. Then essential oil is distilled here from. The oil can be applied to the neck or drunk for improving memory, hearing and sense of smell (Tabernaemontanus, 1687). The use of this plant, native to Syria and grown in herb gardens by European practitioners might have biblical roots, as it was part of incense in the tabernacle (Exodus 30, 3436). The owers of Caryophyllus species (Caryophyllaceae) are crushed with sugar so create a candy Confecta orum Caryophyllum which is consumed to treat fever, strengthen the brain and the memory. Cloves, the highly revered fruits of Syzygium aromaticum (Myrtaceae) were regarded as a similar plant and served as a remedy against weakness of the brain, stroke and loss of memory (Tabernaemontanus, 1687). Another non-native plant used in a confectum was the fruit of Anacardium orientale (Anacardiaceae). It was processed to a Confectio Sapientum a wisdom candy. Flowers of German chamomile, Matricaria recutita (Asteraceae) are soaked in water. A person

who drinks this at least 23 times a week and washes his feet in it should retain good memory (Tabernaemontanus, 1687). There are numerous recipes for various types of aquavit. Aquavits, literally water of life, are strong alcoholic beverages with very complex modes of preparation. Numerous such drinks, are still widely sold today for medical or recreational purposes. Only one such comprehensive recipe will exemplarily be described here, as further listings would exceed the scale of this review. Tabernaemontanus (1687) lists an aquavit which was claimed to be particularly useful in treating forgetful old people. Arial parts of Achillea millefolium (Asteraceae), Adiantum capillus-veneris (Pteridaceae), Horminum sp. (Lamiaceae), Eryngium caeruleum (Apiaceae), Foeniculum vulgare (Apiaceae), Petroselinum crispum (Apiaceae) and roots of Asparagus ofcinalis (Asparagaceae) and Cichorium endivia (Asteraceae) are extracted with good wine. This concoction is then distilled before cinnamon (Cinnamomum verum, Lauraceae), caraway (Carum carvi, Apiaceae), either lavender (Lavandula angustifolia, Lamiaceae) or valerian (Valeriana celtica, Valerianaceae), ginger (Zingiber ofcinale, Zingiberaceae) and pepper (Piper nigrum, Piperaceae) are added alongside more good red wine. Then the roots of greater galangal (Alpinia galanga, Zingiberaceae), lovage seeds (Levisticum ofcinale, Apiaceae), Caryophyllus sp. (Caryophyllaceae) seeds, nutmeg (Myristica fragrans, Myristicaceae) and nally Piper cubeba (Piperaceae) are placed in the concoction before it is left for 8 days and then again distilled. Finally, to complete the aquavit recipe musk and amber are added. This remedy should be mixed with wine and consumed regularly by old people to strengthen the head, brain and memory according to Tabernaemontanus (1687), who made a strong emphasis on the quality of wine used for its preparation. Half a spoonful of coriander, Coriandrum sativum (Apiaceae) seeds covered in a little sugar can be taken to strengthen head, brain and memory. If so much sugar was used to coat the seeds that they were as large as peas, then the remedy helped patients fall asleep (Tabernaemontanus, 1687). The owers of the Lilly of the Valley, Convallaria majalis (Convallariaceae) should be crushed with sugar to make a candy to treat fever and strengthen the brain, senses and memory (Tabernaemontanus, 1687). Actually two forms of the herb are described, of which one ts the description of Convallaria majalis, and the other one is said to be identical but for the fact that it blooms red. Herba Convalariae contains toxic cardenolides like convallatoxin, convallatoxol, lokundjosid and convallosid, as well as avanoids and saponins (Krenn et al., 1996). It has been used for heart insufciency, and was ofcially listed in the German pharmacopoeia. Herb from Euphrasia ofcinalis complex (Orobanchaceae, formerly included amongst the Scrophulariaceae) is traditionally used in many parts of Europe for ailments of the eyes. Tabernaemontanus (1687) states that the powdered herb, when taken in wine may cure a stupid brain and strengthens the head. It contains various iridoid glycosides, such as aucubin, catalpol and euphrosid, the lignan dehydrodiconiferylalcohol4 -d-glucoside, tannins and avanoids (Sticher and Salama, 1981).

To sharpen senses and memory wine containing marjoram, Origanum majorana (Lamiaceae) should be consumed. It strengthens the head and the inner organs (Tabernaemontanus, 1687). Powdered marjoram can be spread on the tongue to return lost speech and strengthen brain and memory. Snuffed it makes you sneeze and thereby cleanses the brain. In salt and vinegar it is said to help against scorpion bites and in wine it is a diuretic (Fuchs, 1543). Origanum majorana contains large amounts of essential oil consisting mainly of monoterpenes and some sesquiterpenes (Raghavan et al., 1997). Basil, Ocimum basilicum (Lamiaceae) strengthens the heart and head and dispels darkness from the eyes (Fuchs, 1543). Fuchs (1543) recommended smelling the very aromatic owers of Lavandula stoechas (Lamiaceae) in its various geographic forms to strengthen a stupid and dizzy brain. Tabernaemontanus (1687) cites Plinius in warning that ivy (Hedera helix, Araliaceae) should not be consumed because it makes one wrong in ones head and weakens the nerves. In 1978 Brndegaard reported on the traditional use of plants in Denmark, from the Middle Ages through to present times. Based on this, the genus Corydalis (Papaveraceae) was selected for the isolation of compounds and in vitro examinations, as it had been used in the treatment of memory dysfunction. Adsersen et al. (2005) showed that protoberberine and protopine-type alkaloids, common compounds in Corydalis species, are potent AChE inhibitors. The inhibition of the enzyme was examined, with methanolic and aqueous extracts of Corydalis species. Inhibition by methanolic extracts was generally higher than by the water extracts. Tuber- and herb-extracts were assayed at concentrations of 0.1, 0.05 and 0.025 mg/ml. With 92%, 83% and 77% for the methanolic tuber extract of Corydalis cava showed the best results compared to Corydalis intermedia, Corydalis solida and Corydalis solida ssp. slivenensis. Pure protopine had an IC50 value of 50 M (Adsersen et al., 2005). In a passive avoidance task test mice treated with protopine exhibited diminished scopolamine-induced dementia (Kim et al., 1999). Galanthamine is an alkaloid from Galanthus spp. and other Amaryllidaceae, such as Narcissus and Leucojum species. It is a selective and competitive AChE inhibitor. It has been approved and is successfully used as a treatment for AD in numorous countries. Wether or not galanthamine containing plants were traditionally used in Europe to treat dementia is not really clear (Heinrich and Teoh, 2004). It is appellative that a drug for the treatment of the most severe form of dementia was developed from the little snowdrop the rst sign of spring a symbol of regeneration in nature (Heinrich, 2005). Consistent with current aroma therapeutic applications of rosemary Rosmarinus ofcinalis (Lamiaceae) to improve memory, the ancient Greeks considered this herb a stimulator of the mind, in particular the memory. Indeed many early European writings refrain to rosemary to be a memory enhancer (see Perry et al., 1999, and citations therein). In a handwritten folk-medicinal document from the Diemtigtal valley in the Berner Oberland in Switzerland Artemisia absinthium L. (Asteraceae) together and chervil (Anthriscus cerefolium, Apiaceae) water a distilled beverage is recommended to improve memory (Personal communication M.

Kluge, Swiss Pharmaceutical Museum). Artemisia absinthium has a record of use against declining cognitive function (see Wake et al., 2000). An alcohol extract displaced nicotine from nicotine binding receptors (Perry et al., 1996; Wake et al., 2000). H dl et al. (2000) showed -thujon to have GABAA receptor o antagonist activity. These reports should be viewed with caution, considering the toxicity of absinthe, a strong alcoholic drink, which when abused, leads to hallucinations, sleeplessness, tremors, and convulsions, a syndrome known as absinthism. The monoterpene thujon is responsible for these effects (Olsen, 2000; Lachenmeier et al., 2006) (Table 1). 4. The Americas The meaning of the term medicine to Native Americans was quite different from that of Western societies. Illness was regarded as a disharmony or imbalance that may be directly related to spiritual causes, which may have natural, human or supernatural origins. A persons equilibrium can be lost as a result of grief, sadness, hatred or personal wrongdoing (Kavasch and Baar, 1999). The concept of healing is to determine what has to be rectied and to bring the person back into balance. Practices to draw people back into equilibrium, include rituals, sweat lodge rites of purication, spirit feasts, fumigation and smoke therapy, massage, prayers, blessings, incantations and herbals (Vogel, 1970). Despite the vast number of books and references on American Indian medicine and related topics, we only found a few references of plants used in the treatment of AD and related symptoms affecting the memory. One remedy, unknown from which tribe it originated, includes eight different plants: Clematis sp. (Ranunculaceae), Larrea tridentate (Zygophyllaceae), Oplopanax horridus (Araliaceae), Capsicum annuum (Solanaceae), Ginkgo biloba (Ginkgoaceae), Centella asiatica (Apiaceae), Chrysanthemum sp. (Asteraceae) and Rosmarinus ofcinalis (Lamiaceae). A blend of these herbs was administered to assist memory as well as for eczema, emphysema and asthma. It must be remarked that Centella asiatica and Ginkgo biloba are not native to North America but to Asia (Kavasch and Baar, 1999). A tincture of the roots of Lachnanthes tinctoria (Haemodoraceae) was prepared against typhus, pneumonia, various and severe forms of brain diseases, rheumatic wryneck and laryngeal cough. Unfortunately there was no specication given about the various and severe forms of brain diseases. Constituents of Lachnanthes tinctoria are glycosides, chelidonic acid and naphthalene derivatives, as well as phenylphenalenone pigments (Millspaugh, 1974). Nowadays, Lachnanthes tinctoria is a remedy known in homeopathy, amongst others, for pains for in the joints. Mexico is famous for the pre-Columbian Aztecs, whose sophisticated empire came to a dire end with the arrival of Spanish invaders. In 1571 King Philipp II of Spain commissioned a physician to document medicinal remedies used by the Aztecs. Tagetes lucida (Asteraceae) known to the Aztecs as yauhtli was a remedy for ailments such as fever, fear, dementia, lightening stroke and was also used as a diuretic (Ortiz de Montellano,

Table 1 Plants used in Europe in the context of age related CNS disorders Plant Anacardium orientale auct. ex Steud. Artemisia absinthium L. Caryophyllus spp. Convallaria majalis L. Coriandrum sativum L. Corydalis sp. Euphrasia ofcinalis complex Hayne Ferula gummosa Boiss. Matricaria recutita L. Melissa ofcinalis L. Lavendula stoechas L. Ocimum basilicum L. Origanum majorana Moench Peroselinum vulgare (Mill.) Nym. and A.W. Hill Rosmarinus ofcinalis L. Family Anacardiaceae Asteraceae Caryophyllaceae Convallariaceae Apiaceae Papaveraceae Orobanchaceae Apiaceae Asteraceae Lamiaceae Lamiaceae Lamiaceae Lamiaceae Apiaceae Lamiaceae Traditional use A Confectio Sapientuma wisdom candy Traditionally for lost or declining cognitive function Strengthen the brain and the memory A candy to treat fever and strengthen the brain, senses and memory Covered in a little sugar can be taken to strengthen head, brain and memory Several species used in folk medicine for treatment of memory dysfunction Powdered herb when taken in wine may cure a stupid brain and strengthens the brain Oil can be applied to the neck or drunk for improving memory Flowers soaked in water. Drunk and used to wash feet to retain good memory To sharpen the senses and improve memory, strenghtens the brain, clears the head To strengthen a stupid and dizzy brain. for abdominal cramps, upset stomach, nervous migraine, memory, strengthens the heart and head loss and forgetfulness To return lost speech and strengthen brain and memory, cleanses the brain Soaked in good wine can improve brain function and memory As a circulatory stimulant for improving concentration and memory. To stimulate the mind, in particular the memory. Used by herbalists and aromatherapists for memory problems Remedies help those who shiver and suffer the effects stroke and strengthen weak minds and memories, for a sensitive stomach, general debility, irregular menstruation and dementia Remedy against weakness of the brain, stroke and loss of memory This complex aqua vit is prepared stepwise by extraction and distillation of a large number of plants. The remedy should be mixed with wine and consumed regularly by old people to strengthen the head, brain and memory References Tabernaemontanus (1687) Howes et al. (2003) Tabernaemontanus (1687) Tabernaemontanus (1687) Tabernaemontanus (1687) Adsersen et al. (2005) Tabernaemontanus (1687) Tabernaemontanus (1687) Tabernaemontanus (1687) Lonicerus (1679), Perry et al. (1998) and Mills (1993) Tabernaemontanus (1687) Fuchs (1543) and Skas (1980) Fuchs (1543) Lonicerus (1679) Chevallier (1996), Perry et al. (1998) and Price and Price (1995) Tabernaemontanus (1687), Skas (1980), Savelev et al. (2004), Akhondzadeh et al. (2003) and Perry et al. (2003) Tabernaemontanus (1687) Tabernaemontanus (1687)

Salvia ofcinalis L.

Lamiaceae

Syzygium aromaticum (L.) Merrill and Perry Achillea millefolium L. Adiantum capillus-veneris L. Asparagus ofcinalis L. Carum carvi L. Caryophyllus sp. Cichorium endivia L. Cinnamomum verum J. S. Presl Eryngium caeruleum M. Bieb. Foeniculum vulgare Mill. Horminum sp. Lavandula angustifolia Mill. Levisticum ofcinale Koch Myristica fragrans Houtt. Petroselinum crispum (Mill.) Nym. and A.W. Hill Piper cubeba L. Valeriana celtica L. musk and amber are added

Myrtaceae Asteraceae Pteridaceae Asparagaceae Apiaceae Caryophyllaceae Asteraceae Lauraceae Apiaceae Apiaceae Lamiaceae Lamiaceae Apiaceae Myristicaceae Apiaceae Piperaceae Valerianaceae

1990). Originally, Tagetes lucida is native to Mexico, but was soon introduced to Europe as a decorative plant and a substitute for French tarragon. Campherole, tagetiin, tagetone and quercetagritin, avonol-gylcosides, quercetagenin, glucopyranoside, phenolic acids, propanoic acids, avonols, aromatic acids, methoxycoumarin were found to be present in the plant (Aquino et al., 2002). Nowadays cocoa is of great global signicance as good deal of the 3,000,000 tonnes produced each year (WHO, 2007) are

used to meet our craving desire for chocolate. Theobroma cacao (Sterculiaceae), however, was used by the Aztecs as medicine, where potions of ground bark and roots were used to treat stupor (Roeder, 1988). The chemical constituents of Theobroma cacao include sterols, coumarins, catechins, catechol, glycosides, galactosides, tannins, polyphenols, triglycerides, linoleic acids, and alkaloids including caffeine, theophylline, and theobromine, rutin, vitexin. The stimulating effects are most likely only due to caffeine, theophylline, and theobromine.

Table 2 Plants used in North America in the context of age related CNS disorders Plant Erythroxylum catuaba A.J. Silva Family Erythroxylaceae Traditional use It is used as aphrodisiac, stimulant of the CNS, for sexual impotence, general exhaustion, fatigue, poor memory and insomnia related to hypertension Native healers blend these herbs assisting memory, as well as for eczema, emphysema, asthma and other ailments of aging References Taylor (1998)

Capsicum annuum L. Centella asiatica (L.) Urban Chrysanthemum sp. Clematis sp. Ginkgo biloba L. Larrea tridentata (Sess et Moc.) Coville e Oplopanax horridus Sm. Mic. Rosmarinus ofcinalis L. Lachnanthes tinctoria Ell.

Solanaceae Apiaceae Asteraceae Ranunculaceae Ginkoaceae Zygophyllaceae Araliaceae Lamiaceae Haemodoraceae

Kavasch and Baar (1999)

A tincture of the roots was used against typhus and typhoid fevers, pneumonia, various and severe forms of brain diseases, rheumatic wryneck and laryngeal cough

Millspaugh (1974)

Today, in the United States, Medicago sativa (Fabaceae), alfalfa, is considered an invasive plant. In Mexico, it was believed to improve the memory, cure skin eruptions, kidney pain, cough, sore muscles and inammation. Triterpenes, saponins and sapogenins were identied in Medicago sativa (Finkler, 1985) (Table 2). Brugmansia candida (Solanaceae) was used by native El Salvadorian peoples in various cases of memory problems. Five to ten owers were used to make a decoction for one bottle. More than one cup had to be drunk, because the rst couple of cups would not be effective (Gonz lez Ayala, 1994). The genus a Brugmansia is known for toxic tropane alkaloids, so the remedy should be treated with necessary caution. A remedy reported from Guadeloupe was Lantana camara (Verbenaceae), used to medicate memory weakness and enhance intellect and cognition. Tea brewed from the leaves should be drunk before going to bed (M ller-Ebeling and R tsch, 1989). u a It is remarkable that this use of a globally spread toxic invasive plant should have an activity known merely in tiny Guadalupe. Lantana camara contains triterpenes such as the toxins lantaden A and B, essential oil, and sesquiterpenes. Ananas comosus, pineapple (Bromeliaceae) originally cultivated in Central and South America, is used for ailments of the CNS in South American traditional folk medicine. It was also administered for neurasthenia, melancholy, sadness and for weakness of memory (Wolters, 1994). Unfortunately, there was no detailed description about the exact region or tribes where it was used for this purpose. The best known bioactive com-

ponent of the Ananas sp. is the proteolytic enzyme bromelaine, which is responsible for the positive effects on digestion and has recently been advertised for rapid weight-loss. Highest contents of bromelaine occur in the stem and in the fruit. Considering the wide use and popularity of pineapple, astonishingly little is known about the phytochemistry of pineapple plants (Table 3). As in Europe, in Ecuadorian traditional medicine rosemary Rosmarinus ofcinalis is used in connection with AD and dementia, for general symptoms of old age, debility and fatigue. It was also applied for neuralgia, indigestion, pain of nervous origin, circulatory disorders and hypertension (CESA, 1992). CESA (1993), and De Barradas (1957), listed the leaves of Chenopodium ambrosioides (Chenopodiaceae) in the context of dementia symptoms. Its traditional indications include uses for headache, caries, toothache and memory. Lactuca sativa, lettuce (Asteraceae) is, according to Ecuadorian natives, supposed to help with insomnia and weak memory (Schweitzer de Palacios, 1994). In Brazil catuaba has traditionally been used as a stimulant of the CNS with aphrodisiac properties. The source of catuaba is said to be the elusive Erythroxylum catuaba, a poorly dened botanical entity, lacking both proper description and a type specimen. The botanically correct identity the drug may be Erythroxylum vacciniifolium (Erythroxylaceae), Anemopaegma mirandum (Bignoniaceae), Trichilia catigua (Meliaceae) or others (see Kletter et al., 2004). One to three cups of a bark decoction are to be consumed daily against sexual impotence and weakness, agitation, nervousness, neurasthenia, poor memory,

Table 3 Plants used in Central America and the Caribbean Islands in the context of age related brain disorders Plant Brugmansia candida Pers. Lantana camara L. Medicago sativa L. Tagetes lucida Cav. Theobroma cacao L. Family Solanaceae Verbenaceae Fabaceae Asteraceae Sterculiaceae Traditional use Tea or decoction is used for memory problems Tea of the leaves is believed to prevent weakness of memory and enhances intellect and cognition To improve the memory, cure skin eruptions, kidney pain, cough, sore muscles and inammation To treat fever, fear, dementia, lightning stroke and as a diuretic In a potion for stupor References Gonz lez Ayala (1994) a M ller-Ebeling and R tsch (1989) u a Finkler (1985) Ortiz de Montellano (1990) Roeder (1988)

forgetfulness and insomnia. Erythroxylum vaciniifolium bark contains a number of tropane alkaloids (Zanolari et al., 2005). Paullinia cupana (Sapindaceae), guarana, has been used for centuries as an effective tonic, heart tonic, to thin the blood and for mental acuity and to benet long-term memory. Today guarana is used word-wide as a tonifying drink against fatigue (Taylor, 1998). Due to its caffeine content guarana is a substitute for coffee. Other phytochemicals are adenine, catechutannic acid, choline, d-catechin, guanine, guaranine, hypoxanthine, mucilage, saponin, tannins, theobromine, theophylline, timbonin and xanthine. An in vivo study with an interesting outcome on mental insufciency was conducted in 1997. Guarana was administered in single and chronic doses to rats. Physical activity, physical endurance under stress and memory effort increased in both of the doses administered. It is interesting that the whole seed extract of guarana showed better results than a comparable dose of caffeine (Espinola et al., 1997). Colombia hosts a vast diversity of plants and numerous indigenous tribes. The Colombian Indians reputably treat aged members of the clan with care, patience and honour. Over twenty remedies for afictions of old age were described by Richard Evans Schultes (1993a,b), the father of ethnobotany, a most outstanding botanist who spent many years in the North Western Amazone. The Puinave Indians living along the Rio Vaup mixed the e dried leaves of Unonopsis veneciorum (Annonaceae) into the food of elderly patients suffering from not knowing how to talk (Wolters, 1994). Pulverised leaves of Unonopsis stipitata, are added to the food of elderly people who have difculty speaking. The genus Unonopsis has interesting azauorenones and bisaporphinoids (Laprevote et al., 1987, 1988). Warm decoctions of the whole plant of Justicia ideogenes (Acanthaceae) are poured over the lower limbs to treat trembling. Latex from Galactophora crassifolia (Apocynaceae) is used for children with uncontrollable shaking of the head. A root decoction of Mandevilla steyermarkii (Apocynaceae) is administered to the aged and the weak. The latex of Parahamcornia amapa (Apocynaceae) is used against general debility in the Brasilian Amazonas. Vismia tomentosa (Clusiaceae) provides a remedy for the aged who have difculty in understanding instructions, talking and suffering of physical degeneration. Tukano medicine men prepared tea of the leaves of Tabernaemontana heterophylla (Apocynaceae) to give to elderly who were slow and forgetful. The tree contains a number of indole alkaloids (Wolter et al., 1983). Leaves of Lundia erionema (Bignoniaceae) or Memora schomburgkii (Bignoniaceae) are crushed by Vaup s medicine e men and mixed with a palm oil to treat elderly who speak crazily without making sense. Tikuna Indians make a tea from Schlegelia macrophylla (Bignoniaceae) leaves for those who refuse to eat and lose appetite. The Muinane Indians, who live in the area of the Ro Caquet , knew about the properties of the a rather unknown plant called Pagaea recurva (Gentianaceae). A very bitter decoction, made of the whole plant, was prepared and indicated in cases of debilitating forgetfulness among the elderly (Schultes, 1993a,b). Practically nothing is known about the chemistry of this plant. For patients with mental problems, a recipe of the seeds of Barbieria pinnata (Fabaceae) was used.

The seeds are soaked in a fermented drink made of manioc or maize before being administered. Cassia lucens (Fabaceae) represents another remedy with a rather vague indication. This plants most known use is as an insect repellent. Some Kubeo people administer a drink from the dried and powdered leaves to people with poor memory (Schultes, 1993a,b). The gymnosperm Gnetum nodiorum (Gnetaceae) is used by the Wyana tribe in Suriname for cases of physical and mental weakness (Schultes, 1993a,b) (Table 4). 5. Africa The relative numbers of traditional practitioners and doctors in proportion to the population in most African countries demonstrate the importance of traditional medicine. In the Venda area of South Africa, for example, there is one traditional practitioner for every 7001200 people, compared to one university-trained doctor for almost 18,000 people. Drugs used are considered a divine gift, valued as much for its symbolic and spiritual signicance as for its medicinal effect. In addition to plants, healers may employ charms, incantations and casting of spells in their healing methods (Tella, 1979; Helwig, 2006; Kale, 1995). African healing is an inextricable part of African religion (Kale, 1995). This needs to be considered when cures for mental diseases involve practices such as wrapping plants around a persons head or similar pharmacologically less plausible forms of administration. In East Africa, the roots of water lettuce, Pistia stratiotes (Araceae), a perennial oating plant, are wrapped in a rag and tied around a demented persons head. At the same time an infusion of the leaves is poured over the head (Kokwaro, 1976). In South Africa leaves, stems and roots of Asparagus africanus (Asparagaceae) are pounded and soaked in water to make an infusion. Drunken two to three times a day, it should relieve problems of mental disturbance (Kokwaro, 1976). The plant contains steroidal saponins and lignans (Debella et al., 2000). The following three recipes refer to the Yoruba speaking part of West Africa. They are a large linguistic group of 40 million individuals mostly in Nigeria, Benin and Togo. One recipe consists of the leaves of Hydrolea glabra (Hydrophilaceae), the leaves of Digitaria species (Poaceae) and a guinea pig. The ingredients are eaten together with Indian cornmeal and are believed to enhance memory (Fatumbi, 1995). A blend of leaves of Pleiocarpa pycnantha (Apocynaceae), leaves of Spondias mombin (Anacardiaceae) and a fruit of Aframomum melegueta (Zingiberaceae) are administered to gain and retain good memory (Fatumbi, 1995). According to traditional healers a formula consisting of Symphonia globulifera (Clusiaceae), Hydrolea glabra (Hydrophilaceae), and Glyphaea brevis (Tiliaceae) was also given to aid memory. A snake was also added to the concoction (Fatumbi, 1995). In Senegal a maceration of the roots of Ximenia americana (Olacaceae) native to Africa not the Americas, as the name suggests is used to cure leprosy and is applied externally for mental sickness (Sofowora, 1982). Crinum glaucum and Crinum jagus (Amaryllidaceae) have been used in Southwest Nigeria by traditional healers for mem-

Table 4 Plants used in South America in the context of age related CNS disorders Plant Ananas comosus (L.) Merill Barbieria pinnata (Pers.) Baill. Cassia lucens Vog. Chenopodium ambrosioides L. Family Bromeliaceae Fabaceae Fabaceae Chenopodiaceae Traditional use Against neurasthenia, melancholy, sadness, weakness of memory and stupidity The Kubeos prepared a tea of the seeds for elderly men with various mental problems A drink prepared from powdered leaves for people with bad memory For headache, memory, caries and toothache Preparations of the leaves are used to ameliorate the memory The Indios believe that the plant has potential to increase the memory In Brazil, a decoction is used for sexual impotency, agitation, nervousness, neurasthenia, poor memory, forgetfulness and sexual weakness Wyana Indians administered the plant in the treatment of physical and mental weakness Kofan Indians pour warm decoction over lower limbs for palsy-like trembling Lactuca is used for insomnia and believed to help a weak memory Crushed leaves mixed with Jessenis oil are given to elderly who speak crazily without making sense Given to the aged and the sick Amongst the Muinane Indians a decoction of the whole plant was prepared for debiliating forgetfulness in the elderly Is used against general debility in the Brasilian Amazonas Indians used guarana as a heart tonic, energy tonic, to thin the blood, for mental acuity and long-term memory For circulatory disorders, hypertension, pain of nervous origin, indigestion, neuralgia, general debility and fatigue, and for general symptoms of old age Leaves given to people who refuse to eat and lose appetite Tukano Indians prepared a tea of the leaves for the old folks who are slow and forgetful Puinave Indians at Rio Vaup mixed dried leaves in the food of e elderly people who forgot how to talk Added to the food of elderly people who have difculty speaking Yukuna and Makuna Indians prepared the plant for the elderly who suffer difculty in understanding instructions and have physical degeneration and difculty in talking References Wolters (1994) Schultes (1993a,b) Schultes (1993a,b) CESA (1993) CESA (1992) De Barradas (1957) Taylor (1998)

Erythroxylum catuaba A.J.Silva Juniperus brasiliensis Gnetum nodiorum Brongn. Justicia ideogenes Leonard Lactuca sativa L. Lundia erionema De Candolle Mandevilla steyermarkii Woodson Pagaea recurva Benth. Bentham et Hooker l Parahamcornia amapa (Hub.) Ducke Paullinia cupana KUNTH ex. H. B. K Rosmarinus ofcinalis L.

Erythroxylaceae; Cupressaceae Gnetaceae Acanthaceae Asteraceae Aristolochiaceae Apocynaceae Gentianaceae Apocynaceae Sapindaceae Lamiaceae

Schultes, 1993a,b Schultes (1993a,b) Schweitzer de Palacios (1994) Schultes (1993a,b)

Schultes, 1993a,b Schultes (1993a,b) Taylor (1998) CESA (1993)

Schlegia macrophylla Ducke Tabernaemontana heterophylla Vahl. Unonopsis veneciorum (Mart.) R.E. Fries Unonopsis stipitata Diels Vismia tomentosa Ruiz and Pav.

Bignoniaceae Apocynaceae Annonaceae Annonaceae Clusiaceae

Schultes (1993a,b) Schultes (1993a,b) Schultes (1993a,b) Schultes (1993a,b) Schultes (1993a,b)

ory loss and other mental ailments associated with aging. Houghton et al. (2004) isolated alkaloids from the plants and tested their AChE inhibitory properties. Hamayne (IC50 250 M) and lycorine (IC50 450 M) showed only slight activities compared to the positive control physostigmine (IC50 of 0.25 M). A preparation of macerated roots of Opilia celtidifolia (Opiliaceae) is believed to help with mental illness when taken as a beverage for about 1 week (Assi and Guinko, 1991). Triterpenoid saponins were found to be present in the plant (Crespin et al., 1993). The mark of Canthium glabriorum (Rubiaceae) is used for cough and mental diseases (Bep, 1960) (Table 5). 6. Asia Asia is the largest and, with 60% of the worlds population also the most populous continent of the world. It is home to the worlds oldest documented medical systems, traditional Chinese medicine (TCM) and Ayurveda.

6.1. Traditional Chinese medicine (TCM) Chinese herbal medicine is an interesting subject for medicinal plant research. According to But et al. (1980), from 26,092 species listed in Flora Sinica, 4941 (19%) are used medicinally. TCM concepts such as yin, yang and qi are used to describe specic medical states but are difcult to translate into western medical terms. Despite the entirely different underlying philosophical frameworks, there has been a great amount of cooperation between TCM and western medicine in recent years. Using western methods and techniques traditional remedies have been pharmacologically and clinically validated, and many have been shown to have therapeutic value in terms of western medical understanding. Besides herbal therapy acupuncture, moxibustion, massage, hydrotherapy, dietetics and exercise are therapeutic forms in TCM treatment. For detailed information on the spiritual and philosophical aspects of TCM please refer to specialised literature (such as Jiang, 2005).

The club moss Huperzia serrata (Lycopodiaceae) is used in TCM to alleviate problems of memory loss, promote circulation, for fever and inammation (Houghton and Howes, 2005). Qian Ceng Ta is a formula prepared from Huperzia serrata, used in TCM to treat memory loss (Howes et al., 2003). It is reported to be a cognition enhancer that facilitates memory and motor activity in aged persons and was recommended in the treatment of senile dementia, including AD and multi-infarct dementia (Kee, 1999). Huperzine A, an alkaloid from Huperzia serrata, was found to be a reversible AChE inhibitor and is neuroprotective (Skolnick, 1997; Chiu and Zhang, 2000; Yaniv and Bachrach, 2005). It was shown that huperzine A has a neuroprotective effect against -amyloid peptide fragment 2553, oxygen glucose deprivation and against free radical-induced cytotoxicity. It also attenuates apoptosis by inhibiting the mitochondria-caspase pathway. In cortex or synaptic plasma membranes it counteracted N-methyl-d-aspartate-induced toxicity (NMDA) This may be due to the fact that huperzine A facilitates cholinergic neurotransmission by increasing the concentration of acetylcholine in the CNS about 100 times more effectively than tacrine, a drug used for AD (Anekonda and Reddy, 2005). In cell culture studies huperzine A decreased neuronal cell death caused by toxic levels of glutamate (Bores et al., 1996). In rats huperzine A reversed -amyloid-(140) induced decit in learning in a water maze task, and reduced the loss of choline acetyltransferase activity in cerebral cortex, and the neuronal degeneration induced by -amyloid protein-(140). It reversed the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax and P53 proteins as well as reducing apoptosis caused by -amyloid injection. The benecial effects are not conned to the cholinergic system, but also include favourable changes in the expression of apoptosisrelated proteins and in the extent of apoptosis in other regions of the brain (Wang et al., 2001). Huperzine A (400 g) was given daily to 100 patients for 12 weeks. It was reported to be more selective for AChE than BuChE and was less toxic than the synthetic AChE inhibitors donepezil and tacrine (Frank and Gupta, 2005). Possible side effects are nausea, vomiting, diarrhoea and muscle cramps have been observed. Cholinergic effects may also worsen pulmonary and peptic ulcer disease and cardiac arrhythmia (Ott and Owens, 1998). Qingkailing, a traditional Chinese formulation, does not have a direct indication in traditional medicine for dementia or AD therapy. Some recent data, however, indicates a certain potential to be used as such. The herbs Scutellaria spp. (Lamiaceae), Lonicera spp. (Caprifoliaceae), Pittosporum spp. (Pittosporaceae) and Isatis tinctoria (Brassicaceae) are combined with cow-bezoar (Jinzhoun, 1998). It is a remedy used for re-establishing the energy balance and to remove the causes of heat and phlegm, which in TCM are symptoms, associated with dementia. Clinical studies report benecial effects of qingkailing: Patients with dementia following a stroke, received qingkailing intravenous daily, for 30 days. At the same time, a tea was given twice daily. It contained Pinellia ternata (Araceae) tubers, Acorus gramineus (Acoraceae), Angelica

Assi and Guinko (1991) and Langeland and Craddock Burks (2005) Kokwaro (1976)

Kokwaro (1976) and Debella et al. (2000)

Bep (1960) Hostettmann et al. (2006)

Administered for good memory. The two herbs are mixed together with the guinea pig and eaten with Indian cornmeal Roots macerated in water are taken to treat mental illness The roots are wrapped in a rag and tied around the head of a demented person, and at the same time, an infusion of the leaves is poured over the head Extracts of the plants are taken to have a good memory and to keep a good memory

Infusions of Leaves, stems and roots are drunk 23 times a day for the treatment of mental disturbance The mark of this plant is used for coughs and mental diseases For memory loss and other mental symptoms associated with aging

Table 5 Plants used in Africa in the context of age related CNS disorders

Rubiaceae Amaryllidaceae; Amaryllidaceae Hydrophilaceae; Poaceae Opiliaceae Araceae

Tiliaceae Hydrophilaceae Clusiaceae Glyphaea brevis (Spreng.) Mon. Hydrolea glabra Schum. and Thonn. Symphonia globulifera L. A snake

Apocynaceae Anacardiaceae

Zingiberaceae

Canthium glabriorum Hiern. Crinum glaucum A. Chevalier Crinum jagus C. Hydrolea glabra Schum. and Thonn. Digitaria sp. Opilia celtidifolia Guill. and Perr. Pistia stratiotes L.

Aframomum melegueta (Roskoe) K. Schum. Pleiocarpa pycnantha (K. Schum.) Spondias mombin L.

Asparagus africanus Lam.

Ximenia americana L.

Plant

Olacaceae

Liliaceae

Family

A maceration of roots is used in treating leprosy and is applied internally and externally for mental sickness

This recipe is for a good memory, to recall memory and to organise the own memory

Traditional use

Sofowora (1982)

Fatumbi (1995)

Fatumbi (1995)

Fatumbi (1995)

References

dahurica (Apiaceae) roots, Atractylodes macrocephala (Asteraceae), and Pseudostellaria heterophylla (Caryophyllaceae) root. An improvement of intellect by increasing the score 10 points on Hasegawa Dementia Scale was stated by ve patients. Three patients improved 5 or less points, while two patients remained without benet. In a randomized double blind study, with 15 participants with syndromes of vascular dementia, qingkailing was administered i.v. to 10 patients daily for 14 days. The control group (n = 5), received an infusion of chuanxiong piperazine (Ligusticum chuanxiong, Apiacae). The qingkailing group improved their score by 10.4, whereas the score of the control group increased only by 4.9. These studies have, at best, a pilot character and need to be followed up by larger trials. Polygala tenuifolia (Polygalaceae) is used in TCM and Japanese formulas for the treatment of psychoneurological diseases. It is thought to have an effect on the will and mental powers, improving understanding and strengthening the memory. It is also indicated as a cerebrotonic, cardiotonic, sedative and tranquillizer (Howes and Houghton, 2003). 6.2. Korea Oh et al. (2004) lists seven plants in Koreas history of traditional medicine, including Acorus calamus rhizome, Acorus gramineus rhizome, Bupleurum falcatum root, Dioscorea batatas rhizome, Epimedium koreanum herb, Poria cocos sclerotium and Zizyphus jujuba fruit, which are used for the general indication for improvement of cognition and memory function in old age. They were all tested for cholin esterase inhibitory properties using the Ellman colorimetric method. The data revealed that extracts of Acorus gramineus, Dioscorea batatas and Zizyphus jujuba did not show any inhibitory effects on AChE. Signicant dose-dependent inhibition of the enzyme at the high dose of 200 g/ml was observed for methanolic extracts from Acorus calamus and Epimedium koreanum. Paeng-Jo-Yeon-Nyeon-Baek-Ja-In-Hwan (PJBH) is a decoct of 18 dried herbs including the whole plant of Dendrobium moniliforme, seeds of Thuja orientalis (Cupressacae), fruits of Torilis japonica (Apiaceae), Rubus coreanus (Rosaceae), Cornus ofcinalis (Cornaceae) and Schizandra chinensis (Schisandraceae), roots of Morinda ofcinalis (Rubiaceae), Asparagus cochinchinensis (Asparagaceae), Polygala tenuifolia (Polygalaceae), Phlomis umbrosa (Lamiaceae), Panax ginseng (Araliaceae) and Rehmannia glutinosa (Gesneriaceae), stems of Cinnamomum cassia (Lauraceae), rhizome of Acorus calamus (Araceae), Alisma canaliculatum (Alismataceae) and Dioscorea japonica (Dioscuraceae) and leaves of Cistanche salsa (Orobanchaceae). PJBH has an extensive history in Korea, and is also used in TCM to activate brain function, promote memory and lengthen life span. The herbal medicine has shown various activities including immune modulation, anti-infarct, anti-inammatory and anti-allergic effects (Koo et al., 2004). The effects of PJBH on H2 O2 induced injury in PC12 cells was examined and revealed an elevating effect on catalase and glutathione peroxidase activities as well as on cell survival (Koo et al., 2004).

6.3. Japan Choto-San, a remedy from Kampo Japanese traditional medicine adapted from TCM consists of 10 herbs and a sulphate mineral. The formula is composed of the fruit shell of Citrus aurantium (Rutaceae), the tubers of Ophiopogon japonicus (Convallariaceae) and Pinellia ternate (Araceae), the stem including the hooks of Uncaria tomentosa (Rubiaceae), the roots of Panax ginseng (Araliaceae), Ledebouriella seseloides (Apiaceae) and Glyzyrrhiza glabra (Fabaceae), the rhizome of Zingiber ofcinalis (Zingiberaceae), the owers of the Chrysanthemum species and parts of Poria cocos. The traditional indication does not relate to age related brain disorders in particular, but recent data reveals the possible use of Choto-San in the therapy of cognitive disorders (Murakami et al., 2005). Murakami et al. (2005) tried to clarify the mechanisms of action of the Choto-san formula in mice with induced hypoperfusion by permanent occlusion of both the common carotid arteries which induces spatial memory decits and neuronal damage in rodents. Choto-san extract was given orally to mice for 5 days an hour prior to the start of each experiment. Tacrine was used as reference. Choto-san and Choto-san Uncaria-free extract were administered. Choto-san raised the level of ACh, compared to that in the control group, whereas Choto-san Uncaria-free extract had no effect. Choto-san also improved 2VO-induced spatial learning decits, via the stimulation of muscarinic M1 receptor, while Choto-san Uncaria-free extract did not show any improvement. Choto-san extract ameliorated the effect of 2VO in the Morris water maze task whereas the Uncaria-free extract showed no effect. The results suggest that Uncaria plays a key role in the benecial effect of Choto-san on learning and memory impairment caused by chronic hypoperfusion. 6.4. Ayurveda The history of medicine in India can be traced to the remote past. The earliest mention of medicinal use of plants is found in the Rigveda, probably the oldest repositories of human knowledge written between 4500 and 1600 b.c. (Kapoor, 1990). Ayurveda encompasses philosophy, science and religion and is a very complex system of knowledge applied to daily life. Rasayana tantra geriatrics including rejuvenation therapy is one of eight major disciplines in Ayurveda. Caraka Samhita dened rasayana as a treatment to attain longevity, intelligence, freedom from age related disorders, youthful appearance, optimum strength of physique and sense organs, maintain language ability and improve memory (Bala and Manyam, 1999). Rasayana is not merely a drug therapy but a regimen covering the general mode of life, social conduct, behaviour, diet and the use of specic restorative remedies. This process should begin in late adult life or midlife, and may not be effective when started too late as many of the approaches are preventive rather than curative. Some rasayana recipes directly refer to dementia. It is quite remarkable that an ancient medical system includes such a well-elaborated medical theory and treatment for age related problems like dementia, whilst contemporary systems attributed inexplicable phenomena to the spiritual realm.

One preparation is called Aindrarasayana (Bala and Manyam, 1999). Aindri or Brahmi are names for Bacopa monniera, one of six plants in the formula. The other ve are Alternanthera sessilis (Amaranthaceae), Acorus calamus (Araceae), Piper longum (Piperaceae), Convolvulus pluricaulis (Convolvulaceae) and one plant with the Sanskrit name Brahmasuvarcala, which was not identied. Three parts of Aindrarasayana including the salt and two parts of gold oxide are mixed with Aconitum chasmanthum (Ranunculaceae). The mixture is consumed on an empty stomach. Several hours later, when the preparation is digested, honey and a generous amount of butterfat (ghee) should be consumed. Another Ayurvedic formula consists of the juice of Centella asiatica (Apiaceae), the powder of Glycyrrhiza glabra (Fabaceae) mixed with milk, the juice of the stem of Tinospora cordifolia (Menispermaceae) and a paste made of the roots and owers of Convolvulus pluricaulis (Convolvulaceae) mixed together and taken to prevent dementia, retard age and to improve complexion and digestion (Bala and Manyam, 1999). Emblica ofcinalis (Euphorbiaceae) is a native plant with rasayana properties and the main ingredient in this preparation for a disease-free life with long lasting youth, great vigour and no dementia. Terminalia ofcinalis, Acorus calamus, Embelia ribes, Sida spinosa, Semecarpus anacardium, Bacopa monnieri, Aternanthera sessilis, Coelogyne evalis, Boerhaavia diffusa, Desmodium gangeticum, Baliospermum montanum and Polygonatum verticillatum are also added to the mixture. Six plants with Sanskrit names are not identied but also part of the formula (Bala and Manyam, 1999). Another traditional recipe made is prepared with 1000 fruits of Emblica ofcinalis (Euphorbiaceae) and 1000 fruits of Piper longum (Piperaceae). They are dipped in alkaline water prepared from a Butea monosperma (Fabaceae) tree, and then powdered. The powder is mixed four times its weight with honey and ghee, and one-fourth of sugar and stored underground for 6 months. The preparation should be taken life-long from new moon to full moon starting later in youth or middle age. The dose is based on the persons individual digestive ability. This remedy is optimistically recommended for a lifespan of 100 years with full vigour, cognitive function and to preserve youth (Bala and Manyam, 1999). Withania somnifera (Solanaceae) roots are one of the most highly regarded herbs in Ayurvedic medicine and of similar status of ginseng in TCM. They are classed among the Rasayanas rejuvenating tonics used for treating age associated decline in cognitive function (Parrotta, 2001). Steroid lactones such as withanolides A-Y, glycowithanolides, dehydrowithanolide-R, withasomniferin-A, withasomidienone, withasomniferols A-C, withaferin A, withanone have been isolated from the root and leaf (Williamson, 2002). The phytosterols, sitoindosides VIIX and perpetual sitosterol were found, alongside the alkaloids ashwagandhine, ashwaghandhinine, cuscohygrine, anahygrine, tropine, pseudotropine, anaferine, isopelletierine, withasomine, visamine, somniferine, somniferinine, withanine, withaninine, pseudowithaninine and solasodine. There have been numerous studies regarding the cognitive enhancing activities of Withania somnifera. Withanoside IV or

VI produced dendritic outgrowth in normal cortical neurons of isolated rat cells, whereas axonal outgrowth was observed in the treatment with withanolide A in normal cortical neurons (Tohda et al., 2005). Neuritic regeneration or synaptic reconstruction was induced by withanolide A, withanoside IV and VI in amyloid- (2535)-induced damaged cortical neurons. In addition, these components also facilitated the reconstruction of post-synaptic and pre-synaptic regions in neurons, where severe synaptic loss had already occurred. Withania somnifera extract, containing the steroidal substances sitoinodosides VIIX and withaferin A augmented learning acquisition and memory in both young and old rats (Ghosal et al., 1989). It enhanced AChE activity in the lateral septum and globus pallidus and decreased it in the vertical diagonal band. Receptor binding on the muscarinic M1 receptor was enhanced in the lateral and medium septum and in the frontal cortices. M2 receptor binding increased in cortical regions but did neither affect -aminobutyric acid (GABAA ), benzodiazepine, nor NMDA receptor binding. The extract reversed ibotenic acid induced cognitive decit and reversed the reduction in cholinergic markers, such as acetylcholine (Schliebs et al., 1997). Acorus calamus is originally native to Europe, but has been cultivated and naturalized throughout India and Sri Lanka. Sala et al. (1993) list the plant with traditional uses as an intellect-promoting agent against depression, mental disorders and general debility. Acorus calamus is also combined with Polygala root to help maintain mental and intellectual health of the elderly (Hou and Jin, 2005). When powdered, it can be of avail for depressed psychosis and dementia. Further indications include the loss of consciousness, confusion of the mind, forgetfulness, anorexia and epilepsy and as a traditional Ayurvedic medicine to treat memory loss (Howes and Houghton, 2003). Acorus calamus contains essential oil with the main components -asarone and -asarone. Other components found in the plant are caryophyllene, -humulene and sekishone (Hou and Jin, 2005). Methanolic extracts of the roots, which contain essential oil which the toxin -asarone showed inhibitory effect on AChE with an IC50 value of 188 g/ml (Oh et al., 2004). In vitro and in vivo studies have shown Acorus calamus oil to induce malignant tumours, due to -asarone. In view of toxicity, products should contain no or a negligible amount of -asarone, such as that from the Acorus calamus var. americanus (Singh et al., 2001). In mice, the root extract of Acorus calamus protected against acrylamide-induced neurotoxicity and reduced the incidence of paralysis (Shukla et al., 2002). Acorus calamus is registered in the Pakistani Materia Medica where both the roots and rhizomes are used for nervous diseases and disorders, whereas the rhizome is especially indicated in cases of neurological symptoms of the brain (Said and Ahmad, 1986). The seeds of Celastrus paniculatus (Celastraceae) are credited with emetic, diaphoretic, febrifugal and nerve beneting properties and are used in traditional Indian medicine to sharpen the memory, to cure ulcers, gout, sores and rheumatism. The seeds and the seed oil are used as a brain tonic, for diseases of the CNS, epilepsy, oedema, stomach disorders and psychosis. The leaves, roots and bark do not have indications related to AD or dementia, so most in vivo and in vitro pharmacological stud-

ies have focused on seeds and the seed oil (Parrotta, 2001). In rats the oil helped improve learning and memory, and decreased noradrenalin, dopamine and serotonin in the brain (Nalini et al., 1995). It reversed scopolamine induced task decit but this was not associated with an AChE inhibition (Gattu et al., 1997). For more pharmacological information see Howes and Houghton (2003). Traditional indications were found for Convolvulus pluricaulis (Convolvulaceae), a plant common in southern India, where the whole plant is used in various formulae as a nervine tonic for improvement of memory and intellect. The leaves and owers possess hypotensive properties used for treating anxiety neurosis. Furthermore, it is also recommended as a brain tonic to promote intellect and memory, eliminate nervous disorders and to treat hypertension (Bala and Manyam, 1999). The bark, leaves, owers, fruits and pods of Sesbania grandiora (Fabaceae) are used in Ayurvedic medicine. The pods are considered useful for promoting memory power and for resolving glandular tumours or enlargements (Parrotta, 2001). Canscora decusata (Gentianaceae) is a notable Ayurvedic drug for improving memory and intellect. A paste is made of the whole plant, including the owers, to be taken with milk as a nervine tonic and to alleviate memory problems (Parrotta, 2001). Gmelina arborea (Verbenaceae) is used in Ayurvedic medicine to improve digestion, strengthen memory, to overcome giddiness and to treat fever, thirst, emaciation, heart diseases and nervous disorders (Parrotta, 2001). The ripe fruit of Terminalia chebula (Combretaceae) is considered to possess the ability to promote memory, intellect and to prolong life. It is also believed to improve eyesight and has the ability to delay aging. It is suggested that one ripe fruit should be eaten every morning to achieve the listed effects (Vohra and Gupta, 2005). Nardostachys jatamansi (Valerianaceae) is a reputed medhya, an intellect-promoting herb, with various medicinal properties, especially on the nervous system (Joshi and Parle, 2006). A recent study was undertaken to determine the effect of Nardostachys jatamansi as a memory enhancer in mice. An elevated plus maze and a passive avoidance task were employed to evaluate learning and memory parameters. An ethanolic extract of the plant was administered orally for at doses of 50, 100 and 200 mg/kg. Furthermore, diazepam and scopolamine induced amnesia as well as aging induced amnesia was examined. The high dose of 200 mg/kg dose signicantly improved learning and memory in young mice and also reversed amnesia induced by scopolamine and diazepam. It was also claimed to have reversed amnesia due to natural aging of mice (Joshi and Parle, 2006). Bacopa monnieri L. (syn.: B. monniera) (Scrophulariaceae) occupies a predominant position in ayurvedic medicine and is recommended for the management of a range of mental conditions including anxiety, poor cognition and a lack of concentration (Russo and Borelli, 2005), as a nerve tonic, for memory and intelligence improvement (Parrotta, 2001) for an intellect promoting effect and helpful in cases of general debility (Sala et al., 1993). Russo and Borelli (2005) recently provided an update of current knowledge of nootropic effects of Bacopa monnieri.

The effects Bacopa monnieri (40 mg/kg) on learning performance in rats were studied in shock-motivated brightness discrimination reaction and in conditioned ght reaction. In both schedules the treated groups showed a shorter reaction time than the control group. In addition, the rats improved learning capability conrmed by a maze-learning experimental method (Williamson, 2002). Major chemical constituents found in Bacopa monnieri are saponins, triterpenes and dammaranes, such as bacosides A, B, C, bacosaponines D, E and F (Williamson, 2002; Russo and Borelli, 2005). The alkaloids brahmine and herpestine, avonoids such as glucuronyl-7-apigenin and glucuronyl7-luteolin, luteolin-7-glucoside and luteolin, phenylethanoid glycosides, monnierasides IIII and plantainoside B have been isolated. The saponins bacoside A and B have been claimed to be the active principles regarding enhancement of cognitive function (Singh and Dhawan, 1992; Russo and Borelli, 2005). They, apart from facilitating learning and memory in normal rats, inhibited the amnesic effects of scopolamine, electroshock and immobilization stress. Furthermore, Bacopa monnieri has been shown to enhance protein kinase activity in the hippocampus, which could also contribute to its nootropic action. When Bacopa monnieri was administered along with phenytoin for 2 weeks, it signicantly reversed phenytoin-induced impairment in rats (Williamson, 2002). Bacopa monnieri, administered for 2 weeks, reversed the depletion of acetylcholine. Further, it reduced the choline acetylase activity and decreased muscarinic, cholinergic receptor binding in the frontal cortex and hippocampus, induced by neurotoxins, such as colchicine (Russo and Borelli, 2005). In a double blind placebo-controlled trial 76 participants, aged 4065, received capsules of Bacopa monnieri extract equivalent to 69 g of dried rhizome. Effects on anxiety and memory functions were tested. The results did not show any signicant effect on measures of short-term memory, working memory, attention, or the retrieval of information from long-term memory acquired pre-experimentally. No effects on subjective measures of psychological state as depression, anxiety and stress, or everyday memory were observed. There was, however, an activity measured in a task requiring the retention of new information, recalling unrelated word pairs after a short delay (Roodenrys et al., 2002). The medicinal value of Centella asiatica (Apiaceae) is thought to be similar to that of Bacopa monnieri. The whole plant is used as a nervine tonic in various brain diseases and given to children as syrup to increase the memory. It is thought to be effective for memory disorders, impaired intelligence and as a rejuvenator and blood purier. It is used in various skin diseases. In parts of India it is given with milk to improve memory against dementia and aging (Ahuja, 1965). Constituents in Centella asiatica include essential oil, triterpenoid saponins, such as asiaticocide, brahmoside and thankuniside, alkaloids (hydrocotyline) and some bitter principles (Chevallier, 1996). Mook-Jung et al. (1999) tested articoside and 28 derivatives for protective effects against A -induced cell death in

Table 6 Plants used in Asia in the context of age related CNS disorders Origin China Plant Qingkailing (QKL) Isatis tinctoria L. Lonicera sp. Pittosporum sp. Scutellaria sp. cow-bezoar Coptis chinensis Franch. Huperzia serrata Thunb. Family Brassicaceae Caprifoliaceae Pittosporaceae Lamiaceae Ranunculaceae Lycopodiaceae Traditional use QKL is not mentioned as traditional: Studies suggest that the most frequent causes of dementia associated with stroke are heat, phlegm and blood stasis syndromes. Treatment should re-establish the energy balance and remove the causes. QKL resolves phlegm and clears the heat For several conditions including age related cognitive and memory decline Huperzine A is found to be an active cognition enhancer that faciliates memory and motor activity in aged persons Qian Ceng Ta is a traditional Chinese formula to alleviate problems of memory loss. The formula is prepared from Huperzia serrata Huperzia serrata has been used and is still a component of various formulae in traditional Chinese medicine to alleviate problems of memory loss, fever, inammation and for symtomps of aging Effect upon the will and mental powers, improving understanding and strengthening the memory According to ancient Chinese medicinal literature PJBH supplies and nourishes the kidney and consolidates essence, thus activating brain function, promoting memory and lengthening life span. PJBH has an extensive history as a medicinal herb in Korea, and it is possible that widespread PJBH use may contribute to the reduced age-adjusted prevalence of AD in Korea References Jinzhoun (1998)

Houghton and Howes (2005) Kee (1999)

Howes et al. (2003)

Polygala tenuifolia Willd.

Polygalaceae

Ott and Owens (1998), Chiu and Zhang (2000), Anekonda and Reddy (2005), Houghton and Howes (2005), Frank and Gupta (2005) and Houghton et al. (2006) Howes and Houghton (2003)

Korea

Paeng-Jo-Yeon-Nyeon- Baek-Ja-In-Hwa (PJBH) Acorus calamus L. Alisma canaliculatum A.Br. and Bouch e Asparagus cochinchinensis (Lour.) Merr. Cinnamomum cassia Blum. Cornus ofcinalis L. Cistanche salsa C. A. Mey. Dioscorea japonica Thunb. Dendrobium moniliforme (L.) Sw. Eucommia ulmoides Oliv. Morinda ofcinalis How. Panax ginseng C. A. Mey. Phlomis umbrosa Turc. Bull Polygala tenuifolia Willd. Rehmannia glutinosa Gaertn. Rubus coreanus Miq. Schizandra chinensis L. Thuja orientalis (L.) Franco Torilis japonica (Houtt.)

Acoraceae Alismataceae Asparagaceae Lauraceae Cornaceae Orobanchaceae Dioscoraceae Orchidaceae Eucommiaceae Rubiaceae Araliaceae Lamiaceae Polygalaceae Gesneriaceae Rosaceae Schisandraceae Cupressaceae; Apiaceae

Koo et al. (2004)

Table 6 ( Continued ) Origin Japan (Kampo) Plant Choto-san Gypsum brosum Chrysanthmum sp. Citrus aurantium L. Glycyrrhiza glabbra L. Ledebouriella seseloides (Hoffm.) Wolff. Ophiopogon japonicus Thunb. Panax ginseng C. A. Mey. Pinellia ternata Thunb. Poria cocos (Schw.) Wolff Uncaria tomentosa Willd. Zingiberis ofcinalis L. Aindrarasayana Acorus calamus L. Alternanthera sessilis (L.) R. Br. Bacopa monnieri (L). Pennell Convolvulus pluricaulis Choisy Piper longum L. Centella asiatica (L.) Urban Convolvulus pluricaulis Choisy Glycyrrhiza glabra L. Tinospora cordifolia Miers Brahmarasayana Acorus calamus L. Alternanthera sessilis (L.) R. Br. Bacopa monnieri (L.) Pennell Baliospermum montanum (Willd.) Boerhavia diffusa L. Coelogyne evalis Lindl. Emblica ofcinalis Gaertn. Desmodium gangeticum (L.) DC. Embelia ribes (Roxb. ex. Willd.) DC. Polygonatum verticillatum (L.) All. Terminalia chebula Retz. Sida spinosa L. Semecarpus anacardium L. l. Butea monosperma (Lam.) Taub Emblica ofcinalis Gaertn. Piper longum L. Acorus calamus L. Family Sulphate mineral Asteraceae Rutaceae Fabacea Apiaceae Convallariaceae Araliaceae Araceae Polyporaceae Rubiaceae Zingiberaceae Araceae Amaranthaceae Scrophulariaceae Convolvulaceae Piperaceae Apiaceae Convolvulaceae Fabaceae; Menispermaceae Traditional use The Choto-san formula is usually prescribed to middle-age patients of considerable build with a weak physical constitution as well as for chronic headache, painful tension of the shoulders and cervical muscle, vertigo, morning headaches, a heavy feeling of the head, feelings of uprising heat, tinnitus and insomnia References Murakami et al. (2005)

India (ayurveda)

This preparation is considered to alleviate dementia

Bala and Manyam, 1999

This recipe is believed to prevent dementia, improve digestion and complexion

Bala and Manyam (1999)

Araceae Amaranthaceae Schrophulariaceae Euphorbiaceae Nyctaginaceae Orchidaceae Euphorbiaceae Fabaceae Myrsinaceae Liliaceae Combretaceae Malvaceae Anacardiaceae Fabaceae Euphorbiaceae Piperaceae Araceae

Withania somnifera (L.) Dun.

Solanaceae

The fruits of Embilica ofcinalis are steamend to remove the seeds, dried and powdered. The powder is mixed with the juice of fresh Embilica fruit and mixed with the other 17 plants. It is then mixed with the juice of the fruits of Sida spinosa, dried, and ghee and honey are added. It is stored in boluses in a vessel underground surrounded by hemp ashes for 2 weeks. Before administration, oxide of gold, silver, copper and iron are added. Brahmarasayana is thought to create a disease-free, youthful state and signicant vigor and no dementia The formula is recommended for a life span of 100 years, to preserve youth, full vigor and cognitive function The plant is said to be capable of improving memory and intellect, treats various diseases including epilepsy and mental ailments Withania somnifera is used in cases of debility from old age

Bala and Manyam (1999)

Bala and Manyam (1999)

Parrotta (2001)

Ahuja (1965)

B103 cells. Hereby asiatic acid showed the strongest protective effect reducing H2 O2 -induced cell death and lowering intracellular free radical concentration. The triterpene asiatic acid and its derivatives have been also been shown to protect cortical neurons from glutamate-induced excitotoxicity in vitro. Glutamate can induce neuronal degeneration by over-stimulation of NMDA receptors. Some NMDA receptor antagonists like memantine (NamendaTM ), have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe AD (Farlow, 2004). Rao et al. (2005) showed that treatment of mice during postnatal development with Centella asiatica extracts inuences the neuronal morphology and promotes higher brain function later on in life. Centella asiatica extract (100, 200 and 300 mg/kg) showed a dose-dependent protective effect against cognitive decits and oxidative stress in rats. The results indicated improved acquisition and retention of memory. No signicant changes were observed in the locomotive activity. The rats were sacriced on day 21 for estimation of oxidative stress parameters as malondialdehyde (MDA), a marker of lipid peroxidation, SOD, GSH-Px and CAT. A decrease in MDA and an increase in GSH-Px levels were observed in rats treated with the rather high doses of 200 or 300 mg/kg extract (Kumar and Gupta, 2003). In Thailand the leaves of Michelia champaca (Magnoliaceae), a tree valued for its strongly fragrant yellow or white owers, are used in the treatment of brain disorders (Clayton et al., 1994). Michelia champaca contains essential oil, parthenolide and other sesquiterpene lactones (Jacobsson et al., 1995). Two plants were mentioned in the viewed literature on Vietnamese medicine for treating age related dementia (Agence de Coop ration Culturelle et Technique, 1990a,b). Acanthopanax e trifoliatus (Araliaceae) is used as a stimulant and tonic and is believed to ameliorate the memory. Some of the chemical constituents of the leaves of Acanthopanax trifoliatus have are kaur-16-en-19-oic acid, taraxerol, taraxerol acetate (Du and Gao, 1992), lupane-triterpene carboxylic acids, called acantrifoic acid and acantrifoside (Kiem et al., 2004). Dimocarpus longan (Sapindaceae), the source of the delicious longan fruits, is used as a tonic and administered in the treatment for mental deciency, neurasthenia, insomnia and amnesia (Agence de Coop ration Culturelle et Technique, 1990a,b). It could not be e determined what part of this widespread plant is used. In Malaysia Casuarina equisetifolia (Casuarinaceae) a widespread shrub or tree which somewhat resembles pine trees, is used as a sedative for the demented and to treat memory problems (Woodley, 1991). In Tibet Iris germanica (Iridaceae) is believed to be a promoter of intellect and also useful in the treatment of insanity, epilepsy and against evil spirits (Dash, 1994). Centella asiatica already listed in the part on India is also used in Tibet as a promoter of memory and voice and is believed to be rejuvenating in general. Another remedy, believed to prevent aging is ghee, a form of melted butterfat which is said to promote complexion, beauty, voice, intellect, memory and give strength, virility and longevity (Dash, 1994) (Table 6).

Agence de Coop ration e Culturelle et Technique (1990a,b), Du and Gao (1992) and Kiem et al. (2004) Agence de Coop ration e Culturelle et Technique (1990a,b)

Parrotta (2001), Williamson (2002), Tohda et al. (2005), Howes et al. (2003) and Williamson (2002)

Said and Ahmad (1986)

Clayton et al. (1994)

Woodley (1991)

Dash (1994) Apiaceae Centella asiatica (L.) Urban Tibet

Roots and rhizomes are for nervous diseases and disorders. The rhizome is used for curing neurological symptoms of the brain The leaves are used in the treatment of brain disorders It has been used as a stimulant as well as a tonic and believed to ameliorate the memory

Casuarinaceae

Magnoliaceae

Araliaceae

Sapindaceae

Acanthopanax trifoliatus (L.) Merr.

Casuarina equisitifolia L.

Dimocarpus longan Lour.

Michelia champaca L.

Acorus calamus L.

Malaysia

Thailand

Vietnam

Pakistan

Iris germanica L.

Iridaceae

Araceae

It is a promotor of memory and voice and believed to be a rejuvenating agent It is a promotor of intellect and kapha. It is used in the treatment of insanity, epilepsy and evil spirits

The roots are used in the therapy against senile debility and to restore memory loss

It is a tonic remedy used in the treatment for neurasthenia, insomnia, amnesia and mental deciency

It is used as a sedative for demented people

Dash (1994)

7. Conclusions and perspectives Despite the access to a large ethnobotanic orilegium in libraries and databases, the yield in numbers of herbs used for age related dementia turned out to be rather limited for most geographic regions. Various reasons may be responsible for that: On the one side, it can be due to cultural reasons. Both Ayurveda and TCM have clear millennia-old concepts of age related cognitive disorders and corresponding treatments with specic remedies (Yan et al., 2000), whereas folk medicines mostly lack this kind of foundation. Memory loss, confusion and forgetfulness in old age are fatalistically accepted as inevitable part of life, or oftentimes dementia is attributed to madness caused by spiritual and supernatural causes. Also, dementias are diseases which occur at an advanced age which was rarely reached in countries with a low life expectancy. On the other hand, there may also be the difculty of gathering and reporting data, i.e. in translating traditional concepts into scientic terminology. Also, data recording may not have been optimal from todays perspective. Indeed, the interest of Western medicine in Alzheimers disease is a relatively recent phenomenon. Our awareness has substantially increased over the past 20 years, due to signicant scientic progress in the understanding of the disease and the growing socioeconomic issue for our ageing societies. Before, age-related loss of cognitive function was largely considered as a natural phenomenon. Thus, the literature may possibly be negatively biased in the sense that many of the ethnobotanical books originate from a period where ethnobotanists probably paid less attention to information concerning treatments for cognitive disorders. Quite a number of traditionally used medicines were found in European herbals from the 16th and 17th Century, despite the relatively small number of available references. These herbals were sometimes printed in a number of languages, many of which are even available as reprints nowadays (Fuchs, 1543; Pomet, 1717). They formed the basis for what evolved into modern day pharmacopoeias. However, a major part of what was known to the antique and medieval world probably was lost in the early middle ages or has not yet been analyzed by modern science. This can be concluded from some documents long thought lost, which have only recently resurfaced. For example, a medieval account of 412 plants from the late 14th Century was rediscovered in the university library in Basel, Switzerland (Pster, 1961). Unfortunately, these treasures still await their translation and scientic analysis due to lack of funding and qualied philologists. Quite a number remedies for the treatment of age related cognitive disorders were recorded for the Amazonian region by the father of modern ethnobotany, Richard Evans Schultes (Schultes, 1993a,b), who spent many years living with natives and studying their medicinal herbs. A small selection of herbs traditionally used for CNS disorders have been evaluated pharmacologically and regarding their active constituents in terms our modern understanding of brain functions, but so far very little clinical data is available. Many prescriptions that claim to prevent or restore cognitive and memory decits have not shown any actions in established test

systems. Research for new potential drugs, however, is restricted to the pathways known or assumed to be included in the progression of AD, which are frequently based on AChE inhibition. Several traditional remedies have demonstrated interesting in vitro and in vivo activities and provided promising components with potential as therapeutics for neurodegenerative disorders. Most in vitro studies have focussed on inhibition of AChE (Houghton et al., 2006; Mukherjee et al., 2007), because this has so far been the most promising clinical approach for the treatment of AD. For some compounds, clinical data is very limited while others such as galanthamine and huperzine A have already reached widespread clinical use and contribute a great effort in the combat of AD. To date the pathophysiology of AD is not yet nearly claried. Further research will provide better understanding of the molecular pathways involved and hereby lead to the development of additional pharmacological test systems, in which activities may yet be observed. Also, some traditional medical systems such as Ayurveda emphasize health maintenance and disease prevention over curative treatments. Hence, preclinical and clinical research into protective and preventive effects of herbals drugs should be carried out in the future. Interestingly, a large study conducted with Ginkgo extract EGb761 in France over 7 years suggested a preventive effect in an aged population cohort (Andrieu et al., 2003). On the basis of this study, two large interventional studies have been initiated in the USA and in France (Christen, 2004). The outcome of these long-term trials will be important in dening a possible role of natural product based preventive therapy in AD. Acknowledgements Thanks are due to Prof. K. Hostettmann, University of Geneva, for providing access to ethnobotanical literature, and to Dr. M. Kessler and M. Kluge, Swiss Pharmaceutical Museum, Basel, for assistance, valuable information and access to herbals. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jep.2007.07.016. References
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