PHYTOTHERAPY RESEARCH

Phytother. Res. 17, 1–18 (2003)

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ptr.1280

REVIEW ARTICLE
Plants with Traditional Uses and Activities,
Relevant to the Management of Alzheimer’s
Disease and Other Cognitive Disorders

Melanie-Jayne R. Howes,1 Nicolette S. L. Perry2 and Peter J. Houghton2*

1
The Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3AB, UK
2
Department of Pharmacy, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, UK

In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, includ-
ing neurodegenerative diseases such as Alzheimer’s disease (AD) and other memory related disorders.
An ethnopharmacological approach has provided leads to identifying potential new drugs from plant
sources, including those for memory disorders. There are numerous drugs available in Western medicine
that have been directly isolated from plants, or are derived from templates of compounds from plant
sources. For example, some alkaloids from plant sources have been investigated for their potential in AD
therapy, and are now in clinical use (e.g. galantamine from Galanthus nivalis L. is used in the United
Kingdom). Various other plant species have shown favourable effects in AD, or pharmacological activi-
ties indicating the potential for use in AD therapy. This article reviews some of the plants and their
active constituents that have been used in traditional medicine, including Ayurvedic, Chinese, European
and Japanese medicine, for their reputed cognitive-enhancing and antidementia effects. Plants and their
constituents with pharmacological activities that may be relevant to the treatment of cognitive disorders,
including enhancement of cholinergic function in the central nervous system, anti-cholinesterase (anti-
ChE), antiinflammatory, antioxidant and oestrogenic effects, are discussed. Copyright # 2003 John
Wiley & Sons, Ltd.
Keywords: Alzheimer’s disease; dementia; acetylcholinesterase inhibitors; antiinflammatories; antioxidants; nicotine; phyto-
oestrogens; plants.

INTRODUCTION incidence of the disease, or for which a hypothesis has

There are numerous causes of dementia, including Lewy
body disease, Pick’s disease, cerebrovascular disease
and Alzheimer’s disease (AD), the last of which is
reported to be the most common form of dementia
(Evans et al., 1989; Nordberg, 1996). AD, which is
estimated to account for 50%–60% of dementia cases in
persons over 65 years of age (Francis et al., 1999), is a
progressive, neurodegenerative disease that primarily
affects the elderly population, and is a major public
health concern.
The main symptoms associated with AD involve
cognitive dysfunction, primarily memory loss (Des-
granges et al., 1998; Förstl et al., 1995; Grafman et al.,
1990; Grosse et al., 1991). Language deficits, depression,
behavioural problems including agitation, mood distur-
bances and psychosis are also features associated with the
later stages of AD (Kumar et al., 1998; McGuffey, 1997;
Wragg and Jeste, 1989).
The aetiology of AD is still unknown but several
factors have been suggested that appear to reduce the
* Correspondence to: P. J. Houghton, Department of Pharmacy, King’s
College London, Franklin-Wilkins Building, 150 Stamford Street, London
SE1 9NN, UK.
E-mail: peter.houghton@kcl.ac.uk
been put forward based on scientific investigations. It
should be pointed out, however, that none of these
theories have been completely accepted since they are
largely based on epidemiological studies and other
factors might be responsible for the differences observed.
Nevertheless, these factors have been exploited in the
search for drugs to treat AD.
The pathological features that occur in the central
nervous system (CNS) in AD are senile plaque and
neurofibrillary tangle formation, oxidative and inflam-
matory processes and neurotransmitter disturbances. A
consistent neuropathological occurrence associated with
memory loss is a cholinergic deficit, which has been
correlated with the severity of AD (Bierer et al., 1995;
Collerton, 1986; Giacobini, 1990; Perry et al., 1978;
Perry, 1986; Plotkin and Jarvik, 1986; Read, 1987).
Therefore attempts to restore cholinergic function have
been a rational target for drugs used to treat the
symptoms of AD. Approaches to enhance cholinergic
function in AD have included stimulation of cholinergic
receptors (e.g. the stimulation of nicotinic receptors by
nicotine), or by prolonging the availability of acetylcho-
line (ACh) released into the neuronal synaptic cleft.
This may occur by inhibiting ACh hydrolysis by
acetylcholinesterase (AChE), through the use of AChE
inhibitors.
Over the past decade, some AChE inhibitors have

Received 9 October 2002

Copyright # 2003 John Wiley & Sons, Ltd. Accepted 9 October 2002
2 M.-J. R. HOWES ET AL.
been licensed for clinical use for the symptomatic relief
of the early stages of AD, but it should be stressed that
their effect is only to slow down the progression of the
disease and they do not achieve any permanent
improvement. The synthetic drug tacrine (Cognex2)
was the first AChE inhibitor to be licensed, but its
routine use has been restricted by associated hepato-
toxic effects (Hammel et al., 1990; Watkins et al.,
1994). The use of tacrine has been eclipsed by the
newer AChE inhibitors such as donepezil (Aricept2),
rivastigmine (Exelon2) and galantamine (Reminyl2)
(Evans, 2001).
Several studies indicate that oestrogen replacement
therapy (ORT) may also have favourable effects in the
prevention and treatment of AD. ORT in women is
associated with a reduced risk of developing AD and
oestrogen treatment in women with AD is reported to
enhance cognitive function (Birge, 1997; Fillet et al.,
1986; Honjo et al., 1989; Ohkura et al., 1994; Schneider
et al., 1996); but some studies have not shown ORT to
improve cognitive function in AD patients (Mulnard et
al., 2000). Further investigations are necessary to
establish if ORT is an appropriate option for the routine
prevention and treatment of AD.
Other reports have indicated that the use of anti-
inflammatory agents may influence the progression of
AD. There have been several studies to show that non-
steroidal antiinflammatory drugs (NSAIDs) may
reduce the risk of developing AD, and that patients
with rheumatoid arthritis, who often use NSAIDs,
have a lower incidence of AD (Breitner, 1996;
Breitner et al., 1995; Jenkinson et al., 1989; McGeer
et al., 1990; 1996). Therefore the use of antiinflam-
matory drugs may also have potential in the treatment
of AD. Also implicated in the pathology of many
diseases including aging processes, atherosclerosis,
ischaemic heart disease and neurodegenerative dis-
eases including AD, are free radical reactions, which
are reported to initiate cell injury (Maxwell, 1995;
Slater, 1984; Spiteller, 1993). Consequently, the use of
antioxidants may slow AD progression and minimize
neuronal degeneration.
Numerous plants and their constituents are reputed in
traditional practices of medicine to enhance cognitive
function and to alleviate other symptoms of AD,
including depression. The plant constituents may not
only act synergistically with other constituents from the
same plant, but may also enhance the activity of
compounds from other plant species. This approach has
been used in various practices of traditional medicine,
including Ayurveda and traditional Chinese medicine
(TCM) where a mixture of plants is commonly
prescribed. An ethnopharmacological approach has
provided leads to identifying plants and potential new
drugs that are relevant for the treatment of cognitive
disorders, including AD, and may aid the discovery of a
more varied and efficacious selection of drugs for AD
treatment.
This article reviews some of the plants and their active
constituents that have been used in traditional practices
of medicine for their reputed cognitive-enhancing
effects. Plants and their constituents with pharmaco-
logical activities relevant to the treatment of cognitive
disorders, including anticholinesterase (anti-ChE), anti-
inflammatory, antioxidant and oestrogenic effects, are
discussed.
Copyright # 2003 John Wiley & Sons, Ltd.
ACTIVITIES RELEVANT TO THE TREATMENT
OF AD
Antiinflammatory activity
Numerous plants and plant constituents have demon-
strated antiinflammatory properties (Bingöl and Şener,
1995; Deepak and Handa, 2000; Handa et al., 1992;
Hoult and Payà, 1996; Laughton et al., 1991; Skaltsa et
al., 2000; Welton et al., 1986), thus there is potential for
novel antiinflammatory agents to be identified from plant
sources. Novel antiinflammatory drugs may be useful in
AD therapy, with fewer adverse effects than drugs
currently available. For example, numerous flavonoid
compounds (e.g. gossypin, quercetin, gnaphalin) have
been associated with antiinflammatory activity (de la
Puerta et al., 1999; Harborne and Baxter, 1993) and may
have potential in the management of inflammatory
disorders. The structural features of flavonoid molecules
required for cyclo-oxygenase (COX) inhibition have
been reported to be the presence of a pyrocatechol group
in at least one of the flavonoid rings, however, flavones
without such substituents can also inhibit COX (Alcarez
and Ferrándiz, 1987; Welton et al., 1986). Other
compounds, with potential for use in inflammatory
disorders, include ferulic acid, which is an antioxidant
and antiinflammatory compound derived from plants;
ferulic acid ameliorated the b-amyloid-induced reduction
in ACh levels in the cortex and the b-amyloid-induced
inflammatory responses in the hippocampus in mice, and
also improved cognitive function (Yan et al., 2001).
Antioxidant activity
Injury of plant cells, as well as mammalian cells, is
associated with the activation of lipoxygenases, which
catalyse the formation of hydroperoxides of polyunsatu-
rated fatty acids (PUFAs); a hydroperoxide radical may
react with fatty acids to produce dioxoenes, which are
regarded as plant defence compounds (Spiteller, 1993).
The occurrence of oxidative mechanisms in plants may
explain why an abundance of antioxidant compounds
have been identified in plant tissue. Their antioxidant
effects in plants may therefore have relevance in
mammals, particularly in disorders involving oxidative
stress such as AD.
Some plants with antioxidant activity include Aeseclus
hippocastanum, Allium nutans, Artemisia spp., Guiera
senegalensis, Hamamelis virginiana, Rosmarinus offici-
nalis, Salvia officinalis, Taraxacum officinale and
Thymus vulgaris (Aruoma et al., 1996; Bouchet et al.,
1998; Cuvelier et al., 1996; Deans et al., 1993; Hagymási
et al., 2000; Kimura et al., 1985; Masaki et al., 1995;
S̆tajner et al., 1999; Youdim and Deans, 1999).
Phytochemicals with anti-oxidant effects include some
cinnamic acids, coumarins, diterpenes, flavonoids, lig-
nans, monoterpenes, phenylpropanoids, tannins and
triterpenes (Aesbach et al., 1994; Bouchet et al., 1998;
Craig, 1999; Foti et al., 1996; Kelm et al., 2000; Kimura
et al., 1985; Laughton et al., 1989; Lu and Liu, 1991;
Okuda et al., 1983; Ruberto and Baratta, 2000; Sassa et
al., 1990; Schwarz and Ternes, 1992; Seidel et al., 2000;
Youdim and Deans, 2000; Zhu et al., 1999).
Some plants and plant compounds with anti-oxidant
Phytother. Res. 17, 1–18 (2003)
 PLANTS AS A SOURCE OF ANTI-DEMENTIA TREATMENTS
activity have shown favourable effects in the CNS, so
may be appropriate for use in AD treatment. Curcumin
from Curcuma longa reduced lipid peroxidation in rat
brain following oral administration to rats with ethanol-
induced brain injury (Rajakrishnan et al., 1999), and
Bacopa monniera, which is reported to have cognition
enhancing effects, induced a dose related increase in
superoxide dismutase, catalase and glutathione peroxi-
dase activities in the rat frontal cortex, striatum and
hippocampus (Bhattacharya et al., 2000b). In another
study, Thymus vulgaris essential oil maintained higher
PUFA levels in various tissues, including the brain in
rats, indicating protective antioxidant effects (Youdim
and Deans, 1999). Therefore the use of plants and their
constituents, in the diet and as supplements, may be
relevant in slowing AD progression.
Nicotinic receptor stimulation
It is reported that smoking may have protective effects
against AD development and that administration of
nicotine to AD patients and to healthy (non-AD) elderly
people improved cognitive function (Graves and Morti-
mer, 1994; Min et al., 2001; Newhouse and Kelton, 2000;
Sahakian et al., 1989; van Duijn and Hofman, 1991).
However, some cohort studies have shown that smoking
(which has been associated with cancer and cerebrovas-
cular disease) shows either no association with AD risk,
or moderately increases AD risk (Kukull, 2001; Merchant
et al., 1999; Tyas et al., 2000). Nicotine alone, however,
is reported to upregulate nicotinic receptors and to
increase ACh release (Balfour and Fagerström, 1996;
Flores et al., 1992; Whitehouse and Kalaria, 1995). Thus,
nicotinic agonists may enhance cholinergic neurotrans-
mission in AD. The cognition enhancing effects of
nicotine reported may be due to nicotinic receptor
stimulation but nicotine may also protect against AD by
other mechanisms. Nicotine has been shown to inhibit b-
amyloid formation in vitro (Salomon et al., 1996; Zamani
and Allen, 2001), to inhibit the neurotoxic effects of
excitatory amino acids (e.g. glutamate) and to enhance
the effects of nerve growth factor (NGF) (Akaike et al.,
1994; Whitehouse and Kalaria, 1995).
Other compounds, for example lobeline from Lobelia
inflata, that interact with the nicotinic receptor (Decker et
al., 1993; Miller et al., 2000) may also be exploited to
influence cholinergic function in AD. Therefore, nicotine
from Nicotiana tabacum and other Nicotiana spp., or
other nicotinic receptor ligands, may have potential in the
prevention, delay or treatment of AD.
Inhibitors of acetylcholinesterase: alkaloids
Physostigmine. Physostigma venenosum was used tra-
ditionally in Africa as a ritual poison, claimed to
determine the guilt or innocence of persons accused of
a crime (McCaleb, 1990). Treatment with the indole
alkaloid physostigmine (1), an AChE inhibitor isolated
from P. venenosum, has improved cognitive function in
several in vivo studies. For example, physostigmine (1) is
reported to protect mice against cognitive impairment
caused by oxygen deficit, it improved learning in rats
(McCaleb, 1990), and antagonized scopolamine-induced
impairment of cognitive function in rats (Yoshida and
Copyright # 2003 John Wiley & Sons, Ltd.
3
Figure 1. Structures of acetylcholinesterase inhibitors.
Suzuki, 1993). Physostigmine (1), a short-acting rever-
sible AChE inhibitor, is also reported to have shown
significant cognitive benefits in both normal and AD
patients (Shu, 1998; Sitaram et al., 1978), but clinical use
may be limited by its short half-life, which would require
multiple daily dosing.
Physostigmine (1) has been shown to inhibit both G1
and G4 AChE forms, the major AChE isoenzymes present
in mammalian CNS (Ogane et al., 1992). This effect
indicates that physostigmine (1) inhibits CNS AChE but,
as G4 AChE levels are reported to be decreased in AD
brains (Ogane et al., 1992; Younkin et al., 1986), there
may be clinical implications regarding efficacy. An
inhibitor that is more selective for the G1 AChE form
may be more relevant in AD. As well as inhibiting AChE,
physostigmine (1) also inhibited butylcholinesterase
(BuChE) with similar potency, an enzyme not associated
with cholinergic neurotransmission (Otoguro et al.,
1997). Therefore, adverse effects associated with BuChE
inhibition may also occur with physostigmine (1).
However, BuChE has recently been implicated in the
aetiology and progression of AD (Greig et al., 2001).
BuChE inhibition may therefore develop as a therapeutic
target in AD. In view of this, physostigmine (1) may have
superior clinical efficacy to AChE-selective inhibitors,
although the potential clinical advantages of BuChE
inhibition require more thorough investigation.
The chemical structure of physostigmine (1) has
provided a template for the development of rivastigmine
(2), an AChE inhibitor that is licensed for use in the UK
for the symptomatic treatment of mild to moderately
severe AD. Rivastigmine (2), which preferentially
inhibits the G1 form of AChE (Polinsky, 1998), improves
cognition in AD patients, an effect that has been
correlated with the level of AChE inhibition (Agid et
al., 1998; Cutler et al., 1999; Grossberg and Desai, 2001;
Kumar et al., 1999; Spencer and Noble, 1998).
Rivastigmine (2) is reported to inhibit AChE in the
cortex and hippocampus (Polinsky, 1998), brain areas
involved in cognition. Thus, it is apparent that plant-
derived alkaloid AChE inhibitors may be important for
the development of more appropriate drug candidates for
the treatment of AD.
Galantamine. Galanthus nivalis was used traditionally
in Bulgaria and Turkey for neurological conditions (Shu,
1998). Galantamine (3) is an Amaryllidaceae alkaloid
obtained from Galanthus nivalis L. (and also Narcissus
spp. and the Chinese herb Lycorus radiata) (Bores et al.,
1996). Galantamine (3) is reported to be more selective
Phytother. Res. 17, 1–18 (2003)
4 M.-J. R. HOWES ET AL.
for AChE than BuChE, and provides complete oral
bioavailability (Bickel et al., 1991; Fulton and Benfield,
1996; Harvey, 1995). Galantamine (3) is licensed in
Europe for AD treatment and was well tolerated and
significantly improved cognitive function when adminis-
tered to AD patients, in multi-centre randomized
controlled trials (Wilcock et al., 2000; Wilkinson and
Murray, 2001). Galantamine (3) is also reported to
stimulate nicotinic receptors (Pearson, 2001; Woodruff-
Pak et al., 2001), which may also enhance cholinergic
function and memory. This additional activity suggests
that galantamine (3) may have therapeutic advantages
over other AChE inhibitors.
Huperzine A. Huperzia serrata is used in TCM for
promoting circulation, for fever and as an antiinflamma-
tory and analgesic, and the prescription Qian Ceng Ta
(prepared from H. serrata) has been used in TCM to
alleviate problems of memory loss (Foster, 1989;
Skolnick, 1997). Huperzine A (4), isolated from the moss
H. serrata, is a lycopodium alkaloid related to the
quinolizidines and it inhibits AChE in vitro and in vivo
(Ashani et al., 1992; Laganière et al., 1991; McKinney et
al., 1991; Wang et al., 1986). Huperzine A (4) improved
memory retention processes in cognitively impaired aged
and adult rats (Lu et al., 1988). In a multi-centre, double-
blind trial, huperzine A (4) significantly improved
memory and behaviour in AD patients, and was reported
to be more selective for AChE than BuChE and less toxic
than the synthetic AChE inhibitors donepezil and tacrine
(Small et al., 1997; Shu, 1998). Huperzine A (4) is also
reported to decrease neuronal cell death induced by
glutamate toxicity (Skolnick, 1997), it may favourably
affect other neurotransmitter systems to improve memory
(Ou et al., 2001), and it protected cortical neurons against
b-amyloid induced apoptosis in vitro (Xiao et al., 2002).
Huperzine A (4) may also have potential in the attenuation
of memory deficits and neuronal damage that occur after
ischaemia, so may therefore be beneficial in the treatment
of cerebrovascular type dementia (Zhou et al., 2001).
Inhibitors of acetylcholinesterase: terpenoids and
other phytochemicals
Numerous essential oils and their monoterpene constitu-
ents have been investigated for their effects on AChE,
and have shown weak inhibitory activity. For example,
the essential oils from Melissa officinalis and Rosmarinus
officinalis have been reported to inhibit erythrocyte
AChE in vitro (Perry et al., 1996).
There have been conflicting reports regarding the anti-
ChE activity associated with some monoterpenes. Earlier
studies showed that neither 1,8-cineole, nor camphor, nor
borneol (10 4 M) inhibited human erythrocyte AChE in
vitro (Perry et al., 1996), but 1,8-cineole was shown to
inhibit electric eel AChE, the assay concentration being
much greater (0.78 M) (Ryan and Byrne, 1988). More
recently, 1,8-cineole and camphor have shown activity
against human erythrocyte AChE in vitro (IC50: 0.63 mM
and >10 mM, respectively) (Perry et al., 2000a). The
differences observed with the same compound against
enzyme inhibition may be explained by differences in the
AChE subtype, the assay method, or the volatility of the
monoterpenes at different assay temperatures.
Other monoterpenes that are reported to inhibit AChE
Copyright # 2003 John Wiley & Sons, Ltd.
include bornyl acetate, geraniol and limonene, which are
inhibitors of electric eel AChE (Ryan and Byrne, 1988),
g-terpinene, an inhibitor of bovine and human erythrocyte
AChE (Miyazawa et al., 1997; Perry et al., 2000a) and a-
pinene, which also inhibited erythrocyte AChE, and was
a more potent inhibitor than g-terpinene; however these
monoterpene AChE inhibitors were weak compared with
the anti-ChE alkaloid, physostigmine (1) (Perry et al.,
2000a). Citral is also reported to inhibit electric eel AChE
(Ryan and Byrne, 1988), and geraniol and linalool are
weak inhibitors of human erythrocyte AChE (Perry et al.,
2000a). The disesquiterpene gossypol is also a reversible
inhibitor of electric eel AChE (Ryan and Byrne, 1988).
The structural diversity of the active anti-ChE
terpenoids complicates the prediction of potential
structure—activity relationships. One feature associated
with AChE inhibition is a hydrophobic ligand. The
hydrophobic active site of AChE is reported to be
susceptible to hydrophobic interactions (Hansch and
Deutsch, 1966). Monoterpenes consist of a hydrocarbon
skeleton which may contribute to their anti-ChE activity.
However, no relationship between monoterpene lipo-
philicity or between molecular volume was identified in
the study by Perry et al. (2000a). Monoterpenes may be
cyclic (e.g. 1,8-cineole and a-pinene) or acyclic (e.g.
geraniol and linalool), a feature that may also influence
anti-ChE activity. Further investigations may determine
if a cyclic component, or particular functional group
favours AChE inhibition.
Considering the relatively weak anti-ChE activity of
terpenoids reported to date, it is unlikely that they may be
used therapeutically for cognitive disorders. However,
analogues of active terpenoid compounds may be
developed to enhance efficacy.
Other studies have identified the coumarin auraptene
and the sesquiterpene nootkatone from Citrus paradisi as
weak inhibitors of erythrocyte AChE (Miyazawa et al.,
2001). More recently, the stilbene oligomers (‡)-a-
viniferin and kobophenol A, from Caragana chamlague,
have also been identified as reversible and non-compe-
titive inhibitors of AChE (Sung et al., 2002). The
potential clinical relevance of these compounds requires
further investigation, but such findings indicate that
plants may yield novel AChE inhibitors, other than
alkaloids and monoterpenes, which may have advantages
in relation to efficacy and adverse-effect profile.
Phyto-oestrogens
Further research regarding the use of ORT in AD patients
is necessary to establish the potential benefits. However,
there is considerable evidence to suggest that ORT may
have a preventative effect against AD development, and
may be useful in slowing disease progression. Considera-
tion must also be given to the potential adverse effects of
ORT (e.g. carcinogenesis). Phyto-oestrogens (e.g. soy
isoflavones) are reported to improve cognitive function
(in animal studies and in humans), and may offer
protection against AD development (File et al., 2001;
Kim et al., 2001; Pan et al., 2000). The mode of action of
phyto-oestrogens to explain these observations is unclear,
and they may act similarly to ORT or via different
mechanisms. Phyto-oestrogens have not been associated
with the carcinogenic effects of ORT, and may be a more
appropriate alternative in the prevention of AD.
Phytother. Res. 17, 1–18 (2003)
 PLANTS AS A SOURCE OF ANTI-DEMENTIA TREATMENTS 5

Table 1. Some plants and isolated compounds with relevant activities in relation to treatment of cognitive disorders, including
Alzheimer’s disease

Plant Compounds isolated Traditional uses, pharmacological and clinical effects

Angelica archangelica L. Active compounds are Angelica archangelica has been used in TCM for cerebral diseases (Ross,
unknown 2001).
The crude alcohol extract of Angelica archangelica displaced nicotine
binding to nico tine receptors in a concentration dependent manner
(Perry et al., 1996), and inhibited AChE activity in vitro (Park et al., 1996).
Angelica archangelica is also reported to enhance cerebral blood ¯ow
(Ross, 2001).
Artemisia absinthium L. Compounds responsible Artemisia absinthium was used traditionally in European medicine as a
for displacement of restorative of lost or declining cognitive function.
nicotine receptor The crude alcohol extract of Artemisia absinthium displaced nicotine
binding are unknown binding to nicotine receptors in a concentration dependent manner (Perry
et al., 1996; Wake et al., 2000).
Bacopa monniera Compounds responsible Bacopa monniera has been used in Ayurvedic medicine to improve
Wettst. for activity require memory and intellect. Bacop a monniera extract is reported to facilitate
further study, but learning acquisition and showed antioxidant effects in rat frontal cortex,
activity may be due to striatum and hippocampus; bacosides A and B are reported to inhibit the
bacosides A and B amnesic effects of scopolamine in rodents (Bhattacharya et al., 2000b).
(saponins) Bacopa monniera also improved acquisition and memory in mice treated
with the anticonvulsant phenytoin (Vohora et al., 2000) and improved the
performance of rats in various learning situations (Singh and Dhawan,
1982).
Bacopa monniera may also improve cognitive processes in humans
(Stough et al., 2001).
Biota orientalis Endl. Active compounds are Biota orientalis is used in TCM for insomnia and amnesia. An herbal
unknown prescription (S-113m) composed of Biota orientalis, Panax ginseng and
Schisandra chinensis preferentially improved memory registration and
consolidation (rather than memory retrieval) in mice (Nishiyama et al.,
1995b).
Biota orientalis seed extract ameliorated the memory acquisition
disorders induced by amygdala and also basal forebrain lesions in mice
(Nishiyama et al., 1992; Nishiyama et al., 1995a).
Codonopsis pilulosa Active compounds are In TCM, Codonopsis pilulosa root is used for various disorders including
Franch. unknown amnesia, and is believed to promote blood circulation and enhance
vitality (Duke and Ayensu, 1985).
Codonopsis pilulosa extract reduced the impairment of memory
acquisition in vivo (Wang et al., 1998) and has shown nootropic effects
(Zhang and Liu, 1990).
Coptis chinensis Franch. Berberine, jatrorrhizine Coptis chinensis has been used in TCM for several conditions. A
and palmatine methanol extract fraction of Coptis chinensis, and jatrorrhizine and
(alkaloids) berberine, are inhibitors of monoamine oxidase (Kong et al., 2001),
indicating potential antidepressant activity.
Coptis chinensis, berberine and palmatine are AChE inhibitors (Huang,
1993; Park et al., 1996).
Coptis chinensis improved a scopolamine-induced learning and memory
de®cit in rats (Hsieh et al., 2000) and has shown antiin¯ammatory
(CueÂllar et al., 2001) and antioxidant activities (Liu and Ng, 2000; Song et
al., 1992).
Crocus sativus L. Crocin (carotenoid) Crocus sativus was used in TCM to treat disorders of the nervous system.
Crocus sativus extract and crocin improved ethanol-induced impairment
of learning behaviour in mice (Abe and Saito, 2000; Sugiura et al., 1995).
Crocin suppressed TNF-a-induced apoptosis of neuronally differentiated
PC-12 cells in vitro (Soeda et al., 2001).
Evodia rutaecarpa Dehydroevodiamine Evodia rutaecarpa is used in TCM for cardiotonic and analgesic effects.
Hook.f. & Thoms. and rutaecarpine Rutaecarpine inhibited COX-2 activity in vitro, and rutaecarpine and
(alkaloids), and limonin limonin were antiin¯ammatory in vivo (Matsuda et al., 1998; Moon et al.,
(nor-triterpenoid) 1999).
Evodia rutaecarpa and dehydro-evodiamine inhibited AChE in vitro, and
reversed scopolamine-induced memory impairment in rats (Park et al.,
1996). Dehydroevodiamine increased cerebral blood ¯ow in vivo (Haji et
al., 1994).

Copyright # 2003 John Wiley & Sons, Ltd. Phytother. Res. 17, 1–18 (2003)
6 M.-J. R. HOWES ET AL.

Table 1. Continued

Plant Compounds isolated Traditional uses, pharmacological and clinical effects

Hypericum perforatum Hypericin and Hypericum perforatum was used in Portuguese folk medicine for its
L. and Hypericum hyperforin (quinones) tranquillizing properties, and in Turkey for neurological disorders (Ross,
calycimum L. 2001). Hyperforin improved memory acquisition and consolidation, and
completely reversed scopolamine-induced amnesia in mice, indicating
that hyperforin (and Hypericum perforatum) may enhance cognitive
function (Klusa et al., 2001).
Hypericum perforatum extract has also shown antioxidant activity in vitro
(Hunt et al., 2001; Zheng and Wang, 2001), antiin¯ammatory activity in
vivo (Kumar et al., 2001) and anxiolytic effects in vivo (Coleta et al., 2001).
Hypericum perforatum and Hypericum calycinum were as effective as
anti depressant drugs (e.g. desipramine) in animal models (O È ztuÈrk et al.,
1996).
Hypericum perforatum possibly affects neuronal 5-HT uptake
mechanisms, and may enhance both 5-HT and noradrenaline
transmission in forebrain limbic brain circuits, which are important for
mood control (Misane and Ogren, 2001).
Meta-analyses and systematic reviews of published trials indicate
Hypericum perforatum is more effective than placebo for the treatment of
mild/moderate depression, and in some cases is of similar effectiveness
to standard antidepressants (Whiskey et al., 2001).
Lippia stoechadifolia H. Pulegone-1, 2-epoxide Pulegone-1, 2-epoxide is an insecticidal compound from Lippia
B. ‡ K. (monoterpene) stoechadifolia (Grundy and Still, 1985a). Pulegone-1, 2-epoxide was
shown to inhibit AChE in vitro (Grundy and Still, 1985b).
Magnolia of®cinalis Honokiol and magnolol The bark of the root and stem of Magnolia of®cinalis has been used in
Rehder & Wilson (biphenolic lignans) TCM to treat anxiety and nervous disturbances; the anxiolytic effects of
honokiol (Kuribara et al., 1999; Kuribara et al., 2000) and magnolol have
been attributed to their ability to potentiate GABAergic
neurotransmission (Squires et al., 1999).
A traditional Chinese prescription (Banxia Houpu), consisting of Pinellia
ternata, Poria cocos, Magnolia of®cinalis, Perilla frutescens and Zinziber
of®cinale, was antidepressant in vivo (Luo et al., 2000).
Honokiol and magnolol increased ChAT activity and inhibited AChE
activity in vitro, and increased hippocampal ACh release in vivo (Hou et
al., 2000).
Magnolia of®cinalis extract (Zhou and Xu, 1992), magnolol (Chen et al.,
2001; Kong et al., 2000; Lo et al., 1994) and honokiol (Chiu et al., 1997; Lo
et al., 1994) are reported to have antioxidant activity, and magnolol
protected neurons against chemical hypoxic damage or necrotic cell
death in cortical neuron-astrocyte cultures in vitro (Lee et al., 1998).
Magnolol showed antiin¯ammatory activity in vitro and in vivo, perhaps
via inhibition of COX and 5-LOX (Wang et al., 1992, 1995).

that strengthens nervous function and memory. It is

PHARMACOLOGICAL BASIS OF PLANTS USED
TRADITIONALLY FOR COGNITIVE
DISORDERS
Some plants that are used to treat the symptoms of
cognitive disorders such as AD, and plants that have
shown activities that may be useful in the treatment of
AD are discussed below. Various other plant species have
shown favourable effects in relation to cognitive
disorders, or relevant pharmacological activities indicat-
ing the potential for use in AD therapy (insecticidal
activity, for example, which may be an indication of anti-
ChE activity), some of which are summarized in Table 1.
Centella asiatica L
Centella asiatica (Umbelliferae) leaf is an ancient
Ayurvedic remedy, which is used as a revitalizing herb
Copyright # 2003 John Wiley & Sons, Ltd.
reported to restore youth, memory and longevity
(Kapoor, 1990). For example, an Ayurvedic formulation
composed of four herbs, including C. asiatica, is used to
retard age and prevent dementia, and the herb combined
with milk is given to improve memory (Manyam, 1999).
The herb is also taken as a tonic for poor digestion and
rheumatism; the latter suggesting it may have antiin-
flammatory effects. C. asiatica is also used in TCM for
combating physical and mental exhaustion (Brinkhaus et
al., 2000; Duke and Ayensu, 1985).
An essential oil (0.1% of the plant), containing
monoterpenes and sesquiterpenes, has been extracted
from C. asiatica leaf (Asakawa et al., 1982; Brinkhaus et
al., 2000). The monoterpenes present in the essential oil
from C. asiatica include bornyl acetate, a-pinene, b-
pinene and g-terpinene (Asakawa et al., 1982), which are
known to inhibit AChE (Miyazawa et al., 1997; Perry et
al., 2000a; Ryan and Byrne, 1988). Various alkaloids
have also been isolated from C. asiatica, including
Phytother. Res. 17, 1–18 (2003)
 PLANTS AS A SOURCE OF ANTI-DEMENTIA TREATMENTS
hydrocotylin (Duke and Ayensu, 1985), but they have not
yet been evaluated for activity against AChE.
Some studies have been conducted regarding the
pharmacological basis of the reputed antiamnesic effect
of C. asiatica. An alcohol extract of the leaves is reported
to be tranquillizing in rats, an activity that was attributed
to a triterpene, brahmoside (Kapoor, 1990; Sakina and
Dandiya, 1990). In mice, an extract of C. asiatica leaf
was sedative, antidepressant and showed cholinomimetic
activity, which was blocked by atropine (Sakina and
Dandiya, 1990). These results indicate that C. asiatica
may be appropriate to treat symptoms of depression and
anxiety in AD, and may also enhance cholinergic activity
and thus, cognitive function. The mechanism for the
potential cholinergic effects of the herb remains to be
established. An aqueous extract of C. asiatica leaf
improved learning and memory processes in rats, and
modulated dopamine, 5-hydroxytryptamine (5-HT) and
noradrenaline systems in rat brain in vivo (Nalini et al.,
1992). These results suggest that the more polar
compounds (perhaps triterpene saponins) present in C.
asiatica leaf may enhance cognitive function by influen-
cing neurotransmitter systems in the CNS. The triterpene
asiatic acid and its derivatives have been shown to protect
cortical neurons from glutamate-induced excitotoxicity
in vitro (Lee et al., 2000). Further studies are necessary to
confirm this to identify any potential relevance in AD
treatment.
Ginkgo biloba L
Ginkgo biloba (Coniferae) has been used in TCM for
respiratory disorders, and its use in Western medicine for
circulatory disorders dates back to the 1960s (Kenner and
Requena, 1996). G. biloba has been used traditionally in
Iran to improve memory loss associated with blood
circulation abnormalities (Ross, 2001). This herb has
been subjected to numerous investigations regarding its
potential in cognitive disorders. The G. biloba extract
EGb 761 has shown favourable effects on cerebral
circulation and neuronal cell metabolism (Heiss and
Zeiler, 1978; Loffler et al., 2001; Tea et al., 1987), on the
muscarinic cholinergic system (Kristofiková et al., 1992),
and showed antioxidant activity (Barth et al., 1991;
Marcocci et al., 1994; Topic et al., 2002). EGb761 was
also neuroprotective against b-amyloid- and NO-induced
toxicity in vitro (Bastianetto et al., 2000a, 2000b), and
could reduce apoptosis both in vitro and in vivo
(Schindowski et al., 2001; Yao et al., 2001).
G. biloba extracts have also been evaluated for their
effect on cognitive function. Treatment with G. biloba
extracts attenuated scopolamine-induced amnesia in rats
(Chopin and Briley, 1992), enhanced memory retention
in young and old rats (Petkov et al., 1993) and improved
short-term memory in mice (Stoll et al., 1996).
The clinical efficacy of G. biloba extracts, including
EGb 761, was observed (modest improvements in
cognitive function) following administration to AD and
non-AD patients in various studies, including rando-
mized, double-blind, placebo-controlled, multi-centre
trials (Hofferberth, 1994; Kanowski et al., 1997; Le Bars
et al., 1997, 2000; Oken et al., 1998; Rigney et al., 1999).
The compounds responsible for these observations
require further investigation, but activity is perhaps due
to vasodilatory flavonoids, although other mechanisms of
Copyright # 2003 John Wiley & Sons, Ltd.
7
action may also be responsible for the favourable effects
observed. For example, ginkgolide B from G. biloba is a
platelet-activating factor (PAF) antagonist (Braquet et
al., 1994), which indicates activity against inflammatory
processes.
It is apparent that G. biloba can be useful in the
treatment of AD symptoms, but further research is
necessary to identify appropriate dosing regimens, the
potential effects of long-term use, interactions with other
medicines, and standardization of extracts must also be a
consideration.
Melissa officinalis L
Melissa officinalis (Labiatae) leaf has been used as a
medicinal plant for more than 2000 years. In traditional
European medicine M. officinalis was used as a calming
and strengthening remedy and to treat migraines,
melancholia, neuroses and hysteria, and the plant has
been acclaimed for promoting long life and for restoring
memory (Bisset, 1994; Kenner and Requena, 1996;
McVicar, 1994; Yarnell, 1998). In 1751, the herbalist
John Hill stated that M. officinalis was ‘Good for
disorders of the head and stomach’ (Crellin and Philpott,
1990), indicating potential benefits for the use of Melissa
officinalis for CNS disorders. In Arabic medicine it was
used to treat depression (McVicar, 1994), and it was also
used traditionally in Greek medicine to treat hysteria
(Malamas and Marselos, 1992). The Commission E
Monograph in Germany approves the use of M. officinalis
for nervous insomnia. In modern alternative medicine, M.
officinalis essential oil is used in aromatherapy to
alleviate depression and insomnia (McVicar, 1994).
The primary monoterpenes identified in the essential
oil of M. officinalis include citral (geranial and neral)
(Bisset, 1994; Guenther, 1949; Şarer and Kökdil, 1991;
Tittel et al., 1982) which is a weak inhibitor of AChE
(Ryan and Byrne, 1988).
M. officinalis has been the subject of research
regarding its potential as a sedative and anxiolytic,
activities that may be appropriate to provide symptomatic
relief for behavioural problems such as agitation in AD.
M. officinalis leaf was reported to alleviate mild anxiety
and nervousness in a double-blind study, and in
combination with Valeriana officinalis root, was reported
to be as effective as triazolam, and did not cause
drowsiness or impair concentration the next day (Yarnell,
1998). A hydroalcohol (30% ethanol) extract of M.
officinalis leaf was sedative in mice and potentiated
barbiturate induced sleep, but the M. officinalis essential
oil did not demonstrate these sedative effects (Soulimani
et al., 1991).
Other activities of M. officinalis leaf extracts that may
be useful for AD therapy include antioxidant effects
(Hohmann et al., 1999; Lamaison et al., 1991; Marinova
and Yanishlieva, 1997; Tagashira and Ohtake, 1998) and
binding to muscarinic and nicotinic receptors in vitro
(Perry et al., 1996; Wake et al., 2000), which suggests
that favourable effects on cholinergic function may occur
in AD patients.
Polygala tenuifolia Willd
Polygala tenuifolia (Polygalaceae) root is used in TCM
Phytother. Res. 17, 1–18 (2003)
8 M.-J. R. HOWES ET AL.
Table 2. Inhibition of acetylcholinesterase by extracts and oils of sage
Plant extract/compound Assay concentration
Positive controls
Tacrine
Physostigmine
Test substances
S. of®cinalis oil
S. of®cinalis ethanol extract (dried)
S. lavandulaefolia oil
as a cardiotonic and cerebrotonic, as a sedative and
tranquillizer, and for amnesia, forgetfulness, neuritis,
nightmares and insomnia (Chang and But, 1987; Duke
and Ayensu, 1985). According to the Chinese Materia
Medica, the root is supposed to have a special effect upon
the will and mental powers, giving strength of character,
improving understanding, strengthening the memory, and
increasing physical powers.
There have been numerous studies regarding the
reputed memory enhancing potential of P. tenuifolia
root. For example, the traditional Chinese prescription
DX-9386, composed of four herbs (Panax ginseng,
Polygala tenuifolia, Acorus gramineus and Poria cocos)
has shown favourable effects in relation to AD symptoms
in several animal models. DX-9386 improved motor
activity, reduced lipid peroxidation, ameliorated memory
impairment and prolonged the lifespan of senescence
accelerated mice and, ameliorated the ethanol- and
scopolamine-induced memory impairment in mice
(Nishiyama et al., 1994a, 1994b, 1994c, Zhang et al.,
1994b). Further investigations are required to clarify the
contribution of each of the four herbs in DX-9386 to the
observed pharmacological activities.
Kami-utan-to (KUT), a prescription containing 13
herbs including P. tenuifolia root, is used in traditional
Japanese medicine to treat psychoneurological diseases.
KUT dose-dependently upregulated choline acetyltrans-
ferase (ChAT) activity and increased nerve growth factor
(NGF) secretion in vitro, and improved passive avoid-
ance behaviour and induced ChAT activity in the cerebral
cortex of aged rats, and in scopolamine-induced memory
impaired rats in vivo (Yabe et al., 1997; Yamada and
Yabe, 1997). The effects on ChAT activity and NGF
secretion in vitro were not as pronounced when treated
with KUT in the absence of P. tenuifolia root, but P.
tenuifolia root extract alone did upregulate ChAT activity
and increase NGF secretion in vitro (Yabe et al., 1997;
Yamada and Yabe, 1997). The cinnamic acid derivative
sinapinic acid, from P. tenuifolia root increased ChAT
activity in the frontal cortex in brain-lesioned rats (Yabe
et al., 1997). These results suggest that P. tenuifolia root,
particularly the cinnamic acid derivatives, significantly
contribute to the pharmacological activities of KUT, and
may explain the reputed beneficial effects of KUT in
Japanese medicine. KUT treatment in AD patients is also
reported to improve memory-related behaviour (Yamada
and Yabe, 1997). P. tenuifolia also inhibited AChE
activity in vitro (Park et al., 1996).
An aqueous extract of P. tenuifolia root inhibited
interleukin-1 (IL-1) mediated tumour necrosis factor
(TNF) secretion by astrocytes in vitro (Kim et al., 1998)
and also dose-dependently inhibited ethanol-induced IL-
Copyright # 2003 John Wiley & Sons, Ltd.
% Inhibition (SD)
2
2.0  10 mM 50  0.1
2
4.5  10 mM 50  0.1
0.1 mg/mL 52.4  0.8
2.5 mg/mL 68.2  15.6
0.1 mg/mL 63.0  3.7
1 secretion in vitro (Koo et al., 2000). This suggests that
the reputed favourable effects of the herb in CNS
disorders, may also involve antiinflammatory activity,
but this requires confirmation in vivo. The aqueous
extract of P. tenuifolia root is also reported to prolong
hexobarbital sleeping time in mice (due to onjisaponin F)
(Chang and But, 1987; Huang, 1993; Tang and
Eisenbrand, 1992). Thus, it may have potential as a
tranquillizer.
Salvia lavandulaefolia Vahl. and Salvia officinalis L
Research into historical literature has revealed that some
activities of sage, particularly its reputation as being good
for the memory, may be relevant to AD treatment (Perry
et al., 1998). Thus in his late 16th century English herbal,
Gerard writes about sage ‘It is singularly good for the
head and brain and quickenethe the nerves and memory’.
Culpeper, writing about 50 years later says that ‘It also
heals the memory, warming and quickening the senses’
whilst Hill in 1756 poignantly encapsulates the tragic
effects associated with ageing by stating ‘Sage will retard
that rapid progress of decay that treads upon our heels so
fast in latter years of life, will preserve faculty and
memory more valuable to the rational mind than life
itself’ (Perry et al., 2001). These ancient reports, together
with current usage, which indicates that sage might
possess antiinflammatory properties and also alleviate
conditions associated with oestrogen imbalance. Newall
et al., (1996), suggest that sage might be of possible use
in AD. Numerous in vitro and in vivo tests have been
employed to monitor the effects of sage extracts on some
of the factors associated with AD, or with a reduction in
its incidence.
Cholinesterase inhibition in vitro. An ethanol extract,
the steam-distilled oil of S. officinalis (Labiatae) and the
oil of S. lavandulaefolia (Labiatae) have been investi-
gated for anti-ChE activity. It was found that all three
samples gave inhibition of AChE at quite low concentra-
tions (Perry et al., 1996) (Table 2). This activity was of
considerable interest since previous AChE inhibitors
were amines, the naturally occurring types being the
alkaloids, and these compounds were not known to exist
in the Salvia species tested.
The cholinesterase inhibition shown by the S. lavan-
dulaefolia oil was likely to be due to the cyclic
monoterpenes 1,8-cineole and a-pinene, which were
shown to inhibit AChE in vitro, with some contribution
from other constituents perhaps by acting synergistically
(Perry et al., 2001). However, the monoterpenes were
Phytother. Res. 17, 1–18 (2003)
 PLANTS AS A SOURCE OF ANTI-DEMENTIA TREATMENTS
considerably less active, by a factor of at least 103, than
the alkaloid inhibitors such as physostigmine (1) (Perry et
al., 2000a). It was also reported that the inhibitory
activities of the major terpene constituents did not readily
account for the inhibitory effect of the total S.
lavandulaefolia essential oil. It was calculated that 50%
enzyme inhibition for the oil would occur at approxi-
mately 160 mg/L if the values of the constituent terpenes
individually were taken into account—approximately
5000 times the concentration of the essential oil
(0.03 mg/L) providing 50% inhibition. This suggested
either that there was a high degree of synergy in the
combined action of the terpenes, or, less likely, that there
was present in the oil an as yet unidentified minor
constituent of high potency.
Antioxidant activity in vitro. An aqueous methanol
extract of S. officinalis dose-dependently inhibited lipid
peroxidation (Hohmann et al., 1999). Several antioxidant
compounds have been identified in S. officinalis, includ-
ing caffeic acid, carnosic acid, carnosol, rosmarinic acid
(Cuvelier et al., 1996; Wang et al., 2000), salvianolic
acids I, K and L and various other phenolic compounds
(Lu and Foo, 2001, 2001b; Wang et al., 1999). Weak
antioxidant effects were also shown to be present in an
ethanol extract of S. lavandulaefolia (when compared
with the standard antioxidant 10 mM propyl gallate), and
both the water-soluble and chloroform-soluble fractions
of this extract gave similar activity (Perry et al., 2001).
Some of the individual components of the volatile oil
from S. lavandulaefolia have been investigated and
antioxidant effects were observed with 1, 8-cineole, a-
pinene and b-pinene, but a prooxidant effect was given
by camphor, a relatively major component of the oil
(Perry et al., 2001). Given that the monoterpenoids with
antioxidant activity in this study were present in the
essential oil at a slightly higher relative percentage
(collectively over 30%) than camphor (27% of essential
oil), the prooxidant activity of camphor may not have its
effect in the whole essential oil. Further investigations are
necessary, in particular in vivo, before characterizing any
of the extracts or oil constituents as antioxidant or
prooxidant.
Effect of extract on eicosanoid synthesis in vitro. An
ethanol extract of S. lavandulaefolia showed only weak
inhibition of eicosanoid synthesis, giving only about 10%
inhibition of thromboxane-B2 (TXB2) synthesis but more
inhibition (60%) of leukotriene B4 (LTB4) synthesis;
fractionation of the ethanol extract was conducted to give
a chloroform-soluble portion and a water-soluble frac-
tion, the latter was found to be less active (Perry et al.,
2001).
Hexane and chloroform extracts of S. officinalis dose-
dependently inhibited croton oil-induced ear oedema in
mice, with the main active compound being identified as
ursolic acid, but the methanol extracts and the essential
oil were much less active (Baricevic et al., 2001). The
essential oil constituents of S. lavandulaefolia have also
been evaluated for antiinflammatory effects. The S.
lavandulaefolia oil constituent a-pinene (comprising
5% of the essential oil) was the only constituent present
which gave significant activity (52% inhibition at
200 mM) and showed weak selectivity for inhibition of
LTB4 generation. LTB4 is produced via the enzyme 5-
lipoxygenase (5-LOX), the gene of which is upregulated
Copyright # 2003 John Wiley & Sons, Ltd.
9
during neurodegeneration and although the role of this
inflammatory mediator in AD is not entirely apparent,
selective inhibition over cyclo-oxygenase (COX) may be
relevant therapeutically (Sugaya et al., 2000).
Oestrogenic activity in vitro. Dose-dependent oestro-
genic activity was present in the ethanol extract (which
appeared to be concentrated in the water-soluble fraction)
of S. lavandulaefolia (Perry et al., 2001). S. lavandulae-
folia essential oil showed oestrogenic activity in vitro,
which was not dose dependent and of the five
monoterpenoid constituents of S. lavandulaefolia essen-
tial oil screened, only geraniol (0.1 mM–2 mM; <1% of
essential oil) exhibited oestrogenic activity (which was
weak in comparison with the standard oestrogenic
compound, 17b-oestradiol (1000 nM) (Perry et al.,
2001). The potential oestrogenic activity of the sage
extracts and essential oil constituents require further
investigation.
In vivo and clinical studies. Oral administration of S.
lavandulaefolia essential oil (in a standard dose of
sunflower oil) once daily for 5 days to rats, decreased
striatal AChE activity with doses of 20 mL and at doses of
50 mL, a decrease in AChE activity was observed in both
the striatum and the hippocampus compared with the
control treated rats (administered sunflower oil alone); at
neither dose was there a change in the AChE activity in
the cortex of the S. lavandulaefolia treated group
compared witht the control group (Perry et al., 2001).
Thus, it is apparent that following oral administration,
one or more constituents of the S. lavandulaefolia oil or
their metabolites, reach the brain (crossing the gastro-
intestinal and blood–brain barriers) and inhibit AChE in
select brain areas, consistent with evidence of inhibition
of the brain enzyme in vitro (Perry et al., 1996).
So far, no clinical studies on patients with AD have
been reported but a recent study describes the effect of
sage in healthy volunteers (Kennedy et al., 2001). In this
placebo-controlled, double-blind, balanced, cross-over
design study, 20 participants received 50 mL, 100 mL and
150 mL of a standardized oil extract of S. lavandulaefolia
and vehicle (sunflower oil) alone. Doses were adminis-
tered on different days, each separated by a 7-day wash-
out period using a pseudo-random treatment order.
There were a number of significant effects on
cognition associated with the lowest (50 mL) dose of
Salvia. These included improvements in both immediate
and delayed word recall scores coupled with decrements
in both accuracy and speed of attention. The same dose
was associated with reductions in self-rated ‘alertness’ at
2.5 h and ‘calmness’ at 4 h and 6 h. Following the 150 mL
dose both ‘calmness’ and ‘contentedness’ were reduced
across most time-points. These results represent the first
systematic evidence that Salvia is capable of acute
modulation of mood and cognition in healthy young
adults.
Salvia miltiorrhiza Bung
Throughout history Salvia miltiorrhiza (Labiatae) has
been used for the treatment of a variety of medical
conditions. The dried root of S. miltiorrhiza is red in
colour, and was therefore used in folk medicine for the
management of blood disorders. It is prescribed in TCM
Phytother. Res. 17, 1–18 (2003)
10 M.-J. R. HOWES ET AL.
to stabilize the heart and calm nerves (Huang, 1993).
Official indications for the root include treatment of
blood circulation disorders, insomnia, neurasthenia and
alleviation of inflammation (Tang and Eisenbrand, 1992).
S. miltiorrhiza, or Chinese sage, has been the subject of
thorough investigation, and consequently numerous
pharmacological activities that may be relevant in CNS
disorders, including AD, have been identified. S.
miltiorrhiza has been employed for the treatment of
cerebral vascular disease, and there are several studies to
investigate possible mechanisms for the protective effect
of S. miltiorrhiza against cerebral ischaemia.
S. miltiorrhiza root has been implicated in attenuating
dysfunction of vasoactive intestinal peptide (VIP), a
neuropeptide distributed within the gastrointestinal tract
and CNS, which may participate in the changes that occur
in cerebral ischaemia (Kuang et al., 1989). Distribution
abnormalities of the neuropeptide substance P have also
been associated with some CNS disorders, including AD.
Decreased levels of substance P have been suggested as a
consequence of neuronal damage following cerebral
ischaemia; S. miltiorrhiza root has been implicated in
protecting neurons from ischaemia (Kuang et al., 1991),
and so may actively protect against cerebral ischaemia
and perhaps other CNS disorders via this mechanism.
Other beneficial effects of S. miltiorrhiza root against
cerebral ischaemia have also been explored. S. miltior-
rhiza root may inhibit neuronal cell death by inhibition of
presynaptic glutamate release (Kuang and Xiang, 1994),
and it has been suggested that inhibition of nitric oxide
(NO) formation may also explain CNS protective effects
observed with S. miltiorrhiza root (Kuang et al., 1996a).
It should also be considered that the biological function
of NO has been suggested to involve the effects of
excitatory amino acids, including their effects on brain
development, learning and memory (Moncada et al.,
1991). This physiological role may aid the explanation of
the effects of S. miltiorrhiza root on the CNS. Further
investigations indicate S. miltiorrhiza root may modify
ischaemic cell changes by modulating somatostatin, a
CNS neuropeptide that has been implicated in learning
and memory (Kuang et al., 1993).
S. miltiorrhiza root may offer an additional therapeutic
approach to management of stroke and ischaemia.
Reperfusion to aid recovery of ischaemia can cause
further brain damage. During reperfusion, metabolism of
free fatty acids from the breakdown of lipid membranes
during ischaemia has been proposed to generate oxygen
free radicals leading to further brain injury (Traystman et
al., 1991). S. miltiorrhiza root has been shown to offer
protection against this process by reducing lipid peroxi-
dation (Kuang et al., 1996b; Liu et al., 1992; Peigen et
al., 1996; Zhao et al., 1996).
The anti-oxidant effects of S. miltiorrhiza root have
been studied and several compounds have been identified
with significant antioxidant activity. Several quinones
isolated from S. miltiorrhiza root have demonstrated an
antioxidant effect in lard, with dihydrotanshinone,
tanshinone I, methylene tanshinquinone and cryptotan-
shinone providing significant antioxidant activity; tan-
shinone IIa has shown no antioxidant activity (Weng and
Gordon, 1992; Zhang et al., 1990). Other components of
S. miltiorrhiza root have displayed antioxidant effects
including salvianolic acids A and B (compounds found to
protect against memory impairment induced by cerebral
ischaemia in mice (Du et al., 2000; Guanhua and Juntian,
Copyright # 2003 John Wiley & Sons, Ltd.
1997)), rosmariquinone (also known as miltirone) and
several other phenolic compounds (Huang and Zhang,
1992; Kang et al., 1997; Liu et al., 1992; Weng and
Gordon, 1992). Such antioxidant compounds may be
useful in AD therapy.
‘Salvia compositus’ is a herbal mixture of the Chinese
herbs S. miltiorrhiza and Delbergia odorifera, which has
been used traditionally for management of coronary heart
disease (Fan et al., 1979). Investigations suggest this
herbal remedy has a potential role in antioxidation of
lipids (Zhang et al., 1994a), and in amelioration of
cerebral oedema (Kuang et al., 1995), providing further
evidence for therapeutic advantage in cerebral disorders.
‘Salvia compositus’ has shown effects on electrical
activities of the cerebral cortex, showing a CNS
depressant action (Fan et al., 1979). There are also
reports of S. miltiorrhiza root being analgesic and
sedative. A reduction in the spontaneous activity of
mice, and increased duration of the hypnotic action
induced by chloral hydrate and barbiturates in the
presence of S. miltiorrhiza root have been observed
(Huang, 1993; Chang and But, 1987). Further investiga-
tion has established a structure–activity relationship for
rosmariquinone, a quinone isolated from S. miltiorrhiza
root, as an active central benzodiazepine receptor ligand
(Chang et al., 1991). Rosmariquinone and perhaps other
quinones from S. miltiorrhiza may explain the tranquil-
lizing effects observed, and could be developed as
anxiolytic agents for managing the behavioural distur-
bances often observed in AD patients.
Tanshinones isolated from S. miltiorrhiza root have
demonstrated antiinflammatory activity in mice and were
active against 5-LOX in porcine leukocytes, but were not
as active as the crude extracts (Chang and But, 1986;
Paulus and Bauer, 2000). The tanshinones are also
reported to show weak oestrogenic activity (Chang and
But, 1986). These activities require further investigation
for confirmation, but could be relevant in AD therapy.
Other studies have reported other Salvia species to
have pharmacological activities, or reputed activities in
traditional medicine, that may be relevant in the
treatment of various CNS disorders. For example, S.
guaranitica has been used by Amazonian Indians for its
sedative action; this use may be explained by the
constituents cirsiliol and a caffeic acid ethyl ester, which
are benzodiazepine receptor ligands (Marder et al.,
1996). Further assessment of the relevance of Salvia
species in CNS disorders, is discussed by Perry et al.
(2000b).
Withania somnifera (L.) Dun
Withania somnifera (Solanaceae) root (ashwagandha) is
one of the most highly regarded herbs in Ayurvedic
medicine and its use dates back almost 4000 years. It is
classed among the rejuvenative tonics (‘Rasayanas’),
which was emphasized by the Ayurvedic scholar Charaka
(10BC) who wrote about W. somnifera, ‘One obtains
longevity, regains youth, gets a sharp memory and
intellect and freedom from diseases, gets a lustrous
complexion, and strength of a horse’ (Upton, 2000). The
herb is also traditionally used to treat inflammatory
conditions, such as arthritis.
Nicotine is reported to be present in W. somnifera root
(Kapoor, 1990), but some investigations have not
Phytother. Res. 17, 1–18 (2003)
 PLANTS AS A SOURCE OF ANTI-DEMENTIA TREATMENTS
detected its presence (Das et al., 1964; Schwarting et al.,
1963). The presence of nicotine may explain the reputed
activity of W. somnifera in Ayurvedic medicine,
considering that nicotine has been associated with
cognitive enhancement and protection against AD
development (Graves and Mortimer, 1994; Newhouse
and Kelton, 2000; Sahakian et al., 1989; van Duijn and
Hofman, 1991).
There have been numerous studies regarding the
cognitive enhancing activities of W. somnifera. For
example some steroidal derivatives that have been
isolated from W. somnifera root are the sitoindosides IX
and X, which augmented learning acquisition and
memory in both young and old rats (Ghosal et al.,
1989). The mechanisms for this effect are unclear, but
may involve modulation of cholinergic neurotransmis-
sion, as an extract containing the sitoindosides VII–X
and withaferin A (a steroidal withanolide aglycone also
from W. somnifera root) was administered to mice and
effects on the neurotransmitter systems in the brain were
observed. The results showed that the extract enhanced
AChE activity in the lateral septum and globus pallidus
and decreased AChE activity in the vertical diagonal
band, enhanced muscarinic M1 receptor binding in the
lateral and medial septum and in the frontal cortices, and
increased muscarinic M2 receptor binding sites in
cortical regions, but did not affect g-aminobutyric acid
(GABA)A, benzodiazepine receptor binding, nor N-
methyl-D-aspartate (NMDA) or amino-3-hydroxy-5-
methylisoxasole-4-propionic acid (AMPA) glutamate
receptor subtypes (Schliebs et al., 1997). The extract
containing the sitoindosides VII–X and withaferin A
also reversed the ibotenic acid-induced cognitive deficit
and reversed the reduction in cholinergic markers (e.g.
ACh, ChAT) in rats (Bhattacharya and Kumar, 1995).
The reputed cognition enhancing effects of W. somni-
fera root may therefore be explained by a preferential
action on cholinergic neurotransmission in the cortical
and basal forebrain, brain areas involved in cognitive
function. These observations indicate that the sitoindo-
sides VII–X and withaferin A could have potential in
AD therapy.
The root extract of W. somnifera also reversed
scopolamine-induced disruption of acquisition and atten-
tion, and attenuated amnesia following electroconvulsive
shock in mice, effects that are possibly attributed to the
root extract having nootropic activity (Dhuley, 2001).
A methanol extract of W. somnifera root dose-
dependently promoted dendrite formation in human
neuroblastoma cells in vitro (Tohda et al., 2000). If this
effect occurred in the CNS, treatment of AD patients with
the root extract may promote synaptic formation, which
involves neurite outgrowth; thus cholinergic function
may be enhanced. A root preparation of W. somnifera has
also been shown to significantly reduce the number of
degenerating cells in the hippocampal brain region of
stressed rats, which indicates the root extract may have
potential neuroprotective effects in neurodegenerative
disorders (Jain et al., 2001).
The glycowithanolides showed anxiolytic and anti-
depressant activities in rats (Bhattacharya et al., 2000c),
which may be applicable in the symptomatic treatment of
AD. An alkaloid extract also had tranquillizing effects in
vivo, and potentiated barbiturate-, ethanol- and urethane-
induced hypnosis in mice (Malhotra et al., 1965). The
pharmacological basis for these observations is unknown,
Copyright # 2003 John Wiley & Sons, Ltd.
11
but could reflect the reported GABA-mimetic effect of W.
somnifera extract (Mehta et al., 1991).
W. somnifera root and some constituents are also
reported to have antioxidant and antiinflammatory
activities, which may also be relevant in AD therapy.
The crude extract is reported to inhibit lipid peroxidation
in vitroand in vivo (Dhuley, 1998; Panda et al., 1997).
The root extract and the glycowithanolides (consisting of
equimolar concentrations of sitoindosides VII–X and
withaferin A) are hepatoprotective in rats and mice, an
effect attributed to the antioxidant activity against hepatic
lipid peroxidation (Bhattacharya et al., 2000a; Chaurasia
et al., 2000).
The compounds responsible for antioxidant activity
include the withanolides (Bhattacharya et al., 2001; Mills
and Bone, 2000; Mishra et al., 2000; Scartezzini and
Speroni, 2000; Upton, 2000), but other compounds in the
root may also be antioxidant. The glycowithanolides
decreased lipid peroxidation in various tissues including
the brain in rodents, and both the glycowithanolides and
the sitoindosides (VII–X) enhanced catalase and glu-
tathione peroxidase activities in rat frontal cortex and
striatum (Bhattacharya et al., 1997, 2001; Chaurasia et
al., 2000).
A root extract was effective against arthritis in rats
(Begum and Sadique, 1988) and reduced serum protein
levels (e.g. a2-macroglobulin, an indicator of inflamma-
tory conditions) (Anbalagan and Sadique, 1981a, 1981b,
1985), and in a double-blind, placebo-controlled, cross-
over study, treatment in patients with osteoarthritis
resulted in an improvement in symptoms (Kulkani et
al., 1991). W. somnifera administration to mice treated
with a carcinogen reduced IL-1 and TNF-a levels
(Dhuley, 1997), which may also be relevant in AD,
considering the possible involvement of these inflamma-
tory mediators in senile plaque formation and neurode-
generation. W. somnifera leaves are also reported to have
antiinflammatory activity (Sudhir et al., 1986). The
numerous pharmacological activities of W. somnifera
root indicate that this herb may have multiple beneficial
effects in AD patients; this also emphasizes the
advantages that the complex mixture of an extract may
have over a pure compound.
CONCLUSIONS
It is apparent that a variety of plants show, or have the
potential to show, numerous activities that may be
relevant to the treatment of neurodegenerative disorders
such as AD. The majority of studies have focused on the
anti-ChE alkaloids, such as physostigmine (1) and
galantamine (3). This is perhaps a reflection of the
relative success of the use of AChE inhibitors in AD
patients, and a lack of understanding of the pathological
mechanisms that occur in AD and the subsequent targets
for treatment. Although some plants, such as Ginkgo
biloba and Withania somnifera, have shown beneficial
effects on cognitive function, further studies regarding
the compounds responsible for activity are necessary, to
identify which compounds are responsible for the
pharmacological activities observed, or if compounds
act synergistically to enhance activity. For many of the
plants and compounds that have demonstrated activities
relevant to AD therapy, the clinical data are very limited.
Phytother. Res. 17, 1–18 (2003)
12 M.-J. R. HOWES ET AL.
Clinical efficacy and potential toxicity of active plants
and compounds in larger trials requires further assess-
ment, before recommendations concerning their routine
use can be identified.
In conclusion, it is apparent that the pharmacological
activities of plants often appear to reflect their uses in
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