www.elsevier.com/locate/brainresrev

Brain Research Reviews

Review

Can herbs provide a new generation of drugs for treating

Alzheimer’s disease?

Thimmappa S. Anekonda, P. Hemachandra Reddy*

Neurogenetics Laboratory, Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA

Accepted 16 September 2005

Available online 2 November 2005

Abstract

The overall aim of this review is to discuss cellular mechanisms at work in the progression of AD and current therapeutic strategies for

treating AD, with a focus on the potential efficacy of herbal treatments. Recent advances in molecular, cellular, and animal model studies

have revealed that formation of the 4-kDa amyloid beta peptide is a key factor in the development and progression of AD. Several cellular

changes have been identified that are related to amyloid beta plaques and neurofibrillary tangles found in the autopsied brains of AD patients

and in AD animal models. Several therapeutic strategies have been developed to treat AD, including anti-inflammatory, anti-oxidant, and

anti-amyloid approaches. Recently, herbal treatments have been tested in animal and cellular models of AD and in clinical trials with AD

subjects. In AD animal models and cell models, herbal extracts appear to have fewer adverse effects than beneficial effects on Ah and

cognitive functions. These extracts have multi-functional properties (pro-cholinergic, anti-oxidant, anti-amyloid, and anti-inflammatory), and

their use in the treatment of AD patients looks promising. The chemical compositions of herbs and their potential for alleviating or reducing

symptoms of AD or for affecting the disease mechanism need to be further studied.

D 2005 Elsevier B.V. All rights reserved.

Theme: Disorders of the nervous system

Topic: Degenerative disease: Alzheimer’s—miscellaneous

Keywords: Alzheimer’s disease; Animal model; Bioavailability; Herbal drug; In vitro model; Mitochondria

Contents

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1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. Cellular changes in AD progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Therapeutic strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Herbal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.1. Herbs tested for anti-Ah and related effects in AD models . . . . . . . . . . . . . . . . . . . . . . . . .

4.1.1. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.1.2. In vitro models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.2. Herbs tested for anti-oxidant or anti-apoptotic effects in AD models . . . . . . . . . . . . . . . . . . . .

4.2.1. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.2.2. In vitro models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

0165-0173/$ - s

doi:10.1016/j.br

Abbreviation

BBB, blood–b

pheochromocyto

* Correspondi

E-mail addr

50 (2005) 361 – 376

ee front matter D 2005 Elsevier B.V. All rights reserved.

ainresrev.2005.09.001

s: Ah, amyloid beta; AChE, acetylcholinesterase; AD, Alzheimer’s disease; APP, amyloid precursor protein; ATP, adenosine triphosphate;

rain barrier; FAD, familial Alzheimer’s disease; FDA, Federal Drug Administration; NFTs, neurofibrillary tangles; PC12 cells,

ma cells; ROS, reactive oxygen species; SAD, sporadic Alzheimer’s disease; NO, nitric oxide; TrkA, tyrosine kinase receptor A

ng author. Fax: +1 503 418 2501.

ess: reddyh@ohsu.edu (P.H. Reddy).

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T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376362

4.3. Herbs tested for inhibiting AChE or NMDA receptors and enhancing synaptic functions in AD models .

4.3.1. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.3.2. In vitro models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.4. Herbs tested for anti-inflammatory effects in AD models . . . . . . . . . . . . . . . . . . . . . . . . . .

4.5. Mixtures of herbs for treating AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5. Clinical trials on herbal drugs, using AD patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6. What makes herbs particularly suitable for treating AD?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.1. Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.2. The blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.3. Toxic and adverse drug effects and drug-drug interaction. . . . . . . . . . . . . . . . . . . . . . . . . .

6.4. Synergistic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

1. Introduction

Alzheimer’s disease (AD) is a complex, multifactorial,

heterogeneous mental illness, which is characterized by an

age-dependent loss of memory and an impairment of

multiple cognitive functions [82,112,113,126,139]. AD is

associated with the presence of intracellular neurofibrillary

tangles (NFTs) and extracellular amyloid beta (Ah)plaques, loss of neuronal subpopulations, synaptophysin

immunoreactivity of presynaptic terminals, loss of chol-

inergic fibers, proliferation of reactive astrocytes and

microglia, and mitochondrial dysfunction [43,56,79,112,

114,115,126,127,138,142]. With human life span increas-

ing and with decreasing cognitive functions in elderly

individuals with AD-related dementia, AD has become a

major health problem in society. Early detection, preven-

tion, and therapeutic interventions are urgently needed to

minimize the ill effects of this devastating disease [113].

Based on a survey of PubMed literature on herbal

medicines used in cellular studies of AD, studies of animal

models of AD, and clinical trials using AD patients, we

investigated herbal medicines as an intervention for treating

AD patients. This review begins with a discussion of

cellular mechanisms that are involved in AD development

and progression and then reviews current therapeutic

strategies for AD that involve herbal medicines.

2. Cellular changes in AD progression

AD occurs in both familial and sporadic forms. In

familial AD (FAD), mutations in the amyloid precursor

protein (APP), presenilin 1, and presenilin 2 genes are the

currently known causal factors. These genetic mutations

inherit in an autosomal dominant fashion. FAD constitutes

only 2–3% of the total number of AD patients [112], and it

has an early age of onset (younger than 65 years of age).

Sporadic AD (SAD) constitutes the vast majority of AD

cases, and it has a late age of onset (65 years of age and

older). The causes of SAD are still unknown [126].

Histological, pathological, molecular, cellular, and gene

expression studies of AD have revealed that multiple

cellular pathways are involved in AD progression [113].

Pathologically, there are no differences between FAD and

SAD [126]. In patients with SAD, pathological changes

including Abeta production and deposits, NFTs, synaptic

damage, and neuronal loss occur latter than in patients with

FAD [43,56,79,112,114,115,126,127,138,142]. In FAD,

genetic mutations accelerate the disease process [126],

whereas in SAD, in the absence of genetic mutation,

cellular changes that control AD progression take more

time to develop [113]. It is possible that several factors are

involved in causing SAD, the major one of which is aging

[126]. Other factors that have been implicated are the

apolipoprotein genotype (ApoE4) [108,109], mitochondrial

defects [112], insulin-dependent diabetes [26,107], environ-

mental conditions [56], and diet [56].

In FAD, recent molecular, cellular, and animal model

studies have provided evidence that a 4-kDa peptide, a

cleavage product of APP due to h and g secretases, is a key

factor in AD development and progression [113,126]. The

formation of the 4-kDa Ah peptide in the brains of AD

patients is a progressive and sequential process. Initially,

soluble monomeric and oligomeric forms of 40–42-amino

acid residues (Ah1–40, shorter form; and Ah1–42, longerform) accumulate and later become insoluble fibrils and Ahdeposits. In recent studies of triple transgenic mice that

express 3 transgenes related to AD (AD-PS1, AD-APP, and

FTD-tau), Ah plaques were found in mice at 5 months of age,

and NFTs were found at 12 months, suggesting that Ahproduction is critical and may facilitate tau pathology [94].

Further, synaptic changes that occur in the triple transgenic

mouse line have been directly associated with Ah production

[94,95]. In addition, Ah immunotherapy studies of triple

transgenic mice showed a reduction in not only extracellular

Ah plaques but also in intracellular Ah accumulation, which

led to the clearance of early tau pathology, suggesting that

early Ah production is critical for subsequent cellular

changes seen in these mice, including the synaptic damage,

hyperphosphorylation of tau and NFTs [94,95].

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376 363

The Ah plaques in the AD transgenic mice were also

found to be associated with activated microglia and

astrocytes and to trigger inflammatory responses [56].

However, astrocytes and microglia were found to proliferate

in the vicinity of Ah and to clear Ah deposits [56]. Yet in

other studies, interactions among Ah, glia, and astrocytes

were found to cause inflammation in the AD brain, which

can lead to altered neuronal homeostasis and oxidative

injury. Based on this last set of evidence, Ah oligomers have

been hypothesized to cause oxidative injury, which can lead

to altered kinases and phosphatases [56].

In addition to findings of inflammatory changes in AD,

recent molecular, cellular, and animal model studies have

revealed that mutant APP and/or Ah enters mitochondria

and interacts with the Ah-induced alcohol dehydrogenase

protein, disrupts electron transport, generates reactive oxy-

gen species (ROS, a term used to describe free radicals

derived from molecular oxygen in the mitochondria), and

inhibits cellular ATP [112]. These results suggest that

mutant APP and Ah interactions with mitochondrial

proteins cause mitochondrial dysfunction in AD [7,74,112].

In SAD, aging plays a significant role in AD progression

[126]. In addition, mitochondrial defects [24,79,112] and

ApoE4 allele are major initiating factors [108,109] of AD

progression. ApoE4 and ROS (generated by mitochondrial

defects) activate h and g secretases of APP and generate Ahpeptides [61,108]. It has been proposed that chronic ROS

exposure can result in oxidative damage to mitochondrial

and cellular proteins, lipids, and nucleic acids, resulting in a

shut-down of mitochondrial energy production [112].

Defective mitochondria in AD neurons may not move

effectively and may not supply necessary cellular ATP at

nerve terminals (such as dendritic spines and synapses) for

normal neural communication. The low levels of cellular

ATP at nerve terminals may lead to the loss of synapses and

synaptic function and may ultimately cause cognitive

decline in AD patients [112].

3. Therapeutic strategies

There is a large body of evidence suggesting that the

accumulation of Ah is a major causative factor in AD

pathogenesis. As a result, therapeutic strategies aiming to

decrease mutant APP and/or Ah levels are currently a major

focus in AD research. Approaches for decreasing Ah levels

include inhibiting the generation of Ah [57], reducing soluble

Ah levels [97,149], and enhancing Ah clearance from the

brain [27,28,34,88,95,124]. Molecular, cellular, and animal

model studies revealed that AD progression involves such

cellular changes as inflammatory responses, mitochondrial

dysfunction, oxidative damage, synaptic failure, and hyper-

phosphorylation of tau, all of which are directly related to Ahproduction and aging [56,66,94,95,97,112,113,149].

Both passive and active immunization of Ah in AD

transgenic mouse models have promised that Ah levels can

be reduced in the brains of AD mice [27,28,34,97,124]. With

encouraging results from in vivo studies that have aimed to

abolish Ah in cellular and animal models of AD, immuno-

therapy research has moved quickly to human clinical trials

by Elan Pharmaceuticals [123]. Unfortunately, their phase II

clinical trials with AD patients as subjects were stopped

because a small percentage developed symptoms of aseptic

meningoencephalitis [123]. Before resuming immunotherapy

in clinical trials, several issues need to be addressed: (1) the

long-term consequences of Ah immunization for the AD

brain (2) while clearing Ah deposits in the AD brain, the

consequences of glial and Ah interactions, and the down-

stream effects of AD progression, and (3) the relationship

between the clearing of Ah and the improvement of cognitive

functions in AD patients.

Anti-inflammatory therapy has been used to treat AD

patients. Inflammation is an important component in the

pathogenesis of AD, consisting of the activation of both

microglia and astrocytes. Recent histological studies

revealed the presence of activated microglia and reactive

astrocytes in and around extraneuronal Ah plaques, which

are thought to facilitate the clearing of Ah deposits from the

brain parenchyma [56]. In Ah-induced inflammation in AD,

microglia can activate and differentiate into phagocytic

CD11b+ cells that in turn secrete IL-1h, TNF-a, nitric oxide(NO), free radicals, and chemokines, and that activate

complement via an innate pathway [86]. Thus generated,

NO can cause T cell apoptosis. Microglia can also differ-

entiate into CD11c antigens presenting both Th1 and Th2

cells via an adaptive pathway, which in AD can suppress the

innate pathway by secreting anti-inflammatory cytokines

(IL-4, IL-10, TGF-h) [86]. However, there is increasing

evidence to suggest that the chronic activation of microglia,

presumably via the secretion of cytokines and reactive

molecules [1,140], may exacerbate plaque pathology as well

as enhance the hyperphosphorylation of tau and the

formation of NFTs [94,95]. Thus, the suppression of

microglial activity in the AD brain has been considered a

possible therapeutic strategy to treat AD patients [56].

Along these lines, anti-inflammatory drugs, particularly

non-steroidal anti-inflammatory drugs, have shown to lessen

the effects of AD pathology [32,33,62].

Oxidative stress is a major factor involved in the

development and progression of AD and other forms of

dementia. A large body of data suggests that free radical

oxidative damage—particularly of neuronal lipids [72,80,

81], proteins [17,75], and nucleic acids [75]—is extensive in

the brains of AD patients. Increased oxidative stress is

thought to result in the generation of free radicals and ROS,

which is reported to be released by microglia activated by

Ah [84,106]. Using a Tg2576 mouse model of AD and

treating the Tg2576 mice with a vitamin E-supplemented

diet, in vivo studies reported decreased levels of Ah1–40and Ah1–42, suggesting that vitamin E may have a direct

effect on AD pathology. Several recent anti-oxidant studies

using AD patients revealed beneficial effects of diets

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376364

supplemented with vitamin E [89,90,161]. The pathological

effects of oxidative stress are yet to be assessed in patients

treated with anti-oxidants. Other studies have shown

beneficial effects of several other anti-oxidants, such as

melatonin, Gingko, and alpha lipoic acid, supplemented in

the water or in the diet of transgenic mouse models of AD

[31,147]. These studies found that the anti-oxidant therapies

are safe and produce no adverse effects. Using in vitro cell

culture and transgenic mouse models of AD, several

laboratories around the world are currently involved in

developing anti-oxidant therapies.

There are only four drugs that the Federal Drug

Administration (FDA) has approved and that are currently

available for treating AD patients in the United States. Three

of the drugs—Tacrine (CognexR), Donepezil (AriceptR),and Rivastigmine (ReminylR)—inhibit acetylcholinesterase

(AChEI) either selectively or non-selectively, but they have

resulted in various adverse drug effects [6]. In two recent

studies, AD patients treated with Donepezil showed rescued

APP metabolism [40,168] or a slow-down in the progres-

sion of hippocampal atrophy, a surrogate of disease

progression. Thus, Donepezil was shown to provide neuro-

protective effects [40]. Memantine (NamendaR), the fourth

and most recently approved drug, non-competitively inhibits

NMDA receptors, prevents glutamate excitotoxicity, and

shows minimal adverse drug effects in AD patients [6]. All

four of these drugs improved the cognitive functions of AD

patients symptomatically and have thus improved the

quality of life for these patients; however, these drugs do

not modify the disease mechanism in the long run. Thus,

when patients no longer take the drugs, their symptoms of

AD return. The paucity of drugs currently available for

treating AD and their limited targets in AD pathology call

for the development of a new generation of drugs that not

only affect cholinergic functions associated with AD but

also target other cellular pathways in AD pathogenesis.

4. Herbal drugs

Over 35,000 plant species currently used for medicinal

purposes around the world possess more than 4000

flavonoid (polyphenolic) structures, terpenes, and phyto-

chemicals, such as alkaloids [76–78,154]. These plant

drugs provide numerous health benefits, including anti-

psychotic, anti-fatigue, anti-depressant, anxiolytic, hyp-

notic, anti-inflammatory, anti-oxidant, anti-neoplastic,

anti-arthritic, anti-diabetic, and anti-lipogenic effects

[29,92,152]. The drugs showing anti-depression, anti-

inflammatory, anti-oxidant, and anti-psychotic benefits

may be particularly beneficial to AD patients because in

the late stages of disease progression, AD patients exhibit

psychotic changes in addition to cellular changes relating

to inflammation, oxidation, and infection.

However, there are problems surrounding the preparation

of herbal drugs, including significant variations across

batches of the drugs since their bioactivity varies consid-

erably due to differences in plant-growth environments [83].

This limitation has prompted pharmaceutical companies to

use single molecules of synthetic compounds in drug

therapies. Although herbal drugs promise significant health

benefits, they have been found to be either ineffective or

effective but showing excessive adverse drug effects,

especially when administered to treat complex diseases,

such as cancer, osteoporosis, and AD.

A large segment of the public finds solace in herbs, in

part believing that herbs are natural and hence safer than

synthetic drugs, and that a complex mixture of herbs can

effectively treat complex diseases. These beliefs may

account for the sudden increase in herbal use in the last

decade [111]. The United States market for just herbal

supplements now exceeds $7 billion per year [36]. In 2002,

the projected worldwide sales of plant-derived pharmaceut-

icals and their precursors exceeded $30 billion [111]. Today,

one in three Americans uses herbal supplements, with

consumption much greater among women [87,141], patients

undergoing surgery [9], and the elderly population.

The complex pathology of AD and heterogeneous

pharmacological effects of herbal extracts pose difficult

challenges in the development of herbal drugs for AD

treatment [45]. However, the number and quality of recent

studies suggest that herbal drugs and AD pathology are at a

new crossroad. Here, we identify herbal extracts that have

been found to affect AD pathomechanisms, highlighting

interactions of Ah, mitochondrial anti-oxidant mechanisms,

inflammatory pathways, and cholinergic and glutamergic

functions in presynaptic and postsynaptic neurons. We draw

on recent reviews of herbal extracts affecting the central

nervous system and age-related dysfunctions [2,3,8,18,

39,46–48,58,59,77,101,102,119,121,131,134,135,137,

144,159].

4.1. Herbs tested for anti-Ab and related effects in AD

models

4.1.1. Animal models

Table 1A summarizes studies of herbal extract/chemical

treatments that have anti-amyloid effects, including anti-hand anti-g secretases and pro a-secretase, and that used

mouse and rat models of AD. Curcumin, a bioactive

compound present in the Indian spice turmeric (Curcuma

longa), reduced accumulations of Ah plaques in the brains

of aged Tg2576 mice [157]. In the same mouse model, a

Ginkgo biloba extract prevented an age-dependent decline

in spatial cognition and enhanced the metabolic rate of the

Tg2576 brain via increased levels of protein carbonyls,

although the extract did not change Ah plaque burdens or

protein oxidation levels [136].

In a gene expression study with adult C57BL6 mice,

EGb 761, a common extract of G. biloba, increased the

mRNA expression of transthyretin (a Ah sequester) in the

hippocampus and increased tyrosine/threonine phosphatase

Table 1

Herbal extracts/chemicals tested for their anti-amyloid effects in animal and in vitro models of Alzheimer’s disease

Plant extracts Models and oxidants Effects of plant extracts References

(A) Animal models

Curcumina Tg2576 mice;

Ah1–40, Ah1–42Blocked the aggregation, oligomer, and fibril

formation in vivo and in vitro

Yang et al. [157]

Ginkgo biloba

extract

Tg2576 mice and wild-type mice Prevented age-dependent decline in spatial

cognition

Stackman et al. [136]

EGb 761b C57BL6 mice Increased the mRNA expression of

transthyretin, tyrosine/threonine phosphatase

1 and microtubule-associated tau

Rimbach et al. [118];

Watanabe et al. [151]

EGb761 Sprague–Dawley rats Increased the release of a-APPs Colciaghi et al. [23]

Huperzine Ac Sprague–Dawley rats; Ah1–40 Reversed the Ah-induced down-regulation

of APP secretion and protein kinase C

Zhang et al. [166]

Dipsacus asper

extract

Sprague–Dawley rats; aluminum

chloride-induced AhAmeliorated the performance impairment

in a passive avoidance task and suppressed

the over-expression of hippocampal Ah

Zhang et al. [165]

Nicotined Holtzman rats Increased the expression of transthyretin in

the brainstem and hippocampus

Li et al. [65]

Nicotined APPsw mice Reduced insoluble amyloid Ah1–40 and

Ah1–42 peptides in the brain cortex

Hellstrom-Lindahl et al. [41];

Nordberg et al. [93]

(B) In vitro models

Curucuma longa

compounds

Rat pheochromocytoma cells;

Ah25–35, Ah1–42Protected against Ah insult Park and Kim [98]

Curcumin Biochemical assay; Ah1–40, Ah1–42 Inhibited Ah fibril formation Ono et al. [96]

Eugenol and h-asaronee Rat PC12 cells; Ah1–40 Attenuated cell death by blocking Ah-inducedCa2+ intake

Irie and Keung [49]

Tenuigeninf Neuroblastoma cells Suppressed the secretion of Ah by inhibiting

BACE1 or h-secretaseJia et al. [51]

Indirubinsg Insect Sf9 cells and tau phosphorylation

in vitro; slices from adult mouse brain

striatum

Inhibited glycogen synthase kinase-3h and

cyclin-dependent kinase-5

Leclerc et al. [64]

a Curcumin, a bioactive compound from the rhizome of Indian spice, turmeric (Curcuma longa).b EGb 761, a standard total extract from the leaves of Ginkgo biloba.c Huperzine A, an alkaloid derived from a Chinese herb, club moss (Huperzia serrata).d Nicotine, a bioactive compound from the leaves of tobacco (Nicotiana tabaccum).e Eugenol and h-asarone, essential oil from Rhizoma acori graminei.f Tenuigenin, a bioactive compound from Polygala tenuifolia.g Indirubins, extracted from Qing Dai (Indigo naturalis), and isatan plants or molluscs.

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376 365

1 and microtubule-associated tau in the cortex [151].

Transthyretin is known to participate in the transport of

thyroxin and in retina-binding proteins, to function as the

carrier of Ah in cerebrospinal fluid, and to prevent Ahaggregation and fibril formation [85]. Tyrosine/threonine

phosphatase 1 and tau are involved in the formation and

disintegration of NFTs in the AD brain. An increase in

tyrosine/threonine phosphatase 1 may play a role in

dephosphorylating the hyperphosphorylated microtubule

that is associated with tau [118,151].

In a Sprague–Dawley rat model of AD, EGb 761

increased the release of a-secretase of APPs in a PKC-

independent manner by affecting the cleavage of APP a-

secretase [23]. In this same rat model, huperzine A (a potent

cholinesterase inhibitor), an extract of club moss (Huperzia

serrata), reversed the Ah-induced down-regulation of APP

secretion and the protein kinase C [166]. The root extract of

Dispacus asper, another Chinese herb, ameliorated the

impairment of cognitive dysfunction in a passive avoidance

task and suppressed the over-expression of hippocampal Ahthat had been induced by aluminum chloride [165].

Treatments with nicotine, a bioactive compound found in

tobacco, not only increased the expression of transthyretin

in the brainstems and hippocampi of Holtzman rats [65] but

also attenuated insoluble amyloid Ah1–40 and Ah1–42peptides in the brain cortices of APPsw mice [41,93].

4.1.2. In vitro models

Herbal treatments in vitro have also conferred protection

against Ah-induced toxicity in various cell culture systems

(Table 1B). Curucuma longa extracts prevented Ah fibril

formation [96] and protected pheochromocytoma cells (PC12

cells) [98] from the insults caused by Ah oligomers and

fibrils. In brain sections from AD patients and Tg2576 mice

[157], curcumin effectively blocked Ah1–40 aggregation

and Ah1–42 fibril and oligomer formation. Eugenol and h-asarone, derived from Rhizoma acori graminei, rescued

PC12 cells from death by blocking Ah-induced Ca2+ intake

[49]. EGb 761-treated hippocampal slices from rat brains

showed an increased release of soluble APPs (sAPPs) [23],

and mutant embryonic kidney cells from humans that were

treated with huperzine A reversed the Ah-induced down-

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376366

regulation of APP secretion and PKC activity [166]. In

addition, tenuigenin (Polygala tenuifolia) suppressed the

secretion of Ah in neuroblastoma cells by inhibiting BACE1

or h-secretase [51]. In insect Sf9 cells and in the brain

striatum of adult mice, indirubins, derived from Qing Dai

(Indigo naturalis) and from isatan plants or molluscs,

inhibited glycogen synthase kinase-3h and cyclin-dependent

kinase-5, which are responsible for the abnormal hyper-

phosphorylation of tau [64]. Thus, the findings from cell

culture systems generally support those of animal model

studies in terms of the influence of herbal drugs on preventing

Ah formation and aggregation.

4.2. Herbs tested for anti-oxidant or anti-apoptotic effects in

AD models

4.2.1. Animal models

Oxidative events in mitochondria are known to generate

accumulations of ROS in several age-related diseases

including AD. Recent studies strongly suggest that such

events are the primary factors that initiate SAD [105]. As

shown in Table 2A, only a limited number of studies have

used animal models for testing anti-oxidant effects of herbs

compared to animal models used for testing other effects of

herbs. In a morphometric study using Wistar rats, EGb 761-

treated, vitamin E-deficient rats showed increased popula-

tions and increased densities of synaptic mitochondria, a

disproportionate number of small-sized synapses and

improved physiological adaptive capacity [15]. An anti-

oxidant treatment combining G. biloba, vitamin E, pycno-

genol, and ascorbyl palmitate reduced periodic acid Schiff-

positive inclusion bodies and reduced apoptotic cells in the

hippocampus of ApoE-deficient mice on a C57B1/6J hybrid

background. This anti-oxidant treatment also increased the

life span of the mice [148].

EGb 761 increased the resistance of both wild-type and

aging mutant Caenorhabditis elegans (worms) to acute

oxidative and thermal stress and increased their lifespan

[156]. Egb761 also attenuated an age-related accumulation

of H2O2-related ROS [131]. In male Wistar rats, resveratrol,

a bioactive compound in red wine, and Centella asiatica, an

Ayurvedic Indian medicinal herb, both prevented intra-

cerebroventrical, straptozotocin-induced cognitive impair-

ment and oxidative stress [128,147]. This rat model for

memory impairment is well known for SAD, as it directly

alters glucose levels in the brain and energy metabolism in

the mitochondria.

4.2.2. In vitro models

Table 2B summarizes herbs tested for their anti-oxidant

and anti-apoptotic effects in cell culture systems. EGb 761

and its bioactive compounds appear to be tested the most

frequently in several systems, such as PC12 cells [30,132,

158,167], hippocampal cells from Sprague–Dawley rats

[11,12,13], human neuroblastoma cells [14,73], and post-

mortemAD brain slices [110]. In these systems, anti-oxidants

against several oxidants—including Ah peptide(s) (25–35,

1–40, 1–42), H2O2, antimycin, xanthine, serum deprivation,

staurosporine, sodium nitroprusside, or prion protein, and

EGb 761—showed classic anti-oxidant effects. The anti-

oxidants prevented the toxic effects of Ah fibrils; decreased

ROS-induced c-Myc, p53, Bax, and caspase-3 activity, which

led to reduced apoptosis, prevented a reduction in cyto-

chrome c levels, attenuated DNA fragmentation, restored

mitochondrial function, reduced the formation of toxic cyclo-

oxygenases, and protected cells against lipid oxidation.

Similar anti-oxidant effects were also conferred by C. longa

[60] and aged garlic extracts [99] on PC12 cells subjected to

oxidant assaults. In other studies, ginsenoside Rg1 (a ginseng

extract) [20], red-wine crude extracts [120], resveretrol [50],

Bacopa monniera [16], and epigallocatechum gallate (a

green tea extract) [21], showed strong anti-oxidant effects and

protected cell cultures from cytotoxic oxidants.

4.3. Herbs tested for inhibiting AChE or NMDA receptors

and enhancing synaptic functions in AD models

4.3.1. Animal models

Inhibition of AChE and NMDA receptors is one of the

main therapeutic strategies for treating AD patients. Indeed,

three of the four FDA-approved AD drugs were designed,

based on their AChE inhibitory effects, and the fourth FDA-

approved AD drug, mematine, was developed primarily to

attenuate the expression of NMDA receptors [100]. Inter-

estingly, few herbs seem to inhibit the expression both

AChE and NMDA receptors [37,155,163]. Using the

Sprague–Dawley rat cortex, Liang and Tang [67] compared

the in vivo effects of huperzine A with Donepezil and

Rivastigmine in terms of their effects on acetylcholine and

the activity of acetylcholinesterase (Table 3A). They found

that huperzine A increased the concentration of acetylcho-

line and inhibited acetylcholinesterase more efficiently than

did injections of Donepezil and Rivastigmine. They also

found that huperzine A not only penetrated the blood–brain

barrier (BBB) more efficiently but also showed long-lasting

inhibitory effects on AChE.

Wang et al. [150] reported that anisodamine, extracted

from the Chinese herb Anisodus tanguticus, produced

cholinomimetic effects in mice when combined with the

peripheral muscarinic blocker pilocarpine. When pilocar-

pine was administered alone, anisodamine effectively

blocked cholineacetylesterase activity, but it initiated typical

cholinergic side effects, such as diarrhea, hypersalivation,

and bradycardia [150]. These adverse effects were nearly

eliminated with the administration of anisodamine in

combination with pilocarpine. In another recent in vivo

study with an ICR mice model of AD, scopolamine-induced

memory deficits caused by acetylcholinesterase activity

were reversed with green tea extract [55].

Nearly 50% of the cortical tyrosine kinase receptor A

(TrkA) is lost in the early stages of AD progression [25].

Nicotine treatment of Wistar rats increased the expression of

Table 2

Herbs tested for antioxidant- or antiapoptosis-related effects in AD models

Plant extracts Models and oxidants Effects of plant extracts References

(A) Animal models

EGb 761a Wistar rats deficient in vitamin E Increased the proportion of

small-sized synapses and

mitochondrial density

Bertoni-Freddari et al. [15]

Ginkgo biloba,

Vitamin E, Pycnogenol,

Ascorbyl palmitate

ApoE-deficient mice Increased the life span and

reduced periodic acid Schiff-

positive inclusion bodies and

apoptotic cells

Veurink et al. [148]

EGb 761 Kaempferol

Quercetin

Mutant C. elegans worm Attenuated age-related

accumulation of ROS

Smith and Luo [131]

EGb 761 C. elegans worm Increased resistance to acute

oxidative and thermal stress,

and increased life span

Wu et al. [156]

Resveratrolb Male Wistar rats; Intracerebroventrical

straptozotocin model of SAD

Prevented ICV STZ-induced

cognitive impairment and

oxidative stress

Sharma and Gupta [128]

Centella asiatica extract Male Wistar rats; Intracerebroventrical

straptozotocin model of SAD

Increased cognitive behavior

and prevented oxidative stress

Veerendra Kumar and Gupta [147]

(B) In vitro models

EGb 761 and its active

compounds

Rat PC12 cells; hippocampal cells from

Sprague–Dawley rats; neuroblastoma

cells from human AD brains

Prevented the formation of

Ah-derived diffusible ligands

or toxic fibrils; decreased

ROS-induced c-Myc, p53, Bax,

and caspase-3 activity leading

to reduced apoptosis; prevented

a reduction in cytochrome c

levels; attenuated DNA

fragmentation; restored

mitochondrial function; reduced

formation of toxic cyclo-oxigenases;

protected cells against lipid oxidation

Eckert et al. [30]; Smith et al. [132];

Yao et al. [158]; Zhou and Zhu [167];

Bastianetto and Quirion [11]; Bastianetto

et al. [12,13]; Bate et al. [14]; Luo et al.

[73]; Ramassamy et al. [110]

Curcuma longa extract Rat PC12 cells; Pyrogallol, H2O2 Rescued cells from cell death and

increased anti-oxidant enzyme

activity

Koo et al. [60]

Aged garlic extract and

S-allylcysteinecRat PC12 cells; Ah25–35 Suppressed ROS, caspase-3, and DNA

fragmentation; protected cells from

apoptosis

Peng et al. [99]

Ginseoside Rg1d Cortical cells from Sprague–Dawley rats Reduced apoptosis Chen et al. [20]

Red wine crude extract

and resveratrol

human umbilical vein endothelial cells

and PC12 cells; Ah25–35, Ah1–42Protected cells from ROS; prevented

DNA fragmentation

Russo et al. [120]; Jang and Surh [50]

Bacopa monniera extract Astrocytes from Wistar albino rat

brains; S-nitroso-N-penicillamine

Inhibited DNA fragmentation

and ROS formation

Bhattacharya et al. [16]

Epigallocatechin gallatee Hippocampal neurons from

Sprague–Dawley rats; Ah25–35Protected cells against apoptosis Choi et al. [21]

a EGb 761, a standard total extract from the leaves of Ginkgo biloba.b Aged garlic extract and S-allylcysteine derived from the bulbs of garlic (Allium sativum).c Ginseoside Rg1, a bioactive compound from the roots of ginseng (Panax ginseng).d Resveretrol, a bioactive compound from the seeds of red grapes (Vitis vinifera).e Epigallocatechin gallate, a bioactive compound from the leaves of green tea (Camellia sinensis).

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376 367

TrkA in the hippocampus [52]. In the cholinergic neurons of

the basal forebrain from AD patients, TrkA was found to

serve as a receptor for the nerve growth factor, a critical

trophic factor for the survival of neurons. Based on the effects

of nicotine on acetylcholine-receptor antagonists, Jonnala et

al. [52] suggest that the neuroprotective action of nicotine

may be mediated via a central a7 acetylcholine receptor.

In a recent study of the cerebral cortex and hippocampus

of wild-type mice, Ah25–35 treatment caused impaired

learning memory and a reduction in the expression of

phosphorylated neurofilament H, an axonal marker, and

synaptophysin, a synaptic marker [145]. These mice

recovered these functions when treated with Rb1 (a

protopanaxadiol-type saponin) and MI (a derivative of

Rb1), both of which are extracted from the Vietnamese

ginseng (Panax vietnamensis).

4.3.2. In vitro models

Table 3B summarizes in vitro effects of herbs on the

inhibition of AChE and NMDA receptors, which are

Table 3

Herbs tested in animal models for inhibitory effects on cholinesterase and N-methyl-d-aspartate receptors

Plant extracts Models and oxidants Effects References

(A) Animal models

Huperzine Aa Male Sprague–Dawley rats Increased the concentration of acetylcholine;

inhibited acetylcholine esterase

Liang and Tang [67]

Anisodamineb Kunming mice Provided cholinomimetic effects when

anisodamine was combined with peripheral

muscarinic blockers

Wang et al. [150]

Green tea extract ICR mice; Scopolamine Reversed memory deficits by inhibiting

AChE activity

Kim et al. [55]

Nicotinec Wistar rats Increased the expression of TrkA receptors Jonnala et al. [52]

Ginsenoside Rb1 and MId Mouse model of AD Recovered impaired learning and memory;

increased axonal density and synaptophysin

expression in cerebral cortex and

hippocampus

Tohda et al. [145]

(B) In vitro models

Huperzine A In vitro cholinesterase inhibition assay Huperzine A dimers inhibited AChE more

potently than they inhibited the monomers

Wong et al. [155]

Huperzine A Cortex or synaptic plasma membranes Inhibited NMDA-induced toxicity Gordon et al. [37]

Huperzine A Hippocampal neurons from

Sprague–Dawley rats

Inhibited an NMDA receptor-induced current Zhang and Hu [163]

EGb 761e Ginkgolides

A, B, C, and J, and

bilobalide

Hippocampal and cerebellar neurons

from Wistar rats

Blocked glycine-activated chloride channels;

weakly inhibited an NMDA receptor-activated

current

Chatterjee et al. [19]

Ginkgo biloba Rat PC12 cells; Ah1–42 Inhibited Ah-derived diffusible ligands and the

formation of oligomers

Chromy et al. [22]

Ptychopetalum olacoides

extract

Frontal cortex, hippocampus, and striatal

neurons of male Wistar rats (in vitro)

and of male Swiss albino mice (ex vivo)

Inhibited AChE in vitro and ex vivo Siqueira et al. [129]

Alkaloids and plant extracts

from narcissus

Microplate assay Seven alkaloids showed AChE inhibitory activity Lopez et al. [71]

Zeatinf Rat PC12 cells Inhibited AChE activity Heo et al. [42]

Salvia lavandulaefolia and

other Salvia species

In vitro studies Inhibited AChE activity Perry et al. [103,104],

Ren et al. [116],

Savelev et al. [122]

a Huperzine A, an alkaloid derived from a Chinese herb, club moss (Huperzia serrata).b Anisodamine, a bioactive compound from anisodamine (Anisodus tanguticus).c Nicotine, a bioactive compound from the leaves of tobacco (Nicotiana tabaccum).d Ginseoside Rb1, a bioactive compound from the roots of Vietnamese ginseng (Panax vietnamensis); MI = 20-O–d-glucopyranosyl-20(S)-protopanaxadiol,

a metabolite of Rb1.e EGb 761, a standard total extract from the leaves of Ginkgo biloba.f Zeatin, a bioactive compound derived from the dried plants of Fiatoua villosa.

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376368

associated with AD progression. Huperzine A dimers rather

than monomers more potently inhibited AChE [155].

Huperzine A inhibited NMDA-induced toxicity in the

cortex, synaptic plasma membranes [37], and hippocampal

neurons [163]. The in vivo effects of the ginsenoside-

derivative MI were repeated in cultured rat cortical neurons,

where MI treatment exerted axonal extension of the neurons

in an in vitro cell culture system [145]. Similar to the in vivo

effect of huperzine A, nicotine treatment of PC12 neuronal

cells showed an increased expression of TrkA receptors

[52].

Chatterjee et al. [19] studied G. biloba constituents for

their impact on ion channels. They showed that bilobalide

weakly inhibited NMDA receptor-activated currents and the

ginkgolides A, B, C, and J, and blocked glycine-activated

chloride channels in the pyramidal hippocampal neurons of

the rat. At a low concentration (1 Ag/ml), G. biloba was also

found to protect PC12 cells from spontaneously formed Ah-derived diffusible ligands [22]. These ligands attenuate

oxidative metabolism and vesicle trafficking, alter NGF-

dependent ERK stimulation, and activate Rac 1 stimulation.

All these events play a critical role in hippocampal long-

term potentiation.

Ptychopetalum olacoides, a traditional Amazonian herb,

inhibited AChE activity in the frontal cortex, hippocampi,

and striatal neurons of 3-month-old male Wistar rats and of

12-month-old male Swiss albino mice [129]. In a microplate

assay that measured AChE activity, 23 pure alkaloids and

plant extracts from 26 species of the genus Narcissus from

Amaryllidaceae were tested [71]. In this study, seven

alkaloids belonging to galantamine and lycorine skeleton-

type, as well as three Narcissus species (N. confusus, N.

perez-chiscanoi, and N. Assoanus), showed AChE inhibitory

activity. Zeatin, derived from Fiatoua villosa, also inhibited

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376 369

AChE activity in PC12 cells of the rat [42]. In addition,

several species of Salvia (S. lavendulefolia, S. officinalis,

and S. multiorrhiza) showed both AChE inhibitory and anti-

oxidant activities [103,116,122], thus suggesting they may

be useful for dementia therapy [102,105].

4.4. Herbs tested for anti-inflammatory effects in AD models

Non-steroidal anti-inflammatory drugs are known to

slow down cognitive impairment in patients with mild and

moderate AD. Many herbs are known for their NSAID

activity. Curcumin treatment of Tg2576 mice suppressed the

activity of pro-inflammatory cytokine IL-1h and the

astrocyte inflammatory marker GFAP and reduced oxidative

damage and plaque burdens [68]. In THP-1 and peripheral

blood monocytes, Giri et al. [35] showed that curcumin

treatment inhibited Ah1–40, and Ah1–42-induced the

activation of EGR-1, Erk1/2, Elk-1, and the expression of

cytokines (TNF-a and IL-1h), chemokines (MIP-1h, MCP-

1 and IL-8), chemokine receptor-5, and MAP kinase.

In human peripheral blood mononuclear cells, Nelumbo

nucifera, a Chinese herb, suppressed phytohemagglutinin-

induced activated PBMC proliferation by arresting the

transition from G1 to the S phase of the cell cycle, reduced

the expression of cyclin-dependent kinase-4 following PHA

treatment, and suppressed the expression of IL-2, IL-4, IL-

10, and IFN-g [69]. Overall, these studies provide evidence

of the positive effects of herbal extracts on inflammation in

AD models.

Table 4

Herbal mixtures studied as potential treatments for AD

Plant extracts Models and oxidants

Yukmijihwang-tanga (6 herbs).

Chinese traditional medicine

Male Sprague–Dawley rats

ESP-102b, a combined extract

(3 herbs); Korean herbal

medicine

Male ICR mice; Mixed cortical

cells from Sprague–Dawley rats;

Scopalamine, Ah25–35, Glutamate

Naoweikangc (2 herbs). Chinese

traditional medicine

Male Sprague–Dawley rats; Ah1–40

‘‘Kami-untan-to’’d, Kampo medicine

(13 herbs). Traditional Chinese

and Japanese medicine

Male ddY mice; Thiamine-deficient

(TD) feeding

Zhokumei-toe, a Kampo formula

(9 herbs). Traditional Chinese

and Japanese medicine

Male ddY mice; Ah25–35

a Yukmijihwang-tang, a mixture of 6 herbs: Rehmannia radix (19.83%), Disco

cortex radicis (21.45%), and Alismatis radix (20.92%).b ESP-102, a standardized combined extract of Angelica gigas, Saururus chinec Naoweikang, a mixture of 3herbs: ginseng (Ginsenosides Rg1 and Re, 35%),d Kami-untan-to, a combination of 13 types of dried medicinal herbs; daily dos

Citrus unshiu (3.0 g of peel), Phyllostachys nigra (3.0 g of stalk), Zizyphus jujuba

(2.0 g of root), Panax ginseng (2.0 g of root), Rehmanii glutinosa (2.0 g of root),

Glycyrrhiza glabra (2.0 g of root), and Zingiber officinable (0.5 g of rhizome).e Zhokumei-to, a combination of crude drugs from 9 herbs: Prunus armeniaca (4

Angelica autiloba (3 g), Cnidium officinale (2 g), Zingiber officinale (2 g), Glyc

4.5. Mixtures of herbs for treating AD

Table 4 lists mixtures of herbs and their uses. Besides

complex extracts and single-herb pure bioactive com-

pounds, mixtures of several herbs have been traditionally

used for treating dementia. More recently, these mixtures

have shown potential for AD treatment. In a recent study,

Rho et al. [117] treated male Sprague–Dawley rats with

yukmijihwang-tang, a traditional Chinese medicine contain-

ing six different herbs. Yukmijihwang-tang increased the

expression of transthyretin and PEP-19, a neuron-specific

protein that inhibits apoptosis in the hippocampus. Another

traditional Chinese medicine, naoweikang, a combination of

G. biloba and Panax ginseng, increased the level of AChE

in the brains of Sprague–Dawley rats following an Ah1–40insult [70]. The Korean herbal medicine ESP-2, which

contains a combination of extracts from three herbs,

effectively inhibited AChE activity, alleviated scopal-

amine-induced memory impairment in ICR mice, and

protected rat neurons from Ah or glutamate-induced neuro-

toxicity [53].

Two traditional Chinese and Japanese herbs (called

‘‘Kampo’’) have been studied for their effects in AD mouse

models. In the ddY mouse model of AD, Kami-untan-to, a

mixture of 13 herbs used in Chinese Japanese herbal

medicine, inhibited thiamine-deficient, feeding-induced

learning and memory impairment, increased choline acetyl

transferase activity, and increased the survival rate of the

mice [91]. In the same mouse model, Zhokumei-to, a

Drug effects References

Increased the expression of transthyretin

and PEP-19, a neuron-specific protein

that inhibits apoptosis

Rho et al. [117]

Alleviated scopolamine-induced memory

impairment; inhibited AChE activity in

mice; protected neurons from Ah or

glutamate-induced neurotoxicity

Kang et al. [53]

Increased the level of AChE in the

whole brain

Liu et al. [70]

Increased the survival rate of mice and

inhibited TD-induced learning and

memory impairment and ChAT activity

Nakagawasai et al. [91]

Repaired Ah-induced memory

impairment; increased the expression of

synaptophysin levels in the cortex and

hippocampus

Tohda et al. [145]

reae radix (20.05%), Corni fructus (41.64%), Hoelen (1.11%), Mountain

nsis, and Schizandra chinensis in a 8:1:1 ratio.

Ginkgo biloba (Ginkgolides, 20%), and Ginkgoflavones (16%).

age: Pinellia ternate Breit (3.0 g of tuber), Poria cocos (3.0 g of fungus),

(2.0 g of seed), Scrophularia ningpoensis (2.0 g of root), Polygala tenuifolia

Zizyphus jujuba (2.0 g of fruit), Citrus aurantium (2.0 g of immature fruit),

g), Ephedra sinica (3 g), Cinnamomum cassica (3 g), Panax ginseng (3 g),

yrrhiza uralensis (2 g), and Gypsum fibrosum (6 g).

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376370

mixture of nine herbs, repaired Ah-induced memory

impairment and increased the expression of synaptophysin

in the cortex and hippocampus [145].

5. Clinical trials on herbal drugs, using AD patients

Of the 40 or so clinical trials conducted for treating

cerebral insufficiency with G. biloba, only eight were

judged adequate in terms of appropriateness of experimental

design [3]. Among these eight, seven studies showed

positive effects of EGb 761. Even in widely investigated

EGb 761, only a few clinical trials specifically focused on

AD patients [46,125]. We discuss some of the recent studies

designed specifically to determine the effects of herbal

drugs on AD patients.

In a randomized, double-blind, placebo-controlled

study, Le Bars [63] reported that AD patients who were

administered EGb 761 (240 mg/day) for 52 weeks showed

improvements in visual constructional impairment, a lesser

degree of worsening in verbal deficits, and minimal

improvement in both visual and verbal deficits. Similarly,

AD patients with presenile and senile primary degenerative

dementia, and multi-infarct dementia of mild to moderate

severity showed cognitive improvements when treated with

EGb 761 [54]. In contrast, AD patients (66–76 years of

age) who were treated with EGb 761 (240 or 160 mg/day)

for 24 weeks showed no improvement in vascular

dementia or in age-associated memory impairment com-

pared to AD patients treated with placebos [146]. Thus,

there is some disagreement about the therapeutic effects of

EGb 761 on AD patients.

In another clinical study, huperzine A was administered

to AD patients in 300 Ag/day doses for the first 2–3

weeks and then 400 Ag/day for the next 4–12 weeks.

These patients significantly improved in their cognitive,

non-cognitive, and ADL functions [164]. In placebo-

controlled, double-blind, randomized clinical trials, Melissa

officinalis and Salvia officinalis administered to patients

with mild and moderate AD significantly improved their

cognitive functions [4,5]. In addition, Melissa oil (M.

officinalis) and lavender oil (Lavendula officinalis), forms

of aromatherapies, also improve behavioral and psycho-

logical symptoms in severe cases of dementia [10,38,44,

130,133,143].

Most of the huperzine A clinical trials have been

conducted in China thus far. However, recently in the United

States, to determine the effectiveness of huperzine A on AD

patients, the National Institute on Aging and Alzheimer’s

Disease Cooperative Study have collaboratively initiated a

phase II clinical trial (http://www.ClinicalTrials.gov). More

recently, the John Douglas French Foundation Institute for

the Study of Aging has initiated a phase II clinical trial to

determine the effects of curcumin on AD patients. Slowly but

steadily, herbal drugs are entering AD clinical trials in the

United States.

6. What makes herbs particularly suitable for treating AD?

The three most important criteria in selecting drugs for

treating AD also apply to herbal drugs: the bioavailability of

herbals, the ability of herbs to cross the BBB, and the lack

of adverse effects associated with the herbal treatments. In

addition, herbal drugs appear to meet a fourth criterion: they

result in a synergistic effect.

6.1. Bioavailability

Bioavailability has been broadly defined as ‘‘absorption

and utilization of a nutrient’’ [61]. Herbal extracts, once

consumed, must penetrate the intestinal barrier and enter

the systemic circulation system. There is growing evidence

of the bioavailability and bioefficacy of plant flavonoids

(flava-based herbs), but that the bioavailability of herbs

varies considerably across different types of flavonoids and

that the most abundantly consumed polyphenol is not

necessarily the most readily bioavailable [78,154]. Accord-

ing to these studies, isoflavones (e.g., soybeans, grape

seeds, and red clover) and gallic acid (walnuts) are the

most readily bioavailable, followed by catechins (green

and black tea), flavones (cocoa, chocolate, red wine), and

quercetin glucosides (onion, apple, tea, broccoli, red wine,

and ginkgo). The least absorbed polyphenols are proan-

thocyanidins (e.g., pine bark, grape seeds, cranberries),

galloylated tea catechins, and anthocyanins (black currant,

elderberries, red grapes, strawberries, blueberries). The

extent to which the human colon can absorb plant drugs

depends on the metabolic activity of microflora in the

intestine and hepatic activity. There is considerable person-

to-person variation in these processes [154].

6.2. The blood–brain barrier

Herbal extracts, once administered, must pass through

the BBB to be effective in the central nervous system. The

BBB is made of a dense layer of endothelial cells that create

a barrier between the blood and brain parenchyma, which

primarily consists of astrocytes and microglia. In the BBB,

a layer of endothelial cells is different from a layer of

endothelial cells in other tissues. The layer of endothelial

cells in the BBB has a low density of pinocytotic vessels

and contains brain microvessels and specific efflux trans-

porters that selectively control the flow of molecules from

cerebrovascular circulation into the brain [160]. In addition,

the BBB expresses numerous types of efflux transporters,

such as P-glycoprotein, multi-drug resistance associated

protein, and monocarboxylic acid transporters. To gain

entry into different parts of the brain, flavonoids exhibit

either stimulatory or inhibitory interactions with one or

many of these transporters directly or indirectly [160]. For

example, quercetin and kaempferol, both bioactive com-

pounds found in ginkgo, stimulate P-glycoprotein trans-

porters, while resveratrol, found in grape seeds, inhibits

T.S. Anekonda, P.H. Reddy / Brain Research Reviews 50 (2005) 361–376 371

them. The extent to which an herbal drug can readily

penetrate the BBB determines its bioavailability. The herbal

drug must interact with specific brain cells or must be able

to flow through intercellular space in order to manifest its

desired effects.

6.3. Toxic and adverse drug effects and drug-drug interaction

Few clinical and toxicological studies have been con-

ducted to determine the adverse effects of herbal treatments

even in the most widely used herbal treatments. Assessing

the adverse effects of herbal treatments is affected by the

conditions in which an herb is administered. For example,

certain herbal drugs taken before surgery may adversely

affect perioperative patient care [9]. Eight commonly used

herbs in the United States have been identified as having

adverse perioperative affects: echinacea, ephedra, garlic,

ginkgo, ginseng, kava, St. John’s Wort, and valerian. Of

these, as discussed, garlic, ginkgo, and ginseng may have a

role in treating AD. The main concern with garlic, ginkgo,

and ginseng is that they can inhibit platelet formation,

activate other platelet inhibitors, and prevent blood clotting

in humans. Thus, 2–7 days prior to surgery, patients are

counseled not to consume these herbs [9].

In clinical trials investigating the effects of ginkgo

treatment on AD, ginkgo was found not to have any serious

adverse effects [77], but there were non-serious side effects,

including mild skin allergies, gastro-intestinal upset, and

headaches. In a recent clinical study of 50 AD patients,

ginkgo treatments were found generally safe. Mortality rates

of AD patients treated with ginkgo were no different from

mortality rates of patients treated with a placebo [146].

However, the AD patients treated with ginkgo reported

marginal adverse effects, such as dizziness, nervousness,

and headaches.

In a clinical trial to determine the effects of M. officinalis

on AD patients, AD patients treated with this herb exhibited

mild but relatively stronger adverse effects in terms of

vomiting, dizziness, wheezing, abdominal pain, and nausea,

than did AD patients treated with a placebo [5]. Studies

have also found relatively fewer adverse side effects with

huperzine A (an acetylcholinesterase inhibitor) compared to

commercial cholinesterase inhibitors [162]. Although these

studies suggest that herbal treatments may result in only

mild discomfiture, the potential toxicological adverse effects

of the herb need to be further assessed.

6.4. Synergistic interactions

A synergy is the interaction of two or more agents or

forces, the combined effect of which is greater than the sum of

their individual effects. Synergistic interactions can occur in a

single herb due to the presence of dozens of bioactive

compounds. For example, G. biloba possesses several

ginkgolides and bilobalides. Eastern herbal medicines,

including traditional Chinese and Indian Ayurveda medical

approaches, are based on the synergistic interactions among

constituent bioactive compounds. Table 4 lists synergistic

effects flowing from different combinations of herbs.

Recently, in a study of AD patients treated with phytomedi-

cines, Williamson [153] provided many examples of syner-

gistic interactions that result in both positive and adverse

effects.

It is difficult to assess synergy in an herbal treatment

because of the large number of constituent herbs or active

compounds in a single herb. Perhaps one of the greatest

challenges in determining the efficacy of herbal treatments

is to prove the existence of synergy. Increasing numbers of

studies are employing more advanced tools and techniques

to unravel the secrets of cellular pathways in disease

progression and pathology of AD patients.

7. Concluding remarks

Tremendous progress has been made in developing

strategies to treat AD. Some of these strategies include

anti-inflammatory, anti-amyloid, anti-oxidant, and pro-chol-

inergic medicines. A successful application of a therapeutic

strategy in clinical trials requires a clearer understanding of

both the adverse and beneficial effects of the drugs.

Currently available FDA-approved drugs treat AD sympto-

matically and provide temporary relief from dementia.

However, these drugs are frequently associated with adverse

drug effects and do not cure the disease by modifying its

pathology. There remains an urgent need for developing

alternative approaches to AD therapeutics. Recently, herbal

drugs have been systematically tested in animal and cell

models of AD and, to lesser extent, in clinical trials. Herbal

drugs are relatively less toxic, can readily cross the BBB,

and are bioavailable to exert multiple synergistic effects,

including improved cognitive and cholinergic functions.

Thus, herbal drugs appear to be a promising alternative

medicine in treating AD patients. However, to determine

their adverse effects in AD patients, we need further

research on each herb in terms of pathology and phenotypic

behavior in well-designed clinical trails.

Acknowledgments

The authors thank Sandra Oster, Neurological Sciences

Institute, Oregon Health and Science University, for editing

the manuscript. This research was supported, in part, by the

American Federation for Aging Research and NIH

#AG22643.

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