Natural products inhibitors of the enzyme acetylcholinesterase.pdf

Received 10/26/05. Accepted 04/13/06

Revista Brasileira de Farmacognosia

Brazilian Journal of Pharmacognosy

16(2): 258-285, Abr./Jun. 2006

Natural products inhibitors of the enzyme acetylcholinesterase

José M. Barbosa Filho 1* , Karina C. Paula Medeiros 1 , Margareth de Fátima F.M. Diniz 1 ,

Leônia M. Batista 1 , Petrônio F. Athayde-Filho 1 , Marcelo S. Silva 1 , Emídio V.L. da-Cunha 1 ,

Jackson R.G. Silva Almeida 2 , Lucindo J. Quintans-Júnior 2

1 Laboratório de Tecnologia Farmacêutica “Delby Fernandes de Medeiros”, Universidade Federal da Paraíba,

Caixa Postal 5009, 58051-970, João Pessoa, PB, Brazil,

2 Universidade Federal do Vale do São Francisco, Caixa Postal 252,

56306-410, Petrolina, PE, Brazil

RESUMO: “Produtos naturais inibidores da enzima acetilcolinesterase”. A Doença de

Alzheimer (DA) é uma patologia neurodegenerativa, progressiva, que afeta principalmente a

população idosa, responsável por 50-60% dos casos de demência em pessoas com mais de 65

anos de idade. Os principais sintomas associado a DA envolve deﬁ ciência orgânica cognitiva,

principalmente perda de memória. Outras características associadas com os estágios avançados

de DA inclui déﬁ cit na linguagem, depressão, problemas de comportamento, inclusive agitação,

alterações de humor e psicose.Um dos mais promissores caminhos para tratar esta doença é

aumentar o nível de acetilcolina no cérebro usando inibidores da acetilcolinesterase (AChE). Este

trabalho teve como objetivo revisar a literatura das plantas e substâncias encontradas nas plantas,

inibidores da enzima acetilcolinesterase. Foram levantadas 309 plantas e 260 substâncias isoladas

de plantas que foram classiﬁ cados em grupos químicos adequados, os modelo testados, e suas

atividades. Foram consultados 175 referências.

Unitermos: Inibidores da Acetilcolinesterase, AchE, doença de Alzheimer, distúrbios

neurodegenetivos, plantas medicinais, produtos naturais, revisão.

ABSTRACT: Alzheimer’s disease (AD) is a progressive, neurodegenerative pathology that

primarily affects the elderly population, and is estimated to account for 50-60% of dementia cases in

persons over 65 years of age. The main symptoms associated with AD involve cognitive dysfunction,

primarily memory loss. Other features associated with the later stages of AD include language

deﬁ cits, depression, behavioural problems including agitation, mood disturbances and psychosis.

One of the most promising approaches for treating this disease is to enhance the acetylcholine

level in the brain using acetylcholinesterase (AChE) inhibitors. The present work reviews the

literature on plants and plant-derived compounds inhibitors of enzyme acetylcholinesterase. The

review refers to 309 plant extracts and 260 compounds isolated from plants, which are classiﬁ ed

in appropriate chemical groups and model tested, and cites their activity. For this purpose 175

references were consulted.

Keywords: Acetylcholinesterase inhibitors, AChE, Alzheimer’s disease, neurodegenerative

disorders, medicinal plants, natural products, review.

INTRODUCTION

and cognitive deﬁ cits of the patients by diminishing the

breakdown of acetylcholine at the synaptic site in the

brain. However, the therapeutic window is small, and

testing of the inhibitory effect on acetylcholinesterase

(AChE) in erythrocytes has been proposed as a guide to

the efﬁ cacy and safety of putative therapies.

Alzheimer’s disease is a progressive

degenerative neurologic disorder resulting in impaired

memory and behavior. Epidemiological data indicate a

potentially considerable increase in the prevalence of the

disease over the next two decades (Johnson et al., 2000).

AD affects up to 5% of people over 65 years, rising to

20% of those over 80 years (Camps et al., 2000a). Most

treatment strategies have been based on the cholinergic

hypothesis which postulated that memory impairments

in patients suffering from this disease result from a

The enzyme acetylcholinesterase (AChE)

catalyses the hydrolysis of the ester bound of acetylcholine

(ACh) to terminate the impulse transmitted action of ACh

through cholinergic synapses (Stryer, 1995). Although

the basic reason of Alzheimer’s disease (AD) is not

clear so far, AD is ﬁ rmly associated with impairment in

cholinergic transmission. A number of AChE inhibitors

have been considered as candidates for the symptomatic

treatment of AD as the most useful relieving strategy

(Howes et al., 2003).

Reversible inhibitors of cholinesterase are

currently used in clinical trials examining the treatment

of Alzheimer’s disease. Anticholinesterase may interact

with the central cholinergic system to improve memory

* E-mail: jbarbosa@ltf.ufpb.br, Tel./Fax: + 55-83-32167364

ISSN 0102-695X

258

José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al.

deﬁ cit of cholinergic function in brain. Cholinergic

neurotransmission is specially affected in patients

with Alzheimer’s disease. One of the most promising

approaches for treating this disease is to enhance the

acetylcholine level in brain using acetylcholinesterase

inhibitors (Enz et al., 1993). Several AChE inhibitors

are being investigated for the treatment of Alzheimer’s

disease. However, only tacrine ( 1 ), donezepil ( 2 ),

rivastigmine ( 3 ) and galanthamine ( 4 ) have been approved

by the Food and Drug Administration in the United States

(Zarotsky et al., 2003). Among the other strategies under

investigation, monoamine oxidase B (MAO-B) inhibitors

have also been proposed for the treatment of AD. Recent

studies have shown that MAO-B activity can increase up

to 3-fold in the temporal, parietal and frontal cortex of AD

patients compared with controls. This increase in MAO-B

activity produces an elevation of brain levels of hydroxyl

radicals, which has been correlated with the development

of Aβ plaques. Aβ is the main component of the senile

plaques found in AD brains and any compound able to

inhibit its aggregation might be regarded as potentially

useful in the treatment of the disease (Bruhlmann et al.,

2001).

Nature is a rich source of biological and

chemical diversity. The unique and complex structures of

natural products cannot be obtained easily by chemical

synthesis. A number of plants in the world have been

used in traditional medicine remedies. Huperzine A ( 5 ) is

a natural compound ﬁ rst isolated from Chinese medicine

Huperzia serrata (Thumb.) in 1986, is a potent, reversible

and selective inhibitor of AChE.

In a previous paper this research group has

reviewed crude plant extracts and chemically deﬁ ned

molecules with potential antitumor activity for mammary

(Moura et al., 2001), cervical (Moura et al., 2002) and

ovarian neoplasias (Silva et al ., 2003), as inhibitors of

HMG CoA reductase (Gonçalves et al., 2000), central

analgesic activity (Almeida et al., 2001), employed in

prevention of osteoporosis (Pereira et al., 2002), for the

treatment of Parkinson’s disease (Morais, 2003), with

antileishmanial (Rocha et al., 2005), hypoglycaemic

(Barbosa-Filho et al., 2005) and antiinﬂ ammatory

activity (Falcão et al., 2005, Barbosa-Filho et al.,

2006). The present work reviews the literature on plants

and plant-derived compounds inhibitors of enzyme

acetylcholinesterase.

MATERIALS AND METHODS

The keywords used for this review were

medicinal plants, natural products, and acetylcholinesterase

inhibitors. The search perfound using Chemical Abstracts,

Biological Abstracts and the data bank of the University

of Illinois at Chicago, NAPRALERT (Acronym for

NAtural PRoducts ALERT), updated to December 2004.

The references obtained were later consulted.

NH 2

MeO

( 1 )

( 2 )

( 3 )

MeO

NH 2

( 5 )

( 6 )

( 4 )

Figure 1. Representative examples of synthetic (1-3) and natural (4-6) products inhibitors of the enzyme acetylcholinesterase

259

Rev. Bras. Farmacogn.

Braz J. Pharmacogn.

16(2):abr/jun. 2006

Natural products inhibitors of the enzyme acetylcholinesterase

RESULTS AND DISCUSSION

However, its severe side effects such hepatotoxicity and

gastrointestinal upset, represent an important drawback

(Camps et al., 2000). The results of the studies on

tacrine spurred the development of other centrally

acting reversible AChE inhibitors, such as the recently

marketed galanthamine (Nivalin ® ), donezepil (Aricept ® )

and rivastigmine (Exelon ® ) or the natural product (-)-

huperzine A, which is currently undergoing extensive

clinical trials, showing considerable promise for the

palliative treatment of AD.

Galanthamine, a long acting, selective,

reversible and competitive AChE inhibitor, is considered

to be more effective in the treatment of AD and to have

fewer limitations (Rhee et al., 2001). Recently it has

reported wich because of bioavailability problems and

possible side-effects, there still is great interest in ﬁ nding

better AChE inhibitors.

Donezepil was developed in order to overcome

the disadvantages of physostigmine and tacrine, and later

approved by the FDA for treatment of AD. It is highly

selective for acetylcholinesterase with a signiﬁ cantly

lower afﬁ nity for butyrylcholinesterase (Racchi et al.,

2004).

Rivastigmine is a carbamilating, pseudo-

irreversible acetylcholinesterase inhibitor which in

preclinical biochemical studies has shown a signiﬁ cant

nervous system selectivity (Racchi et al., 2004).

(-)-Huperzine A is a natural compound ﬁ rst

isolated from Chinese medicine Huperzia serrata

(Thumb.) in 1986. It is a potent, reversible and

selective inhibitor of AChE with a rapid absorption and

penetration into the brain in animal tests. Compared

to tacrine, physostigmine ( 6 ), galanthamine and

donezepil, huperzine A possesses a longer duration of

action and higher therapeutic index, and the peripheral

cholinergic side effects are minimal at therapeutic

doses (Camps et al., 2000; Li et al., 2004). Huperzine A

possesses higher selectivity and has almost no effect on

butyrylcholinesterase. In China, huperzine A has already

been approved as a palliative drug for AD (Högenauer et

al., 2001).

We founded 260 chemically deﬁ ned natural

molecules reported in the literature, which have been

evaluated for acetylcholinesterase inhibition. The

compounds tested, which have been isolated and identiﬁ ed

belong to the classes of alkaloids (139), monoterpenes

(27), coumarins (18), triterpenes (17), ﬂ avonoids (14),

benzenoids (13), diterpenes (8), oxygen heterocycles

(5), sesquiterpenes (5), stilbenes (3), lignans (2), sulfur

compounds (2), proteids (2), polycyclic (1), quinoid (1),

benzoxazinone (1), carotenoid (1) and alycyclic (1).

Consultation of various types of literature

sources resulted in elaboration of a list of natural

products (Table 1 and 2) evaluated speciﬁ cally for

acetylcholinesterase inhibition. It should be noted that

most of references cited are not ﬁ rst-hand observations,

but secondary sources. For details on the models or

mechanism-based bioassays utilized for selecting plant

extracts and pure compounds against acetylcholinesterase,

the original references should be consulted.

Plant extracts inhibitors of acetylcholinesterase

enzyme

Acetylcholine is a neurotransmitter inhibited

primarily by acetylcholinesterase (AChE) and secondly

by butyrylcholinesterase (BChE), considered to play a

role in the pathology of AD (Hebert et al., 1995). Despite

the unknown etiology of AD, elevation of acetylcholine

amount through AChE enzyme inhibition has been

accepted as the most effective treatment strategy against

AD. Therefore, AChE inhibitors have become the

remarkable alternatives in treatment of AD. However,

the present drugs (tacrine, rivastigmine and donezepil)

with AChE inhibitory activity possess some side effects

(Schneider, 2001). Consequently, it is compulsory to

develop new drugs in order to combat AD (Viegas-Junior

et al., 2004).

The history of drug discovery showed that

plants are highly rich sources in the search for new active

compounds and they have become a challenge to modern

pharmaceutical industry. Many synthetic drugs owe their

origin to plant-based complementary medicine. Since

AD, one of the most common cause of death worldwide,

has become a threaten to public health, new treatment

strategies based on medicinal plants have been focused

(Howes et al., 2003; Orhan et al., 2004).

A recent study with Brazilian plants showed

excellent results for the species Amburana cearensis,

Lippia sidoides, Paullinia cupana, Plathymiscium

ﬂ oribundum and Solanum asperum (Trevisan; Macedo,

2003). Since the plants have been used in treatment

of memory disfunction in some folk medicines since

centuries the present study presents a review of 309

plants belong to 92 botanical families tested against

acetylcholinesterase inhibition. The plants are listed in

Table 1, in alphabetical order of their family, scientiﬁ c

name, country, plant part used, type of extract, dose/

concentration, result and references.

Chemically-deﬁ ned molecule as inhibitors of

acetylcholinesterase enzyme

CONCLUSION

The prototype for the centrally acting AChE

inhibitors was tacrine, the ﬁ rst drug to be approved in

the United States (Cognex ® ) for the treatment of AD.

The present work shows that most of the

plant extracts tested showed inhibitory activity against

acetylcholinesterase and they could be considered for

Rev. Bras. Farmacogn.

Braz J. Pharmacogn.

16(2):abr/jun. 2006

260

José M. Barbosa Filho, Karina C. Paula Medeiros, Margareth de Fátima F.M. Diniz, et al.

further studies in the treatment of AD. In particular,

the species belonging to Amaryllidaceae, Apiaceae,

Asteraceae, Fabaceae and Fumariaceae were the most

studied. Since most of acetylcholinesterase inhibitors

are known to contain nitrogen, the higher activity

of these extracts may be due to their rich alkaloidal

content. The alkaloids are the major compounds isolated

from this species and shows inhibitory activity for the

acetylcholinesterase. More research is needed to further

explore the actions of this alkaloids in the search of

promising treatment for AD.

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ACKNOWLEDGEMENTS

The authors wish to express their sincere thanks

to the College of Pharmacy, The University of Illinois

at Chicago, Chicago, Illinois 60612-7231, U.S.A., for

helping with the computer-aided NAPRALERT search

and CNPq/CAPES/Brazil for ﬁ nancial support.

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