Acetylcholinesterase inhibitors from plants.
Inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is considered as a promising strategy for the treatment of neurological disorders such as Alzheimer's disease, senile dementia, ataxia and myasthenia gravis. A potential source of AChE inhibitors is certainly provided by the abundance of plants in nature. This article aims to provide a comprehensive literature survey of plants that have been tested for AChE inhibitory activity. Numerous phytoconstituents and promising plant species as AChE inhibitors are being reported in this communication.
[c] 2007 Elsevier GmbH. All rights reserved.
Keywords: Plants; Botanicals; Acetylcholinesterase inhibition; Acetylcholine; Alzheimer's disease
Principal role of acetylcholinesterase (AChE) is the termination of nerve impulse transmission at the cholinergic synapses by rapid hydrolysis of acetylcholine (ACh). Inhibition of AChE serves as a strategy for the treatment of Alzheimer's disease (AD), senile dementia, ataxia, myasthenia gravis and Parkinson's disease (Anonymous, 2000; Brenner, 2000; Rahman and Choudhary, 2001). There are a few synthetic medicines, e.g. tacrine, donepezil, and the natural product-based rivastigmine for treatment of cognitive dysfunction and memory loss associated with AD (Oh et al., 2004). These compounds have been reported to have their adverse effects including gastrointestinal disturbances and problems associated with bioavailability (Schulz, 2003; Melzer, 1998), which necessitates the interest in finding better AChE inhibitors from natural resources.
AD is one of the most common forms of dementia affecting so many elderly people. Besides the neuropathologic hallmarks of this disease, namely neurofibrillary tangles and neuritic plaques, it is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, particularly affecting cholinergic neurons in the basal forebrain (Price, 1986; Kasa et al., 1997). The evidence stems from data of several authors that demonstrated the reduction in activity of enzymes involved in the synthesis of acetylcholine, i.e. choline acetyl transferase or excess degradation of ACh by AChE (Davies and Maloney, 1976; Sims et al., 1983; DeKosky et al., 1992). The first AChE inhibitors (AChEIs) specifically approved for the treatment of AD was introduced in 1993 as 1, 2, 3, 4-tetrahydro-9-aminoacridine (tacrine) (Whitehouse, 1993). Currently, several AChE inhibitors, such as donepezil (Kelly et al., 1997), galantamine (Scott and Goa, 2000) and rivastigmine (Gottwald and Rozanski, 1999) are available for the symptomatic treatment of patients with mild-to-moderate AD. Cholinesterase inhibitory therapy may be considered, by its pharmacological nature, as a simple symptomatic short-term intervention. However, data emerging from long-term mostly open label trials is that the maintenance of the clinical effect can be prolonged to at least 1 year. In some clinical studies, the data indicate that beneficial effects can be maintained for up to 36 months; These effects of stabilization of the cognitive status of the patients suggest conceivably a structural effect of the treatment on pathological features of the disease; Giacobini (2002) suggested that the effects may arise from the interaction of these drugs with the amyloid cascade, influencing the expression and/or the metabolic processing of the amyloid precursor protein (APP) and slowing down one of the major pathological steps of the disease process. In traditional practices of numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases and different neuropharmacological disorders. Ethnopharmacological approach and bioassay-guided isolation have provided a lead in identifying potential AChE inhibitors from plant sources, including those for memory disorders. This article highlights on the plants and/or their active constituents so far reported to have AChE inhibitory activity.
Several methods for screening of AChE inhibitory activity from natural resources has been reported based on Ellman's reactions (Ellman et al., 1961). Moreover, Spectrophotometric determination thin-layer chromatography method (Ingkaninan et al., 2000; Marston et al., 2002) and micro-plate assay (Ingkaninan et al., 2000, Brlihlmann et al., 2004) have been reported to be useful. HPLC method for detection of AChE inhibition on immobilized AChE column (Andrisano et al., 2001) and HPLC with on-line coupled UV-MS-biochemical detection for AChE inhibitory activity (Ingkaninan et al., 2000) have also been reported.
Plants as a source of acetylcholinesterase inhibitors
A variety of plants has been reported to show AChE inhibitory activity and so may be relevant to the treatment of neurodegenerative disorders such as AD. A list of plants reported to have significant AChE inhibitory activity is shown in Table 1.
Bacopa monniera and Ginkgo biloba are well-known cognitive enhancers in Indian and Chinese traditional medicine systems. Standardized extracts of Bacopa monniera and G. biloba both showed a dose-dependent inhibitory effect on AChE activity (Das et al., 2002). Eighty percent methanolic extract of Myricaria elegans Royle was found to have significant AChE inhibitory activity (Ahmad et al., 2003).
Methanolic extracts of seven herbs Acorus calamus, Acorus gramineus, Bupleurm facaltum, Dioscorea batatas, Epimedium koreanum, Poria cocos and Zizyphi jujuba, used in traditional Korean medicine for improvement of memory and cognition in old age have been tested for cholinesterase inhibitory properties and significant inhibition of the enzyme was shown by extracts from Acorus calamus and E. koreanum (Oh et al., 2004). Ingkaninan et al. (2000, 2003) screened the methanolic extracts of 32 plants used in Thai traditional rejuvenating and neurotonic remedies, for inhibitory activity on AChE and found that the extracts from roots of Stephania suberosa and Tabernaemontana divaricata showed significant inhibitory activity.
The chloroform:methanol (1:1) extracts of a number of the plant species namely Corydalis solida (L.) Swartz subsp. solida and Glaucium corniculatum (L.) J. H. Rudolph (Papaveraceae), Rhododendron ponticum L. subsp. ponticum and Rhododendron luteum Sweet. (Ericaceae), Buxus sempervirens L. (Buxaceae), Vicia faba L. (Fabaceae), Robinia pseudoacacia L. (Caeselpiniaceae), Tribulus terrestris L. and Zygophyllum fabago L. (Zygophyllaceae), Lycopodium clavatum L. (Lycopodiaceae), Fumaria vaillantii Lois., Fumaria capreolata L., Fumaria kralikii Jordan, Fumaria asepala Boiss., Fumaria densiflora DC., Fumaria flabellata L., Fumaria petteri Reichb. subsp. thuretii (Boiss.) Pugsley, Fumaria macrocarpa Boiss. ex Hausskn., Fumaria cilicica Hauskkn., Fumaria parviflora Lam. and Fumaria judaica Boiss. (Fumariaceae) were screened for their anti-cholinesterase activity (Orhan et al., 2004). The extracts of Rhododendron ponticum, Rhododendron luteum, Corydalis solida, Glaucium corniculatum, and Buxus sempervirens showed remarkable inhibitory activity above 50% inhibition rate at 1 mg/ml.
Amongst plants that have been investigated for dementia therapy, Salvia is one of the most numerous genera within the family Lamiaceae and grows in many parts of the world. It causes inhibition of AChE as well as nicotinic activity (Perry et al., 2000, 2001).
Phytoconstituents having acetylcholinesterase inhibitory activity
Work on new bioactive compounds from medicinal plants has led to the isolation and structure elucidation of a number of exciting new pharmacophores. A list of phytoconstituents having significant AChE inhibitory activity is provided in Table 2 and structures of these compounds are shown in Fig. 1. Physostigma venenosum was used traditionally in Africa as a ritual poison, claimed to determine the guilt or innocence of person accused of a crime. Treatment with the indole alkaloid physostigmine , an AChE inhibitor isolated from P. venenosum, has improved cognitive function in several in vivo studies. Physostigmine, a short-acting reversible AChE inhibitor, is also reported to have shown significant cognitive benefits in both normal and AD patients, but clinical use may be limited by its short half-life, which would require multiple daily dosing (Da-Yuan et al, 1996; Mukherjee, 2001).
Chemical structure of physostigmine has provided a template for the development of rivastigmine , an AChE inhibitor that is licensed for use in the UK for the symptomatic treatment of mild-to-moderately severe AD (Foye et al., 1995). Rivastigmine is reported to inhibit AChE in the cortex and hippocampus, 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 (Foye et al., 1995).
Galanthus nivalis was used traditionally in Bulgaria and Turkey for neurological conditions. Galantamine  is an Amaryllidaceae alkaloid obtained from Galanthus nivalis L. Galantamine is reported to be more selective for AChE than butyrylcholinesterase, and provides complete oral bioavailability. It is licensed in Europe for AD treatment, was well tolerated and significantly improved cognitive function when administered to AD patients, in multi-center randomized-controlled trials (Lopez et al., 2002). Initially derived from extracts of snowdrop and daffodil bulbs, this phenanthrene alkaloid is now synthetically produced. It is a reversible competitive AChE inhibitor that also allosterically modulates nicotinic receptors (this effect is probably independent of its cholinesterase inhibition). It has an elimination half-life of about 6h. Metabolism produces four compounds, one of which is more active as a cholinesterase inhibitor than galantamine itself. Over 2000 patients have been involved in double-blind placebo-controlled trials of galantamine where positive effects on cognitive symptoms have been associated with significant benefits in activities of daily living (Da-Yuan et al, 1996). Other Amaryllidaceae alkaloids such as assoanine , epinorgalantamine , oxoassoanine , sanguinine , 11-hydroxygalantamine  have also been reported to possess AChE activity (Lopez et al., 2002).
The lycopodium alkaloid huperzine A  related to the quinolizidines, is a potent, yet reversible, inhibitor of AChE and is used in China for treating patients with myasthenia gravis and AD. The source of huperzine A is Huperzia serrata, a moss that has been used for treating contusions, strains, hematuria and swelling in Chinese folk medicine (Wang and Tang, 1998). It improved memory retention processes in cognitively impaired aged and adult rats (Raves et al., 1997). In a multicenter, double blind trial, huperzine A significantly improved memory and behavior in AD patients, and was reported to be more selective for AChE than butyrylcholinesterase and less toxic than the synthetic AChE inhibitors donepezil and tacrine. It may also have potential in the attenuation of memory deficits and neuronal damage that occurs after ischemia, so may therefore is beneficial in the treatment of cerebrovascular-type dementia (Raves et al., 1997).
Numerous essential oils and their monoterpene constituents 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 (Howes et al., 2003a, b). Other monoterpenes that are reported to inhibit AChE include geraniol, 3-carene, [alpha]-caryophyllene and limonene. The structural diversity of the active anticholinesterase 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. Monoterpenes consist of a hydrocarbon skeleton, which may contribute to their anti-cholinesterase activity. Monoterpenes may be cyclic (e.g. 1,8-cineole and [alpha]-pinene) or acyclic (e.g. geraniol and linalool), a feature that may also influence anti-cholinesterase activity. Further investigations may determine if a cyclic component or particular functional group favors AChE inhibition. Considering the relatively weak anti-cholinesterase 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.
More recently, the stilbene oligomer viniferin  from Caragana chamlague, has also been identified as reversible and non-competitive inhibitor of AChE (Da-Yuan et al, 1996). Structure-activity relationship suggested that the nitrogen substituents at C-3 and/or C-20 of steroidal skeleton and the hydrophobic properties of the pregnane skeleton are the key structural features contributed to the inhibitory potency of pregnane-type steroidal alkaloids against AChE (Khalid et al., 2004).
Bioassay-guided fractionation of the methanolic extract resulted in the isolation of three furanocoumarins, isoimperatorin, imperatorin and oxypeucedanin as active principles from the methanolic extract of the roots of Angelica dahurica, which inhibited AChE activity in a dose-dependent manner (Kim et al., 2002). In a bioassay-guided search for AChE inhibitors four isoquinoline alkaloids, corynoxidine, protopine, palmatine and berberine have been isolated from the methanolic extract of the aerial parts of Corydalis speciosa (Kim et al., 2004). Bioassay-directed phytochemical investigations on a number of medicinal plants of Pakistan and Iran have led to the isolation of AChE inhibitors such as buxamine B , N, N-dimethyl buxapapine , sarsalignone  and vaganine  (Rahman and Choudhary, 2001). Indole alkaloids coronaridine , voacangine , voacangine hydroxyindolenine and rupicoline  isolated from the chloroform extract of stalk of Tabernaemontana australis showed anti-cholinesterasic activity at the same concentration as the reference compounds physostigmine and galantamine, by thin-layer chromatography assay using the modified Ellman's method (Andrade et al., 2005). Ursolic acid  obtained from Origanum majorana has also been reported to possess AChE inhibitory activity (Chung et al., 2001).
[FIGURE 1 OMITTED]
[FIGURE 1 CONTINUED OMITTED]
Acetylcholinesterase (AchE) inhibitors have therapeutic applications in Alzheimer's disease (AD), senile dementia, ataxia, myasthenia gravis and Parkinson's disease. Central cholinergic system is considered as the most important neurotransmitter system involved in the regulation of cognitive functions. Cholinergic neuronal loss in hippocampal area is the major feature of AD and enhancement of central cholinergic activity by use of anti-cholinesterase is presently the mainstay of the pharmacotherapy of senile dementia of Alzheimer type (Enz et al., 1993; Siddiqui and Levey, 1999). The search for plant derived inhibitors of AChE has accelerated in view of the benefits of these drugs not only in the treatment of AD but in other forms of dementia, such as dementia with Lewy bodies (Perry et al., 1994), vascular dementia (Erkinjuntti et al., 2002) and Down's syndrome (Kishnani et al., 1999). Along with the prototype inhibitor of AChE physostigmine, obtained from the plant Physostigma venenosum, other molecules with highly significant anti-cholinesterase activity are huper-zine-A, galantamine, [alpha]-viniferin and ursolic acid obtained from Huperzia serrata, Galanthus nivalis and Narcissus sp., Caragana chamlague and Origanum majorana, respectively.
Majority of studies have focused on the anticholinesterase alkaloids, such as physostigmine and galantamine. So far, more than 35 alkaloids have been reported to have AChE inhibitory activity. The other major classes of compound reported to have such activity are the terpenoids, glycosides and coumarins. Plants belonging to families Acanthaceae, Apocynaceae, Amaryllidaceae, Angelicae, Araceae, Asclepiadaceae, Berberidaceae, Buxaceae, Combretaceae, Compositae, Coniferae, Cyperaceae, Ebenaceae, Ericaceae, Euphorbiaceae, Fumariaceae, Gentianaceae, Guttiferae, Lamiaceae, Leguminosae, Lilliaceae, Lycopodiaceae, Malvaceae, Magnoliaceae, Menispermaceae, Mollugi-naceae, Moraceae, Musaceae, Nelumbonaceae, Papaveraceae, Piperaceae, Rubiaceae, Rutaceae, Sapotaceae, Solanaceae and Tamaricaceae have been reported to have AChE inhibitory potential. For many of the plants and compounds that have demonstrated activities anti-cholinesterase activity relevant to AD therapy, the clinical data are very limited. Clinical efficacy and potential toxicity of active plants and compounds in larger trials requires further assessment, before recommendations concerning their routine use can be identified.
The authors wish to express their gratitude to the Commonwealth Scholarship Commission, Association of Commonwealth Universities, UK, for the Commonwealth Academic Staff Fellowship Award to Dr. Pulok K. Mukherjee through the selection made from the University Grants Commission (UGC), India. Thanks are also due to the Department of Biotechnology (DBT), Government of India for providing financial assistance through research project to the School of Natural Product Studies, Jadavpur University.
Ahmad, W., Ahmad, B., Ahmad, M., Iqbal, Z., Nisar, M., Ahmad, M., 2003. In vitro inhibition of acetylcholinesterase, butyrylcholinesterase and lipoxygenase by crude extract of Myricaria elegans Royle. J. Biol. Sci. 3, 1046-1049.
Andrade, M.T., Lima, J.A., Pinto, A.C., Rezende, C.M., Carvalho, M.P., Epifanio, R.A., 2005. Indole alkaloids from Tabernaemontana australis (Muell. Arg) Miers that inhibit acetylcholinesterase enzyme. Bioorg. Med. Chem. 13, 4092-4095.
Andrisano, V., Bartolini, M., Gotti, R., Cavrini, V., Felix, G., 2001. Determination of inhibitors' potency ([IC.sub.50]) by a direct high performance liquid chromatographic method on an immobilized acetylcholinesterase column. J. Chroma-togr. B 753, 375-383.
Anonymous, 2000. Compendium of Pharmaceuticals and Specialties, 25th ed. Canadian Pharmacists Association, Toronto, Canada.
Ashani, Y., Grunwald, J., Kronman, C., Velan, B., Shafferman, A., 1994. Role of tyrosine 337 in the binding of huperzine A to the active site of human acetylcholinesterase. Mol. Pharmacol. 45, 555-560.
Brenner, G.M., 2000. Pharmacology. W.B. Saunders Company, Philadelphia.
Brlihlmann, C., Marston, A., Hostettmann, K., Carrupt. P.A., Testa, B., 2004. Screening of non-alkaloidal natural compounds as acetylcholinesterase inhibitors. Chem. Biodivers. 1, 819-829.
Chung, Y.K., Heo, H.J., Kim, E.K., Kim, H.K., Huh, T.L., Lim, Y., Kim, S.K., Shin, D.H., 2001. Inhibitory effect of ursolic acid purified from Origanum majorana L on the acetylcholinesterase. Mol. Cells 11, 137-143.
Das, A., Shanker, G., Nath, C., Pal, R., Singh, S., Singh, H.K., 2002. A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba anticholinesterase and cognitive enhancing activities. Pharmacol. Biochem. Behav. 73, 893-900.
Davies, P., Maloney, A.J., 1976. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2, 1403.
Da-Yuan, Z., Dong-Lu, B., Xi-Can, T., 1996. Recent studies on traditional Chinese medicinal plants. Drug Dev. Res. 39, 147-157.
DeKosky, S.T., Harbaugh, R.E., Schmitt, F.A., Bakay, R.A., Chui, H.C., Knopman, D.S., 1992. Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical, neuropathological and cognitive correlations. Ann. Neurol. 32, 625-632.
Ellman, G.L., Courtney, K.D., Andres, V., Featherstone, R.M., 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7, 88-95.
Enz, A., Amstutz, R., Boddeke, H., Gmelin, G., Malanowski, J., 1993. Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer's disease. Prog. Brain Res. 98, 431-438.
Erkinjuntti, T., Kurz, A., Gauthier, S., Bullock, R., Lilienfeld, S., Damaraju, CV., 2002. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet 359, 1283-1290.
Foye, W.O., Lemke, T.L., Williams, D.A., 1995. Principles of Medicinal Chemistry, fourth ed. Williams and Wilkins, USA.
Giacobini, E., 2002. Long term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer's disease. J. Neural Transmission Suppl, 181-187.
Gottwald, M.D., Rozanski, R.I., 1999. Rivastigmine a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. Expert Opin. Invest. Drugs 8, 1673-1682.
Hillhouse, B.J., Ming, D.S., French, C.J., Neil Towers, G.H., 2004. Acetylcholine esterase inhibitors in Rhodiola rosea. Pharm. Biol. 42, 68-72.
Howes, M.J., Houghton, P.J., 2003a. Plants used in Chinese and Indian traditional medicine for improvement of memory and cognitive function Pharmacology. Biochem. Behav. 75, 513-527.
Howes, M.R., Perry, N.S.L., Houghton, P.J., 2003b. Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Phytother. Res. 17, 1-18.
Ingkaninan, K., Best, D., Heijden, V.D., Hofte, A.J.P., Karabatak, B., Irth, H., Tjaden, U.R., Greef, V.D., Verpoorte, R., 2000. High-performance liquid chromatography with on-line coupled UV, mass spectrometric and biochemical detection for identification of acetylcholinesterase inhibitors from natural products. J. Chromatogr. A 872, 61-73.
Ingkaninan, K., Temkitthawon, P., Chuenchom, K., Yuyaem, T., Thongnoi, W., 2003. Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. J. Ethnopharmacol. 89, 261-264.
Karczmar, A., 1998. Invited review: anticholinesterases: dramatic aspects of their use and misuse. Neurochem. Int. 32, 401-411.
Kasa, P., Rakonczay, Z., Gulya, K., 1997. The cholinergic system in Alzheimer's disease. Prog. Neurobiol. 52, 511-535.
Kelly, C.A., Harvey, R.J., Cayton, H., 1997. Drug treatments for Alzheimer's disease. Br. Med. J. 314, 693-694.
Khalid, A., Haq, Z.U., Ghayur, M.N., Feroz, F., Rahman, A.U., Gilani, A.H., Choudhary, M.I., 2004. Cholinesterase inhibitory and spasmolytic potential of steroidal alkaloids. J. Steroid Biochem. Mol. Biol. 92, 477-484.
Kim, D.K., 2002. Inhibitory effect of corynoline isolated from the aerial parts of Corydalis incisa on the acetylcholinesterase. Arch. Pharm. Res. 25, 817-819.
Kim, D.K., Lim, J.P., Yang, J.H., Eom, D.O., Eun, J.S., Leem, K.H., 2002. Acetylcholinesterase inhibitors from the roots of Angelica dahurica. Arch. Pharm. Res. 25, 856-859.
Kim, D.K., Lee, K.T., Baek, N.I., Kim, S.H., Park, H.W., Lim, J.P., Shin, T.Y., Eom, D.O., Yang, J.H., Eun, J.S., 2004. Acetylcholinesterase inhibitors from the aerial parts of Corydalis speciosa. Arch. Pharm. Res. 27, 1127-1131.
Kishnani, P.S., Sullivan, J.A., Walter, B.K., Spiridigliozzi, G.A., Doraiswamy, P.M., Krishnan, K.R.R., 1999. Cholinergic therapy for Down's syndrome. Lancet 353, 1064-1065.
Lee, K.Y., Sung, S.H., Kim, Y.C., 2003. New acetylcholinesterase-inhibitory pregnane glycosides of Cynanchum atratum roots. Helvetica Chim. Acta 86, 474-483.
Lopez, S., Bastida, J., Viladomat, F., Codina, C., 2002. Acetylcholinesterase inhibitory activity of some Amaryllidaceae alkaloids and Narcissus extracts. Life Sci. 71, 2521-2529.
Marston, A., Kissling, J., Hostettmann, K., 2002. A rapid TLC bioautographic method for the detection of acetylcholinesterase and butyrylcholinesterase inhibitors in plants. Phytochem. Anal. 13, 51-54.
Melzer, D., 1998. New drug treatment for Alzheimer's diseases: lessons for healthcare policy. BMJ 316, 762-764.
Mukherjee, P.K., 2001. Evaluation of Indian traditional medicine. Drug Inf. J. 35, 620-623.
Oh, M.H., Houghton, P.J., Whang, W.K., Cho, J.H., 2004. Screening of Korean herbal medicines used to improve cognitive function for anti-cholinesterase activity. Phytomedicine 11, 544-548.
Orhan, I., Sener, B., Choudhary, M.I., Khalid, A., 2004. Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some Turkish medicinal plants. J. Ethnopharmacol. 91, 57-60.
Perry, E.K., Haroutunian, V., Davis, K.L., 1994. Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease. Neuroreport 5, 747-749.
Perry, E.K., Pickering, A.T., Wang, W.W., Houghton, P.J., Perry, N.S.L., 1998. Medicinal plants and Alzheimer's disease: integrating ethnobotanical and contemporary scientific evidence. J. Altern. Complem. Med. 4, 419-428.
Perry, N., Court, G., Bidet, N., Court, J., Perry, E., 1996. European herbs with cholinergic activities: potential in dementia therapy. Int. J. Geriatric Psychiatry 11, 1063-1069.
Perry, N.S.L., Houghton, P.G., Theolad, A.E., Jenner, P., Perry, E.K., 2000. In vitro inhibition of human erythrocyte acetylcholinesterase by Salvia lavandulaefolia essential oil and constituent terpenes. J. Pharm. Pharmacol. 52, 895-902.
Perry, N.S.L., Houghton, P.G., Sampson, J., Theolad, A.E., Hart, S., Lis-balchin, M., Hoult, J.R.S., Evans, P., Jenner, P., Milligan, S., Perry, E.K., 2001. In vitro activities of Salvia lavandulaefolia (Spanish Sage) relevant to treatment of Alzheimer's disease. J. Pharm. Pharmacol. 53, 1347-1356.
Price, D.L., 1986. New perspectives on Alzheimer's disease. Neuroscience 9, 489-512.
Rahman, A.U., Choudhary, M.I., 2001. Bioactive natural products as a potential source of new pharmacophores a theory of memory. Pure Appl. Chem. 73, 555-560.
Raves, M.L., Harel, M., Pang, Y.P., Silman, I., Kozikowski, A.P., Sussman, J.L., 1997. Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A. Nat. Struct. Biol. 4, 57-63.
Rhee, I.K., Meent, M.V., Ingkaninan, K., Verpoorte, R., 2001. Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining. J. Chromatogr. A 915, 217-223.
Rizzi, A., Schuh, R., Bruckner, A., Cvitkovich, B., Kremser, L., Jordis, U., Frohlich, J., Kuenburg, B., Czollner, L., 1999. Enantiomeric resolution of galantamine and related drugs used in anti-Alzheimer therapy by means of capillary zone electrophoresis employing derivatized cyclodextrin selectors. J. Chromatogr. B 730, 167-175.
Roddick, J.G., 1989. The acetylcholinesterase inhibitory activity of steroidal glycoalkaloids and their aglycones. Phytochemistry 28, 2631-2634.
Scott, L.J., Goa, K.L., 2000. Galantamine: a review of its use in Alzheimer's disease. Drugs 60, 1095-1122.
Schulz, V., 2003. Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trial and guidelines fail to consider. Phytomedicine 10, 74-79.
Siddiqui, M.F., Levey, A.I., 1999. Cholinergic therapies in Alzheimer's disease. Drugs of Future 24, 417-444.
Sims, N.R., Bowen, D.M., Allen, S.J., Smith, C.C., Neary, D., Thomas, D.J., 1983. Presynaptic cholinergic dysfunction in patients with dementia. J. Neurochem. 40, 503-509.
Siqueira, I.R., Fochesatto, C., Lourenco da Silva, A., Nunes, D.S., Battastini, A.M., Netto, C.A., Elisabetsky, E., 2003. Ptychopetalum olacoides, a traditional Amazonian nerve tonic possesses anticholinesterase activity. Pharmacol. Biochem. Behav. 75, 645-650.
Sung, S.H., Kang, S.Y., Lee, K.Y., Park, M.J., Kim, J.H., Park, J.H., Kim, Y.C., Kim, J., Kim, Y.C., 2002. (+)-[alpha]-Viniferin, a stilbene trimer from Caragana chamlague inhibits acetylcholinesterase. Biol. Pharm. Bull. 25, 125-127.
Tang, X.C., Kindel, G.H., Kozikowski, A.P., Hanin, I., 1994. Comparison of the effects of natural and synthetic huperzine-A on rat brain cholinergic function in vitro and in vivo. J. Ethnopharmacol. 44, 147-155.
Urbain, A., Marston, A., Queiroz, E.F., Ndjoko, K., Hostettmann, K., 2004. Xanthones from Gentiana campestris as new acetylcholinesterase inhibitors. Planta Med. 70, 1011-1014.
Wang, T., Tang, X.C., 1998. Reversal of scopolamine-induced deficits in radial maze performance by (-)-huperzine A: comparison with E2020 and tacrine. Eur. J. Pharmacol. 349, 137-142.
Whitehouse, P.J., 1993. Cholinergic therapy in dementia. Acta Neurol. 149, 42-45.
Pulok K. Mukherjee (a,b,*), Venkatesan Kumar (b), Mainak Mal (b), Peter J. Houghton (a)
(a) Department of Pharmacy, Pharmacognosy Research Laboratories, Franklin-Wilkins Building, King's College London, 150 Stamford Street, London SE1 9NH, UK
(b) School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
*Corresponding author. School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India. Tel./fax: +91 33 24146046.
E-mail address: firstname.lastname@example.org (P.K. Mukherjee).
Table 1. Plants with acetylcholinesterase inhibitory activity Parts Plant Family used Type of extract Abutilon indicum Linn. Malvaceae Whole Methanolic Acanthus ebracteatus Vahl. Acanthaceae Aerial Methanolic part Aegle marmelos (Linn.) Rutaceae Fruit Methanolic Correa ex Roxb. pulp Albizia procera (Roxb.) Leguminosae Bark Methanolic Benth. Bacopa monniera Linn. Scrophulariaceae Whole Ethanolic Butea superba Roxb. Leguminosae Root Methanolic barks Buxus sempervirens Linn. Buxaceae Whole Chloroform: methanol (1:1) Carthamus tinctorius Linn. Compositae Flower Methanolic Cassia fistula Linn. Leguminosae Roots Methanolic Corydalis solida Linn. Papaveraceae Whole Chloroform: methanol (1:1) Cyperus rotundus Linn. Cyperaceae Whole Methanolic Euphorbia antiquorum Linn. Euphorbiaceae Stem Methanolic Fumaria vaillantii Lois. Fumariaceae Whole Chloroform: methanol (1:1) Fumaria capreolata Linn. Fumariaceae Whole Chloroform: methanol (1:1) Fumaria kralikii Jordan Fumariaceae Whole Chloroform: methanol (1:1) Fumaria asepala Boiss. Fumariaceae Whole Chloroform: methanol (1:1) Fumaria densiflora DC. Fumariaceae Whole Chloroform: methanol (1:1) Fumaria flabellate Linn. Fumariaceae Whole Chloroform: methanol (1:1) Fumaria petteri Reichb Fumariaceae Whole Chloroform: subsp. thuretii (Boiss.) methanol (1:1) Fumaria macrocarpa Boiss. Fumariaceae Whole Chloroform: ex Hausskn. methanol (1:1) Fumaria cilicica Hausskn. Fumariaceae Whole Chloroform: methanol (1:1) Fumaria parviflora Lam. Fumariaceae Whole Chloroform: methanol (1:1) Fumaria judaica Boiss. Fumariaceae Whole Chloroform: methanol (1:1) Ginkgo biloba Linn. Coniferae Whole Ethanolic Glaucium corniculatum Papaveraceae Whole Chloroform: (Linn.) J.H. Rudolph. methanol (1:1) Lycopodium clavatum Linn. Lycopodiaceae Whole Chloroform: methanol (1:1) Mammea harmandii Kosterm. Guttiferae Flower Methanolic Melissa officinalis Linn. Lamiaceae Aerial Volatile oil part Michelia champaca Linn. Magnoliaceae Leaf Methanolic Mimosa pudica Linn. Leguminosae Whole Methanolic Mimusops elengi Linn. Sapotaceae Flower Methanolic Musa sapientum Linn. Musaceae Fruit Methanolic Myricaria elegans Royle Tamaricaceae Aerial Methanolic Nelumbo nucifera Gaertn. Nelumbonaceae Stamen Methanolic Paederia linearis Hook. f. Rubiaceae Whole Methanolic Piper interruptum Opiz Piperaceae Stems Methanolic Piper nigrum Linn. Piperaceae Seeds Methanolic Plumbago indica Linn. Plumbaginaceae Root Methanolic Ptychopetalum olacoides Olacaceae Root Ethanol Benth. Rhododendron luteum Sweet. Ericaceae Whole Chloroform: methanol (1:1) Rhododendron ponticum Ericaceae Whole Chloroform: Linn. subsp. Ponticum methanol (1:1) Rhodiola rosea Linn. Crassulaceae Root Methanol Salvia lavandulaefolia Lamiaceae Whole Steam distilled Vahl. oil Salvia officinalis Linn. Lamiaceae Whole Ethanol 95% Steam distilled oil Stephania suberosa Forman. Menispermaceae Roots Methanolic Streblus asper Lour. Moraceae Seed Methanolic Tabernaemontana divaricata Apocynaceae Roots Methanolic (Linn.) R. Br. Ex Terminalia bellirica Combretaceae Fruit Methanolic (Gaertn.) Roxb. Tiliacora triandra Menispermaceae Root Methanolic (Colebr.) Diel Vicia faba Linn. Fabaceae Whole Chloroform: methanol (1:1) Activity (% inhibition) Plant (concentration) References Abutilon indicum Linn. 30.66[+ or -]1.06 Ingkaninan et al. (0.1 mg/ml) (2003) Acanthus ebracteatus Vahl. 36.19[+ or -]8.00 Ingkaninan et al. (0.1 mg/ml) (2003) Aegle marmelos (Linn.) 44.65[+ or -]3.04 Ingkaninan et al. Correa ex Roxb. (0.1 mg/ml) (2003) Albizia procera (Roxb.) 40.71[+ or -]0.46 Ingkaninan et al. Benth. (0.1 mg/ml) (2003) Bacopa monniera Linn. 42.9[+ or -]1.2 Das et al, (2002) (0.1 mg/ml) Butea superba Roxb. 55.87[+ or -]5.83 Ingkaninan et al. (0.1 mg/ml) (2003) Buxus sempervirens Linn. 61.76[+ or -]0.76 Orhan et al. (2004) (1 mg/ml) Carthamus tinctorius Linn. 30.33[+ or -]9.22 Ingkaninan et al. (0.1 mg/ml) (2003) Cassia fistula Linn. 54.13[+ or -]3.90 Ingkaninan et al. (0.1 mg/ml) (2003) Corydalis solida Linn. 87.56[+ or -]1.24 Orhan et al. (2004) (1 mg/ml) Cyperus rotundus Linn. 44.19[+ or -]2.27 Ingkaninan et al. (0.1 mg/ml) (2003) Euphorbia antiquorum Linn. 42.31[+ or -]9.10 Ingkaninan et al. (0.1 mg/ml) (2003) Fumaria vaillantii Lois. 94.23[+ or -]0.47 Orhan et al. (2004) (1 mg/ml) Fumaria capreolata Linn. 96.89[+ or -]0.17 Orhan et al. (2004) (1 mg/ml) Fumaria kralikii Jordan 84.98[+ or -]1.07 Orhan et al. (2004) (1 mg/ml) Fumaria asepala Boiss. 91.99[+ or -]0.70 Orhan et al. (2004) (1 mg/ml) Fumaria densiflora DC. 93.42[+ or -]0.92 Orhan et al. (2004) (1 mg/ml) Fumaria flabellate Linn. 92.14[+ or -]1.01 Orhan et al. (2004) (1 mg/ml) Fumaria petteri Reichb 89.45[+ or -]0.86 Orhan et al. (2004) subsp. thuretii (Boiss.) (1 mg/ml) Fumaria macrocarpa Boiss. 93.43[+ or -]0.64 Orhan et al. (2004) ex Hausskn. (1 mg/ml) Fumaria cilicica Hausskn. 88.03[+ or -]0.65 Orhan et al. (2004) (1 mg/ml) Fumaria parviflora Lam. 87.02[+ or -]0.31 Orhan et al. (2004) (1 mg/ml) Fumaria judaica Boiss. 96.47[+ or -]0.63 Orhan et al. (2004) (1 mg/ml) Ginkgo biloba Linn. 50% (268.33 [micro]g) Das et al. (2002) Perry et al. (1998) Glaucium corniculatum 86.55[+ or -]0.67 Orhan et al. (2004) (Linn.) J.H. Rudolph. (1 mg/ml) Lycopodium clavatum Linn. 49.85[+ or -]1.33 Orhan et al. (2004) (1 mg/ml) Mammea harmandii Kosterm. 33.63[+ or -]8.00 Ingkaninan et al. (0.1 mg/ml) (2003) Melissa officinalis Linn. -- Perry et al. (1998) Michelia champaca Linn. 34.88[+ or -]4.56 Ingkaninan et al. (0.1 mg/ml) (2003) Mimosa pudica Linn. 21.40[+ or -]6.68 Ingkaninan et al. (0.1 mg/ml) (2003) Mimusops elengi Linn. 32.81[+ or -]5.36 Ingkaninan et al. (0.1 mg/ml) (2003) Musa sapientum Linn. 29.14[+ or -]4.73 Ingkaninan et al. (0.1 mg/ml) (2003) Myricaria elegans Royle 74.8% (0.2 Ahmad et al. (2003) [micro]g/ml) Nelumbo nucifera Gaertn. 23.77[+ or -]2.83 Ingkaninan et al. (0.1 mg/ml) (2003) Paederia linearis Hook. f. 29.31[+ or -]6.39 Ingkaninan et al. (0.1 mg/ml) (2003) Piper interruptum Opiz 65.16[+ or -]8.13 Ingkaninan et al. (0.1 mg/ml) (2003) Piper nigrum Linn. 58.02[+ or -]3.83% Ingkaninan et al. (0.1 mg/ml) (2003) Plumbago indica Linn. 30.14[+ or -]3.28 Ingkaninan et al. (0.1 mg/ml) (2003) Ptychopetalum olacoides Dose dependent activity Siqueira et al. Benth. at doses of 50 and (2003) 100 mg/kg, i.p. Rhododendron luteum Sweet. 76.32[+ or -]0.58 Orhan et al. (1 mg/ml) (2004) Rhododendron ponticum 93.03[+ or -]1.12 Orhan et al. Linn. subsp. Ponticum (1 mg/ml) (2004) Rhodiola rosea Linn. 42.00[+ or -]3.20 Hillhouse et al. (10 g/1) (2004) Salvia lavandulaefolia 63.0[+ or -]3.7 Perry et al. (1996, Vahl. (0.1 [micro]g/ml) 2000, 2001) Salvia officinalis Linn. 68.2[+ or -]15.6 Perry et al. (1996, (2.5 mg/ml) 2000, 2001) 52.4[+ or -]0.8 (0.1 [micro]g/ml) Stephania suberosa Forman. 91.93[+ or -]10.80 Ingkaninan et al. (0.1 mg/ml) (2003) Streblus asper Lour. 30.51[+ or -]4.21 Ingkaninan et al. (0.1 [micro]g/ml) (2003) Tabernaemontana divaricata 93.50[+ or -]0.37 Ingkaninan et al. (Linn.) R. Br. Ex (0.1 mg/ml) (2003) Terminalia bellirica 39.68[+ or -]8.15 Ingkaninan et al. (Gaertn.) Roxb. (0.1 mg/ml) (2003) Tiliacora triandra 42.29[+ or -]2.89 Ingkaninan et al. (Colebr.) Diel (0.1 mg/ml) (2003) Vicia faba Linn. 45.23[+ or -]1.03 Orhan et al. (2004) (1 mg/ml) Table 2. Phytoconstituents having acetylcholinesterase inhibitory activity Name of alkaloid Class Sources Alkaloids Assoanine Steroidal alkaloid Narcissus assoanus Buxamine B Steroidal alkaloid Bucus hyrcana Bucus papillosa Coronaridine Indole alkaloid Tabernaemontana australis Corynoline Isoquinoline alkaloid Corydalis incisa N, N-dimethyl Steroidal alkaloid Bucus papillosa buxapapine Epinorgalantamine Steroidal alkaloid Narcissus confuses N. Perezchiscanoi Narcissus leonensis N. legionensis Narcissus poeticus Galantamine Steroidal alkaloid Galanthus nivalis Narcissus confuses Lycorus radiate (-)-Huperzine A Quinolizidine alkaloid Huperzia serrata Huperzia dalhousieana 11-Hydroxygalantamine Steroidal alkaloid Narcissus poeticus Oxoassoanine Steroidal alkaloid Narcissus assoanus Palmatine Isoquinoline alkaloid Corydalis speciosa Physostigmine Indole alkaloid Physostigma venenosum Protopine Isoquinoline alkaloid Corydalis speciosa Rupicoline Indole alkaloid Tabernaemontana australis Sanguinine Steroidal alkaloid Eucharis grandiflora Sarsalignone Steroidal alkaloid Sarcococca saligna [alpha]-Solanine Glycoalkaloid Solanum tuberosum Vaganine Steroidal alkaloid Sarcococca saligna Voacangine Indole alkaloid Tabernaemontana australis Voacangine Indole alkaloid Tabernaemontana australis hydroxyindolenine Glycosides Name of glycoside Class Sources Cynatroside A Pregnane glycoside Cynanchum atratum Cynatroside B Pregnane glycoside Cynanchum atratum Norswertianolin Bellidin 8-O-[beta]- Gentiana cambpestris glucopyranoside Swertianolin Bellidifolin Gentiana cambpestris 8-O-[beta]- glucopyranoside Flavonoids, Xanthones, Stilbene oligomers and others Name of compound Class Sources (+)-[alpha]-Viniferin Stilbene oligomer Caragana chamlague Bellidin Xanthone Gentiana cambpestris Bellidifolin Xanthone Gentiana cambpestris Ursolic acid Hydroxy-heptamethyl- Origanum majorana icosahydropicene carboxylic acid Name of alkaloid Plant family Activity Alkaloids Assoanine Amaryllidaceae 50% inhibition at 3.87[+ or -]0.24 [micro]M Buxamine B Buxaceae 50% inhibition at 7.56[+ or -]0.008 [micro]M Coronaridine Apocynaceae Minimum concentration of 25 [micro]M to produce detectable spot in TLC Corynoline Papaveraceae 50% inhibition at 30.6 [micro]M N, N-dimethyl Buxaceae 50% inhibition at buxapapine 7.28[+ or -]0.06 [micro]M Epinorgalantamine Amaryllidaceae 50% inhibition at 9.60[+ or -]0.65 [micro]M Galantamine Amaryllidaceae 50% inhibition at 1.07[+ or -]0.18 [micro]M (-)-Huperzine A Lycopodiaceae 50% inhibition at [10.sup.-4] [micro]M 11-Hydroxygalantamine Amaryllidaceae 50% inhibition at 1.61[+ or -]0.21 [micro]M Oxoassoanine Amaryllidaceae 50% inhibition at 47.21[+ or -]1.13 [micro]M Palmatine Papaveraceae 50% inhibition at 5.8 [micro]M Physostigmine Leguminosae 50% inhibition at 6 x [10.sup.-4] [micro]M Protopine Papaveraceae 50% inhibition at 16.1 [micro]M Rupicoline Apocynaceae Minimum concentration of 25 [micro]M to produce detectable spot in TLC Sanguinine Amaryllidaceae 50% inhibition at 0.10[+ or -]0.01 [micro]M Sarsalignone Buxaceae 50% inhibition at 7.028[+ or -]0.007 [micro]M [alpha]-Solanine Solanaceae 44.3% inhibition at 10 [micro]M Vaganine Buxaceae 50% inhibition at 8.59[+ or -]0.155 [micro]M Voacangine Apocynaceae Minimum concentration of 25 [micro]M to produce detectable spot in TLC Voacangine Apocynaceae Minimum concentration of hydroxyindolenine 25 [micro]M to produce detectable spot in TLC Glycosides Name of glycoside Plant family Activity Cynatroside A Asclepiadaceae 50% inhibition at 6.4 [micro]M Cynatroside B Asclepiadaceae 50% inhibition at 3.6 [micro]M Norswertianolin Coniferae Minimum concentration of 1.20 [micro]M to produce detectable spot in TLC Swertianolin Coniferae Minimum concentration of 0.18 [micro]M to produce detectable spot in TLC Flavonoids, Xanthones, Stilbene oligomers and others Name of compound Plant family Activity (+)-[alpha]-Viniferin Leguminosae 50% inhibition at 2.0 [micro]M Bellidin Coniferae Minimum concentration of 0.03 [micro]M to produce detectable spot in TLC bioassay Bellidifolin Coniferae Minimum concentration of 0.15 [micro]M to produce detectable spot in TLC Ursolic acid Lamiaceae 50% inhibition at 7.5 [micro]M Name of alkaloid References Alkaloids Assoanine Lopez et al. (2002) Buxamine B Rahman and Choudhary (2001) Coronaridine Andrade et al. (2005) Corynoline Kim (2002) N, N-dimethyl Rahman and Choudhary (2001) buxapapine Epinorgalantamine Lopez et al. (2002) Galantamine Rhee et al. (2001); Rizzi et al. (1999); Ingkaninan et al. (2003); Lopez et al. (2002) (-)-Huperzine A Tang et al. (1994) Orhan et al. (2004); Ashani et al. (1994) 11-Hydroxygalantamine Lopez et al. (2002) Oxoassoanine Lopez et al. (2002) Palmatine Kim et al. (2004) Physostigmine Karczmar (1998) Protopine Kim et al. (2004) Rupicoline Andrade et al. (2005) Sanguinine Lopez et al. (2002) Sarsalignone Rahman and Choudhary (2001) [alpha]-Solanine Roddick (1989) Me Gehee et al. (2000) Vaganine Rahman and Choudhary (2001) Voacangine Andrade et al. (2005) Voacangine Andrade et al. (2005) hydroxyindolenine Glycosides Name of glycoside References Cynatroside A Lee et al (2003) Cynatroside B Lee et al (2003) Norswertianolin Urbain et al. (2004) Swertianolin Urbain et al. (2004) Flavonoids, Xanthones, Stilbene oligomers and others Name of compound References (+)-[alpha]-Viniferin Sung et al. (2002) Bellidin Urbain et al. (2004) Bellidifolin Urbain et al. (2004) Ursolic acid Chung et al. (2001)
|Printer friendly Cite/link Email Feedback|
|Author:||Mukherjee, Pulok K.; Kumar, Venkatesan; Mal, Mainak; Houghton, Peter J.|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Apr 1, 2007|
|Previous Article:||An extract of Pelargonium sidoides (EPs 7630) inhibits in situ adhesion of Helicobacter pylori to human stomach.|
|Next Article:||Safety evaluation of BacoMind[TM] in healthy volunteers: a phase I study.|