Anticholinesterase potential of phytoextracts and their bioactive compounds: a promising therapeutic agent against Alzheimer’s disorder

doi:10.15406/mojtr.2018.01.00018

MOJ

eISSN: 2641-9300

Tumor Research

Mini Review Volume 1 Issue 2

Anticholinesterase potential of phytoextracts and their bioactive compounds: a promising therapeutic agent against Alzheimer’s disorder

Atanu Bhattacharjee

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Department of Pharmacy, Assam down town University, India

Correspondence: Atanu Bhattacharjee, Department of Pharmacy, Assam Down Town University, India, Tel 91-8073612051

Received: March 27, 2018 | Published: April 9, 2018

Citation: Bhattacharjee A. Anticholinesterase potential of phytoextracts and their bioactive compounds: a promising therapeutic agent against Alzheimer’s disorder. MOJ Tumor Res. 2018;1(2):84-88. DOI: 10.15406/mojtr.2018.01.00018

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Abstract

Alzheimer's disease (AD) is a dynamic neurodegenerative pathological condition described by low level of neurotransmitter acetylcholine (ACh) in the cerebrum. It is an irreversible age-related type of dementia that gradually dissolves the mind and burglarizes the individual memory and psychological abilities and causes changes in identity and conduct. Amid a decade ago, critical development in Alzheimer's commonness has lighted the significance of more looks into in the pursuit of new medication. One of the major clinical advances in the treatment of AD have been the utilization of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors to reduce ACh level in cerebrum albeit cholinergic mixes with nicotinic and muscarinic agonist properties additionally have pulled in some intrigue. At present, there are extremely constrained drugs accessible to treat AD and the greater part of the treatment is accessible just to postpone the progress of indications and symptomatic alleviation for a brief timeframe. Restorative plants speak to a lot of undiscovered store of characteristic prescriptions and potential wellspring of common AChE inhibitors. The basic assorted variety of their phytoconstituents makes them an important wellspring of novel lead mixes for the mission of medications to treat AD. Consequently, methodical ethnopharmacological screening of these plants may give valuable leads in the disclosure of new medications for AD treatment. With this background, a precise review is prepared to deliver up to date information in different phytoextracts and their derivatives alongside their conceivable activity on cholinergic sensory system to ease AD treatment. Electronic database were used for searching the information related to studies performed in plants during last decades.

Keywords: Alzheimer’s disease, Acetylcholine, Acetylcholinesterase, Butyrylcholinesterase, Medicinal plant.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with progressive dementia, a deterioration of memory and cognition.¹ AD causes changes in normal physiological behaviors of elderly patients, with duration of 09 years between beginning of symptoms and demise and has been risen as one of the deadliest issue in created countries. By 2040, World Health Organization (WHO) evaluated around 71% of the dementia cases will happen in developing nations.^2‒4 The role of neurotransmitter acetylcholine (ACh) with cognitive function is clinically established now.⁵ One of the neurotic signs of AD is loss of cholinergic cell in basalis of Meynert and hippocampus resulting reduce level of Ach in cerebrum.⁶ Subsequently, repletion of Ach levels in brain has been exploited therapeutically amid most recent couple of decades to accomplish symptomatic help in AD.⁷ In light of these etiologies a few pharmacological procedures with various conceivable targets are under scrutiny⁸ and the main line remedial approach includes re-foundation of ACh levels, with the hindrance of cholinesterases viz. acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and also monoamine oxidase (MAO) enzymes.^9,10 AChE basically acts by termination of nerve impulses at the cholinergic neural connections by quick hydrolysis of Ach to choline and acetic acid. This inhibition alleviates half-life of AChE and in this manner increasing concentration at synapses.¹¹ In fact, tacrine was the first clinically proven AChE inhibitor acquainted with enhances Ach level at the nerve ending. Afterward, second era inhibitors are presented however coming about symptoms and cost factor made their use constrained.¹² Medicinal plants and their concentrates are assuming an indispensable part in the present treatment of psychological issue either as standard or integral drug with specific reference to their ethnopharmacological perspectives.^13,14 Basically, in Ayurveda (Traditional Indian medicinal system), these restorative plants were named "medharasayanas" (Sanskrit: "medha" implies intellect/cognition and "rasayana" implies revival.¹⁵ Medharasayanas incorporate a gathering of four therapeutic plants with multifold benefits, particularly to enhance memory and acumen by Prabhava (specific action) viz. Mandukaparni (Centella asiatica; Family: Umbelliferae), Yastimadhu (Glycirrhiza glabra; Family: Leguminosae), Guduchi (Tinospora cordifolia; Family: Menispermaceae) and Shankhapushpi (Convolvulus pleuricaulis; Family: Convolvulaceae).¹⁶ Traditional Indian medicinal plants like Ashwagandha (Withania somnifera; Family: Solanaceae), Brahmi (Bacopa monnieri; Family: Scophulariaceae), Jyothishmati (Celastrus panniculata; Family: Celastraceae), Kushmanda (Benincasa hispida; Family: Cucurbitaceae), Vacha (Acorus calamus; Family: Araceae) and Jatamamsi (Nardostachys jatamamsi; Family: Valerianaceae) are very much archived in Ayurveda and other traditional messages as brain tonics and memory enhancers.¹⁷ Indian turmeric (Curcuma longa; Family: Zingiberaceae) contains curcumin, a demonstrated cell reinforcement and anticholinesterase activity, is observed to be exceptionally compelling to defer the movement of AD.¹⁸ Cholinesterase inhibitors inhibit the hydrolysis of ACh by inhibitin AChE and thereby increase the availability of acetylcholine in brain specifically in cholinergic synapse.¹⁹ However, this approach is limited to patients who have intact and functionally active presynaptic neurons capable of synthesizing and releasing ACh. Therefore, AChE inhibitors are useful in the early and moderate stages of AD.²⁰ Recent studies indicated that cholinesterase inhibitors might play a modulatory role on Ab plaque deposition via suppressing amyloid precursor protein (APP) expression.²¹ Medicinal plants have been the single most productive source of lead molecule for the development of drugs, and over a hundred new products are already in clinical development.²² Indeed, several pharmacological screenings showed the efficacy of these medicinal plants extracts alone or in combination along with their active constituents to encounter AD.²³ The discoveries of exploratory results on different medicinal plants influencing cholinergic neurotransmission pertinent to the treatment of AD are given underneath (Table 1).

Family	Common name	Source	Parts used	Type of extract	Method and % of cholinesterase inhibition		Reference
					AchE	BchE
Araceae	Sweet Flag	Acorus calamus	Rhizome	Methanol	96 well plate; 50% (791.35μg/ml)*	ND	8
Brassicaceae	White mustard	Brassica alba	Seed	Ethanol	UV spectroscopy; 50% (84.3±1.36μg/ml)*	ND	24
Capparidaceae	Varuna	Crataeva nurvala	Stem bark	Chloroform	UV spectophotometry; 2.38±0.160 (µMoles/min/g of tissue)	ND	11
Caryophyllaceae	Clove	Eugenia caryophyllus	Flower bud	Essentail oil	96 well plate; 50.45±0.003 (100µg/ml)	96 well plate; 49.76±0.005 (100 µg/ml)	25
Combretaceae	Bohera	Terminalia bellirica	Fruit	Methanol	TLC and 96 well plate; 39.68±8.15 (0.1mg/ml)	ND	26
	Haritaki	Terminalia chebula	Fruit	Methanol	96 well plate; 89.00±1.00 (5 mg/ml)	96 well plate; 95.00±1.00 (5mg/ml)	26
Convolvulaceae	Shankhapushpi	Convolvulus pluricaulis	Whole plant	Methanol	TLC and 96 well plate; 2.22±1.17 (100µg/ml)	ND	26
Dioscoreaceae	Aerial yam	Dioscorea bulbifera	Whole plant	Methanol	96 well plate; 79.00±2.00 (5mg/ml)	96 well plate; 82.00±2.00 (5mg/ml)	26
Fumariaceae	Indian Fumitory	Fumaria asepala	Whole plant	Chloroform: methanol (1:1)	96 well plate; 91.99±0.70 (1mg/ml)	96 well plate; 93.12±0.28 (1mg/ml)	26
Ginkgoaceae	Ginkgo	Ginkgo biloba	Whole plant	Ethanol	96 well plate; 50% (268.33µg/ml)*	ND	26
Hyperaceae	St. Johns Wort	Hypericum perforatum	Aerial part	Methanol	UV spectophotometry; 73.5±2.40 (400µg/ml)	UVspectophotometry; 50.5 ± 0.70 (400mg/ml)	26
Lamiaceae	Lavender	Lavandula angustifolia	Aerial parts	Ethanol	UV spectophotometry; 64.30±9.00 (1mg/ml)	ND	26
	Menthe/Pudina	Mentha spicata	Whole plant	Methanol	TLC and 96 well plate; 15.00±0.00 (0.1mg/ml)	ND	26
	Sage	Salvia albimaculata	Whole plant	Petroleum ether	96 well plate; 89.40±2.07 (1mg/ml)	96 well plate; 73.90±0.76 (1 mg/ml)	26
Leguminosae	White siris	Albizia procera	Bark	Methanol	TLC and 96 well plate; 40.71±0.46 (0.1mg/ml)	ND	26
	Indian Laburnum	Cassia fistula	Root	Methanol	TLC and 96 well plate; 54.13±3.90 (0.1mg/ml)	ND	26
	Touch me not/Lajjavati	Mimosa pudica	Whole plant	Water	TLC and 96 well plate; 1.68±0.22 (100µg/ml)	ND	26
	Licorice	Glycyrrhiza glabra	Root	Methanol	96 well plate; 50% (418±30.7µg/ml) *	ND	27
Fagaceae	Menthi	Trigonella foenum graecum	Seeds	Hydro alcohol	TLC and 96 well plate; 50% (6±0.9µg/ml)	ND	28
Lythraceae	Pomegranate	Punica granatum	Fruit	Methanol	96 well plate; 50% (77± 6.2µg/ml) *	ND	26
Nelumbonaceae	Indian lotus	Nelumbo nucifera	Stamen	Methanol	TLC and 96 well plate; 23.77±2.83 (0.1mg/ml)	ND	23
Rubiaceae	Indian Madder	Rubia cordifolia	Stem	Methanol	TLC and 96 well plate; 22.12±2.22 (100µg/ml)	ND	22
Scrophulariaceae	Brahmi	Bacopa monniera	Whole plant	Ethanol	96 well plate; 42.90±1.20 (0.1mg/ml)	ND	18
Solanaceae	Aswagandha	Withania somnifera	Root	Methanol	TLC and 96 well plate; 75.95±0.16 (100µg/ml)	ND	26
			Root	Aqueous	TLC and 96 well plate; 24.60±0.38 (100µg/ml)	ND	26
Umbelliferae	Mandookparni	Centella asiatica	Whole plant	Hydroalcohol	96 well plate; 50% (106.55µg/ml)*	ND	26
Valerianaceae	Indian Valerian	Nardostachys jatamansi	Rhizomes	Methanol	96 well plate; 50% (562.21µg/ml)*	ND	26
Zingiberaceae	Galanga	Alpinia galanga	Rhizomes	Methanol	TLC and 96 well plate; 16.98±0.37 (100µg/ml)	ND	26
Zygophyllaceae	Land-Caltrops/ Gokhru	Tribulus terrestris	Whole plants	Chloroform: methanol (1:1)	96 well plate; 37.89±0.77 (1mg/ml)	96 well plate; 78.32±1.27 (1mg/ml)	26

Table 1 Medicinal plants affecting cholinergic neurotransmission
ND, not done; *, represents IC50

Lead phytomolecules affecting cholinergic neurotransmission

Bioactive phytoconstituents resulted from isolation and characterization of natural flora and fauna have always been an important reservoir of drugs. The majority of the compounds examined till date affecting cholinergic neurotransmission and aiding protection against AD are primarily derived from plants sources.²⁴ A list of phytoconstituents having significant AChE inhibitory activity is provided in Table 2. Natural alkaloids with AChE inhibitory activity viz. physostigmine, huperzine-A, galan- thamine, are successfully practiced to encounter progression of AD.^25‒29 Stilbene oligomer viz. a-viniferin and triterpenoid viz. ursolic acid are another highly potential lead molecule with AChE inhibitory activity.^30,31 The other major classes of phytoconstituents reported to have such activity are the flavonoids, glycosides and coumarins.³² Although, with enormous efforts structure activity relationship (SAR) of few isolated bioactive compounds have been established but most of them are yet to be finalized. Moreover, cellular based mechanism of action, clinical efficacy and toxicity profile of these phytoextracts and their derivatives requires further assessment, before proceeding towards clinical trials and final approval to encounter AD.

Chemical nature of phytoconstituents
Alkaloid
	Class	Source	Family	Activity on AchE		References
Assoanine	Steroidal alkaloid	Narcissus assoanus	Amaryllidaceae	50% inhibition at 3.87±0.24 pM		29
Buxamine B	Steroidal alkaloid	Bums hyrcana	Buxaceae	50% inhibition at 7.56±0.008 pM		29
Epinorgalantamine	Steroidal alkaloid	Narcissus confuses	Amaryllidaceae	50% inhibition at 9.60±0.65 pM		29
Galantamine	Steroidal alkaloid	Galanthus nivalis	Amaryllidaceae	50% inhibition at 1.07±0.18 pM		29
Sanguinine	Steroidal alkaloid	Eucharis grandeora	Amaryllidaceae	50% inhibition at 0.10±0.01 pM		29
Oxoassoanine	Steroidal alkaloid	Narcissus assoanus	Amaryllidaceae	50% inhibition at 47.21±1.13 pM		29
a-Solanine	Glycoalkaloid	Sarcococca saligna	Buxaceae	50% inhibition at 8.59±0.155 pM		30
Vaganine	Steroidal alkaloid	Solanum tuberosum	Solanaceae	50% inhibition at 7.028±0.007 pM		30
Physostigmine	Indole alkaloid	Physostigtna venenosiun	Fabaceae	50% inhibition at 6±1.0 pM		31
Coronaridine	Indole alkaloid	Tabernaernontana austral	Apocynaceae	Minimum concentration of 25 pM to produce detectable spot in TLC		28
Voacangine	Indole alkaloid	Tabernaentontana austral	Apocynaceae	Minimum concentration of 25pM to produce detectable spot in TLC		28
Rupicoline	Indole alkaloid	Tabernaetnontana australis	Apocynaceae	Minimum concentration of 25µM to produce detectable spot in TLC		6
Retamine	Quinolizidine alkaloid	Genista aucheri	Fabaceae	AchE and BchE inhibition (%) at 1 mg/ml at 15.0±1.08 & 66.3±0.88 respectively		17
Corynoline	Isoquinoline alkaloid	Corydalis incisa	Papaveraceae	50% inhibition at 30.6 pM		28
Palmatine	Isoquinoline alkaloid	Corydath speciosa	Papaveraceae	50% inhibition at 5.8 pM		28
(-)-Huperzine A	Quinolizidine alkaloid	Huperzia serrate	Lycopodiaceae	50% inhibition at 10.1 pM		31
*Glycoside*
Cynatroside A	Pregnant glycoside	Cynanchum frown	Asclepiadaceae	50% inhibition at 6.4 pM		31
Cynatroside B	Pregnant glycoside	Cynanchum stratum	Asclepiadaceae	50% inhibition at 3.6pM		31
Norswertianolin	Ggluco pyranoside	Gentiana cambpestris	Coniferae	Minimum concentration of 1.20nM to produce detectable spot in TLC		31
Swertianolin	Bellidifolin 8-o-13 glucopyranoside	Gentians cambpestris	Coniferae	Minimum concentration of 0.18nM to produce detectable spot in TLC		31
*Others*
Scopoletin	Coumarin	Vaccinium oldhami	Ericaceae		IC50 value of 79μM	14
Murranganin	Coumarins	Murraya paniculata	Rutaceae		IC50 value of 79.1μM	7
Viniferin	Stilbene oligomer	Caragana chantlague	Leguminosae		50% inhibition at 2.0pM	5
Bellidin	Xanthone	Centime cambpestris	Coniferae		Minimum concentration of 0.03 nM to produce detectable spot in TLC bioassay	14
Ursolic acid	Triterpenoids	Origami majorana	Lamiaceae		50% inhibition of AChE and BchE at 75.87±0.92 & 32.21±0.88 respectively	18
Capsaicin	Pungent principle	Capsicum annum	Solanaceae		50% inhibition of AChE and BchE at 62.7±0.79 and 75.3±0.98 respectively	18
Viniferin	Polyphenol	Caragana chamlague	Leguminosae		IC50 values of 2.0mM	31
Kobophenol A	Polyphenol	Caragana chamlague	Leguminosae		IC50 value of 115.8mM	31
Curcuminoids	Triterpene	Curcuma longa	Ziniberaceae		IC50 value of 19.67mM	31