Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer’s disease

Summary

Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β‐amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances. Approximately, 60%‐80% of all cases of dementia in the world are patients with AD. In view of the continuous rise of this disease especially in the aged population, there is a dire need to come up with a novel compound and/or mixture that could work against this devastating disease. In this regard, the best is to rely on natural compounds rather than synthetic ones, because natural compounds are easily available, cost‐effective, and comparatively less toxic. To serve this purpose, lately, scientific community has started exploring the possibility of using different polyphenols either solitary or in combination that can serve as therapeutics against AD. In the current article, we have summarized the role of various polyphenols, namely quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, and caffeic acid as an inhibitor of cholinesterase for the treatment of AD. We have also tried to uncover the mechanistic insight on the action of these polyphenols against AD pathogenicity.

1. INTRODUCTION

Alzheimer’s disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder.1, 2, 3 A recent report suggests that it affects around 36 million people worldwide which account around 60%‐80% of all cases of dementia.4 It is characterized by an aberration in multiple interactive systems and molecular pathways, which ultimately leads to memory loss and cognitive dysfunction.5 The exact mechanisms involved in AD progression and pathology are still mysterious. However, the excessive deposition of β‐amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising hyperphosphorylated tau proteins, is proposed as the possible cause of this disorder.3, 6

According to the amyloid hypothesis, AD is characterized by the disturbances in amyloid precursor protein pathway that leads to the abnormal clearance of β‐amyloid.7 Accumulated β‐amyloid polymerizes to form soluble oligomers or insoluble amyloid fibrils and deposits as senile plaques especially in the area of brain parenchyma and cerebral blood vessel walls which has been considered as the important causative of AD.8 The extent of abnormal accumulation of amyloid plaques has been considered as one of the significant pathological features of AD.9 The β‐amyloid further induces pathogenic events and alter tau proteins. Hyperphosphorylation of tau proteins causes their aggregation and fibrillization in neurons that affect normal neuronal transport.10 Moreover, intraneuronal aggregates of hyperphosphorylated and misfolded tau proteins are known as neurofibrillary tangles (NFTs). Accumulation of NFTs in neurons causes neuronal loss and synaptic pathology which are also distinguished features of AD.11

The involvement of cholinergic system has been suggested as the earliest and most studied molecular events in AD pathophysiology. It is defined as the primary degenerative process that can damage cholinergic neurons in the brain and results in cognitive impairment. Neurofibrillary alterations and β‐amyloid pathology interact with cholinergic receptors and accelerate the progression of AD.12 The cholinergic hypothesis has served the basis for the majority of treatment strategies and drug development approaches toward AD till date. Cholinesterases belong to hydrolase group of enzymes that regulates cholinergic nerve and neuromuscular transmission and terminates the action of acetylcholine (ACh) by splitting it into acetate and choline.3, 6, 13 Among cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are the 2 important enzymes involved in the termination of cholinergic neurotransmission. AChE is a serine hydrolase involved in the termination of chemical transmission at cholinergic synapses and secretory organs by catalyzing the hydrolysis of the neurotransmitter “acetylcholine”.14 BChE is also a serine hydrolase involved in the hydrolysis of esters of choline that also include acetylcholine.13

Enzyme inhibitors are molecules that interact with the enzyme to thwart it from working in the normal manner. They have great physiological and medical significance. There are various types of inhibitors reported in the scientific literature, such as nonspecific, irreversible, and reversible (competitive and noncompetitive).13, 15 The primary therapeutic stratagem against AD till date engrosses the use of cholinesterase inhibitors (ChEIs) which increase residual cholinergic activity, improve cognition and global performance, and reduce behavioral disturbances. For the treatment of AD, some potent and quickly absorbed acetyl cholinesterase inhibitors (AChEIs), such as phenserine, tolserine, and esolerineare, are reported in the scientific literature.16 Several naturally derived AChEIs have also been reported in the literature. Huperzine A and huperzine B,17 Nelumbo nucifera, Himatanthus lancifolius extract,18 galangin,19 and cardanol derivatives20 are some of the examples in this category. However, preclinical, clinical safety, and toxicity of these compounds have yet to be identified. Based on the recent developments in the scientific field and emphasis of the scientific community on the usage of natural compounds for the treatment of various human diseases, we have summarized the role of various polyphenols such as quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, and caffeic acid as an inhibitor of cholinesterase for the treatment of AD. We have also tried to uncover the mechanistic insight on the action of these polyphenols against AD pathogenicity.

2. POLYPHENOLS

Over the past 3 decades, plant‐derived products are high on demand because of their immense therapeutic potential.21, 22 Similarly, the story of polyphenols made a prime shift from its fundamental role in plant protection to important human therapeutic agents. The structure of polyphenols is characterized by the presence of multiple units of phenol which provides specific physical, chemical, and biological properties. They represent a preponderant class of phytochemicals, widely distributed among the plant kingdom where more than 8000 phenolic structures are known.23 Polyphenols are classified by their source of origin, biological function, and chemical structure.24 According to the chemical structure and the presence of functional groups, polyphenols are generally classified as phenolic acids, flavonoids, and phenolic amides.25 Benzoic acid and cinnamic acid are the most important examples of phenolic acids. On the other hand, flavanoids are the most common group of polyphenols which is ubiquitous in nature. This class of polyphenols includes flavones, flavonols, flavanones, flavanonols, proanthocyanidins, and anthocyanidins.26 Polyphenols are found either in esters, polymers, or glycosylated forms and must be hydrolyzed by the intestinal enzymes or by the colonic microflora before absorption. The bioavailability of dietary polyphenols is highly variable among different individuals due to the composition of colonic microbiota.27 In addition, the absorption and bioavailability of the dietary polyphenols also defer among different polyphenols. The metabolism of polyphenols could lead to extensive modifications to exert their potential biological activities.28 Several studies highlighted the byzantine role of polyphenols in the reduction in initiation and progression of various diseases.26, 29, 30 However, the mechanisms of polyphenols action on imperative cellular events have not been completely elucidated till date. Phenolic compounds interact with amino acid residues defining the active site of AChE via a hydrogen bond, hydrophobic, and π–π interaction.31 Multiple hydroxyl groups in the phenolic compound are believed to enhance the inhibitory action of AChE because of stronger binding capacity.32 These inhibitory actions explain the inhibitory potential of most of the phenolic compounds but not all follow the same mode of action.33 To summarize our article, different polyphenols and their mode of action have been listed in the Table 1. The basic structure of all polyphenols mentioned in this article has also been depicted in the Figure 1. In the following section, we have highlighted several polyphenols individually or in combination that has been reported for their potential against AD.

Table 1.

Different polyphenols and their mode of actions

Polyphenol	Source of extraction	Enzyme inhibition	IC50	Medium	References
Quercetin	Agrimonia pilosa ledeb, Calendula officinalis Gossypium herbaceamPurified form Purified form	AChE, BChE	19.8 μmol/L 36.47 μmol/L 50.99 μmol/L 0.18 mmol/L 3.60 μmol/L	In vitro In vitro In vitro Ex vivo In vitro	33, 37, 39, 44
Resveratrol	Vitis amurensis Purified form	AChE, BChE	1.66 μmol/L 1.56 μmol/L	In vitro In vitro	54, 57, 60
Curcumin	Purified form Purified form Curcuma longa	AChE, BChE	58.08 μmol/L 19.67 μmol/L 51.8 μmol/L	In vitro In vitro In vitro	65, 73, 74, 76
Gallocatechins	Purified form Purified form Camellia sinensis var. assamica	AChE	248 g/mL 18.5 μmol/L 2.49 μmol/L	Ex vivo Ex vivoIn vitro	85, 88, 91
Cinnamic acid	Purified form Acacia honey Ocimum americanumOcimum africanumOcimum basilicum	AChE	8.6 nmol/L 88.5 μmol/L 2.57 mg/mL 3.40 mg/mL 6.62 mg/mL	In vitro In vitro In vitro In vitro In vitro	98, 100, 101
Caffeine and caffeic acid	Camellia sinensis	AChE	336.8 μmol/L	In vitro	110

Figure 1.

The basic structure of quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, and caffeic acid

3. QUERCETIN

Quercetin (3,5,7,3′,4′‐pentahydroxyflavone) is a polyphenolic flavonol molecule present in many fruits and vegetables such as onions, apples, berries, peanuts, soybeans, potatoes, broccoli, grapes, citrus fruits, and tea.34 Several reports highlighted the potential of quercetin against behavioral deficits in different animal models.35, 36

One in vitro study reported potential inhibitory activity of aglycones–quercetin against both AChE (IC₅₀ = 353.86 μmol/L) and butyrylcholinesterase (BChE) (420.76 μmol/L) in a concentration‐dependent manner compared with standard inhibitor galanthamine.37 They also noted quercetin ability to tightly bind with these enzymes and exhibited a number of strong hydrogen bonds with several important amino acid residues and a number of hydrophobic interactions against both enzymes.37 Another in vitro study reported substantial inhibitory potential of quercetin against AChE (76.2%) and BChE (46.8%) at 3.3 mmol/L concentration.38 Jung and Park39 reported potential AChE inhibitory activity (IC₅₀ = 19.8 μmol/L) of quercetin isolated from ethyl acetate extract of the whole plants of Agrimoniapilosa ledeb and suggested it as a possible therapeutic agent for the treatment of AD. However, the dose‐dependent AChE‐mediated inhibition by quercetin and its derivatives are reported to be less effective compared with clinically used tacrine (IC₅₀ = 0.1 μmol/L; a well‐known AD drug).40 Marigold (Calendula officinalis) is a widespread medicinal plant that has been reported for its potential anti‐AChE activity. Quercetin derivatives, such as quercetin‐3‐O‐(2′′,6′′‐di‐acetyl)‐glucoside (IC₅₀ = 36.47 μmol/L) and quercetin‐3‐O‐(2′′,6′′‐di‐rhamnosyl)‐glucoside (IC₅₀ = 94.92 μmol/L) extracted from this plant, are suggested to decrease the activity of AChE by binding with its active sites.41 The high potency of quercetin and its glucosides as AChE inhibitor has been reported in several other studies too.33, 38, 39

Extracts of Gossypium herbaceam have been used to treat mental retardation and have been reported for anti‐AChE activities. The extract of this herb contains complex mixture of flavonoids that include quercetin, isoquercetrin, and quercimeritrin. Among these, quercetin (IC₅₀ = 50.99 μmol/L) and quercimeritrin (IC₅₀ = 52.3 μmol/L) have been noted to possess significant AChE inhibitory activity, almost similar to huperzine A, the well‐known AChE inhibitor.42 A significant AChE inhibitory activity with walnut (Juglans regia L.) and strawberry (Fragaria ´ananassa L.) aqueous extract has also been suggested due to the presence of quercetin 3‐galactoside.43 Similarly, antioxidant potential and AChE inhibitory activity of aqueous tea infusions, prepared from walnut, peppermint (Mentha piperita), strawberry (Fragaria ananassa), lemon balm (Melissa officinalis), sage (Salvia officinalis), and immortelle (Helichrysum arenarium) have also been reported.43

Quercetin (0.1‐0.4 mmol/L) has also been reported to significantly inhibit AChE (IC₅₀ = 0.18 mmol/L) and BChE (IC₅₀ = 0.203 mmol/L) along with a strong inhibition of Fe⁽²⁺⁾‐induced lipid peroxidation and radical scavenging abilities in rats’ brain homogenates.44 The inhibition of cholinesterases (ChEs) and antioxidative properties are possible mechanisms of action of quercetin for the management of oxidative stress‐induced neurodegeneration.

In one in vitro study33 approx. 98% inhibitory activity of AChE at 100 μmol/L of quercetin concentration (IC₅₀ = 3.60 μmol/L) was reported. The authors suggested the presence of phenylchroman backbone present in quercetin is the reason behind noted AChE inhibition. In addition, the position, number, substitution of hydroxyl groups and the oxidation state of C‐ring of the flavonoid structure could also determine the effectiveness of AChE inhibition.33 Quercetin increases synaptic transmission by the inhibition of AChE activity in peripheral lymphocytes of cadmium‐treated adult male Wistar rats.45 Recently, Carla et al46 reported a significant decrease in AChE activity especially in hippocampus region with 22.5 mg/kg of quercetin treatment in ovariectomized Wistar rats. In addition to the AChE inhibition, 20 and 50 mg/kg of quercetin have also been reported to influence cerebral blood flow and cholinergic dysfunction in the brain of adult male Swiss albino mice.47 Consumption of a diet rich in quercetin has also been suggested to prevent dementia associated with vascular and neurodegenerative disorders.48 Future studies are advocated to better understand the mechanism of quercetin interaction in the brain that will highlight the significance of this compound against neurodegenerative disease.

4. RESVERATROL

Resveratrol (3, 5, 4′‐trihydroxy‐trans‐stilbene) is a polyphenol found in several plants, especially in grapes’ skin and seeds. It is a phytoalexin that acts against pathogens including bacteria and fungi.49 It has also been reported for their diverse biological activities such as antioxidant, antiinflammatory, phytoestrogenic, vasorelaxing, cardioprotective, and anticarcinogenic.50, 51, 52 Several studies also reported neuroprotective potential of resveratrol that includes the reduction in amyloid neuropathology, oligomerization of Aβ, cholinergic neurotransmission, and expression of brain‐derived neurotrophic factor.53, 54, 55, 56 In addition, resveratrol has also been reported to reduce neurodegeneration in the hippocampus and prevents cognitive decline in mouse models.49 Several lines of evidence highlighted the role of resveratrol in cholinergic inhibition that points their possible use for the treatment of AD.54, 57, 58 Jang et al57 reported potential cholinesterase inhibition and Aβ aggregation by resveratrol oligomers (10 μg/mL) isolated from Vitis amurensis. Among the isolated resveratrol oligomers, vitisin A and heyneanol A have been reported for better dose‐dependent inhibitory potential compared with standard inhibitor (galantamine) on both AChE and BChE. However, further studies are recommended to optimize the dose of these compounds as dual AChE‐BChE inhibitors. Another study reported approx 46% inhibition in AChE activity after the treatment with 135 μg resveratrol in helminth parasite, Raillietina echinobothrida.58 Similarly, Schmatz et al54 also reported a significant reduction in AChE activity especially in the cerebral cortex and hippocampus region treated with 10 mg/kg of resveratrol in male Wistar rats. In the consecutive study, the same group59 reported prevention in the pathological increase in AChE activity in cerebral cortex synaptosomes by 10 mg/kg of resveratrol in diabetic rats. Recently, the kinetic analysis suggested mixed type of inhibition pattern (IC₅₀ values in the range of 1.56‐2.11 μmol/L) by pyridoxine–resveratrol hybrids.60 The specific AChE inhibitory activity noted by these hybrids is their simultaneous binding to catalytic and peripheral anionic site of AChE.60 However, one study also reported nonsignificant inhibition of AChE or change in kinetic parameters upon incubation with resveratrol.61 This study raises concerns about the poor bioavailability of resveratrol with reduced concentrations at targeted sites. In view of contradictory results reported in the literature, the successful clinical application of resveratrol is a major challenge for the pharmaceutical industry. Nevertheless, researchers have also tried different approaches to improve the solubility and bioavailability of trans‐resveratrol metabolism.62

5. CURCUMIN

Curcumin is the main polyphenolic component of turmeric (Curcuma longa) and used for the treatment of several human diseases that include multiple myeloma, AD, psoriasis, pancreatic cancer, and myelodysplastic syndrome.63, 64, 65 They are also an effective therapeutic agent against the human immunodeficiency virus (HIV).66, 67 Several studies reported curcumin as antioxidant, antiinflammatory, anticarcinogenic, and antimicrobial agent.65, 68 Curcumin has also been reported for antiamyloidogenic effects against Alzheimer’s β‐amyloid fibrils in vitro.64 Moreover, cognitive enhancing properties of curcumin have also been highlighted in the scientific literature.69, 70, 71 Nevertheless, limited information is available on their mechanism of action on cholinesterases.

In one study, Abbasi et al65 reported moderate inhibitory action by O‐substituted synthetic derivatives of curcumin against AChE and BChE at 0.5 mmol/L concentration. Presence of 2 aromatic rings and the distance between these 2 allow curcumin and its derivatives to favorably interact with both the quaternary and peripheral sites of AChE. Hydrogen bonds can also be formed with the quaternary and acyl sites, which further stabilize the curcumin–AChE complex.72 In one ex vivo study, Ahmed and Gilani73 reported AChE inhibitory and memory‐enhancing potential of curcuminoids (a mixture of curcumin, bisdemethoxycurcumin, and demethoxycurcumin) at 10 mg/kg concentration in rats. This study reported pronounced dose‐dependent AChE inhibitory activity by curcuminoids, and all individual components, especially in frontal cortex and hippocampus region. This group also suggested possible use of curcuminoids for the treatment of AD because of their better therapeutic profile compared with curcumin alone. Recently, Kalaycıoğlu et al74 also reported similar results of AChE inhibition with curcuminoids in an in vitro study. Among curcuminoids, bisdemethoxy curcumin (IC₅₀ = 2.14 μmol/L) has been noted for best AChE inhibition potential followed by demethoxycurcumin (IC₅₀ = 19.7 μmol/L), whereas curcumin exhibited weak inhibitory activity (IC₅₀ = 51.8 μmol/L). The same study also reported the inhibitory activity of bisdemethoxycurcumin (IC₅₀ = 67.2 μmol/L) against BChE whereas curcumin and demethoxycurcumin did not exhibit any inhibitory activity against this enzyme.74 In one study, Wolkmer et al75 reported the inhibition of AChE and improved immunological response in Wistar rats fed daily with curcumin (0.1 mL/kg body weight). Recently, Akinyemiet al76 reported curcumin (12.5 mg/kg for a period of 7 days)‐mediated episodic memory improvement that takes place via inhibition of AChE activities in a cadmium‐exposed albino rats.

6. GALLOCATECHINS (EC, EGC, EGCG)

Gallocatechins, (‐)‐epigallocatechin, (‐)‐epicatechin, (‐)‐epicatechin‐3‐gallate, and epigallocatechin gallate (EGCG) are the major components in green tea.26 Protective action of gallocatechins against bacterial and viral infection as well as a plethora of other health problems in humans has been reported in the scientific literature.22, 26, 77, 78 Several neuroprotective effects of EGCG include amelioration of β‐amyloid‐induced neurotoxicity,79 modulation of protein‐kinase c signaling,80 facilitation of cholinergic transmission,81 enhanced neurite outgrowth,82 and improved cognitive performance.83

A study reported significant inhibitory effect (71% inhibition) by tea polyphenol with IC₅₀ = 248 g/mL on AChE activity in scopolamine‐induced amnesic mice.84 Kaur et al85 reported a significant decrease in AChE activity especially in both cerebrum and cerebellum regions of the rat brain treated with 0.5% green tea for 8 weeks. Owing to their high potential, the use of green tea is believed to be useful for the treatment of AD and other age‐related memory impairments. Additionally, Zhang et al86 reported the complementary effect of green tea polyphenol (EGCG) that increases huperzine A‐induced inhibition of AChE. Based on this study, EGCG has been suggested as a supplement with huperzine A for the treatment of AD.86 EGCG has also been reported to reverse the rise in AChE activity induced by streptozotocin in rats.87 Another in vivo study reported green tea leaf extract containing epigallocatechin‐3‐gallate and epicatechin ameliorates AChE levels in aluminum chloride‐treated rats possibly due to the antioxidant effect of catechins.88 AChE activity has been noted to increase in aged rats fed with phenolic compound compared with no change in the brain AChE activity in young rats.89 In silico study by Ali et al90 also suggested EGCG as AChE inhibitor. Recently, Salazar et al61 reported inhibition in human erythrocyte AChE at different concentrations (3‐200 μmol/L) of EGCG with IC₅₀ value of 18.5 μmol/L. In one in vitro study by Wang et al91 AChE inhibitory potential of different hydroxyl cinnamoylated catechins viz. epigallocatechin‐3‐O‐caffeate (IC₅₀ = 2.49 μmol/L), epigallocatechin‐3‐O‐p‐coumarate (IC₅₀ = 11.41 μmol/L) and epigallocatechin‐3‐O‐ferulate (IC₅₀ = 62.26 μmol/L) isolated from Zijuan tea (Camellia sinensis var. assamica) has been reported. Molecular modeling simulation confirms tight binding of all 3 catechins with AChE to generate strong AChE inhibitory activity.91

7. CINNAMIC ACID AND ITS DERIVATIVES

Cinnamic acid is naturally occurring bioactive compound abundantly present in fruits, vegetables, and whole grains.92 It can generally be obtained from cinnamon (Cinnamomum cassia), citrus fruits, grape, tea, cocoa, spinach, celery, and brassica vegetables.92, 93 It could be easily absorbed from the small intestine through various mechanisms.94 Several studies highlighted their role as an antioxidant, antiinflammatory, antidiabetic, and anticancer agents.92, 95, 96 They also possess various pharmacological properties that can work against diverse neurological disorders.97, 98 A cinnamic acid 2,3‐dimethyl derivative extracted from the leaves of pycnanthus angolensis has been reported for its potential cholinesterase inhibitory activity.99 Recently, a docking study suggested an interaction of N‐benzyl pyridinium moiety with the catalytic anionic site of AChE and the interaction of heterocyclic moiety with the peripheral anionic site of AChE that leads to stacking interactions.98 The hybrid of cinnamic acid with benzyl pyridinium is suggested to be a dual‐acting AChE.98 Novel cinnamic acid derivative, E)‐4‐(3‐(3,4‐dimethoxyphenyl)acrylamido)‐1‐(3‐methylbenzyl) pyridin‐1‐ium bromide, has been reported to possess high AChE inhibitory potential in the range of 7.5‐30 nmol/L concentrations with IC₅₀ values of 8.6 nmol/L. This inhibitor has been noted to have more than threefold higher inhibitory potential compared with standard AChE inhibitor, donepezil. Moreover, this derivative has also been reported for anti‐Alzheimer’s properties such as inhibition of Aβ aggregation, neuroprotection against amyloid‐induced toxicity, and ability to penetrate the blood‐brain barrier. This novel compound has been suggested as a lead compound for the treatment of AD.98 Cinnamic acid derivatives, 3‐methyl‐3‐butenyl‐trans‐caffeate (57.14%) and 3,4 dimethoxycinnamic acid (56.4%) extracted from Egyptian propolis (bee glue), have also been reported for their AChE inhibitory activity via blockage of AChE active site.100 Similarly, acacia honey produced by Apis mellifera has also been reported for potent inhibitory potential of brain AChE in a concentration‐dependent pattern.101 The noted inhibitory activity is because of the presence of phenolic compounds such as p‐hydroxybenzoic acid, cinnamic acid, and chrysin in this honey. Achillea millefolium extract is rich in polyphenols that include cinnamic acid derivatives.102 The extract of this plant has been noted to competitively inhibit AChE and also has high antioxidant properties and is suggested as a potential therapeutic agent against AD.103 In one in vitro study by Farag et al104 AChE inhibitory activity with the extract of ocimum (sweet basil) was reported. Three species of Ocimum viz. O. americanum (IC₅₀ = 2.57 mg/mL), O. africanum (IC₅₀ = 3.40 mg/mL), and O. basilicum (IC₅₀ = 6.62 mg/mL) extracts have been noted for AChE inhibitory activity that relates with the presence of hydroxyl cinnamates conjugates.104 However, further clinical studies are required to understand the full potential of cinnamic acid and its derivatives in the management of AD.

8. CAFFEINE AND CAFFEIC ACID

Caffeine (1,3,7‐trimethylpurine‐2,6‐dione) is a well‐known plant alkaloid and central nervous system stimulant found in Coffea arabica.22 Caffeine has been known for its use as a stimulant supplement which is based on nonselective adenosine receptor antagonism.105 Additional targets include acetylcholine‐, epinephrine‐, norepinephrine‐, serotonin‐, dopamine‐, and glutamate‐mediated neurotransmission.106, 107 Caffeic acid (3,4‐dihydroxycinnamic acid) is a phenolic (nonflavonoid) catecholic compound abundantly present in almost all plants and dietary substances.108

Caffeine has been reported as a selective noncompetitive inhibitor of AChE.105 However, it is a weak inhibitor compared with tacrine or donepezil (well‐known AD drugs). Because of lesser toxicity compared with above‐mentioned drugs, higher dose of caffeine can easily be given to patients with AD.105 Caffeine intake (past or current habitual coffee or tea consumption) can lead to better cognitive response compared with AChE inhibitor treatment in female patients with AD.109 Recent literature suggests that moderate short‐term consumption (50 mg/kg body weight) of a combination of caffeine and caffeic acid can effectively improve brain function via rise in the antioxidant status, decreased lipid peroxidation and inhibition in AChE, adenosine deaminase and arginase activities in the rat brain and cerebral cortex.108 Jo et al110 reported AChE inhibitory potential of tea plant Camellia sinensis L. Water and methanol extracts of tea seed and pericarp containing caffeine and other phenolic compounds have been noted to act against AD.

9. OTHER POLYPHENOLS

Several other polyphenols have also been reported for their significant AChE inhibiting potential. Among them, tiliroside, galangin, linarin, naringenin, sophoflavescenol, cycloartenol, p‐hydroxybenzoic acid, vanilloloside, 5′‐O‐methyladenosine, papyriflavonol, and broussoflavonol are some of the examples.19, 111, 112, 113 For the easy understanding of our article, we focused on the well‐known and easily available polyphenols only. A generalized mode of possible polyphenols action on neurotransmission has been depicted in the Figure 2.

Figure 2.

Cartoon image depicting possible mode of polyphenols action on neurotransmission. The formation of ACh takes place for a short time before it is metabolized by AChE ultimately leading to neurotransmission to postsynaptic neurons. The binding polyphenols to active site of AChE or BChE result in the inhibition of these enzymes

10. SUMMARY AND FUTURE PERSPECTIVES

Based on the current article, it is quite clear that different polyphenols could be used for the treatment of AD. However, the mechanism of their action needs to be further studied. In addition, one also needs to consider the physiological concentrations, specificity and potency of each polyphenol under deliberation. One could improve the above‐mentioned drawbacks by the use of proper delivery system like nanobased drug delivery system. We would also like to highlight here that the binding of some of the mentioned polyphenols is much better with the membrane‐bound enzyme compared with its soluble form. Therefore, caution should be taken while screening AChE inhibitors. In fact, testing compounds with the soluble form of the enzyme may underestimate the activity of some of these potential inhibitors; hence, it would be advisable not to use them as a sole model system for screening. Along with that consideration must also be given to the likelihood that although individual components of plants may have significant specific therapeutical effects, their potential might be even superior when these components are consumed in assorted combinations.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Jabir NR, Khan FR, Tabrez S. Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer’s disease. CNS Neurosci Ther. 2018;24:753–762. 10.1111/cns.12971