Review Article A Review on Potential Mechanisms of ...downloads.hindawi.com/journals/aps/2016/8964849.pdfglycosides []. Table shows the main ingredients of T. chebula and their chemical

Review ArticleA Review on Potential Mechanisms of Terminalia chebula inAlzheimerrsquos Disease

Amir R Afshari1 Hamid R Sadeghnia12 and Hamid Mollazadeh2

1Pharmacological Research Center of Medicinal Plants School of Medicine Mashhad University of Medical SciencesMashhad 917794-8564 Iran2Neurocognitive Research Center School of Medicine Mashhad University of Medical Sciences Mashhad 917794-8564 Iran

Correspondence should be addressed to Hamid Mollazadeh mollazadehh901mumsacir

Received 25 November 2015 Revised 7 January 2016 Accepted 10 January 2016

Academic Editor Berend Olivier

Copyright copy 2016 Amir R Afshari et alThis is an open access article distributed under theCreative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The current management of Alzheimerrsquos disease (AD) focuses on acetylcholinesterase inhibitors (AChEIs) and NMDA receptorantagonists although outcomes are not completely favorable Hence novel agents found in herbal plants are gaining attentionas possible therapeutic alternatives The Terminalia chebula (Family Combretaceae) is a medicinal plant with a wide spectrumof medicinal properties and is reported to contain various biochemicals such as hydrolysable tannins phenolic compounds andflavonoids so it may prove to be a good therapeutic alternative In this research we reviewed published scientific literature foundin various databases PubMed Science Direct Scopus Web of Science Scirus and Google Scholar with the keywords T chebulaAD neuroprotection medicinal plant antioxidant ellagitannin gallotannin gallic acid chebulagic acid and chebulinic acid Thisreview shows that T chebula extracts and its constituents have AChEI and antioxidant and anti-inflammatory effects all of whichare currently relevant to the treatment of Alzheimerrsquos disease

1 Introduction

Alzheimerrsquos disease (AD) is the leading cause of neurode-generative disease in the geriatric population accounting forapproximately 5million cases of dementia in theUSA accord-ing to estimates from the Alzheimerrsquos Association in 2015Since the disease incidence increases with the progressionof age the risk of developing AD doubles every 5 yearsbeginning at age 65 Given the growing elderly populationin developed countries projections of future AD prevalenceshow a fourfold increase through 2050 Consequently ADhas become a major economic health burden because ofaccrued high healthcare costs morbidity and mortality nottomention the financial burden it has on familymembers andcaregivers due to lost wages and productivity [1]

The pathogenesis of AD is very complicated but typi-cally cerebral atrophy is clearly evident in postmortem andimaging studies Combined cortical limbic and subcorticalpathology leads to dementia typical of AD Classic micro-scopic features include neurofibrillary tangles and senileplaques Also the clinical features of AD are commonly

characterized by psychopathological signs such as languagedeterioration memory loss visuospatial impairment andpoor judgment [2] Additionally in AD there is a gradualloss of various neurotransmitters particularly in the basalforebrain Cholinergic transmission is the earliest and mostconspicuously affected in AD The nucleus basalis in thebasal forebrain is affected comparatively early in the processand acetylcholine levels inside the spinal fluid and brainof AD patients quickly reduce with the progression of thedisease This fact supports the cholinergic hypothesis thatacetylcholine diminution results in the cognitive declineobserved in AD patients finally go to the first symptomatictreatment of AD [3]

Most of the drugs presently available to treat ADare acetylcholinesterase inhibitors (AChEIs) tacrine [4]rivastigmine [5] donepezil [6] and galantamine [7] butunfortunately all of these drugs have limited effectivenessand side effects [4] On the other hand medicinal plants arestarting to take an important role in disease treatment in par-ticular to treat psychiatric and neurological disorders Onereason is because of the discontentment with conventional

Hindawi Publishing CorporationAdvances in Pharmacological SciencesVolume 2016 Article ID 8964849 14 pageshttpdxdoiorg10115520168964849

2 Advances in Pharmacological Sciences

Figure 1 T chebula tree and fruits

treatments and another is because patients are seeking greaterself-control over their healthcare decisions [8]

It seems that due to the indiscriminate and excessive useof drugs their costs side effects and interactions herbalmedicines can be a suitable alternative to treat diseasesbecause of their low costs availability and fewer drug inter-actions [9]Therefore the search for a new pharmacotherapyfrom medicinal plants to treat neurodegenerative disordershas remarkably advanced and there are several studies anddocuments that indicate a significant role of herbalmedicinesin the treatment of AD [10ndash12] One particular herbal remedyis Terminalia chebula Retz (Combretaceae) because of itsnumerous and different types of phytoconstituents such aspolyphenols terpenes anthocyanins flavonoids alkaloidsand glycosides In traditional medicine the fruits of the Tchebula which hold various chemically active compoundsresponsible for its medicinal properties have been used inUnani Ayurveda and homeopathic medicine since antiquityto treat geriatric diseases and improve memory and brainfunction [13 14] It is also commonly used to treat numerousdiseases such as cancer cardiovascular diseases paralysisleprosy ulcers gout arthritis epilepsy cough fever diarrheagastroenteritis skin disorders urinary tract infection andwound infections [15 16] Recent studies show that T chebulais effective in the treatment of diabetes [17] bacterial andfungal infections [18 19] immunodeficiency diseases [20 21]hyperlipidemia [22] liver diseases [15 23] stomach ulcer[24] andwounds [25] Other pharmacological properties andbeneficial effects of T chebula are summarized in Table 1

Hence this review article aims to sum up the publishedliterature on the pharmacology and phytochemistry of Tchebula and its effects on the progression and treatment ofADin order to call attention to this plant as a novel alternative inthe treatment of Alzheimerrsquos disease

2 Terminalia chebula Retzius

Terminalia chebula Retzius (Family Combretaceae) as ashade and ornamental tree with 250 species is a medicinalplant that grows in the Middle East and tropical regions suchas India China andThailand It can grow to be 25 meters talland has a variable appearance and spreading branches Thecolor of the bark is dark brown and is usually cracked Leavesare thin elliptic-oblong cordiform at the base elliptical and7ndash12 cm long and 4ndash65 cm in width and have a leathery

form with entire margins The upper surface of the leavesis glabrous opposite of the surface beneath The flowers arefutile with a white to yellowish color and unsightly odorFlowers have 5ndash7 cm long spikes simple or branched about4mm across The ovary is inferior with 10 stamens Fruitsare yellow to orange-brown when ripe and 25ndash5 cm long andunruffled with an ovate-drupe shape [15 61]

Moreover it is called by various names by the local peopleFor example in theThai language the plantrsquos commonname isldquoKot Phung Plardquo and in Indian it is called ldquoKadukkaairdquo andits other names are Black Myrobalan Ink Tree or ChebulicMyrobalan (Figure 1) [15]

21 Scientific Classification Its classification is KingdomPlantae Division Magnoliophyta Class MagnoliopsidaOrder Myrtales Family Combretaceae Genus Terminaliaand Species Chebula [15]

22 Phytochemical Compositions of T chebula

221 Hydrolysable Tannins Tannins as a part of the phenoliccompounds are oligomeric andhavemultiple structural unitswith free phenolic groups and their molecular weight rangesfrom 500 to 3000D The fruit pulp and dried pericarp of theseeds contain the highest amount of tannins [62] Tanninsconsist of hydrolysable and nonhydrolysable tannins andhydrolysable tannins (ie gallotannins and ellagitannins) arethe main compounds in T chebula

Gallotannins and ellagitannins are polymers found inthe fruits of T chebula [63] Gallotannins contain gallic acidthat has esterified and bonded with the hydroxyl group of apolyol carbohydrate such as glucose [64] Ellagitannins areformed when oxidative linkage occurs in the galloyl groupsin 12346-pentagalloyl glucose Ellagitannins differ fromgallotannins in that their galloyl groups are linked throughCndashC bonds whereas the galloyl groups in gallotannins arelinked by depside bonds [65 66]

Chebulagic acid a benzopyran tannin is widely dis-tributed in several plant families the Combretaceae [67]Euphorbiaceae Leguminosae Anacardiaceae and Fabaceae[31] Also in the Combretaceae Family chebulagic acid isthe main constitute of the fruits T bellerica T chebula andEmblica officinalis [68]

Chebulinic acid also known as 136-tri-O-galloyl-24-chebuloyl-120573-D-glucopyranoside is an ellagitannin found in

Advances in Pharmacological Sciences 3

Table 1 Structure and pharmacological properties of T chebula active ingredients

Compound Category Chemical structure Pharmacologicalproperties

Gallotannins Hydrolysabletannin

OH

OH

HO

OO

OO

O

O

HO

HO

OH

O

HO

OH

OH

O

HO OH

OH

O

O

O

OH

OH

OH

Antimicrobial [26]antioxidant [27]

Ellagitannins Hydrolysabletannin

OH

OHHO

O

OO

O

O

OH

OH

OH

OHO

HO

OH

OO

OO

HO

OH

OH

OH

OH

OH

OH

Anti-inflammatoryanticancer

cardiovascularprotection [28]antioxidant

chemopreventiveantiapoptotic

anti-hepatocellularcarcinoma

(Anti-HCC) [29]

Gallic acid Phenoliccompound

OHO

HOOH

OH

Anti-inflammatory[30] antimutagenic

[31]cardioprotective

[32]antioxidant [33]anticancer [34]

antimicrobial [35]neuroprotective

[36]immunosuppressive

[37]improved cognition

[38]


Table 1 Continued


Chebulic acid Phenoliccompound

OO

HO

OH

OH

OHO

OHO

HO

OAnti-HCV [39]antidiabetic [40]hepatoprotective


[37]

Chebulagic acid Hydrolysabletannin

OH

HO

O

O

HO

HO

HO

HO

OO

O OO

OH

OHOHO

O

O

HO

O

O

O

OHOH

OHO

Hepatoprotective[41] antiviral [42]immunosuppressive[43] antidiabetic

[44 45]neuroprotective

[46]antiangiogenesis

[47]antiproliferative

[48]anti-inflammatory

[44]

Chebulinic acid Hydrolysabletannin

OHHO

HOO

O

OO

O

OH

OH

OH

O

O

O O

OHO

HO

HO

O

O

HO OH

OHOHO

O

Antisecretorycytoprotective [49]antiangiogenesis

[50]antitumor [51]


Table 1 Continued


Ellagic acid Phenoliccompound

O

O

O

HO

HO

OOH

OH

Antioxidant [52]anti-inflammatory[53] anti-diabetes-induced sexualdysfunction [54]hepatoprotective

[55] antiarrhythmic[56] cognitive

enhancer [57 58]

Anthraquinoneglycosides

Phenoliccompound

O

OH

OH

OOH

O

HO

O H

OH

HO

OH

HHO

HNeuroprotective[59] antidiabetic

[60]

the fruits of T chebula or in the leaves of T macroptera[31 68]

222 Phenolic Compounds Phenolic compounds includeellagic acid a natural potent phenolic antioxidant found inthe fruits of T chebula [13] gallic acid a trihydroxybenzoicacid found as a part of hydrolysable tannins [69] tannic acida polymer of gallic acid molecules and glucose [70] andchebulic acid another phenolic compound in the ripe fruitsof T chebula and a component of transformed ellagitanninssuch as chebulagic acid or chebulinic acid [41]

Glycosides are other phenolic compounds that are widelypresent in the Terminalia rhubarb Senna and Aloe speciesThe pericarp of the T chebula fruit contains anthraquinoneglycosides [71] Table 1 shows the main ingredients of Tchebula and their chemical structures

223 Miscellaneous Compounds In addition to the abovethere are some other compounds that are also present andcontribute towards the activity of the plant such as palmitic[72] stearic [73] oleic [74] linoleic [75] and arachidic acids[76] which are present in the fruit kernels

224Methods of Search This research included articles from1960 to 2015 that were found in various electronic databasesPubMed Science Direct Scopus Web of Science Scirus andGoogle Scholar by using the search words T chebula ADneuroprotection medicinal plant antioxidant ellagitanningallotannin gallic acid chebulagic acid and chebulinic acidOnly current articles that reported the effects of T chebula onAD were included in our study Then a comparison of therelated mechanisms and evaluation of pharmacology effectsin the treatment and progression of AD was done

23 T chebula and Alzheimerrsquos Disease

231 Acetyl Cholinesterase (AChE) One of the hypothesesabout AD is acetylcholine (ACh) deficiency in the synapticcleft of the cerebral cortex that causes memory distur-bance Acetyl cholinesterase also known as AChE or acetyl-hydrolase is a hydrolase that hydrolyzes the neurotransmitteracetylcholine AChE is found at mainly neuromuscular junc-tions and cholinergic brain synapses where its activity servesto terminate synaptic transmission It is the primary target ofinhibition by organophosphorus compounds such as nerveagents and pesticides AChE has a very high catalytic activityeach molecule of AChE degrades about 25000 molecules ofACh per second approaching the limit allowed by diffusionof the substrate [77] During neurotransmission ACh isreleased from the nerve into the synaptic cleft and binds toACh receptors on the postsynaptic membrane relaying thesignal from the nerve AChE also located on the postsynapticmembrane terminates the signal transmission by hydrolyz-ing Ach [78] AChE is found in many types of conductingtissue central and peripheral tissues motor and sensoryfibers nerve andmuscle and cholinergic and noncholinergicfibers The activity of AChE is higher in motor neurons thanin sensory neurons [79] AChE is also found on the red bloodcell membranes [80] Traditionally necrosis is the pathwaythat had been thought to cause cell death in AD howevernow it is thought that ACh containing neurons are the mostimportant pathway of neuronal death in AD The cell deathmechanisms in AD are deposition of A120573 reduced energymetabolism andor mitochondrial dysfunction excitotoxic-ity and oxidative stress and free radical production Thesefour mechanisms contribute to necrosis in various diseasessuch as stroke and AD Inflammatory responses and theireffects on trophic factor function have also been proposed as


amain factor for cell death inADAChE induces an apoptoticand necrotic cell death by inducingmembrane depolarizationand NMDA receptor activation with consequent Ca2+ influxand modulation of the 1205727 nicotinic acetylcholine receptor inhippocampal cultures Therefore AChE has a main role inneurodegeneration and AChEIs could be effective in neuro-protection [81ndash83] Increasing expression of splice variantsof AChE (R and S) as neuroprotective forms of AChE withAChEIs has been effective in preventing the progressionof AD In a study expression of AChE-R and AChE-Sdecreased over a period of 12 months in untreated patientsIn contrast treatment with tacrine causes an upregulation inboth variants (up to 117) [84]

Inhibition of AChE leads to accumulation of ACh in thesynaptic cleft and results in impeded neurotransmission [78]The acetyl cholinesterase inhibitors (AChEIs) attenuate thecholinergic deficit underlying the cognitive and neuropsy-chiatric dysfunctions in patients with neurodegenerativedisorders So inhibition of brain AChE has been the majortherapeutic target of treatment strategies for AD Parkinsonrsquosdisease senile dementia ataxia and myasthenia gravis [85]There are a few synthetic medicines with this mechanism forexample tacrine donepezil and the natural product-basedrivastigmine to treat cognitive dysfunction and memoryloss associated with AD [86] However these compoundshave been reported to have their adverse effects includinggastrointestinal disturbances and problems associated withbioavailability which necessitates the interest in findingbetter AChE inhibitors from natural sources [87]

In this section we discuss the effectiveness of T chebulaand its constituents on brain functions

232 Anticholinesterase Properties Anticholinesterase prop-erties ofT chebula have been reported inmany studies [3 88ndash95] In Sancheti et alrsquos study the inhibitory effects of Tchebula on AChE and butyrylcholinesterase (BChE) werereported In the in vitro studymethanolic crude extract of thefruits ofT chebulawith a concentration of 5mgmL inhibitedAChE and BChE about 89 and 95 respectively Sanchetiet al extracted 12346-penta-O-galloyl-120573-D-glucose (PGG)with a gallotannin structure from T chebula by chromato-graphic methods and they showed it to be the most potentAChE and BChE inhibitor Bioassay of PGG exhibited itsconcentration-dependent inhibitory activity on AChE andBChE with IC

50values of 299 plusmn 03 120583M and 276 plusmn 02 120583M

respectively Then for deducing the inhibitory activity ofPGG a TLC assay was done with tacrine as a positivecontrol and the AChE inhibitory effect was visualized clearlyin the assay [88] In addition to the inhibitory effect ofmethanolic fruit extracts of T chebula on AChE the ethylacetate fraction shows relatively remarkable AChE inhibitoryactivity Sulaiman et al showed that ethyl acetate fractionwithdoses of 1 5 15 and 25mgmL inhibited AChE by 29363244 4582 and 6232 respectively This fraction wasmore potent than the chloroform and methanolic fraction inAChE inhibition [91] In a similar in vitro study Vinutha etal used the methanolic and aqueous extracts of the fruit of Tchebula and the data showed that IC

50values of the aqueous

extract of T chebula (minimum inhibition 1245) are more

potent than the methanolic extract (minimum inhibition121) [3]

In addition to the effects of gallotannins on AChEinhibition tannic acid as an active component of T chebulahas a potential inhibition effect on AChE Upadhyay andSingh showed the competitive inhibition of AChE by tannicacid in vivo and in vitro This study focused on the effects oftannic acid from the T chebula fruit In vivo treatment with80 of LC

50of tannic acid during 96 h caused a remarkable

inhibition in AChE activity in the nervous tissue of Lym-naea acuminate Furthermore maximum inhibition of AChEactivity was detected when the tissue was exposed to 80 ofLC50of tannic acid for 96 h so inhibition of AChE was time-

and dose-dependent in the 96 h process In vitro treatmentshowed that tannic acid caused dose-dependent AChE inhi-bition significantly such that 004mMof tannic acid reducedthe AChE activity to 37 of the control in the nervous tissueof L acuminata [92] In addition another in vivo research onAChE activity showed that tannic acid completely neutralizedthe AChE activity in Naja kaouthia venom [96]

Parle and Vasudevan in their in vivo study showedthat Abana (a mixture of medicinal plants containing Tchebula) with doses of 50 100 and 200mgkg administeredorally for 15 days can reduce the brain AChE activity inyoung and aged mice Passive avoidance apparatus and mazetests were performed on day 16 and the results showed aremarkable dose-dependent reduction in transfer latency anda significant increase in step-down latency tests indicatingsignificant improvement in memory [93]

Another similar study was done by Dhivya et al In this invitro study AChE inhibitory activity of various plant speciescontaining T chebula was reported to have AChE inhibitionof 4106 plusmn 56 (01mgmL) as well [95]

In a similar study AChE inhibition of the methanolicextract of T chebula showed a moderate inhibition with anextractwith IC

50value of 180plusmn 146120583gmL and the percentage

of AChE inhibition was 4106 plusmn 56 at 01mgmL [97] Inaddition the percentage of AChE inhibition in the extractof T chebula was 13 (IC

50not detected) [14] Furthermore

in another research T chebula could inhibit 89 of AChEactivity (5mgmL) and 95 of BChE activity (5mgmL) [88]

Gallic acid and ellagic acid as phenolic compounds in thefruits of T chebula could also inhibit AChE Nag and De intheir study showed that the inhibitory effect of themethanolicextract of T chebula (gallic acid 025120583g ellagic acid 008 120583g)has a linear relationship with increasing dosage (IC

50 1096)

[89]

233 Anti-Inflammatory Properties Cyclooxygenase (COX)and 5-lipoxygenase (5-LOX) are the key enzymes that areinvolved in inflammation Reddy et al investigated chebu-lagic acid as a COX-LOX dual inhibitor from the ethanolicextract of fruits of T chebula The results showed that chebu-lagic acid has a potent COX-LOXdual inhibition activity withIC50values of 15plusmn 0288 092plusmn 0011 and 21 plusmn 0057 120583M for

COX-1 COX-2 and 5-LOX respectively [76]The water soluble fraction of T chebula (WFTC) was

effective against systemic and local anaphylaxis Shin etal showed that the injection of WFTC with doses of


001ndash10 gkg inhibited anaphylactic shock 100 WhenWFTC was pretreated at concentrations ranging from 0005to 10 gkg the serum histamine levels were reduced dose-dependently In addition this study showed that WFTCincreased anti-dinitrophenol and IgE-induced tumor necro-sis factor- (TNF-) 120572 production [98]

Lee et al in their study showed that gallic acid (25120583g)suppressed nuclear factor kappa B (NF-120581B) activity andcytokine release It also remarkably reduced the cyclic AMPresponse element binding proteinp300 (CBPp300 a NF-120581B coactivator) gene expression acetylation levels andCBPp300 histone acetyltransferase activity Therefore gallicacid derived from the extracts of several plants especially Tchebulawas shown to exert anti-inflammatory activity via thedownregulation of the NF-120581B pathway in the development ofinflammatory diseases both in vitro and in vivo [30 99ndash101]

Kim et al showed that the inhibition ofNF-120581B acetylationwith gallic acid resulted in reduced cytokine production inmicroglia cells and the protection of neuronal cells fromamyloid 120573- (A120573-) induced neurotoxicity In addition thisresearch showed a restorative effect of gallic acid on A120573-induced cognitive dysfunction inmice in Y-maze and passiveavoidance tests Therefore gallic acid has several roles inneuroinflammatory diseases including (1) preventing A120573-induced neuronal cell death by inhibiting RelA (as a geneencoding NF-120581B) acetylation and cytokine production (2)protecting neuronal cells from primary microglia-mediatedA120573 neurotoxicity (3) restoring A120573-induced memory deficitsin mice and (4) suppressing in vivo cytokine production byinhibiting RelA acetylation in brain [101] Another similarstudy showed that polyphenolic extracts (containing gallicacid) of medicinal plants such as T chebula are able to inhibitA120573 aggregation reduce A120573 production and protect againstA120573 neurotoxicity in vitro [102] Kim et al reported theinhibitory effects of gallic acid on inflammatory responses viaNF- 120581B and p38 mitogen-activated protein kinase pathways[103]

In another study chebulagic acid showed a potent anti-inflammatory effect in lipopolysaccharide- (LPS) stimulatedRAW 2647 (mouse macrophage cell line) Reddy and Red-danna showed the effectiveness of chebulagic acid againstinflammatory diseases by different mechanisms such as inhi-bition of nitric oxide (NO) and prostaglandin E

2production

downregulation of iNOS (inducible nitric oxide synthases)COX-2 5-LOX TNF-120572 interleukin 6 and inhibitory effectson NF-120581B and decreases in nuclear p50 and p65 proteinlevels In addition the generation of reactive oxygen species(ROS) and phosphorylation of p38 ERK 12 and JNK in LPS-stimulated RAW 2647 cells was suppressed by chebulagicacid in a concentration-dependent manner [44] In anotherresearch chebulagic acid from the immature seeds of Tchebula significantly suppressed the onset and progressionof collagen induced arthritis in mice [104] In a similarstudy the aqueous extract of the dried fruit of T chebulashowed an anti-inflammatory effect by inhibiting iNOS[105] Patil et al in their study showed that administratingthe fruit of T chebula (500mgkg) via inhibition of iNOSexpression can be significantly effective in the progressionof inflammation [106] In vivo anti-inflammatory activity

of T chebula fruit extract at different doses (range 50to 500mgkg) was evaluated against carrageenan-inducedinflammation in rats In this study Bag et al reported that250mgkg (administrated orally) caused a 6996 reductionin carrageenan-induced rat paw edemaThis finding suggeststhat free radical quenching may be one of the mechanismsfor its anti-inflammatory activity [107] Triphala an IndianAyurvedic herbal formulation containing T chebula at adosage of 1 gkg showed an anti-inflammatory effect Sabinaand Rasool in their research showed that the mechanismsof anti-inflammatory properties of this plant include (a)inhibition of lysosomal enzyme release (b) a significantdecrease of inflammatorymediator TNF-120572 and (c) a decreaseof beta-glucuronidase and lactate dehydrogenase enzymesrelease The anti-inflammatory effect of Triphala might bedue to the presence of phenolic components and flavonoids[108] In another study Ramani and Pradhan showed that theacetone extract of T chebula fruits had a significant effect oncontrolling Complete Freundrsquos Adjuvant-induced arthritisThis effect leads to a good reduction in paw edema andjoint thickness (reduction of ESR values and RF values) incomparison with dexamethasone [109]

234 Antioxidant Properties Decreases in antioxidantdefense or increases in oxidant status in the body tend to leadto the condition called oxidative stress which plays a majorrole in neurological degeneration such as AD [110] Reactiveoxygen species and oxidative stress increase the formation ofamyloid-120573 and senile plaques in the brain are the hallmarkof AD [111] High lipid content deficient antioxidant valuesand high oxygen consumption in the brain are the reasonsthe central nervous system is vulnerable to oxidative stressIncreased lipid peroxidation decreased glutathione levelsincreased dopamine turnover and elevated iron and alu-minum levels in the brain support the role of oxidative stressin Parkinsonrsquos Amyotrophic Lateral Sclerosis and AD [112]

In Table 2 we have summarized the roles of oxidativestress in the pathogenesis and progression of AD Thusreducing oxidative stress by enhancing antioxidant defense ordecreasing the production of reactive oxygen species may beeffective in treating AD

Antioxidant effects of T chebula extract (100 120583gmL)were compared with reference radical scavengers such asquercetin gallic acid and t-butylhydroquinone and Tchebula extract showed 95 activity with IC

5022 120583gmL [14]

Terminalia species such as T chebula and T arjuna with ahigh content of phenolic constituents showed strong antiox-idant and antiaging properties [88] Oral administration ofaqueous extracts of T arjuna causes significant elevationin the activities of antioxidant enzymes such as superoxidedismutase catalase and glutathione S-transferaseThe strongantioxidant action of the aqueous extract of the Terminaliaspecies may play a role in treating age-related diseases such asAD [127] A similar study done byMathew and Subramanianshowed that the antioxidant activity of themethanolic extractof T chebula (01mgmL) and IC

50was 863 and 05 120583gmL

respectively In this study the highest amount of antioxidantactivity among 20 plants was found in T chebula due to thepresence of gallic acid and ellagic acid All 20 plants used in


Table 2 Major effects of oxidative stress in the pathogenesis of Alzheimerrsquos disease

Effects ofROS Result Biological evidence(s)

Proteinoxidation

Increasedprotein carbonyl

content

Increased protein oxidation in frontal pole and occipital pole [113]Decreased ratio of (MAL-6)(WS) in AD hippocampus andinferior parietal lobule decreased the WS ratio in in vitro modelsof human synaptosomes oxidation by ROS [114]

DNAoxidation

Direct damageto DNAstructure

3-fold increase in mitochondrial DNA oxidation in parietal cortexin AD [115]Increase in oxidative damage to nuclear DNA in AD comparedwith age-matched control subjects [116]8-hydroxy-2-deoxyguanosine as a marker of DNA oxidationincreases in AD [117]

Lipidperoxidation

Brainphospholipid

damage

Increased TBARS levels in AD in hippocampus piriform cortexand amygdala [118]Increased lipid peroxidation of AD brain homogenates in vitro dueto Fe-H

2O2[119]

Increased apoptosis in cultured DS and AD neurons inhibited byantioxidant enzymes [112 120]Decrease in PC PE phospholipid precursors choline andethanolamine in hippocampus and inferior parietal lobule in AD[121]Increased aldehydes as a cytotoxic agent in the brain of ADpatients [122]

Antioxidantenzymes

Changes inenzymescontents

Elevated GSH-Px GSSG-R and CAT activity in hippocampus andamygdala in AD [118]Many studies showed no elevation in enzyme activity [123 124] ordecrease in activity [125]

AGEformation

Pathologicalchanges inprotein

structure andaction

Accelerates aggregation of soluble nonfibrillar A120573 and tau [126]

MAL-6 weakly immobilized protein bound spin labelWS strongly immobilized protein bound spin label TBARS thiobarbituric acid reactive substances DSDown syndrome PC phosphatidylcholine PE phosphatidylethanolamine GSH-Px glutathione peroxidase GSSG-R glutathione reductase CAT catalaseAGE advanced glycation end products

this study were traditional neuroprotective plants that havebeen used for many years and among them T chebula wasthemost potent antioxidant andmoderate inhibition of AchE[97] In the evaluation of antioxidant anti-inflammatorymembrane-stabilizing and antilipid peroxidative effects ofthe hydroalcoholic extract of T chebula fruits in arthriticdisorders Bag et al showed that the fruit extract of T chebula(10 to 100 120583gmL) in carrageenan-induced inflammation inrats reduced the formation of thiobarbituric acid reactivesubstances in the liver with IC

509496mgkgThe IC

50of the

extract in DPPH radical-scavenging activity was 4214 120583gmL[107] Antilipid peroxidative capacity of T chebula wasattributed to higher phenolic content reducing ability Fe(II)chelating ability and free radical-scavenging activity In Khanet alrsquos study the aqueous extracts of yellow T chebula andblack T chebula showed IC

50values of 2024plusmn 09 120583gmL and

1733 plusmn 11 120583gmL in the scavenging of the DPPH radical inmice brains respectively [128] In an in vitro study done toinvestigate the biological activities of phenolic compoundsand triterpenoid constituents of T chebula 9 phenoliccompounds and 8 triterpenoids were extracted Radical-scavenging activities of the phenolic compounds were higher

than the triterpenoids compounds and had potent inhibitoryactivities against melanogenesis at a concentration of 10120583Mand the IC

50was 14ndash109 120583M These results showed that

T chebula with a high content of polyphenolic ingredientswas a potent antioxidant [16] The extract of the driedfruit pulp of T chebula (600mgkg) could diminish aceticacid-induced colitis in rats with antioxidant effects (freeradical-scavenging antioxidant enzymes enhancing activityand decreasing lipid peroxidation) [129]

In the evaluation of neuroprotective effects the inhibitionof H2O2-induced PC12 cell death by T chebula was investi-

gated H2O2at 40 120583M for 12 h decreased cell viability to 59

Also all of the methanol water and 95 ethanol extractsof T chebula increased cell viability at 05ndash50120583gmL dose-dependently and among them the water extract was morepotent Antioxidant effects of the extracts were comparedand the results showed that methanol extract had goodantioxidant activity based on the luminol-H

2O2-horseradish

peroxidase assay and the water extract was shown to havegood antioxidant activities in cupric sulfate phenanthroline-H2O2and luminol-H

2O2assays Also 95 ethanol extract

showed good antioxidant activity in the pyrogallol-luminol


assay [130] Effects of T chebula seed extracts on brain-derived neurotrophic factor (BDNF) Cu Zn-superoxide dis-mutase (SOD1) and Mn-superoxide dismutase (SOD2) wereevaluated by Park et al Extract with a dose of 100mgkg oncea day was administrated to gerbils for 7 days before inductionof transient cerebral ischemia and the neuroprotective effectof the extract was evaluated in the CA1 hippocampal regionon the fourth day after ischemia-reperfusion induction Theresults showed that astrocytes and microglia remarkablydecreased in the ischemic group compared with the vehicle-treated group and neuron nucleus (as the positive neuron)was distinctively abundant (62) compared to the vehicle-treated ischemia group (62 versus 122) Protein levels andactivity of SOD1 SOD2 and BDNF were much higher inthe treated group These results confirmed the neuroprotec-tive effects of T chebula extracts against neuronal damagein hippocampus [131] Recently we have found that thealcoholic extract of T chebula fruits significantly protectsagainst quinolinic acid-induced neurotoxicity by alleviatingthe oxidative stress parameters (unpublished data)

Many studies used T chebula to modulate the oxidativestress adverse effects in various models of oxidation damageand aging [132ndash134]T chebula could enhance the antioxidantdefense and modulate oxidative stress due to aging in theliver and kidney of aged rats compared to young albino rats[133] and could protect hepatocytes from damage due tooxidative stress and enhanced total thiol content [41] Manystudies have shown the antioxidant activity of T chebulain various in vivo and in vitro models [16 135 136] Inaddition most of the researchers agree with this hypothesisthat ldquopharmacophore which contains large numbers of ndashOHgroup (such as polyphenols) has greater anti-aging proper-ties than those with less numbers of ndashOH groupsrdquoThereforetwo constituents that are potent phenolic compounds areellagic acid and 4-O-xyloside of ellagic acid These activeingredients were investigated for their activities on freeradical-scavenging elastase inhibition expression of matrixmetalloproteinase-1 (MMP-1) and type I collagen synthesisin normal human fibroblast cells Thus ellagic acid may beuseful for the geriatric population [137 138]

According to the points mentioned above regarding theantioxidant activity of T chebula and the important role ofoxidative stress in the pathogenesis of AD we can concludethat the use of this plant may be effective against theprogression of AD

3 Conclusion

Alzheimerrsquos disease is a debilitating dementia and only alimited number of therapeutic options are currently availableto modify the manifestations of the disease T chebulahas pharmacological activities relevant to dementia therapy(Figure 2) Different extracts from T chebula have exhibitedconcentration-dependent inhibitory activities on AChE andBChE Such AChE activities are also described for its activeingredients such as PGG gallic acid ellagic acid and tannicacid Anti-inflammatory properties of T chebula have beenwell documented in different experimental systems that couldbe attributed to chebulagic or gallic acid T chebula with a

Terminalia chebula

Anti-Alzheimerrsquos mechanisms

GallotanninTannic acidGallic acidEllagic acid Chebulagic acid

Ellagic acidGallic acid

Ellagitannins

GallotanninEllagitannins

Gallic acidEllagic acid

Anticholinesterase

Anti-inflammatory

Antioxidant

Figure 2 Anticholinesterase anti-inflammatory and antioxidantproperties of T chebula relevant to anti-Alzheimerrsquos therapy

high content of phenolic constituents exhibits strong antioxi-dant and neuroprotective properties in vitro and in vivo Theefficacy ofT chebula in treating AD should be compared withthe current standard pharmacological treatment in animaland clinical testing and researches Such studies shouldinclude the identification of the active principle(s) in orderto improve the validation of the clinical trials Until then thisreview provides some evidences on the benefits of T chebulain the treatment of Alzheimerrsquos disease

Conflict of Interests

The authors confirm that there is no conflict of interests

References

[1] Y Stern ldquoCognitive reserve and Alzheimer diseaserdquo AlzheimerDisease amp Associated Disorders vol 20 no 2 pp 112ndash117 2006

[2] H-R Adhami H Farsam and L Krenn ldquoScreening of medi-cinal plants from Iranian traditional medicine for acetyl-cholinesterase inhibitionrdquo Phytotherapy Research vol 25 no 8pp 1148ndash1152 2011

[3] B Vinutha D Prashanth K Salma et al ldquoScreening of selectedIndian medicinal plants for acetylcholinesterase inhibitoryactivityrdquo Journal of Ethnopharmacology vol 109 no 2 pp 359ndash363 2007

[4] K Chopra S Misra and A Kuhad ldquoCurrent perspectives onpharmacotherapy of Alzheimerrsquos diseaserdquo Expert Opinion onPharmacotherapy vol 12 no 3 pp 335ndash350 2011

[5] S Lopez J Bastida F Viladomat and C Codina ldquoAcetyl-cholinesterase inhibitory activity of some Amaryllidaceae alka-loids and Narcissus extractsrdquo Life Sciences vol 71 no 21 pp2521ndash2529 2002

[6] G L Ellman K D Courtney V Andres Jr and R M Fea-therstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[7] I K Rhee M van de Meent K Ingkaninan and R VerpoorteldquoScreening for acetylcholinesterase inhibitors from Amarylli-daceae using silica gel thin-layer chromatography in combina-tion with bioactivity stainingrdquo Journal of Chromatography Avol 915 no 1-2 pp 217ndash223 2001


[8] P Anand and B Singh ldquoA review on cholinesterase inhibitorsforAlzheimerrsquos diseaserdquoArchives of Pharmacal Research vol 36no 4 pp 375ndash399 2013

[9] M M Dirin S Mousavi A R Afshari K Tabrizian and MH Ashrafi ldquoPotential drug-drug interactions in prescriptionsdispensed in community and hospital pharmacies in East ofIranrdquo Journal of Research in Pharmacy Practice vol 3 no 3 pp104ndash107 2014

[10] B H May M Lit C C L Xue et al ldquoHerbal medicine fordementia a systematic reviewrdquo Phytotherapy Research vol 23no 4 pp 447ndash459 2009

[11] S Akhondzadeh and S H Abbasi ldquoHerbal medicine inthe treatment of Alzhelmerrsquos diseaserdquo American Journal ofAlzheimerrsquos Disease and other Dementias vol 21 no 2 pp 113ndash118 2006

[12] L L D Santos-Neto M A de Vilhena Toledo P Medeiros-Souza and G A de Souza ldquoThe use of herbal medicinein Alzheimerrsquos diseasemdasha systematic reviewrdquo Evidence-BasedComplementary and Alternative Medicine vol 3 no 4 pp 441ndash445 2006

[13] A Saleem M Husheem P Harkonen and K Pihlaja ldquoInhibi-tion of cancer cell growth by crude extract and the phenolics ofTerminalia chebula retz fruitrdquo Journal of Ethnopharmacologyvol 81 no 3 pp 327ndash336 2002

[14] S K Ali A R Hamed M M Soltan et al ldquoIn-vitro evaluationof selected Egyptian traditional herbal medicines for treatmentof Alzheimer diseaserdquo BMC Complementary and AlternativeMedicine vol 13 no 1 p 121 2013

[15] R Rathinamoorthy and GThilagavathi ldquoTerminalia chebulamdashreview on pharmacological and biochemical studiesrdquo Interna-tional Journal of PharmTech Research vol 6 no 1 pp 97ndash1162014

[16] AManosroi P Jantrawut EOgihara et al ldquoBiological activitiesof phenolic compounds and triterpenoids from the Galls ofTerminalia chebulardquo Chemistry amp Biodiversity vol 10 no 8 pp1448ndash1463 2013

[17] N K Rao and S Nammi ldquoAntidiabetic and renoprotectiveeffects of the chloroform extract of Terminalia chebula Retzseeds in streptozotocin-induced diabetic ratsrdquo BMC Comple-mentary and Alternative Medicine vol 6 no 1 article 17 2006

[18] K Aneja and R Joshi ldquoEvaluation of antimicrobial propertiesof fruit extracts of Terminalia chebula against dental cariespathogensrdquo Jundishapur Journal of Microbiology vol 2 no 3pp 105ndash111 2009

[19] B Dutta I Rahman and T Das ldquoAntifungal activity of Indianplant extracts antimyzetische Aktivitat indischer Pflanzenex-trakterdquoMycoses vol 41 no 11-12 pp 535ndash536 1998

[20] V Aher and A Wahi ldquoImmunomodulatory activity of alcoholextract of Terminalia chebula retz combretaceaerdquo Tropical Jour-nal of Pharmaceutical Research vol 10 no 5 pp 567ndash575 2011

[21] M-J Ahn C Y Kim J S Lee et al ldquoInhibition of HIV-1 integrase by galloyl glucoses from Terminalia chebula andflavonol glycoside gallates from Euphorbia pekinensisrdquo PlantaMedica vol 68 no 5 pp 457ndash459 2002

[22] V Maruthappan and K S Shree ldquoHypolipidemic activityof Haritaki (Terminalia chebula) in atherogenic diet inducedhyperlipidemic ratsrdquo Journal of Advanced Pharmaceutical Tech-nology and Research vol 1 no 2 pp 229ndash235 2010

[23] S Srigopalram and I A Jayraaj ldquoEffect of Terminalia chebularetz on den induced hepatocellular carcinogenesis in experi-mental ratsrdquo International Journal of Pharmacy and Pharmaceu-tical Sciences vol 4 no 2 pp 440ndash445 2012

[24] P Sharma T Prakash D Kotresha et al ldquoAntiulcerogenicactivity of Terminalia chebula fruit in experimentally inducedulcer in ratsrdquo Pharmaceutical Biology vol 49 no 3 pp 262ndash268 2011

[25] M P Singh and C S Sharma ldquoWound healing activity ofTerminalia chebula in experimentally induced diabetic ratsrdquoInternational Journal of PharmTech Research vol 1 no 4 pp1267ndash1270 2009

[26] C EngelsMKnodler Y-Y Zhao RCarleMGGanzle andASchieber ldquoAntimicrobial activity of gallotannins isolated frommango (Mangifera indica L) kernelsrdquo Journal of Agriculturaland Food Chemistry vol 57 no 17 pp 7712ndash7718 2009

[27] X Zhao H Sun A Hou Q Zhao T Wei and W Xin ldquoAnti-oxidant properties of two gallotannins isolated from the leavesof Pistacia weinmannifoliardquo Biochimica et Biophysica Acta(BBA)mdashGeneral Subjects vol 1725 no 1 pp 103ndash110 2005

[28] E Sangiovanni U Vrhovsek G Rossoni et al ldquoEllagitanninsfrom Rubus berries for the control of gastric inflammation invitro and in vivo studiesrdquo PLoS ONE vol 8 no 8 Article IDe71762 2013

[29] R H Hussein and F K Khalifa ldquoThe protective role of ellagi-tannins flavonoids pretreatment againstN-nitrosodiethylamineinduced-hepatocellular carcinomardquo Saudi Journal of BiologicalSciences vol 21 no 6 pp 589ndash596 2014

[30] W Lee S Y Lee Y Son and J Yun ldquoGallic acid decreasesinflammatory cytokine secretion through histone acetyltrans-ferasehistone deacetylase regulation in high glucose-inducedhuman monocytesrdquo Journal of Medicinal Food vol 18 no 7 pp793ndash801 2015

[31] HWalia and S Arora ldquoTerminalia chebulamdashapharmacognisticaccountrdquo Journal of Medicinal Plants Research vol 7 no 20 pp1351ndash1361 2013

[32] D H Priscilla and P S M Prince ldquoCardioprotective effectof gallic acid on cardiac troponin-T cardiac marker enzymeslipid peroxidation products and antioxidants in experimen-tally induced myocardial infarction in Wistar ratsrdquo Chemico-Biological Interactions vol 179 no 2-3 pp 118ndash124 2009

[33] L D Reynolds and N G Wilson Scribes and Scholars Cam-bridge University Press Cambridge UK 1974

[34] H-H Ho C-S Chang W-C Ho S-Y Liao C-HWu and C-J Wang ldquoAnti-metastasis effects of gallic acid on gastric cancercells involves inhibition of NF-120581B activity and downregulationof PI3KAKTsmall GTPase signalsrdquo Food and Chemical Toxi-cology vol 48 no 8-9 pp 2508ndash2516 2010

[35] M A Farag D A Al-Mahdy R Salah El Dine et al ldquoStruc-turemdashactivity relationships of antimicrobial gallic acid deriva-tives from pomegranate and acacia fruit extracts against potatobacterial wilt pathogenrdquo Chemistry amp Biodiversity vol 12 no 6pp 955ndash962 2015

[36] A Ibrahim R El Kareem and M Sheir ldquoElucidation of acryl-amide genotoxicity and neurotoxicity and the protective roleof gallic acid and green teardquo Journal of Forensic Toxicology ampPharmacology vol 4 no 1 article 1 2015

[37] S-I Hamada T Kataoka J-T Woo et al ldquoImmunosuppressiveeffects of gallic acid and chebulagic acid on CTL-mediatedcytotoxicityrdquo Biological and Pharmaceutical Bulletin vol 20 no9 pp 1017ndash1019 1997

[38] A Sarkaki H Fathimoghaddam S M T Mansouri M S Kor-rani G Saki and Y Farbood ldquoGallic acid improves cognitivehippocampal long-term potentiation deficits and brain damageinduced by chronic cerebral hypoperfusion in ratsrdquo PakistanJournal of Biological Sciences vol 17 no 8 pp 978ndash990 2014


[39] O S Ajala A Jukov and C-M Ma ldquoHepatitis C virus inhibi-tory hydrolysable tannins from the fruits ofTerminalia chebulardquoFitoterapia vol 99 pp 117ndash123 2014

[40] A T Pham K E Malterud B S Paulsen D Diallo andH Wangensteen ldquo120572-Glucosidase inhibition 15-lipoxygenaseinhibition and brine shrimp toxicity of extracts and isolatedcompounds from Terminalia macroptera leavesrdquo Pharmaceuti-cal Biology vol 52 no 9 pp 1166ndash1169 2014

[41] H-S Lee S-H Jung B-S Yun and K-W Lee ldquoIsolation ofchebulic acid from Terminalia chebula Retz and its antioxidanteffect in isolated rat hepatocytesrdquo Archives of Toxicology vol 81no 3 pp 211ndash218 2007

[42] Y Yang J Xiu J Liu et al ldquoChebulagic acid a hydrolyzabletannin exhibited antiviral activity in vitro and in vivo againsthuman enterovirus 71rdquo International Journal of Molecular Sci-ences vol 14 no 5 pp 9618ndash9627 2013

[43] R Banerjee GMukherjee andK C Patra ldquoMicrobial transfor-mation of tannin-rich substrate to gallic acid through co-culturemethodrdquo Bioresource Technology vol 96 no 8 pp 949ndash9532005

[44] D B Reddy and P Reddanna ldquoChebulagic acid (CA) attenuatesLPS-induced inflammation by suppressing NF-120581B and MAPKactivation in RAW 2647 macrophagesrdquo Biochemical and Bio-physical Research Communications vol 381 no 1 pp 112ndash1172009

[45] Y-N Huang D-D Zhao B Gao et al ldquoAnti-hyperglycemiceffect of chebulagic acid from the fruits of Terminalia chebulaRetzrdquo International Journal of Molecular Sciences vol 13 no 5pp 6320ndash6333 2012

[46] H J Kim J Kim K S Kang K T Lee and H O Yang ldquoNeu-roprotective effect of chebulagic acid via autophagy inductionin SH-SY5Y cellsrdquo Biomolecules andTherapeutics vol 22 no 4pp 275ndash281 2014

[47] A P Athira A Helen K Saja P Reddanna and P R Sud-hakaran ldquoInhibition of angiogenesis in vitro by chebulagic acida COX-LOX dual inhibitorrdquo International Journal of VascularMedicine vol 2013 Article ID 843897 8 pages 2013

[48] N Kumar D Gangappa G Gupta and R Karnati ldquoChebulagicacid from Terminalia chebula causes G1 arrest inhibits NF120581Band induces apoptosis in retinoblastoma cellsrdquo BMC Comple-mentary and Alternative Medicine vol 14 article 319 2014

[49] V Mishra M Agrawal S A Onasanwo et al ldquoAnti-secretoryand cyto-protective effects of chebulinic acid isolated from thefruits of Terminalia chebula on gastric ulcersrdquo Phytomedicinevol 20 no 6 pp 506ndash511 2013

[50] K Lu D Chakroborty C Sarkar et al ldquoTriphala and its activeconstituent chebulinic acid are natural inhibitors of vascularendothelial growth factor-amediated angiogenesisrdquo PLoS ONEvol 7 no 8 Article ID e43934 2012

[51] Z-C Yi Z Wang H-X Li M-J Liu R-C Wu and X-HWang ldquoEffects of chebulinic acid on differentiation of humanleukemia K562 cellsrdquo Acta Pharmacologica Sinica vol 25 no 2pp 231ndash238 2004

[52] T Tanaka I Kouno and G-I Nonaka ldquoGlutathione-mediatedconversion of the ellagitannin geraniin into chebulagic acidrdquoChemical and Pharmaceutical Bulletin vol 44 no 1 pp 34ndash401996

[53] M Mansouri A Hemmati B Naghizadeh S Mard A Rezaieand B Ghorbanzadeh ldquoA study of the mechanisms underlyingthe anti-inflammatory effect of ellagic acid in carrageenan-induced paw edema in ratsrdquo Indian Journal of Pharmacologyvol 47 no 3 pp 292ndash298 2015

[54] S Goswami M Vishwanath S Gangadarappa R Razdan andM Inamdar ldquoEfficacy of ellagic acid and sildenafil in diabetes-induced sexual dysfunctionrdquo Pharmacognosy Magazine vol 10supplement 3 pp 581ndash587 2014

[55] W R Garcıa-Nino and C Zazueta ldquoEllagic acid pharmaco-logical activities and molecular mechanisms involved in liverprotectionrdquo Pharmacological Research vol 97 pp 84ndash103 2015

[56] M Dianat N Amini M Badavi and Y Farbood ldquoEllagicacid improved arrhythmias induced by CaCL2 in the rat stressmodelrdquoAvicenna Journal of Phytomedicine vol 5 no 2 pp 120ndash127 2015

[57] M Dolatshahi Y Farbood A Sarkaki S M T Mansouri andA Khodadadi ldquoEllagic acid improves hyperalgesia and cogni-tive deficiency in 6-hydroxidopamine induced rat model ofParkinsonrsquos diseaserdquo Iranian Journal of Basic Medical Sciencesvol 18 no 1 pp 38ndash46 2015

[58] Y Farbood A Sarkaki M Dianat A Khodadadi M K Had-dad and SMashhadizadeh ldquoEllagic acid prevents cognitive andhippocampal long-term potentiation deficits and brain inflam-mation in rat with traumatic brain injuryrdquo Life Sciences vol 124pp 120ndash127 2015

[59] C Wang D Zhang H Ma and J Liu ldquoNeuroprotective effectsof emodin-8-O-120573-d-glucoside in vivo and in vitrordquo EuropeanJournal of Pharmacology vol 577 no 1ndash3 pp 58ndash63 2007

[60] Y-L Xu L-Y Tang X-D Zhou G-H Zhou and Z-J WangldquoFive new anthraquinones from the seed of Cassia obtusifoliardquoArchives of Pharmacal Research vol 38 no 6 pp 1054ndash10582015

[61] P C Gupta ldquoBiological and pharmacological properties ofTerminalia chebula retz (haritaki)- an overviewrdquo InternationalJournal of Pharmacy and Pharmaceutical Sciences vol 4 sup-plement 3 pp 62ndash68 2012

[62] A Bag S K Bhattacharyya and R R Chattopadhyay ldquoThedevelopment of Terminalia chebula Retz (Combretaceae) inclinical researchrdquo Asian Pacific Journal of Tropical Biomedicinevol 3 no 3 pp 244ndash252 2013

[63] I Mueller-Harvey ldquoAnalysis of hydrolysable tanninsrdquo AnimalFeed Science and Technology vol 91 no 1-2 pp 3ndash20 2001

[64] N Lokeswari and K J Raju ldquoOptimization of gallic acid pro-duction from terminalia chebula byAspergillus nigerrdquo E-Journalof Chemistry vol 4 no 2 pp 287ndash293 2007

[65] R Niemetz and G G Gross ldquoEnzymology of gallotannin andellagitannin biosynthesisrdquo Phytochemistry vol 66 no 17 pp2001ndash2011 2005

[66] T Yoshida Y Amakura andM Yoshimura ldquoStructural featuresand biological properties of ellagitannins in some plant familiesof the order myrtalesrdquo International Journal of Molecular Sci-ences vol 11 no 1 pp 79ndash106 2010

[67] P-S Chen and J-H Li ldquoChemopreventive effect of punicalagina novel tannin component isolated from Terminalia catappa onH-ras-transformed NIH3T3 cellsrdquo Toxicology Letters vol 163no 1 pp 44ndash53 2006

[68] QHan J Song CQiao LWong andHXu ldquoPreparative isola-tion of hydrolysable tannins chebulagic acid and chebulinicacid from Terminalia chebula by high-speed counter-currentchromatographyrdquo Journal of Separation Science vol 29 no 11pp 1653ndash1657 2006

[69] H K Sharma S Soni P Kaushal and C Singh ldquoEffect ofprocess parameters on the antioxidant activities of bioactivecompounds from Harad (Terminalia chebula retz) Shilpa SoniHK Sharma Pragati Kaushal andC Singh FoodEngineeringamp


Technology Department Sant Longowal Institute of EngineerirdquoAgricultural Engineering International CIGR Journal vol 17 no2 2015

[70] G K B Lopes H M Schulman and M Hermes-Lima ldquoPoly-phenol tannic acid inhibits hydroxyl radical formation fromFenton reaction by complexing ferrous ionsrdquo Biochimica etBiophysica Acta (BBA)mdashGeneral Subjects vol 1472 no 1-2 pp142ndash152 1999

[71] S Surveswaran Y-Z Cai H Corke and M Sun ldquoSystematicevaluation of natural phenolic antioxidants from 133 Indianmedicinal plantsrdquo Food Chemistry vol 102 no 3 pp 938ndash9532007

[72] P Onial R Dayal M Rawat and R Kumar ldquoUtilization ofTerminalia chebula Retz fruits pericarp as a source of naturaldye for textile applicationsrdquo Indian Journal of Natural Productsand Resources (IJNPR) vol 6 no 2 pp 114ndash121 2015

[73] H G Kim J H Cho E Y Jeong J H Lim S H Lee and HS Lee ldquoGrowth-inhibiting activity of active component isolatedfrom Terminalia chebula fruits against intestinal bacteriardquo Jour-nal of Food Protection vol 69 no 9 pp 2205ndash2209 2006

[74] P Onial M Rawat and R Dayal ldquoChemical studies of fattyoil of Terminalia chebula seeds kernelsrdquo Analytical ChemistryLetters vol 4 no 5-6 pp 359ndash363 2014

[75] X Zhang C Chen S He and F Ge ldquoSupercritical-CO2fluid

extraction of the fatty oil in Terminalia chebula and GC-MSanalysisrdquo Journal of Chinese Medicinal Materials vol 20 no 9pp 463ndash464 1997

[76] D B Reddy T CM Reddy G Jyotsna et al ldquoChebulagic acid aCOXndashLOX dual inhibitor isolated from the fruits of TerminaliachebulaRetz induces apoptosis in COLO-205 cell linerdquo Journalof Ethnopharmacology vol 124 no 3 pp 506ndash512 2009

[77] P Anand B Singh and N Singh ldquoA review on coumarins asacetylcholinesterase inhibitors for Alzheimerrsquos diseaserdquo Bioor-ganic and Medicinal Chemistry vol 20 no 3 pp 1175ndash11802012

[78] M Pohanka ldquoAlpha7 nicotinic acetylcholine receptor is a targetin pharmacology and toxicologyrdquo International Journal of Mole-cular Sciences vol 13 no 2 pp 2219ndash2238 2012

[79] J R Suarez-Lopez J H Himes D R Jacobs Jr B H Alexanderand M R Gunnar ldquoAcetylcholinesterase activity and neurode-velopment in boys and girlsrdquo Pediatrics vol 132 no 6 ppe1649ndashe1658 2013

[80] C F Bartels T Zelinski and O Lockridge ldquoMutation at codon322 in the human acetylcholinesterase (ACHE) gene accountsfor YT blood group polymorphismrdquo The American Journal ofHuman Genetics vol 52 no 5 pp 928ndash936 1993

[81] S Greenfield and D J Vaux ldquoParkinsonrsquos disease Alzheimerrsquosdisease and motor neurone disease identifying a commonmechanismrdquo Neuroscience vol 113 no 3 pp 485ndash492 2002

[82] T Day and S A Greenfield ldquoA peptide derived from acetyl-cholinesterase induces neuronal cell death characterisation ofpossible mechanismsrdquo Experimental Brain Research vol 153no 3 pp 334ndash342 2003

[83] P T Francis A Nordberg and S E Arnold ldquoA preclinical viewof cholinesterase inhibitors in neuroprotection do they pro-vide more than symptomatic benefits in Alzheimerrsquos diseaserdquoTrends in Pharmacological Sciences vol 26 no 2 pp 104ndash1112005

[84] T Darreh-Shori E Hellstrom-Lindahl C Flores-Flores Z ZGuan H Soreq and A Nordberg ldquoLong-lasting acetylcho-linesterase splice variations in anticholinesterase-treated

Alzheimerrsquos disease patientsrdquo Journal of Neurochemistry vol88 no 5 pp 1102ndash1113 2004

[85] A Borisovskaya M Pascualy and S Borson ldquoCognitive andneuropsychiatric impairments in Alzheimerrsquos disease currenttreatment strategiesrdquo Current Psychiatry Reports vol 16 no 9pp 1ndash9 2014

[86] M H Oh P J HoughtonW KWhang and J H Cho ldquoScreen-ing of Korean herbal medicines used to improve cognitive func-tion for anti-cholinesterase activityrdquo Phytomedicine vol 11 no6 pp 544ndash548 2004

[87] V Schulz ldquoGinkgo extract or cholinesterase inhibitors inpatients with dementia what clinical trials and guidelines failto considerrdquo Phytomedicine vol 10 no 4 pp 74ndash79 2003

[88] S Sancheti S Sancheti B-H Um and S-Y Seo ldquo12346-penta-O-galloyl-120573-D-glucose a cholinesterase inhibitor fromTerminalia chebulardquo South African Journal of Botany vol 76 no2 pp 285ndash288 2010

[89] G Nag and B De ldquoAcetylcholinesterase inhibitory activity ofTerminalia chebula Terminalia bellerica and Emblica officinalisand some phenolic compoundsrdquo International Journal of Phar-macy and Pharmaceutical Sciences vol 3 no 3 pp 121ndash124 2011

[90] A P Murray M B Faraoni M J Castro N P Alza and VCavallaro ldquoNatural AChE inhibitors from plants and their con-tribution to Alzheimerrsquos disease therapyrdquo Current Neurophar-macology vol 11 no 4 pp 388ndash413 2013

[91] C Sulaiman C Sadashiva S George and I BalachandranldquoAcetylcholinestrase inhibition and antioxidant activity of Ter-minalia chebula Retzrdquo Journal of Tropical Medicinal Plants vol13 no 2 pp 125ndash127 2012

[92] A Upadhyay and D K Singh ldquoInhibition kinetics of certainenzymes in the nervous tissue of vector snail Lymnaea acumi-nata by active molluscicidal components of Sapindus mukorossiand Terminalia chebulardquo Chemosphere vol 85 no 6 pp 1095ndash1100 2011

[93] M Parle and M Vasudevan ldquoMemory enhancing activity ofAbana an indian ayurvedic poly-herbal formulationrdquo Journalof Health Science vol 53 no 1 pp 43ndash52 2007

[94] H Walia J Kaur and S Arora ldquoAntioxidant efficacy of fruitextracts of Terminalia chebula prepared by sequential methodusing TA-102 strain of Salmonella typhimuriumrdquo Spatula DDvol 2 no 2 pp 165ndash171 2012

[95] P Dhivya M Sobiya P Selvamani and S Latha ldquoAn approachto Alzheimerrsquos disease treatment with cholinesterase inhibitoryactivity from various plant speciesrdquo International Journal ofPharmTech Research vol 6 no 5 pp 1450ndash1467 2014

[96] P Pithayanukul P Ruenraroengsak R Bavovada N Pakmaneeand R Suttisri ldquoIn vitro Investigation of the protective effectsof tannic acid against the activities of Naja kaouthia VenomrdquoPharmaceutical Biology vol 45 no 2 pp 94ndash97 2007

[97] M Mathew and S Subramanian ldquoIn vitro screening for anti-cholinesterase and antioxidant activity ofmethanolic extracts ofayurvedic medicinal plants used for cognitive disordersrdquo PLoSONE vol 9 no 1 Article ID e86804 2014

[98] T Y Shin H J Jeong D K Kim et al ldquoInhibitory action ofwater soluble fraction of Terminalia chebula on systemic andlocal anaphylaxisrdquo Journal of Ethnopharmacology vol 74 no 2pp 133ndash140 2001

[99] K-C Choi Y-H Lee M G Jung et al ldquoGallic acid suppresseslipopolysaccharide-induced nuclear factor-120581B signaling by pre-venting RelA acetylation in A549 lung cancer cellsrdquo MolecularCancer Research vol 7 no 12 pp 2011ndash2021 2009


[100] N D Das K H Jung J H Park et al ldquoTerminalia chebulaextract acts as a potential NF-120581B inhibitor in human lympho-blastic T cellsrdquo Phytotherapy Research vol 25 no 6 pp 927ndash934 2011

[101] M-J Kim A-R Seong J-Y Yoo et al ldquoGallic acid a histoneacetyltransferase inhibitor suppresses 120573-amyloid neurotoxicityby inhibiting microglial-mediated neuroinflammationrdquoMolec-ular Nutrition amp Food Research vol 55 no 12 pp 1798ndash18082011

[102] Y-J Wang P Thomas J-H Zhong et al ldquoConsumption ofgrape seed extract prevents amyloid-120573 deposition and attenu-ates inflammation in brain of an alzheimerrsquos disease mouserdquoNeurotoxicity Research vol 15 no 1 pp 3ndash14 2009

[103] S-H Kim C-D Jun K Suk et al ldquoGallic acid inhibits hist-amine release and pro-inflammatory cytokine production inmast cellsrdquoToxicological Sciences vol 91 no 1 pp 123ndash131 2006

[104] V Nair S Singh and Y K Gupta ldquoAnti-arthritic and diseasemodifying activity of Terminalia chebula Retz in experimentalmodelsrdquo Journal of Pharmacy and Pharmacology vol 62 no 12pp 1801ndash1806 2010

[105] T Moeslinger R Friedl I Volf M Brunner E Koller and PG Spieckermann ldquoInhibition of inducible nitric oxide synthesisby the herbal preparation Padma 28 in macrophage cell linerdquoCanadian Journal of Physiology and Pharmacology vol 78 no11 pp 861ndash866 2000

[106] R Patil B Nanjwade and F Manvi ldquoEvaluation of anti-inflammatory and antiarthritic effect of sesbania grandiflorabark and fruit of Terminalia chebula in ratsrdquo International Jour-nal of Pharmacology and Biological Sciences vol 5 no 1 pp 37ndash46 2011

[107] A Bag S Kumar Bhattacharyya N Kumar Pal and R R Chat-topadhyay ldquoAnti-inflammatory anti-lipid peroxidative antiox-idant and membrane stabilizing activities of hydroalcoholicextract of Terminalia chebula fruitsrdquo Pharmaceutical Biologyvol 51 no 12 pp 1515ndash1520 2013

[108] E P Sabina and M Rasool ldquoAn in vivo and in vitro potential ofIndian ayurvedic herbal formulation Triphala on experimentalgouty arthritis in micerdquo Vascular Pharmacology vol 48 no 1pp 14ndash20 2008

[109] Y R Ramani and S Pradhan ldquoAntiarthritic activity of acetoneextract of Terminalia chebulardquo WebmedCentral Pharmacologyvol 3 no 2 Article IDWMC003057 pp 1ndash9 2012

[110] P Srivastava H N Raut R S Wagh H M Puntambekarand M J Kulkarni ldquoPurification and characterization of anantioxidant protein (sim16 kDa) from Terminalia chebula fruitrdquoFood Chemistry vol 131 no 1 pp 141ndash148 2012

[111] C S Atwood M E Obrenovich T Liu et al ldquoAmyloid-120573 achameleon walking in two worlds a review of the trophic andtoxic properties of amyloid-120573rdquo Brain Research Reviews vol 43no 1 pp 1ndash16 2003

[112] B Uttara A V Singh P Zamboni and R T Mahajan ldquoOxida-tive stress and neurodegenerative diseases a review of upstreamand downstream antioxidant therapeutic optionsrdquo CurrentNeuropharmacology vol 7 no 1 pp 65ndash74 2009

[113] K Hensley N Hall R Subramaniam et al ldquoBrain regional cor-respondence between Alzheimerrsquos disease histopathology andbiomarkers of protein oxidationrdquo Journal of Neurochemistryvol 65 no 5 pp 2146ndash2156 1995

[114] K Hensley J Carney N Hall W Shaw and D A But-terfield ldquoElectron paramagnetic resonance investigations offree radical-induced alterations in neocortical synaptosomal

membrane protein infrastructurerdquo Free Radical Biology andMedicine vol 17 no 4 pp 321ndash331 1994

[115] R X Santos S C Correia X Zhu et al ldquoMitochondrial DNAoxidative damage and repair in aging and Alzheimerrsquos diseaserdquoAntioxidants amp Redox Signaling vol 18 no 18 pp 2444ndash24572013

[116] PMecocci UMacGarvey andM F Beal ldquoOxidative damage tomitochondrial DNA is increased inAlzheimerrsquos diseaserdquoAnnalsof Neurology vol 36 no 5 pp 747ndash751 1994

[117] H-T Lee C-S Lin C-S Lee C-Y Tsai and Y-H WeildquoIncreased 8-hydroxy-21015840-deoxyguanosine in plasma anddecreasedmRNA expression of human 8-oxoguanineDNAgly-cosylase 1 anti-oxidant enzymes mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patientswith systemic lupus erythematosusrdquo Clinical amp ExperimentalImmunology vol 176 no 1 pp 66ndash77 2014

[118] MA LovellWD Ehmann SM Butler andWRMarkesberyldquoElevated thiobarbituric acid-reactive substances and antiox-idant enzyme activity in the brain in Alzheimerrsquos diseaserdquoNeurology vol 45 no 8 pp 1594ndash1601 1995

[119] K V Subbarao J S Richardson and L C Ang ldquoAutopsysamples of Alzheimerrsquos cortex show increased peroxidation invitrordquo Journal of Neurochemistry vol 55 no 1 pp 342ndash3451990

[120] I T Lott ldquoAntioxidants in Down syndromerdquo Biochimica etBiophysica Acta (BBA)mdashMolecular Basis of Disease vol 1822no 5 pp 657ndash663 2012

[121] L Whiley A Sen J Heaton et al ldquoEvidence of altered phos-phatidylcholine metabolism in Alzheimerrsquos diseaserdquoNeurobiol-ogy of Aging vol 35 no 2 pp 271ndash278 2014

[122] R J Mark M A Lovell W R Markesbery K Uchida andM P Mattson ldquoA role for 4-hydroxynonenal an aldehydicproduct of lipid peroxidation in disruption of ion homeostasisand neuronal death induced by amyloid 120573-peptiderdquo Journal ofNeurochemistry vol 68 no 1 pp 255ndash264 1997

[123] A Klugman D P Naughton M Isaac I Shah A Petrocziand N Tabet ldquoAntioxidant enzymatic activities in alzheimerrsquosdisease the relationship to acetylcholinesterase inhibitorsrdquoJournal of Alzheimerrsquos Disease vol 30 no 3 pp 467ndash474 2012

[124] L Balazs and M Leon ldquoEvidence of an oxidative challenge inthe Alzheimerrsquos brainrdquo Neurochemical Research vol 19 no 9pp 1131ndash1137 1994

[125] R A Omar Y-J Chyan A C Andorn B Poeggeler N KRobakis andMA Pappolla ldquoIncreased expression but reducedactivity of antioxidant enzymes in Alzheimerrsquos diseaserdquo Journalof Alzheimerrsquos Disease vol 1 no 3 pp 139ndash145 1999

[126] N Sasaki S Toki H Chowei et al ldquoImmunohistochemical dis-tribution of the receptor for advanced glycation end products inneurons and astrocytes in Alzheimerrsquos diseaserdquo Brain Researchvol 888 no 2 pp 256ndash262 2001

[127] N Verma andM Vinayak ldquoEffect of Terminalia arjuna on anti-oxidant defense system in cancerrdquo Molecular Biology Reportsvol 36 no 1 pp 159ndash164 2009

[128] A Khan H Nazar S M Sabir et al ldquoAntioxidant activityand inhibitory effect of some commonly used medicinal plantsagainst lipid per-oxidation in mice brainrdquo African Journal ofTraditional Complementary and Alternative Medicines vol 11no 5 pp 83ndash90 2014

[129] M K Gautam S Goel R R Ghatule A Singh G Nath and RK Goel ldquoCurative effect of Terminalia chebula extract on acetic


acid-induced experimental colitis role of antioxidants free rad-icals and acute inflammatory markerrdquo Inflammopharmacologyvol 21 no 5 pp 377ndash383 2013

[130] C L Chang and C S Lin ldquoPhytochemical composition anti-oxidant activity and neuroprotective effect of Terminaliachebula Retzius extractsrdquo Evidence-Based Complementary andAlternative Medicine vol 2012 Article ID 125247 7 pages 2012

[131] J H Park H S Joo K-Y Yoo et al ldquoExtract from Terminaliachebula seeds protect against experimental ischemic neuronaldamage via maintaining SODs and BDNF levelsrdquo Neurochemi-cal Research vol 36 no 11 pp 2043ndash2050 2011

[132] M Na K Bae S Sik Kang et al ldquoCytoprotective effect onoxidative stress and inhibitory effect on cellular aging of Termi-nalia chebula fruitrdquo Phytotherapy Research vol 18 no 9 pp737ndash741 2004

[133] R Mahesh S Bhuvana and V M H Begum ldquoEffect of Termi-nalia chebula aqueous extract on oxidative stress and antioxi-dant status in the liver and kidney of young and aged ratsrdquo CellBiochemistry and Function vol 27 no 6 pp 358ndash363 2009

[134] H-Y Cheng T-C Lin K-H Yu C-M Yang and C-C LinldquoAntioxidant and free radical scavenging activities ofTerminaliachebulardquo Biological and Pharmaceutical Bulletin vol 26 no 9pp 1331ndash1335 2003

[135] R Sarkar and N Mandal ldquoHydroalcoholic extracts of Indianmedicinal plants can help in amelioration from oxidative stressthrough antioxidant propertiesrdquo Journal of Complementary andIntegrative Medicine vol 9 no 1 pp 1ndash9 2012

[136] A Manosroi P Jantrawut T Akihisa W Manosroi and JManosroi ldquoIn vitro anti-aging activities of Terminalia chebulagall extractrdquo Pharmaceutical Biology vol 48 no 4 pp 469ndash4812010

[137] K W Lee Y J Kim D-O Kim H J Lee and C Y Lee ldquoMajorphenolics in apple and their contribution to the total antioxi-dant capacityrdquo Journal of Agricultural and Food Chemistry vol51 no 22 pp 6516ndash6520 2003

[138] S C Mondal P Singh B Kumar S K Singh S K Gupta andA Verma ldquoAgeing and potential anti-aging phytochemicals anoverviewrdquo World Journal of Pharmacy and Pharmaceutical Sci-ences vol 4 no 1 pp 426ndash454 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


Figure 1 T chebula tree and fruits

treatments and another is because patients are seeking greaterself-control over their healthcare decisions [8]

It seems that due to the indiscriminate and excessive useof drugs their costs side effects and interactions herbalmedicines can be a suitable alternative to treat diseasesbecause of their low costs availability and fewer drug inter-actions [9]Therefore the search for a new pharmacotherapyfrom medicinal plants to treat neurodegenerative disordershas remarkably advanced and there are several studies anddocuments that indicate a significant role of herbalmedicinesin the treatment of AD [10ndash12] One particular herbal remedyis Terminalia chebula Retz (Combretaceae) because of itsnumerous and different types of phytoconstituents such aspolyphenols terpenes anthocyanins flavonoids alkaloidsand glycosides In traditional medicine the fruits of the Tchebula which hold various chemically active compoundsresponsible for its medicinal properties have been used inUnani Ayurveda and homeopathic medicine since antiquityto treat geriatric diseases and improve memory and brainfunction [13 14] It is also commonly used to treat numerousdiseases such as cancer cardiovascular diseases paralysisleprosy ulcers gout arthritis epilepsy cough fever diarrheagastroenteritis skin disorders urinary tract infection andwound infections [15 16] Recent studies show that T chebulais effective in the treatment of diabetes [17] bacterial andfungal infections [18 19] immunodeficiency diseases [20 21]hyperlipidemia [22] liver diseases [15 23] stomach ulcer[24] andwounds [25] Other pharmacological properties andbeneficial effects of T chebula are summarized in Table 1

Hence this review article aims to sum up the publishedliterature on the pharmacology and phytochemistry of Tchebula and its effects on the progression and treatment ofADin order to call attention to this plant as a novel alternative inthe treatment of Alzheimerrsquos disease

2 Terminalia chebula Retzius

Terminalia chebula Retzius (Family Combretaceae) as ashade and ornamental tree with 250 species is a medicinalplant that grows in the Middle East and tropical regions suchas India China andThailand It can grow to be 25 meters talland has a variable appearance and spreading branches Thecolor of the bark is dark brown and is usually cracked Leavesare thin elliptic-oblong cordiform at the base elliptical and7ndash12 cm long and 4ndash65 cm in width and have a leathery

form with entire margins The upper surface of the leavesis glabrous opposite of the surface beneath The flowers arefutile with a white to yellowish color and unsightly odorFlowers have 5ndash7 cm long spikes simple or branched about4mm across The ovary is inferior with 10 stamens Fruitsare yellow to orange-brown when ripe and 25ndash5 cm long andunruffled with an ovate-drupe shape [15 61]

Moreover it is called by various names by the local peopleFor example in theThai language the plantrsquos commonname isldquoKot Phung Plardquo and in Indian it is called ldquoKadukkaairdquo andits other names are Black Myrobalan Ink Tree or ChebulicMyrobalan (Figure 1) [15]

21 Scientific Classification Its classification is KingdomPlantae Division Magnoliophyta Class MagnoliopsidaOrder Myrtales Family Combretaceae Genus Terminaliaand Species Chebula [15]

22 Phytochemical Compositions of T chebula

221 Hydrolysable Tannins Tannins as a part of the phenoliccompounds are oligomeric andhavemultiple structural unitswith free phenolic groups and their molecular weight rangesfrom 500 to 3000D The fruit pulp and dried pericarp of theseeds contain the highest amount of tannins [62] Tanninsconsist of hydrolysable and nonhydrolysable tannins andhydrolysable tannins (ie gallotannins and ellagitannins) arethe main compounds in T chebula

Gallotannins and ellagitannins are polymers found inthe fruits of T chebula [63] Gallotannins contain gallic acidthat has esterified and bonded with the hydroxyl group of apolyol carbohydrate such as glucose [64] Ellagitannins areformed when oxidative linkage occurs in the galloyl groupsin 12346-pentagalloyl glucose Ellagitannins differ fromgallotannins in that their galloyl groups are linked throughCndashC bonds whereas the galloyl groups in gallotannins arelinked by depside bonds [65 66]

Chebulagic acid a benzopyran tannin is widely dis-tributed in several plant families the Combretaceae [67]Euphorbiaceae Leguminosae Anacardiaceae and Fabaceae[31] Also in the Combretaceae Family chebulagic acid isthe main constitute of the fruits T bellerica T chebula andEmblica officinalis [68]

Chebulinic acid also known as 136-tri-O-galloyl-24-chebuloyl-120573-D-glucopyranoside is an ellagitannin found in





OH

OH

HO

OO

OO

O

O

HO

HO

OH

O

HO

OH

OH

O

HO OH

OH

O

O

O

OH

OH

OH



OH

OHHO

O

OO

O

O

OH

OH

OH

OHO

HO

OH

OO

OO

HO

OH

OH

OH

OH

OH

OH





(Anti-HCC) [29]


OHO

HOOH

OH







[38]


Table 1 Continued



OO

HO

OH

OH

OHO

OHO

HO



[37]


OH

HO

O

O

HO

HO

HO

HO

OO

O OO

OH

OHOHO

O

O

HO

O

O

O

OHOH

OHO






[44]


OHHO

HOO

O

OO

O

OH

OH

OH

O

O

O O

OHO

HO

HO

O

O

HO OH

OHOHO

O


[50]antitumor [51]


Table 1 Continued



O

O

O

HO

HO

OOH

OH



enhancer [57 58]


Phenoliccompound

O

OH

OH

OOH

O

HO

O H

OH

HO

OH

HHO


[60]






























50 1096)

[89]









2production






5022 120583gmL [14]


50was 863 and 05 120583gmL





Proteinoxidation


content


DNAoxidation



Lipidperoxidation

Brainphospholipid

damage


2O2[119]


Antioxidantenzymes



AGEformation


structure andaction




509496mgkgThe IC

50of the










2O2-horseradish








3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





OH

OH

HO

OO

OO

O

O

HO

HO

OH

O

HO

OH

OH

O

HO OH

OH

O

O

O

OH

OH

OH



OH

OHHO

O

OO

O

O

OH

OH

OH

OHO

HO

OH

OO

OO

HO

OH

OH

OH

OH

OH

OH





(Anti-HCC) [29]


OHO

HOOH

OH







[38]


Table 1 Continued



OO

HO

OH

OH

OHO

OHO

HO



[37]


OH

HO

O

O

HO

HO

HO

HO

OO

O OO

OH

OHOHO

O

O

HO

O

O

O

OHOH

OHO






[44]


OHHO

HOO

O

OO

O

OH

OH

OH

O

O

O O

OHO

HO

HO

O

O

HO OH

OHOHO

O


[50]antitumor [51]


Table 1 Continued



O

O

O

HO

HO

OOH

OH



enhancer [57 58]


Phenoliccompound

O

OH

OH

OOH

O

HO

O H

OH

HO

OH

HHO


[60]






























50 1096)

[89]









2production






5022 120583gmL [14]


50was 863 and 05 120583gmL





Proteinoxidation


content


DNAoxidation



Lipidperoxidation

Brainphospholipid

damage


2O2[119]


Antioxidantenzymes



AGEformation


structure andaction




509496mgkgThe IC

50of the










2O2-horseradish








3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table 1 Continued



OO

HO

OH

OH

OHO

OHO

HO



[37]


OH

HO

O

O

HO

HO

HO

HO

OO

O OO

OH

OHOHO

O

O

HO

O

O

O

OHOH

OHO






[44]


OHHO

HOO

O

OO

O

OH

OH

OH

O

O

O O

OHO

HO

HO

O

O

HO OH

OHOHO

O


[50]antitumor [51]


Table 1 Continued



O

O

O

HO

HO

OOH

OH



enhancer [57 58]


Phenoliccompound

O

OH

OH

OOH

O

HO

O H

OH

HO

OH

HHO


[60]






























50 1096)

[89]









2production






5022 120583gmL [14]


50was 863 and 05 120583gmL





Proteinoxidation


content


DNAoxidation



Lipidperoxidation

Brainphospholipid

damage


2O2[119]


Antioxidantenzymes



AGEformation


structure andaction




509496mgkgThe IC

50of the










2O2-horseradish








3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table 1 Continued



O

O

O

HO

HO

OOH

OH



enhancer [57 58]


Phenoliccompound

O

OH

OH

OOH

O

HO

O H

OH

HO

OH

HHO


[60]






























50 1096)

[89]









2production






5022 120583gmL [14]


50was 863 and 05 120583gmL





Proteinoxidation


content


DNAoxidation



Lipidperoxidation

Brainphospholipid

damage


2O2[119]


Antioxidantenzymes



AGEformation


structure andaction




509496mgkgThe IC

50of the










2O2-horseradish








3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of























50 1096)

[89]









2production






5022 120583gmL [14]


50was 863 and 05 120583gmL





Proteinoxidation


content


DNAoxidation



Lipidperoxidation

Brainphospholipid

damage


2O2[119]


Antioxidantenzymes



AGEformation


structure andaction




509496mgkgThe IC

50of the










2O2-horseradish








3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






2production






5022 120583gmL [14]


50was 863 and 05 120583gmL





Proteinoxidation


content


DNAoxidation



Lipidperoxidation

Brainphospholipid

damage


2O2[119]


Antioxidantenzymes



AGEformation


structure andaction




509496mgkgThe IC

50of the










2O2-horseradish








3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




Proteinoxidation


content


DNAoxidation



Lipidperoxidation

Brainphospholipid

damage


2O2[119]


Antioxidantenzymes



AGEformation


structure andaction




509496mgkgThe IC

50of the










2O2-horseradish








3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





3 Conclusion


Terminalia chebula




Ellagitannins



Anticholinesterase

Anti-inflammatory

Antioxidant





References

























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of
















































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of
















Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

Documents

Review Article A Review on Potential Mechanisms of ...downloads.hindawi.com/journals/aps/2016/8964849.pdfglycosides []. Table shows the main ingredients of T. chebula and their chemical