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Review ArticleThe Role of Reactive Oxygen Species in thePathogenesis of Alzheimerrsquos Disease Parkinsonrsquos Disease andHuntingtonrsquos Disease A Mini Review

Shanmugam Manoharan1 Gilles J Guillemin2 Rajagopal Selladurai Abiramasundari1

Musthafa Mohamed Essa3 Mohammed Akbar4 and Mohammed D Akbar4

1Department of Biochemistry and Biotechnology Faculty of Science Annamalai University Annamalainagar Tamil Nadu India2Neuroinflammation Group Department of Biomedical Research Faculty of Medicine and Health Sciences Macquarie UniversitySydney NSW Australia3Department of Food Science and Nutrition Sultan Qaboos University Muscat Oman4SMPT NIAAA National Institutes of Health Rockville MD USA

Correspondence should be addressed to Gilles J Guillemin gillesguilleminmqeduau

Received 8 July 2016 Revised 6 October 2016 Accepted 13 November 2016

Academic Editor Rodrigo Franco

Copyright copy 2016 ShanmugamManoharan et alThis is an open access article distributed under theCreativeCommonsAttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

Neurodegenerative diseases affect not only the life quality of aging populations but also their life spans All forms ofneurodegenerative diseases have a massive impact on the elderly The major threat of these brain diseases includes progressiveloss of memory Alzheimerrsquos disease (AD) impairments in the movement Parkinsonrsquos disease (PD) and the inability to walktalk and think Huntingtonrsquos disease (HD) Oxidative stress and mitochondrial dysfunction are highlighted as a central feature ofbrain degenerative diseases Oxidative stress a condition that occurs due to imbalance in oxidant and antioxidant status has beenknown to play a vital role in the pathophysiology of neurodegenerative diseases including AD PD and HD A large number ofstudies have utilized oxidative stress biomarkers to investigate the severity of these neurodegenerative diseases and medicationsare available but these only treat the symptoms In traditional medicine a large number of medicinal plants have been used totreat the symptoms of these neurodegenerative diseases Extensive studies scientifically validated the beneficial effect of naturalproducts against neurodegenerative diseases using suitable animal models This short review focuses the role of oxidative stress inthe pathogenesis of AD PD and HD and the protective efficacy of natural products against these diseases

1 Introduction

Neurodegenerative diseaseswere believed to be incurable anddebilitating conditions which primarily affected the neuronsin the human brain resulting in the loss of nerve structure andfunction and ultimately leading to the death of nerve cells [1]The major characteristic features of neurodegenerative dis-eases include ataxias (impairment inmovement) and demen-tia (decline inmemory)The threemain types of neurodegen-erative diseases that affect the life quality and life span of theelderly include Alzheimerrsquos disease (AD) Parkinsonrsquos disease(PD) and Huntingtonrsquos disease (HD) [2 3]

2 Alzheimerrsquos Disease

Alzheimerrsquos disease (AD) is one of the most commonneurodegenerative disorders affecting the elderly populationworldwide [4] The specific pathological lesions that werenoticed in AD include deposition of amyloid beta proteinneuronal andor synaptic loss and brain atrophy in specificbrain areas [5] Both the neocortex and hippocampus areaffected and brain plaques and tangles are the major featuresof AD AD symptoms usually start with mild confusion andamnesia and end with a dramatic personality change ADdestroys memory and other important mental functions

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 8590578 15 pageshttpdxdoiorg10115520168590578

2 Oxidative Medicine and Cellular Longevity

Other signs of AD include finding the right words visionspatial issues and impaired reasoning or judgment [6]Worldwide around 16million peoples are affected by AD andover four million Americans are currently affected a figurethat may rise further due to the increase in the life span[7]This age-related progressive neurodegenerative disorderis the fourth leading cause of death in developed nationsand accounts for 70 of dementia in the elderly population[8] It has been suggested the incidence of AD could doubleevery five years beyond the age of 65 [9] Currently availablemedications only treat the symptoms of neurodegenerativediseases

3 Oxidative Stress and Alzheimerrsquos Disease

The etiology of AD is multifactorial Both genetic and envi-ronmental factors are regarded as a risk factor of AD [9 10]Free radicals are chemical species with an unpaired electronand are formed during both physiological and pathologicalprocesses Although reactive oxygen species (ROS) play apivotal role in several cellular and signaling pathways atphysiological concentrations (cell cycle regulation phagocy-tosis and enzyme activation) excessive generation of ROSleads to several harmful effects including DNA lipid andprotein damage [11ndash14] ROS are however scavenged bydefencemechanisms known as enzymatic and nonenzymaticantioxidants An imbalance in this oxidant-antioxidant statuscould determine the extent of cell damage Oxidative damagedue to ROS has been implicated in the pathogenesis ofneurodegenerative diseases cancer diabetes and aging [15]

Mitochondrial dysfunction and enhanced apoptosisaccompanied by a poor antioxidant status are the mecha-nisms for AD pathogenesis Extensive studies pointed outthe role of superoxide anion hydroxyl radical hydrogenperoxide and nitric oxide in the oxidative stress mediatedneurodegeneration in AD [16 17]Microglia activation due toneuronal lesions generates excessive superoxide radicals [18]Higher metabolic demand and the postmitotic nature of glialcells and neurons make them more susceptible to oxidativestress The low rate of brain regeneration and insufficientantioxidant potential in the brain further favors oxidativestress [19] Mitochondrial autophagy serves as a major sourceof ROS production [20]

A120573(1-42) has been recognized as a key factor in the neuro-degeneration inADpatients and itmediates its harmful effectvia inducing oxidative stress in the brain [21ndash23] A positiveassociation has been shown between the amyloid plaque andthe lipid peroxidation markers such as 4-hydroxynonenaland malondialdehyde [24] Elevated lipid peroxidation andinsufficient enzymatic and nonenzymatic antioxidants wereshown in the peripheral tissues of AD patients [25 26] Alarge number of studies have shown an elevated level of lipidperoxidation marker in the brain of AD patients especiallyin the region of the temporal lobe [27ndash29] An increasedlevel of 4-hydroxynonenal the byproduct of oxidative stresshas been reported as well [30 31] Iron-induced oxidativestress as evidenced by iron accumulation in the brain of ADis responsible for neurodegeneration in patients diagnosedwith AD [32] Profound studies explored iron accumulation

in the brain of AD patients and found that as a transitionmetal it is capable of generating hydroxyl radical through theFenton reaction [33 34] 120573-Amyloid could elevate oxidativestress mainly by binding with iron [35] The neuronal deathoccurs due to reactive oxygen species mediated changes inthe neuronal lipid molecules which includes alterations inthe membrane fluidity rigidity permeability and transport[36] It has been noticed that the entorhinal cortex and CAIregion of the hippocampus are the two major susceptiblecerebral regions to oxidative stress [37] Mitochondrial dam-age in AD could lead to excessive generation of ROS andlowered ATP production [38 39] Vitamin E the major lipid-soluble nonenzymatic antioxidant inhibits oxidative damageinduced by A120573(1-42) [40] Diminished levels of reducedglutathione in astrocytes have been reported [41] Melo etal [42] suggested that addition of antioxidants inhibited theactivity of acetylcholine esterase in the neuronal culture Alsosuperoxide dismutase activity was shown to have increasedin the CAI regions of hippocampus and amygdale [43] Thecauses of oxidative stress in AD are given in Figure 1

4 Natural Products and Alzheimerrsquos Disease

Medicinal plants serve as a good source for the treatmentof several illnesses including neurodegenerative diseasesdiabetes mellitus and cancer [44 45] A large number oftherapeutic medicines recommended worldwide for severaldiseases have been identified from medicinal plants Indiantraditional medicine has recommended several medicinalplants for the treatment of neurodegenerative diseases Intraditional medicine several plants have been used to treatthe symptoms of neurodegenerative diseases A large numberof studies scientifically validated the beneficial effects ofnatural products in the treatment of ADusing suitable animalmodels [46 47]

Veerendra Kumar and Gupta [48] explored the neu-roprotective effect of aqueous extract of Centella asiaticain a streptozotocin model of AD in rats They suggestedthat Centella asiatica reduced the oxidative stress as wellDhanasekaran et al [49] pointed out the neuroprotective roleof Centella asiatica in B6C3-Tg(APPswe PSEN1dE9)85 DboJ(PSAPP) mice They concluded that the antioxidant role ofCentella asiaticamodulated the amyloid pathology in PSAPPmice Clementi et al [50] suggested that Aloe arborescensexerted a significant neuroprotective effect in IMR-32 cellsvia reducing the oxidative stress in the cells Gong et al[51] suggested the lotus seed pod Proanthocyanidins was apromising candidate for the treatment of AD as it exhibited asignificant protective effect against cognitive impairment andbrain aging induced by D-galactose Turgut et al [52] pro-posed oxidative stress reduction as amajormechanism for theneuroprotective effect of Capparis spinosa L in D-galactose-induced cognitive impairment Yu et al [53] demonstratedthe neuroprotective role of rutin against amylin-inducedneurocytotoxicity in neuronal cells and concluded that theantioxidant property of rutin might have played a role in theprotection of neuronal cells Mairuae et al [54] showed thein vitro neuroprotective effect of okra in SH-SY5Y cells andsuggested that the antioxidant effect of okra was responsible

Oxidative Medicine and Cellular Longevity 3

Alzheimerrsquos disease(progressive loss of memory)

Oxidative stress

Beneficial natural products with antioxidant properties

Caffeine isothiocyanates citrusflavonoid curculigoside rutin

proanthocyanidins and so on

Higher metabolic demand Mitochondrial dysfunction Microglia activation (excessive superoxide radicals)

Poor antioxidant status

Accumulation of iron and impaired calcium homeostasis

Mitochondrial autophagy

Amyloid plaque Tau aggregation

Excessive generation of reactive oxygen species (Superoxide anion hydroxyl radicals hydrogen

peroxide and nitric oxide)

Centella asiatica Alpinia galangalwalnut Aloe arborescens Capparis

spinosa L Roxburghii Abelmoschusesculentus Linn papaya powder and so on

Figure 1 The causes of oxidative stress in Alzheimerrsquos disease

for the protective role Uddin et al [55] pointed out that thepotent phenolic antioxidants present in the Vanda roxburghiicould be responsible for the inhibition of the activation ofacetylcholinesterase and butyrylcholinesterase Barbagallo etal [56] suggested that fermented papaya powder counter-acted the excessive generation of reactive oxygen speciesin patients diagnosed with AD Lu et al [57] explored theprotective role ofRhubarb extract against irradiation-inducedapoptotic neuronal cell death and excessive ROS generation

Giacoppo et al [58] revealed the neuroprotective effectof isothiocyanates by highlighting their antioxidant potentialas a major mechanism Zhao et al [59] demonstrated theneuroprotective effect of curculigoside on memory impair-ment in APPPSI mutated transgenic mice They suggestedthat its antioxidant character played a major role Muthaiyahet al [60] reported that walnut extract has the ability tocounteract amyloid beta peptide-induced oxidative stress inPC12 cells Hartman et al [61] pointed out that the antioxi-dant polyphenolic substances of pomegranate juice reducedamyloid load and improved behavior in an AD mouseSubash et al [62] suggested that dietary supplementationof dates and figs improved cognitive and behavioral deficitvia maintaining oxidant-antioxidant balances in APPswTg2576 transgenic ADmice Nakajima et al [63] suggested thatnobiletin significantly reduced oxidative stress and improvedthe cognitive impairment in a 3XTg-AD mouse model Sunet al [64] proposed antioxidant potential of saponin as oneof the mechanisms involved in neuroprotection Prasanthiet al [65] showed that caffeine reduced the oxidative stressand improved the cognitive deficits induced by cholesterol-enriched diet in rabbit hippocampus Boyd-Kimball et al[66] reported that glutathione upregulation protected neuron

against oxidative stress and neurotoxicity induced by A(1-42)in theADaffected brainHanish Singh et al [67] reported thatethanolic extract of Alpinia galangal improved the antioxi-dant status and inhibited the acetylcholine esterase activityin AD mice Our research group from Oman reported thebeneficial effects of natural products including pomegranateand figs on AD transgenic mice models [62 68ndash77]

5 Parkinsonrsquos Disease

Parkinsonrsquos disease (PD) the most common neurodegener-ative disease of the elderly is characterized by progressiveloss of muscle control Premature death often results due tocomplications such asmovement impairment-related injuriesor pneumonia [78 79] PD is predominant at the 6thdecade of life and men are 15 to 2 times more likely tocontract the disease than women [80] Head trauma illnessor exposure to environmental toxins is identified as a riskfactor This neurodegenerative disorder is characterized bytremor rigidity bradykinesia and impairment in balance[81] PD also causes cognitive psychiatric autonomic andsensory disturbances Cognitive impairments are commonin a large fraction of patients with PD at initial diagnosisand afflict a majority of patients as the disease progressesThe secondary manifestation includes anxiety insecuritystress confusion memory loss constipation depressiondifficulty in swallowing and excessive salivation diminishedsense of smell increased sweating erectile dysfunction skinproblems and a monotone voice [82 83]

The pathology of PD is characterized by the gradualand selective loss of dopaminergic neurons in the substantianigra pars compacta Imbalance in dopamine metabolism


Parkinsonrsquos disease(impaired movements)


Impaired respiratory chain and somaticmitochondrial DNA mutations Iron accumulation Enhanced dopamine

metabolismIncrease in malondialdehyde and

hydroperoxides in the substantia nigra

Hydroxyl radical accumulation

Oxidative stress


Ceftriaxone quercetin isolecanoricacid carnosic acid hesperidin gallic

acid theaflavin centrophenoxinerutin lycopene and so on

Acacia catechu safflower Ocimumsanctum Buddleja cordata tomato

seeds epicatechin gallate Sidacordifolia Selaginella delicatula

Acanthopanax senticosus and so on

Figure 2 The causes of oxidative stress in Parkinsonrsquos disease

due to oxidative stress has been recognised as a contributorto this disease [84] The major pathological findings includethe presence of Lewy bodies in the substantia nigra andloss of nerve cells in the portions of its ventral tier [85]The treatment modality for PD involves either enhancingthe activities of dopaminergic neuron activity or inhibitingthe cholinergic effects to the stratum While there is nocure for PD medications provide dramatic relief from thesymptoms Recent advancement in medical and surgicaltreatment options has enormously improved the quality andlength of life for patients with PD [86] Worldwide it isthe second most common neurological disease and affectsaround 15 million Americans [87] It has been pointed outthat PDmay double over the next 25 years in theUnited Statesand more than double in the developing nations of Asia andSouth America [88] Research has indicated that 80 of theuntreated PD patients die within 10 to 14 years after the onsetof the disease [89]

6 Oxidative Stress and Parkinsonrsquos Disease

The brain utilizes around 20 of the basal oxygen from thetotal oxygen supplied to the human body ROS mediatedoxidative DNA damage is one of the prominent features inPD [90] Several studies have reported impaired respiratorychain and somatic mitochondrial DNA mutations in thebrain of patients with PD which suggests the extensive roleof oxidative metabolism in PD [91] Enhanced dopaminemetabolism in the brain of patients with PD could accountfor the accumulation of toxic radicals such as hydroxyl in thebrain [92] Iron accumulation in the neurons in the redox

active form plays a crucial role in pathogenesis of thisdisease [93] Accumulation of iron has been reported inthe substantia nigra in patients diagnosed with PD whichsuggests the critical role of iron-induced lipid peroxidationin pathogenesis of PD [94ndash96] The accumulation of lipidperoxidation byproducts has been reported in the serum andcerebral spinal fluid of patientswith PD [97]while an increaseinmalondialdehyde and hydroperoxides has been reported inthe substantia nigra of patients diagnosed with PD [98 99]

Elevated levels of malondialdehyde thiobarbituric acidreactive substance and 4-hydroxy-23-nonenal have beenreported in the substantia nigra and stratum of PD brains[100 101] A twofold increase in protein oxidation has beenshown in the substantia nigra of PD patients comparedto healthy subjects [102] Accumulation of hydroxyl rad-ical due to lowered glutathione content in the brain hasbeen reported in PD patients [103] Lowered activities ofantioxidant enzymes and nonenzymatic antioxidants couldbe responsible for the progression of PD [104 105] Reducedglutathione and increased oxidized glutathione levels havebeen reported in PD patients while lowered glutathionecontent in the substantia nigra due to neuronal loss has beenreported in patients with PD [106ndash109] Decreased activity ofglutathione peroxidase and a decline in glutathione contenthave been reported in the brain of PD patients and reducedglutathione content was found to be decreased in both humanand experimental models of PD [110ndash112] Lowered GSHcontent was reported in the substantia nigra and corpusstriatum of PD patients [113] The causes of oxidative stressin Parkinsonrsquos disease are given in Figure 2


7 Natural Products and Parkinsonrsquos Disease

Extensive studies scientifically explored the protective effectof natural products against Parkinsonrsquos disease using suitableanimal models Weng et al [114] reported that ceftriaxoneprevented the loss of neuronal activity and decreased the neu-rogenesis in the brain of PD rats Sharma et al [115] suggestedthat administration of quercetin attenuated the neuronaldeath and reduced the oxidative stress in aluminium-inducedneurodegeneration in the rat hippocampus Saha et al [116]explored the antineurogenic and antioxidant potential ofAcacia catechu leaf extract using in vitro studies Ren etal [117] reported that safflower flavonoid extract could beused as the herbal therapy for PD treatment De Pedro etal [118] explored the in vitro protective effect of isolecanoricacid against the PD development Wu et al [119] investi-gated the neuroprotective effect of carnosic acid against 6-hydroxydopamine induced neurotoxicity They concludedthat the antioxidant and antiapoptotic potential of carnosicacid could play a protective role in the prevention of neurode-generation Siddique et al [120] demonstrated the neuropro-tective effect ofOcimum sanctum leaf extract in the transgenicDrosophila model of PD Antunes et al [121] suggested thathesperidin attenuated 6-hydroxydopamine induced oxida-tive stress in aged mice Perez-Barron et al [122] exploredthe antioxidant and neuroprotective effect of Buddleja cor-datamethanolic extract in the 1-methyl-4-phenylpyridiniuminduced PD rat model Beppe et al [123] suggested thatthe aqueous extract of Albizia adianthifolia leaves pos-sesses antioxidant potential which was responsible forthe memory-enhancing activities in the rodent model of PD

Gokul and Muralidhara [124] reported that tomato seedsalleviated motor abnormality oxidative impairments andneurotoxicity in a chronic ROT model of neurotoxicity inmice Siddique et al [125] reported that epicatechin gallatedietary supplementation reduced the oxidative stress andapoptosis in the brain of transgenic Drosophila model ofPD Khurana and Gajbhiye [126] showed the ameliorativeeffect of Sida cordifolia against rotenone-induced oxidativestress and neurochemical and behavioral alterations in a ratmodel of PD Chandran and Muralidhara [127] showed theneuroprotective effect of aqueous extract of Selaginella del-icatula in a chronic ROT exposure model of neurotoxicityin mice They suggested that the neuroprotective propertyof Selaginella delicatula is largely attributed to the antiox-idant properties Prakash et al [128] demonstrated the neuro-protective role ofWithania somnifera root extract in parkin-sonismmiceThey suggested thatWithania somnifera extractimproved the behavioral anatomical and biochemical defor-mities Mansouri et al [129] suggested that the neuroprotec-tive effect of oral gallic acid is due to the enhancement of cere-bral antioxidant defense against oxidative stress induced by 6-hydroxydopamine in rats Shalavadi et al [130] suggested thatthe neuroprotective effect of the methanolic extract of Stere-ospermum suaveolens DC could be attributed to its antioxi-dant potential in 6-OHDA induced PD rats Liu et al [131]explored the neuroprotective effect of Acanthopanax sentico-sus in PD Anandhan et al [132] suggested that the neuro-protective effect of theaflavin may be due to its antioxidative

and antiapoptotic activities in chronic MPTPprobenecidinduced PD Some of our research group members reportedthe beneficial effects of natural products on PD animals [133ndash137]

Ahmad et al [138] pointed out that the antioxidantefficacy of sesame seed oil is responsible for the neuropro-tective effect in 6-hydroxydopamine induced neurotoxicityin mice Martins et al [139] demonstrated the protectiveeffect of Melissa officinalis in manganese-induced oxidativestress in chronically exposed mice They concluded thatthe antioxidant potential of this plant is responsible forthe neuroprotective effect Hritcu et al [140] pointed outthat the methanolic extract of Hibiscus asper leaves exertedneuroprotective activity through antioxidant and antiapop-totic activities in PD model Ranpariya et al [141] suggestedthat the antioxidant potential of Matricaria recutita couldbe largely attributed to its neuroprotective activity againstfluoride-induced stress in rats Wang et al [142] suggestedthat the free radical scavenging activity of resveratrol pro-tected the abnormal rotational behavior and the loss andapoptosis of nigral cells in Parkinsonian rats Verma andNehru [143] demonstrated the antioxidant effect of centro-phenoxine against rotenone-induced oxidative stress in PDrodent Kaur et al [144] demonstrated the beneficial effect oflycopene in rotenone-induced model of PD They suggestedthat the therapeutic potential of lycopene is attributed toits antioxidant efficacy Khan et al [145] pointed out thatrutin can protect dopaminergic neurons from oxidativestress in a PD rat Essa et al [146] suggested that walnutpartially reversed MPTP-induced neurodegeneration in amouse model of PDThey suggested that the antioxidant roleof walnut might have played a neuroprotective role Jahromiet al [147] suggested that the antioxidants present in theDecalepis hamiltonii roots attenuated neuromotor deficits intransgenic Drosophila model of PD

Tseng et al [148] showed the protective effect of LiuweiDihuang in Parkinsonrsquos toxin-induced dopaminergic neu-rodegeneration Guo et al [149] suggested that tetram-ethylpyrazine nitrone rescued dopaminergic neurons byreducing ROS and increasing cellular antioxidative defensecapability in the animal models of PD Sudati et al [150]concluded that Valeriana officinalis improved the antioxi-dant defence mechanism in the rotenone-induced toxicityin Drosophila melanogaster Pasban-Aliabadi et al [151]suggested that the protective effect of olive (Olea europaeaL) leaf extract in the 6-hydroxydopamine-induced PC12cell apoptosis is due to their antioxidative and antiapoptoticproperties Kim et al [152] explored the neuroprotective roleof Rhus verniciflua in rotenone model of PD via its antiox-idant efficacy Li and Pu [153] reported that kaempferolinhibited MPTP induced oxidative stress in the mousemodel of PD Liang et al [154] pointed out that tenuigeninexhibited potent neuroprotective effect through antioxidantpotential in a SH-SY5Y cell model with 6-OHDA-inducedinjury Hu et al [155] showed that the ginseng attenuated(MPP(+)) induced cytotoxicity in SH-SY5Y cells throughits antioxidant potential Choi et al [156] suggested thatPolygalae Radix through its antioxidant and antiapoptoticefficacy inhibited the neuronal death in PDmodels Sengupta


et al [157] reported that the hydroxyl scavenging potential ofHyoscyamus niger seeds is responsible for its neuroprotectiveeffect

An et al [158] reported that Acanthopanacis senticosusprevented theMPP+ induced damage in PC12 cells by reduc-ing the levels ofMDA which suggested its antioxidant poten-tial Kim et al [159] pointed out that Chunghyuldan exhibitedneuroprotective effect against ROS-mediated neuronal celldeath in PDmodel Lee et al [160] suggested that Cyperi rhi-zome exhibited the neuroprotective effects through antiox-idant and antiapoptotic activities in an in vitro PD modelShu et al [161] suggested that the neuroprotective effect ofChuanxiong Chatiaomay be associatedwith its potent antiox-idant efficacy in MPTP-induced Parkinsonrsquos mice Shim etal [162] suggested that Uncaria rhynchophylla exhibited neu-roprotective effect through antioxidative and antiapoptoticactivities in PD models Sankar et al [163] suggested thatWithania somnifera root extract exhibited potent neuropro-tective effect by mitigating MPTP-induced oxidative stressin PD mice Ahmad et al [164] showed the neuroprotectiveeffect of Delphinium denudatum via its antioxidant propertyin PD rats Ahmad et al [165] reported that Nardostachysjatamansi attenuated 6-hydroxydopamine-induced parkin-sonism in rats via antilipid peroxidative potential Zhang etal [166] explored the neuroprotective effect of Forsythia sus-pensawith antioxidant property in an experimental model ofrotenone-induced neurotoxicity Lu et al [167] suggested thatresveratrol showed aneuroprotective effect inMPTP-inducedparkinsonism through free radical scavenging potential Alarge number of experimental studies on neurodegenerativediseases highlighted curcumin as a potent neuroprotectiveagent [168] Braidy et al [137] explored the neuroprotectiveeffect of pomegranate extract in MPTP induced oxidativestress in human primary neurons

8 Huntingtonrsquos Disease

Huntingtonrsquos disease (HD) is a devastating familial and inher-ited disease characterized by the progressive loss of brainand muscle function It occurs due to the genetically pro-grammed degeneration of neurons which causes uncon-trolled movements loss of intellectual abilities and emo-tional disturbances HD is caused by a CAG trinucleotideexpansion in exon 1 of the Huntingtin (HTT) gene which islocated on chromosome 4 (4p63) [169] Healthy individualshave 6ndash35 CAG repeats and affected individuals have morethan 36 repeats The accumulation of mutant Huntingtinproteins contains a long polyglutamine region which causesneuronal death and the degeneration of neuronal networkswithin the brain The pathological changes in the cerebralcortex and striatum elicit the development of chorea andcognitive impairments and lead to premature death Thereis a 50 chance that children will inherit HD from HDaffected parents Men and women are equally affected by HDwhich appears during 4th to 5th decade of lifeThe symptomsusually appear between the ages of 35 and 55 However theage of onset and its progression varies from person to person[170]The clinical course ofHD typically progresses over 10 to20 years from a presymptomatic state to complete disability

and death The early symptoms includes tumbling lack offocus concentration and movement problems clumsinesslapses in short-term memory and depression As the diseaseprogresses difficulty in speechweight loss feeding problemsswallowing difficulties uncontrollablemovements of the faceand itching and stumbling are the major symptoms It hasbeen estimated that around 6000 and 30000 people areaffected by HD in UK and USA respectively [171]

9 Oxidative Stress and Huntingtonrsquos Disease

The exact cause of neuronal death in HD is unknownHowever oxidative stressmay play an important roleThe twomajor factors that make the brain more prone to oxidativedamage are higher lipid concentrations and high energyrequirement [172] Compelling data supports a critical rolefor oxidative stress in the pathogenesis of HD a disordercaused by polyglutamine expansion in Huntingtin (Htt)mHTT proteins serve as the source of reactive oxygen species(ROS) due to a significant amount of oxidized proteins inpartially purified mHTT aggregates [173] Though oxidativedamage is not much reported in the early stages of HD itis proposed as one of the major mechanisms in HD as itprogresses [174]

Elevated oxidative stress plays a critical role in thelate stage of HD pathogenesis Impairment in the electrontransport chain andmitochondrial dysfunction are themajormechanisms involved in the ROS mediated etiopathogenesisof HD [175 176] Dysfunction in the oxidative phosphoryla-tion components has been documented in the brain tissuesof HD patients [177] HD patients showed an increasedlevel of oxidative stress markers accompanied by a decreasein antioxidant status compared to healthy subjects [178]ROS mediated oxidative damage to mitochondria has beenpostulated as a reasonable mechanism for the defect inglucose metabolism in the brain tissue of symptomatic HDpatients [179] A positive correlation between plasma lipidperoxidation byproduct and the severity of disease in patientswith HD has been shown [180] Enhanced lipid peroxidationhas been reported in patients with severe symptoms ofHD [178 181] An increase in the plasma lipid peroxida-tion accompanied by reduced glutathione content has beenreported in HD patients [182] The extensive oxidative DNAdamage has been reported in a HD mouse model [183 184]Enhanced oxidative stress and a decline in nonenzymaticantioxidants have been reported in the peripheral blood ofHD patients [185] Stoy et al [186] reported that abnormaltryptophanmetabolism with enhanced oxidative stress couldbe responsible for brain dysfunction in HD Duran et al [187]reported that symptomatic HD patients are more prone tooxidative stress than asymptomatic HD patients The causesof oxidative stress in HD are given in Figure 3

10 Natural Products and HuntingtonrsquosDisease

Researches utilized suitable experimental models to scien-tifically validate the protective efficacy of natural productsagainst HD Oliveira et al [188] suggested that the protective


Huntingtonrsquos disease (inability to walk talk and think)


Protopanaxatriol resveratrol lipoicacid 3-alkyl luteolin and so on

Impairment in electron transport chain andmitochondrial dysfunction

Accumulation of mHTT protein

Imbalance in oxidant-antioxidant status

Higher lipid concentration and high energy requirement

Oxidative stressPoor antioxidant status

Calendula officinalis Ginkgo bilobaolive oil green tea Withaniasomnifera Centella asiaticaConvolvulus pluricaulischoisMatricaria recutita and so on

Figure 3 The causes of oxidative stress in Huntingtonrsquos disease

effect of luteolin derivatives on Huntingtonrsquos mouse striatalcells is due to its antioxidant potential Shivasharan et al[189] showed the protective efficacy of Calendula officinalisflowers in 3-nitropropionic acid-induced HD in rats Theyconcluded that the anti-inflammatory and antioxidant poten-tial of Calendula officinalis might have played a neuropro-tective role Mahdy et al [190] explored the beneficial effectof Ginkgo biloba extract on 3-nitropropionic acid-inducedneurobehavioral changes and striatal lesionsThey concludedthat the antioxidant and antiapoptotic potential of Ginkgobiloba extract might be responsible for the neuroprotectiverole Tasset et al [191] reported that olive oil reduced oxida-tive damage in 3-nitropropionic acid-induced HD in ratsThey concluded that extravirgin olive oil and hydroxytyrosolserved as a powerful brain antioxidant Sagredo et al [192]provided preclinical evidence for the neuroprotective effectof phytocannabinoid-basedmedicines in HD Gao et al [193]investigated the neuroprotective effect of protopanaxatriolagainst 3-nitropropionic acid-induced oxidative stress inexperimental HD Tunez et al [194] showed the protec-tive effect of melatonin in 3-nitropropionic acid-inducedoxidative stress in synaptosomes in rat with HD Theyconcluded that melatonin modified the neural response to 3-nitropropionic acid with the antioxidative mechanism

Rocha-Gonzalez et al [195] reported the neuroprotectiverole of resveratrol against HD Andreassen et al [196] sug-gested that lipoic acid as an antioxidant has the potentialto improve the survival of transgenic mouse models ofHD Ehrnhoefer et al [197] pointed out that green tea(-)-epigallocatechin gallate prevented the early events of HD

pathogenesis such as Huntingtonrsquos misfolding Denny Josephand Muralidhara [198] suggested that fish oil in combinationwith quercetin provided better neuroprotection against 3-nitropropionic acid-induced HD Fu et al [199] suggestedthat trans-(minus)-120576-Viniferin could be considered as a promisingcandidate to treat HD since it increased mitochondrialsirtuin 3 (SIRT3) and activated the AMP-activated proteinkinase Huang et al [200] explored the neuroprotective roleof N(6)-(4-hydroxybenzyl) adenine riboside against experi-mentalHD Ranpariya et al [201] showed the neuroprotectiveeffect of German chamomile against aluminium fluoride-induced oxidative stress in rats P Kumar andA Kumar [202]explored the neuroprotective effect of Withania somniferaroot extract against 3-nitropropionic acid-induced HDTheysuggested that neuroprotective actions ofWithania somniferaare mediated via its antioxidant activity Shinomol andMuralidhara [203] reported that the prophylactic neuropro-tective property of Centella asiatica could be related to theenhancement of GSH thiols and antioxidant machinery inthe brain regions of 3-nitropropionic acid-induced HD pre-pubertal mice Kaur et al [204] suggested that Convolvuluspluricaulis exhibited a potent neuroprotective effect by accel-erating the brain antioxidant defence mechanisms in 3-nitro-propionic acid treated rats Al-Sabahi et al [205] reported thebenefit of pomegranate seed oil on 3-NP induced HD

11 Conclusion

Neurodegenerative diseases impose a significant health bur-den not only to the affected patients but also to their families


and society The incidences of these life threatening disor-ders are rapidly increasing in aged populations worldwideAlthough several mechanisms have been postulated for thepathogenesis of neurodegenerative diseases oxidative stressand mitochondrial dysfunctions are pointed out as a majormechanism At present medications are only available totreat the symptoms of neurodegenerative diseases Severalin vivo and in vitro studies have documented the protectiverole of various natural products or synthetic entities inthe prevention of neurodegenerative diseases However thesolution for these neurodegenerative diseases has not yetbeen foundThus researches are warranted to investigate thenontoxic active constituents found in natural resources whichcould correct the biochemical metabolic and behavioralabnormalities that occur in neurodegenerative diseases

12 Opinion of the Authors

This reviewhighlights the crucial role of oxidative stress in thepathogenesis of various neurodegenerative diseases Basedon the literature researched for this paper it is clear thatoxidative stress mediates its adverse effects either directlycausing neuronal damage or by inducing the harmful effectsof neurotoxicants This review also explores the beneficialeffects of various natural products against neurodegenerativediseases

While many reports have focused on the role of pro-tective efficacy of natural products against oxidative stress-induced neurodegenerative diseases as yet there have beenno effective treatment solutions reported for these diseasesThis indicates that the antioxidants alone are not sufficientto treat neurodegenerative diseases Thus intense researchshould be undertaken to investigate or identify the novelcompounds that could be used to counteract the oxidativestress pathogenesis and for a better therapeutic agent for thetreatment of neurodegenerative diseases

13 Literature Search Strategy

For this study an intense literature search on neurodegener-ative diseases (AD PD and HD) was mainly done throughPubMed articles published from 1982 to 2016 The articleswere then scrutinized and the most relevant selected to writethis review We have also referred to previous review articleson neurodegenerative diseases and the references cited werealso considered The key words used to search the relevantarticles included neurodegenerative diseases Alzheimerrsquosdisease Parkinsonrsquos disease Huntingtonrsquos disease ReactiveOxygen Species antioxidants medicinal plants and so forth

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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upstream and downstream antioxidant therapeutic optionsrdquoCurrent Neuropharmacology vol 7 no 1 pp 65ndash74 2009

[2] M N Rossor N C Fox C J Mummery J M Schott and J DWarren ldquoThe diagnosis of young-onset dementiardquo The LancetNeurology vol 9 no 8 pp 793ndash806 2010

[3] M T Lin and M F Beal ldquoMitochondrial dysfunction andoxidative stress in neurodegenerative diseasesrdquoNature vol 443pp 787ndash795 2006

[4] D A Butterfield and D Boyd-Kimball ldquoAmyloid 120573-peptide(1-42) contributes to the oxidative stress and neurodegenerationfound in Alzheimer disease brainrdquo Brain Pathology vol 14 no4 pp 426ndash432 2004

[5] C A Lemere and E Masliah ldquoCan Alzheimer disease beprevented by amyloid-120573 immunotherapyrdquo Nature ReviewsNeurology vol 6 no 2 pp 108ndash119 2010

[6] L Mosconi A Pupi and M J De Leon ldquoBrain glucosehypometabolism and oxidative stress in preclinical Alzheimerrsquosdiseaserdquo Annals of the New York Academy of Sciences vol 1147pp 180ndash195 2008

[7] C P Ferri M Prince C Brayne et al ldquoGlobal prevalence ofdementia a Delphi consensus studyrdquo The Lancet vol 366 no9503 pp 2112ndash2117 2005

[8] D Pratico ldquoEvidence of oxidative stress in Alzheimerrsquos diseasebrain and antioxidant therapy lights and shadowsrdquo Annals ofthe New York Academy of Sciences vol 1147 pp 70ndash78 2008

[9] F P Joseph C Darrell Jennings J K Richard et al ldquoAssociationof HFE mutations with neurodegeneration and oxidative stressin Alzheimerrsquos disease and correlation with APOErdquo AmericanJournal of Medical Genetics vol 119 pp 48ndash53 2003

[10] T D Bird ldquoGenetic aspects of Alzheimer diseaserdquo Genetics inMedicine vol 10 no 4 pp 231ndash239 2008

[11] E H Verbon J A Post and J Boonstra ldquoThe influence ofreactive oxygen species on cell cycle progression inmammaliancellsrdquo Gene vol 511 no 1 pp 1ndash6 2012

[12] Y Son S Kim H-T Chung and H-O Pae ldquoReactive oxygenspecies in the activation of MAP kinasesrdquoMethods in Enzymol-ogy vol 528 pp 27ndash48 2013

[13] G A Knock and J P T Ward ldquoRedox regulation of proteinkinases as a modulator of vascular functionrdquo Antioxidants andRedox Signaling vol 15 no 6 pp 1531ndash1547 2011

[14] M Lo Conte and K S Carroll ldquoThe redox biochemistry ofprotein sulfenylation and sulfinylationrdquoThe Journal of BiologicalChemistry vol 288 no 37 pp 26480ndash26488 2013

[15] X Chen C Guo and J Kong ldquoOxidative stress in neurodegen-erative diseasesrdquo Neural Regeneration Research vol 7 no 5 pp376ndash385 2012

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[17] K Van Dyke ldquoThe possible role of peroxynitrite in Alzheimerrsquosdisease a simple hypothesis that could be tested more thor-oughlyrdquoMedical Hypotheses vol 48 no 5 pp 375ndash380 1997

[18] K Nakajima and S Kohsaka ldquoMicroglia activation and theirsignificance in the central nervous systemrdquo Journal of Biochem-istry vol 130 no 2 pp 169ndash175 2001

[19] J Friedman ldquoWhy is the nervous system vulnerable to oxidativestressrdquo inOxidative Stress inApplied Basic Research andClinicalPractice N Gadoth and H H Gobel Eds pp 19ndash27 HumanaPress Totowa NJ USA 2011


[20] E Munkacsy and S L Rea ldquoThe paradox of mitochondrial dys-function and extended longevityrdquo Experimental Gerontologyvol 56 pp 221ndash233 2014

[21] S M Yatin M Yatin T Aulick K B Ain and D A ButterfieldldquoAlzheimerrsquos amyloid120573-peptide associated free radicals increaserat embryonic neuronal polyamine uptake and ornithine decar-boxylase activity protective effect of vitamin Erdquo NeuroscienceLetters vol 263 no 1 pp 17ndash20 1999

[22] DA Butterfield andCM Lauderback ldquoLipid peroxidation andprotein oxidation in Alzheimerrsquos disease brain potential causesand consequences involving amyloid 120573-peptide-associated freeradical oxidative stressrdquo Free Radical Biology and Medicine vol32 no 11 pp 1050ndash1060 2002

[23] J Drake C D Link and D A Butterfield ldquoOxidative stressprecedes fibrillar deposition of Alzheimerrsquos disease amyloid 120573-peptide (1ndash42) in a transgenic Caenorhabditis elegans modelrdquoNeurobiology of Aging vol 24 no 3 pp 415ndash420 2003

[24] C A Massaad ldquoNeuronal and vascular oxidative stress inAlzheimerrsquos diseaserdquo Current Neuropharmacology vol 9 no 4pp 662ndash673 2011

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[26] J Greilberger C KoidlMGreilberger et al ldquoMalondialdehydecarbonyl proteins and albumin-disulphide as useful oxidativemarkers inmild cognitive impairment andAlzheimerrsquos diseaserdquoFree Radical Research vol 42 no 7 pp 633ndash638 2008

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[29] D L Marcus CThomas C Rodriguez et al ldquoIncreased perox-idation and reduced antioxidant enzyme activity in AlzheimerrsquosdiseaserdquoExperimentalNeurology vol 150 no 1 pp 40ndash44 1998

[30] S P Gabbita M A Lovell and W R Markesbery ldquoIncreasednuclear DNA oxidation in the brain in Alzheimerrsquo s diseaserdquoJournal of Neurochemistry vol 71 no 5 pp 2034ndash2040 1998

[31] 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

[32] M A Smith P L R Harris L M Sayre and G PerryldquoIron accumulation in Alzheimer disease is a source of redox-generated free radicalsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 94 no 18 pp 9866ndash9868 1997

[33] M A Lovell J D Robertson W J Teesdale J L Campbell andWRMarkesbery ldquoCopper iron and zinc inAlzheimerrsquos diseasesenile plaquesrdquo Journal of the Neurological Sciences vol 158 no1 pp 47ndash52 1998

[34] G Casadesus M A Smith X Zhu et al ldquoAlzheimer diseaseevidence for a central pathogenic role of iron-mediated reactiveoxygen speciesrdquo Journal of Alzheimerrsquos Disease vol 6 no 2 pp165ndash169 2004

[35] C A Rottkamp A K Raina X Zhu et al ldquoRedox-active ironmediates amyloid-120573 toxicityrdquoFree Radical Biology andMedicinevol 30 no 4 pp 447ndash450 2001

[36] M J Rowan I Klyubin Q Wang and R Anwyl ldquoMechanismsof the inhibitory effects of amyloid 120573-protein on synapticplasticityrdquo Experimental Gerontology vol 39 no 11-12 pp 1661ndash1667 2004

[37] E Karelson N Bogdanovic A Garlind et al ldquoThe cerebrocor-tical areas in normal brain aging and in Alzheimerrsquos diseasenoticeable differences in the lipid peroxidation level and inantioxidant defenserdquoNeurochemical Research vol 26 no 4 pp353ndash361 2001

[38] R Castellani K Hirai G Aliev et al ldquoRole of mitochondrialdysfunction in Alzheimerrsquos diseaserdquo Journal of NeuroscienceResearch vol 70 no 3 pp 357ndash360 2002

[39] G E Gibson K-F R Sheu and J P Blass ldquoAbnormalities ofmitochondrial enzymes inAlzheimer diseaserdquo Journal of NeuralTransmission vol 105 no 8-9 pp 855ndash870 1998

[40] S M Yatin S Varadarajan and D A Butterfield ldquoVitamin Eprevents Alzheimerrsquos amyloid 120573-peptide (1-42)-induced neu-ronal protein oxidation and reactive oxygen species produc-tionrdquo Journal of Alzheimerrsquos Disease vol 2 no 2 pp 123ndash1312000

[41] A Y Abramov L Canevari and M R Duchen ldquoChangesin intracellular calcium and glutathione in astrocytes as theprimary mechanism of amyloid neurotoxicityrdquo Journal of Neu-roscience vol 23 no 12 pp 5088ndash5095 2003

[42] J B Melo P Agostinho and C R Oliveira ldquoInvolve-ment of oxidative stress in the enhancement of acetyl-cholinesterase activity induced by amyloid beta-peptiderdquo Neu-roscience Research vol 45 no 1 pp 117ndash127 2003

[43] K Rahman ldquoStudies on free radicals antioxidants and co-factorsrdquoClinical Interventions inAging vol 2 no 2 pp 219ndash2362007

[44] A Singhal O Bangar and V Naithani ldquoMedicinal plantswith a potential to treat Alzheimer and associated symptomsrdquoInternational Journal of Nutrition Pharmacology NeurologicalDiseases vol 2 no 2 pp 84ndash91 2012

[45] P Upadhyay D Panjwani and A K Yadav ldquoNeuropathol-ogy staging and treatment strategies of Alzheimerrsquos diseasean updaterdquo International Journal of Nutrition PharmacologyNeurological Diseases vol 4 no 1 pp 28ndash42 2014

[46] G H Kim J E Kim S J Rhie and S Yoon ldquoThe role ofoxidative stress in neurodegenerative diseasesrdquo ExperimentalNeurobiology vol 24 no 4 pp 325ndash340 2015

[47] M R Ven Murthy P K Ranjekar C Ramassamy and MDeshpande ldquoScientific basis for the use of Indian ayurvedicmedicinal plants in the treatment of neurodegenerative dis-orders 1 Ashwagandhardquo Central Nervous System Agents inMedicinal Chemistry vol 10 no 3 pp 238ndash246 2010

[48] M H Veerendra Kumar and Y K Gupta ldquoEffect of Centellaasiatica on cognition and oxidative stress in an intracerebroven-tricular streptozotocin model of Alzheimerrsquos disease in ratsrdquoClinical and Experimental Pharmacology and Physiology vol 30no 5-6 pp 336ndash342 2003

[49] M Dhanasekaran L A Holcomb A R Hitt et al ldquoCentellaasiatica extract selectively decreases amyloid 120573 levels in hip-pocampus of alzheimerrsquos disease animal modelrdquo PhytotherapyResearch vol 23 no 1 pp 14ndash19 2009

[50] M E Clementi G Tringali D Triggiani and B Giardina ldquoAloearborescens extract protects IMR-32 Cells against Alzheimeramyloid beta peptide via inhibition of radical peroxide produc-tionrdquoNatural Product Communications vol 10 no 11 pp 1993ndash1995 2015


[51] Y-S Gong J Guo K Hu et al ldquoAmeliorative effect of lotusseedpod proanthocyanidins on cognitive impairment and brainaging induced by D-galactoserdquo Experimental Gerontology vol74 pp 21ndash28 2016

[52] N H Turgut H Kara E Arslanbas D G Mert B Tepeand H Gungor ldquoEffect of Capparis spinosa L On cognitiveimpairment induced by D-galactose in mice via inhibition ofoxidative stressrdquo Turkish Journal of Medical Sciences vol 45 no5 pp 1127ndash1136 2015

[53] X-L Yu Y-N Li H Zhang et al ldquoRutin inhibits amylin-induced neurocytotoxicity and oxidative stressrdquo Food andFunction vol 6 no 10 pp 3296ndash3306 2015

[54] N Mairuae J R Connor S Y Lee P Cheepsunthorn and WTongjaroenbuangam ldquoThe effects of okra (Abelmoschus escu-lentus Linn) on the cellular events associated with Alzheimerrsquosdisease in a stably expressed HFE neuroblastoma SH-SY5Y celllinerdquo Neuroscience Letters vol 31 no 603 pp 6ndash11 2015

[55] M N Uddin R Afrin M J Uddin et al ldquoVanda roxburghiichloroform extract as a potential source of polyphenols withantioxidant and cholinesterase inhibitory activities identifica-tion of a strong phenolic antioxidantrdquoBMCComplementary andAlternative Medicine vol 15 no 1 article 195 2015

[56] M Barbagallo F Marotta and L J Dominguez ldquoOxidativestress in patients with Alzheimerrsquos disease effect of extractsof fermented papaya powderrdquo Mediators of Inflammation vol2015 Article ID 624801 6 pages 2015

[57] K Lu C Zhang W Wu M Zhou Y Tang and Y PengldquoRhubarb extract has a protective role against radiation-induced brain injury and neuronal cell apoptosisrdquo MolecularMedicine Reports vol 12 no 2 pp 2689ndash2694 2015

[58] S Giacoppo M Galuppo S Montaut et al ldquoAn overview onneuroprotective effects of isothiocyanates for the treatment ofneurodegenerative diseasesrdquo Fitoterapia vol 106 pp 12ndash212015

[59] L Zhao S Liu Y Wang et al ldquoEffects of curculigoside onmemory impairment and bone loss via anti-oxidative characterin APPPS1 mutated transgenic micerdquo PLoS ONE vol 10 no 7Article ID e0133289 2015

[60] B Muthaiyah M M Essa V Chauhan and A ChauhanldquoProtective effects of walnut extract against amyloid betapeptide-induced cell death and oxidative stress in PC12 cellsrdquoNeurochemical Research vol 36 no 11 pp 2096ndash2103 2011

[61] R E Hartman A Shah A M Fagan et al ldquoPomegranatejuice decreases amyloid load and improves behavior in a mousemodel of Alzheimerrsquos diseaserdquo Neurobiology of Disease vol 24no 3 pp 506ndash515 2006

[62] S Subash M M Essa A Al-Asmi S Al-Adawi R Vaishnavand G J Guillemin ldquoEffect of dietary supplementation of datesin Alzheimerrsquos disease APPsw2576 transgenic mice on oxida-tive stress and antioxidant statusrdquoNutritional Neuroscience vol18 no 6 pp 281ndash288 2015

[63] A Nakajima Y Aoyama E-J Shin et al ldquoNobiletin a citrusflavonoid improves cognitive impairment and reduces solubleA120573 levels in a triple transgenic mouse model of Alzheimerrsquosdisease (3XTg-AD)rdquo Behavioural Brain Research vol 289 pp69ndash77 2015

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[65] J R P Prasanthi B Dasari G Marwarha et al ldquoCaffeineprotects against oxidative stress and Alzheimerrsquos disease-like

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[66] D Boyd-Kimball R Sultana H Mohmmad Abdul and DA Butterfield ldquo120574-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against A120573(1-42)-mediated oxidative stress and neurotoxicity implications forAlzheimerrsquos diseaserdquo Journal of Neuroscience Research vol 79no 5 pp 700ndash706 2005

[67] J C Hanish Singh V Alagarsamy S Sathesh Kumar and YNarsimha Reddy ldquoNeurotransmitter metabolic enzymes andantioxidant status on Alzheimerrsquos disease induced mice treatedwith Alpinia galanga (L) Willdrdquo Phytotherapy Research vol 25no 7 pp 1061ndash1067 2011

[68] M Akbar B-J Song M M Essa and M A KhanldquoPomegranate an ideal fruit for human healthrdquo InternationalJournal of Nutrition Pharmacology Neurological Diseases vol5 no 4 pp 141ndash143 2015

[69] S Subash M M Essa N Braidy et al ldquoDiet rich in date palmfruits improves memory learning and reduces beta amyloidin transgenic mouse model of Alzheimerrsquos diseaserdquo Journal ofAyurveda and Integrative Medicine vol 6 no 2 pp 111ndash1202015

[70] S Subash N Braidy M M Essa et al ldquoLong-term (15mo)dietary supplementation with pomegranates fromOman atten-uates cognitive and behavioral deficits in a transgenic micemodel of Alzheimerrsquos diseaserdquo Nutrition vol 31 no 1 pp 223ndash229 2015

[71] S Subash M Essa A Al-Asmi et al ldquoPomegranate fromoman alleviates the brain oxidative damage in transgenicmouse model of alzheimer1015840s diseaserdquo Journal of Traditional andComplementary Medicine vol 4 no 4 pp 232ndash238 2014

[72] S Subash M M Essa S Al-Adawi M A Memon T Mani-vasagam andM Akbar ldquoNeuroprotective effects of berry fruitson neurodegenerative diseasesrdquo Neural Regeneration Researchvol 9 no 16 pp 1557ndash1566 2014

[73] S Subash M M Essa A Al-Asmi S Al-Adawi and RVaishnav ldquoChronic dietary supplementation of 4 figs onthe modification of oxidative stress in Alzheimerrsquos diseasetransgenic mouse modelrdquo BioMed Research International vol2014 Article ID 546357 8 pages 2014

[74] S Subash M M Essa N Braidy et al ldquoConsumption offig fruits grown in Oman can improve memory anxiety andlearning skills in a transgenic mice model of Alzheimerrsquosdiseaserdquo Nutritional Neuroscience vol 19 no 10 pp 475ndash4832016

[75] M M Essa S Subash C Dhanalakshmi et al ldquoDietary sup-plementation of walnut partially reverses 1-methyl-4-phenyl-1236-tetrahydropyridine induced neurodegeneration in amouse model of Parkinsonrsquos diseaserdquo Neurochemical Researchvol 40 no 6 pp 1283ndash1293 2015

[76] M M Essa S Subash M Akbar S Al-Adawi and GJ Guillemin ldquoLong-Term dietary supplementation ofpomegranates figs and dates alleviate neuroinflammationin a transgenic mouse model of alzheimerrsquos diseaserdquo PLOSONE vol 25 no 10 Article ID e0120964 2015

[77] B Muthaiyah M M Essa M Lee V Chauhan K Kaur andA Chauhan ldquoDietary supplementation of walnuts improvesmemory deficits and learning skills in transgenic mouse modelof Alzheimerrsquos diseaserdquo Journal of Alzheimerrsquos Disease vol 42no 4 pp 1397ndash1405 2014


[78] M M Goldenberg ldquoMedical management of Parkinsonrsquos dis-easerdquo P and T vol 33 no 10 pp 590ndash606 2008

[79] G DeMaagd andA Philip ldquoParkinsonrsquos disease and itsmanage-ment part 1 disease entity risk factors pathophysiology clin-ical presentation and diagnosisrdquo Pharmacy and Therapeutics vol 40 no 8 pp 504ndash532 2015

[80] J Massano and K P Bhatia ldquoClinical approach to Parkinsonrsquosdisease features diagnosis and principles of managementrdquoCold Spring Harbor Perspectives inMedicine vol 2 no 6 ArticleID a008870 2012

[81] J B Leverenz J F Quinn C Zabetian J Zhang K S Montineand T J Montine ldquoCognitive impairment and dementia inpatients with Parkinson diseaserdquo Current Topics in MedicinalChemistry vol 9 no 10 pp 903ndash912 2009

[82] J M Savitt V L Dawson and T M Dawson ldquoDiagnosis andtreatment of Parkinson disease molecules tomedicinerdquo Journalof Clinical Investigation vol 116 no 7 pp 1744ndash1754 2006

[83] W D Parker Jr J K Parks and R H Swerdlow ldquoComplex Ideficiency in Parkinsonrsquos disease frontal cortexrdquo Brain Researchvol 1189 pp 215ndash218 2008

[84] G E Alexander ldquoBiology of Parkinsonrsquos disease pathogenesisand pathophysiology of a multisystem neurodegenerative dis-orderrdquo Dialogues in Clinical Neuroscience vol 6 no 3 pp 259ndash280 2004

[85] S Sarkar J Raymick and S Imam ldquoNeuroprotective andtherapeutic strategies against Parkinsonrsquos disease recent per-spectivesrdquo International Journal ofMolecular Sciences vol 17 no6 article no 904 2016

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[92] M Gerlach K L Double D Ben-Shachar L Zecca M B HYoudim and P Riederer ldquoNeuromelanin and its interactionwith iron as a potential risk factor for dopaminergic neu-rodegeneration underlying Parkinsonrsquos diseaserdquo NeurotoxicityResearch vol 5 no 1-2 pp 35ndash43 2003

[93] J M Gorell R J Ordidge G G Brown J-C Deniau N MBuderer and J A Helpern ldquoIncreased iron-related MRI con-trast in the substantia nigra in Parkinsonrsquos diseaserdquo Neurologyvol 45 no 6 pp 1138ndash1143 1995

[94] A L Friedlich and M F Beal ldquoProspects for redox-basedtherapy in neurodegenerative diseasesrdquo Neurotoxicity Researchvol 2 no 2-3 pp 229ndash237 2000

[95] H T Atasoy O Nuyan T Tunc M Yorubulut A E Unal andL E Inan ldquoT2-weighted MRI in Parkinsonrsquos disease substantianigra pars compacta hypointensity correlates with the clinicalscoresrdquo Neurology India vol 52 no 3 pp 332ndash337 2004

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[97] B A FaucheuxM-EMartin C Beaumont J-J Hauw Y Agidand E C Hirsch ldquoNeuromelanin associated redox-active ironis increased in the substantia nigra of patients with Parkinsonrsquosdiseaserdquo Journal of Neurochemistry vol 86 no 5 pp 1142ndash11482003

[98] D T Dexter C J Carter F R Wells et al ldquoBasal lipid per-oxidation in substantia nigra is increased in Parkinsonrsquos dis-easerdquo Journal of Neurochemistry vol 52 no 2 pp 381ndash389 1989

[99] D T Dexter F R Wells A J Lees et al ldquoIncreased nigral ironcontent and alterations in other metal ions occurring in brainin Parkinsonrsquos diseaserdquo Journal of Neurochemistry vol 52 no 6pp 1830ndash1836 1989

[100] A Yoritaka N Hattori K Uchida M Tanaka E R Stadtmanand Y Mizuno ldquoImmunohistochemical detection of 4-hydrox-ynonenal protein adducts in Parkinson diseaserdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 93 no 7 pp 2696ndash2701 1996

[101] E Floor and M G Wetzel ldquoIncreased protein oxidation inhuman substantia nigra pars compacta in comparison withbasal ganglia and prefrontal cortex measured with an improveddinitrophenylhydrazine assayrdquo Journal of Neurochemistry vol70 no 1 pp 268ndash275 1998

[102] Y Ihara D Chuda S Kuroda and T Hayabara ldquoHydroxylradical and superoxide dismutase in blood of patients withParkinsonrsquos disease relationship to clinical datardquo Journal of theNeurological Sciences vol 170 no 2 pp 90ndash95 1999

[103] S Abraham C C Soundararajan S Vivekanandhan andM Behari ldquoErythrocyte antioxidant enzymes in Parkinsonrsquosdiseaserdquo Indian Journal of Medical Research vol 121 no 2 pp111ndash115 2005

[104] C-M Chen J-L Liu Y-RWu et al ldquoIncreased oxidative dam-age in peripheral blood correlates with severity of Parkinsonrsquosdiseaserdquo Neurobiology of Disease vol 33 no 3 pp 429ndash4352009

[105] D W Dickson ldquoLinking selective vulnerability to cell deathmechanisms in Parkinsonrsquos diseaserdquo The American Journal ofPathology vol 170 no 1 pp 16ndash19 2007

[106] T L Perry D V Godin and S Hansen ldquoParkinsonrsquos diseasea disorder due to nigral glutathione deficiencyrdquo NeuroscienceLetters vol 33 no 3 pp 305ndash310 1982

[107] E Sofic K W Lange K Jellinger and P Riederer ldquoReducedand oxidized glutathione in the substantia nigra of patients withParkinsonrsquos diseaserdquo Neuroscience Letters vol 142 no 2 pp128ndash130 1992

[108] V Dias E Junn and M M Mouradian ldquoThe role of oxidativestress in parkinsonrsquos diseaserdquo Journal of Parkinsonrsquos Disease vol3 no 4 pp 461ndash491 2013

[109] T L Perry and V W Yong ldquoIdiopathic Parkinsonrsquos diseaseprogressive supranuclear palsy and glutathione metabolism inthe substantia nigra of patientsrdquo Neuroscience Letters vol 67no 3 pp 269ndash274 1986

[110] S Surendran and S Rajasankar ldquoParkinsonrsquos disease oxidativestress and therapeutic approachesrdquo Neurological Sciences vol31 no 5 pp 531ndash540 2010

[111] M F Beal ldquoExperimentalmodels of Parkinsonrsquos diseaserdquoNatureReviews Neuroscience vol 2 no 5 pp 325ndash332 2001


[112] B S Todd B Ranjita K S Amy et al ldquoAn in vitro modelof Parkinsonrsquos disease linking mitochondrial impairment toaltered-synuclein metabolism and oxidative damagerdquoThe Jour-nal of Neuroscience vol 22 no 16 pp 7006ndash7015 2002

[113] R K B Pearce A Owen S Daniel P Jenner and C DMarsden ldquoAlterations in the distribution of glutathione inthe substantia nigra in Parkinsonrsquos diseaserdquo Journal of NeuralTransmission vol 104 no 6-7 pp 661ndash677 1997

[114] J Weng M A Tikhonova J Chen et al ldquoCeftriaxone preventsthe neurodegeneration and decreased neurogenesis seen in aParkinsonrsquos disease rat model an immunohistochemical andMRI studyrdquo Behavioural Brain Research vol 305 pp 126ndash1392016

[115] D Sharma W Wani A Sunkaria et al ldquoQuercetin attenuatesneuronal death against aluminum-induced neurodegenerationin the rat hippocampusrdquo Neuroscience vol 324 pp 163ndash1762016

[116] M R Saha P Dey S Begum et al ldquoEffect of Acacia catechu(Lf) willd on oxidative stress with possible implications inalleviating selected cognitive disordersrdquo PLoS One vol 11 no3 Article ID e0150574 2016

[117] R Ren C Shi J Cao et al ldquoNeuroprotective effects of astandardized flavonoid extract of safflower against neurotoxin-induced cellular and animal models of Parkinsonrsquos diseaserdquoScientific Reports vol 6 Article ID 22135 2016

[118] N De Pedro J Cantizani F J Ortiz-Lopez et al ldquoProtectiveeffects of isolecanoric acid on neurodegenerative in vitro mod-elsrdquo Neuropharmacology vol 101 pp 538ndash548 2016

[119] C-R Wu C-W Tsai S-W Chang C-Y Lin L-CHuang and C-W Tsai ldquoCarnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and invitromodel of Parkinsonrsquos disease involvement of antioxidativeenzymes inductionrdquo Chemico-Biological Interactions vol 225pp 40ndash46 2015

[120] Y H Siddique M Faisal F Naz S Jyoti and Rahul ldquoRoleof Ocimum sanctum leaf extract on dietary supplementationin the transgenic Drosophila model of Parkinsonrsquos diseaserdquoChinese Journal of NaturalMedicines vol 12 no 10 pp 777ndash7812014

[121] M S Antunes A T R Goes S P Boeira M Prigol andC R Jesse ldquoProtective effect of hesperidin in a model ofParkinsonrsquos disease induced by 6-hydroxydopamine in agedmicerdquo Nutrition vol 30 no 11-12 pp 1415ndash1422 2014

[122] G Perez-Barron J G Avila-Acevedo A M Garcıa-Bores etal ldquoNeuroprotective effect of Buddleja cordata methanolicextract in the 1-methyl-4-phenylpyridinium Parkinsonrsquos diseaseratmodelrdquo Journal of NaturalMedicines vol 69 no 1 pp 86ndash932015

[123] G J Beppe A B Dongmo H S Foyet et al ldquoMemory-enhancing activities of the aqueous extract of Albizia adianthi-folia leaves in the 6-hydroxydopamine-lesion rodent modelof Parkinsonrsquos diseaserdquo BMC Complementary and AlternativeMedicine vol 14 article 142 2014

[124] K Gokul and Muralidhara ldquoOral supplements of aqueousextract of tomato seeds alleviate motor abnormality oxidativeimpairments and neurotoxicity induced by rotenone in micerelevance to Parkinsonrsquos diseaserdquo Neurochemical Research vol39 no 7 pp 1382ndash1394 2014

[125] Y H Siddique S Jyoti and F Naz ldquoEffect of epicatechin gallatedietary supplementation on transgenic drosophila model ofparkinsonrsquos diseaserdquo Journal of Dietary Supplements vol 11 no2 pp 121ndash130 2014

[126] N Khurana and A Gajbhiye ldquoAmeliorative effect of Sida cordi-folia in rotenone induced oxidative stress model of Parkinsonrsquosdiseaserdquo NeuroToxicology vol 39 pp 57ndash64 2013

[127] G Chandran and M Muralidhara ldquoNeuroprotective effectof aqueous extract of selaginella delicatula as evidenced byabrogation of rotenone-induced motor deficits oxidative dys-functions and neurotoxicity in micerdquo Cellular and MolecularNeurobiology vol 33 no 7 pp 929ndash942 2013

[128] J Prakash S K Yadav S Chouhan and S P Singh ldquoNeuro-protective role of withania somnifera root extract in maneb-paraquat induced mouse model of parkinsonismrdquo Neurochem-ical Research vol 38 no 5 pp 972ndash980 2013

[129] M T Mansouri Y Farbood M J Sameri A SarkakiB Naghizadeh and M Rafeirad ldquoNeuroprotective effectsof oral gallic acid against oxidative stress induced by 6-hydroxydopamine in ratsrdquo Food Chemistry vol 138 no 2-3 pp1028ndash1033 2013

[130] M H Shalavadi V M Chandrashekhar S P Avinash CSowmya and A Ramkishan ldquoNeuroprotective activity of Stere-ospermum suaveolens DC against 6-OHDA induced Parkin-sonrsquos disease modelrdquo Indian Journal of Pharmacology vol 44no 6 pp 737ndash743 2012

[131] S-M Liu X-Z Li YHuo and F Lu ldquoProtective effect of extractof Acanthopanax senticosus harms on dopaminergic neurons inParkinsonrsquos disease micerdquo Phytomedicine vol 19 no 7 pp 631ndash638 2012

[132] A Anandhan K Tamilselvam T Radhiga S Rao MM Essa and T Manivasagam ldquoTheaflavin a black teapolyphenol protects nigral dopaminergic neurons againstchronic MPTPprobenecid induced Parkinsonrsquos diseaserdquo BrainResearch vol 1433 pp 104ndash113 2012

[133] J Nataraj T Manivasagam A J Thenmozhi and M MEssa ldquoLutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorat-ing mitochondrial disruption and oxidative stressrdquo NutritionalNeuroscience vol 19 no 6 pp 237ndash246 2016

[134] J Nataraj T Manivasagam A Justin Thenmozhi and MM Essa ldquoNeuroprotective effect of asiatic acid on rotenone-induced mitochondrial dysfunction and oxidative stress-mediated apoptosis in differentiated SH-SYS5Y cellsrdquo Nutri-tional Neuroscience 2016

[135] C Dhanalakshmi T Manivasagam J Nataraj A Justin Then-mozhi andMM Essa ldquoNeurosupportive role of vanillin a nat-ural phenolic compound on rotenone induced neurotoxicity inSH-SY5Y neuroblastoma cellsrdquoEvidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 626028 11 pages2015

[136] K Tamilselvam N Braidy T Manivasagam et al ldquoNeuropro-tective effects of hesperidin a plant flavanone on rotenone-induced oxidative stress and apoptosis in a cellular model forParkinsonrsquos diseaserdquoOxidative Medicine and Cellular Longevityvol 2013 Article ID 102741 11 pages 2013

[137] N Braidy S Selvaraju M M Essa et al ldquoNeuroprotectiveeffects of a variety of pomegranate juice extracts against MPTP-induced cytotoxicity and oxidative stress in human primaryneuronsrdquo Oxidative Medicine and Cellular Longevity vol 2013Article ID 685909 12 pages 2013

[138] S Ahmad M B Khan M N Hoda et al ldquoNeuroprotectiveeffect of sesame seed oil in 6-hydroxydopamine induced neuro-toxicity inmicemodel cellular biochemical andneurochemicalevidencerdquo Neurochemical Research vol 37 no 3 pp 516ndash5262012


[139] E N Martins N T C Pessano L Leal et al ldquoProtectiveeffect ofMelissa officinalis aqueous extract against Mn-inducedoxidative stress in chronically exposed micerdquo Brain ResearchBulletin vol 87 no 1 pp 74ndash79 2012

[140] L Hritcu H S Foyet M Stefan M Mihasan A E Asongalemand P Kamtchouing ldquoNeuroprotective effect of the methanolicextract ofHibiscus asper leaves in 6-hydroxydopamine-lesionedratmodel of Parkinsonrsquos diseaserdquo Journal of Ethnopharmacologyvol 137 no 1 pp 585ndash591 2011

[141] V L Ranpariya S K Parmar N R Sheth and V M Chan-drashekhar ldquoNeuroprotective activity of Matricaria recutitaagainst fluoride-induced stress in ratsrdquo Pharmaceutical Biologyvol 49 no 7 pp 696ndash701 2011

[142] Y Wang H Xu Q Fu R Ma and J Xiang ldquoProtective effectof resveratrol derived from Polygonum cuspidatum and itsliposomal form on nigral cells in Parkinsonian ratsrdquo Journal ofthe Neurological Sciences vol 304 no 1-2 pp 29ndash34 2011

[143] R Verma and B Nehru ldquoEffect of centrophenoxine againstrotenone-induced oxidative stress in an animal model ofParkinsonrsquos diseaserdquo Neurochemistry International vol 55 no6 pp 369ndash375 2009

[144] H Kaur S Chauhan and R Sandhir ldquoProtective effect oflycopene on oxidative stress and cognitive decline in rotenoneinducedmodel of Parkinsonrsquos diseaserdquoNeurochemical Researchvol 36 no 8 pp 1435ndash1443 2011

[145] M M Khan S S Raza H Javed et al ldquoRutin protectsdopaminergic neurons fromoxidative stress in an animalmodelof Parkinsonrsquos diseaserdquoNeurotoxicity Research vol 22 no 1 pp1ndash15 2012


[147] S R JahromiMHaddadi T Shivanandappa and S R RameshldquoModulatory effect of Decalepis hamiltonii on ethanol-inducedtoxicity in transgenic Drosophila model of Parkinsonrsquos diseaserdquoNeurochemistry International vol 80 pp 1ndash6 2015

[148] Y-T Tseng F-R Chang and Y-C Lo ldquoThe Chinese herbalformula Liuwei dihuang protects dopaminergic neurons againstParkinsonrsquos toxin through enhancing antioxidative defense andpreventing apoptotic deathrdquo Phytomedicine vol 21 no 5 pp724ndash733 2014

[149] B Guo D Xu H Duan et al ldquoTherapeutic effects of multifunc-tional tetramethylpyrazine nitrone on models of Parkinsonrsquosdisease in vitro and in vivordquo Biological and PharmaceuticalBulletin vol 37 no 2 pp 274ndash285 2014

[150] J H Sudati F A Vieira S S Pavin et al ldquoValeriana offic-inalis attenuates the rotenone-induced toxicity in drosophilamelanogasterrdquo NeuroToxicology vol 37 pp 118ndash126 2013

[151] H Pasban-Aliabadi S Esmaeili-Mahani V Sheibani MAbbasnejad A Mehdizadeh and M M Yaghoobi ldquoInhibitionof 6-hydroxydopamine-induced PC12 cell apoptosis by olive(Olea europaea L) leaf extract is performed by its maincomponent oleuropeinrdquo Rejuvenation Research vol 16 no 2pp 134ndash142 2013

[152] K-H Kim K Song S-H Yoon O Shehzad Y-S Kim and JH Son ldquoRescue of PINK1 protein null-specific mitochondrialcomplex IV deficits by ginsenoside Re activation of nitric oxidesignalingrdquo The Journal of Biological Chemistry vol 287 no 53pp 44109ndash44120 2012

[153] S Li and X-P Pu ldquoNeuroprotective effect of kaempferolagainst a 1-methyl-4-phenyl-1236-tetrahydropyridine-inducedmouse model of Parkinsonrsquos diseaserdquo Biological and Pharma-ceutical Bulletin vol 34 no 8 pp 1291ndash1296 2011

[154] Z Liang F Shi Y Wang et al ldquoNeuroprotective effects oftenuigenin in a SH-SY5Y cell model with 6-OHDA-inducedinjuryrdquo Neuroscience Letters vol 497 no 2 pp 104ndash109 2011

[155] S Hu R Han SMak and YHan ldquoProtection against 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis by waterextract of ginseng (Panax ginseng CA Meyer) in SH-SY5Ycellsrdquo Journal of Ethnopharmacology vol 135 no 1 pp 34ndash422011

[156] J G Choi H G Kim M C Kim et al ldquoPolygalae radixinhibits toxin-inducedneuronal death in the Parkinsonrsquos diseasemodelsrdquo Journal of Ethnopharmacology vol 134 no 2 pp 414ndash421 2011

[157] T Sengupta J Vinayagam N Nagashayana B Gowda PJaisankar and K P Mohanakumar ldquoAntiparkinsonian effects ofaqueous methanolic extract of Hyoscyamus niger seeds resultfrom its monoamine oxidase inhibitory and hydroxyl radicalscavenging potencyrdquo Neurochemical Research vol 36 no 1 pp177ndash186 2011

[158] L An S Liu Y Dong B Tang and W Dong ldquoProtective effectof effective part of Acanthopanacis senticosus on damage ofPC12 cells induced by MPP+rdquo Zhongguo Zhongyao Zazhi vol35 no 15 pp 2021ndash2026 2010

[159] H G Kim M S Ju D-H Kim et al ldquoProtective effects ofChunghyuldan against ROS-mediated neuronal cell death inmodels of Parkinsonrsquos diseaserdquo Basic amp Clinical Pharmacologyamp Toxicology vol 107 no 6 pp 958ndash964 2010

[160] C-H Lee D-S Hwang H G Kim et al ldquoProtective effectof Cyperi Rhizoma against 6-hydroxydopamine-induced neu-ronal damagerdquo Journal of Medicinal Food vol 13 no 3 pp 564ndash571 2010

[161] D Shu J He and J Chen ldquoNeuroprotective effects and mech-anisms of Chuanxiong Chatiao pulvis against MPTP-induceddopaminergic neurotoxicity in mice model of parkinsonrsquos dis-easerdquo Zhongguo Zhongyao Zazhi vol 34 no 19 pp 2494ndash24972009

[162] J S Shim H G Kim M S Ju J G Choi S Y Jeong andM S Oh ldquoEffects of the hook of Uncaria rhynchophylla onneurotoxicity in the 6-hydroxydopamine model of Parkinsonrsquosdiseaserdquo Journal of Ethnopharmacology vol 126 no 2 pp 361ndash365 2009

[163] S R Sankar T Manivasagam A Krishnamurti and MRamanathan ldquoThe neuroprotective effect of Withania som-nifera root extract in MPTP-intoxicated mice an analysis ofbehavioral and biochemical variblesrdquo Cellular and MolecularBiology Letters vol 12 no 4 pp 473ndash481 2007

[164] M Ahmad S Yousuf M B Khan et al ldquoProtective effects ofethanolic extract of Delphinium denudatum in a rat model ofParkinsonrsquos diseaserdquo Human and Experimental Toxicology vol25 no 7 pp 361ndash368 2006

[165] M Ahmad S Yousuf M B Khan et al ldquoAttenuation by Nar-dostachys jatamansi of 6-hydroxydopamine-induced parkin-sonism in rats behavioral neurochemical and immunohis-tochemical studiesrdquo Pharmacology Biochemistry and Behaviorvol 83 no 1 pp 150ndash160 2006

[166] S Zhang S-Y Shao X-Y Song et al ldquoProtective effectsof Forsythia suspense extract with antioxidant and anti-inflammatory properties in a model of rotenone inducedneurotoxicityrdquo NeuroToxicology vol 52 pp 72ndash83 2016


[167] K-T Lu M-C Ko B-Y Chen et al ldquoNeuroprotective effectsof resveratrol on MPTP-induced neuron loss mediated by freeradical scavengingrdquo Journal of Agricultural and Food Chemistryvol 56 no 16 pp 6910ndash6913 2008

[168] R B Mythri and M M Srinivas Bharath ldquoCurcumin apotential neuroprotective agent in Parkinsonrsquos diseaserdquo CurrentPharmaceutical Design vol 18 no 1 pp 91ndash99 2012

[169] W J Szlachcic PM SwitonskiW J KrzyzosiakM FiglerowiczandM Figiel ldquoHuntington disease iPSCs show early molecularchanges in intracellular signaling the expression of oxidativestress proteins and the p53 pathwayrdquo DMMDisease Models andMechanisms vol 8 no 9 pp 1047ndash1057 2015

[170] X Li A Valencia E Sapp et al ldquoAberrant Rab11-dependenttrafficking of the neuronal glutamate transporter EAAC1 causesoxidative stress and cell death in Huntingtonrsquos diseaserdquo Journalof Neuroscience vol 30 no 13 pp 4552ndash4561 2010

[171] Y Sari ldquoHuntingtonrsquos disease from mutant huntingtin pro-tein to neurotrophic factor therapyrdquo International Journal ofBiomedical Science vol 7 no 2 pp 89ndash100 2011

[172] F O Walker ldquoHuntingtonrsquos diseaserdquo Lancet vol 369 no 9557pp 218ndash228 2007

[173] B Rotblat A L Southwell D E Ehrnhoefer et al ldquoHACE1reduces oxidative stress and mutant Huntingtin toxicity bypromoting the NRF2 responserdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 111 no8 pp 3032ndash3037 2014

[174] A Johri and M F Beal ldquoAntioxidants in Huntingtonrsquos diseaserdquoBiochimica et BiophysicaActa vol 1822 no 5 pp 664ndash674 2012

[175] E Trushina and C T McMurray ldquoOxidative stress and mito-chondrial dysfunction in neurodegenerative diseasesrdquo Neuro-science vol 145 no 4 pp 1233ndash1248 2007

[176] L M Sayre G Perry and M A Smith ldquoOxidative stress andneurotoxicityrdquo Chemical Research in Toxicology vol 21 no 1pp 172ndash188 2008

[177] D-H Lee R Gold and R A Linker ldquoMechanisms of oxidativedamage in multiple sclerosis and neurodegenerative diseasestherapeutic modulation via fumaric acid estersrdquo InternationalJournal ofMolecular Sciences vol 13 no 9 pp 11783ndash11803 2012

[178] C-M Chen Y-R Wu M-L Cheng et al ldquoIncreased oxidativedamage and mitochondrial abnormalities in the peripheralblood of Huntingtonrsquos disease patientsrdquo Biochemical and Bio-physical Research Communications vol 359 no 2 pp 335ndash3402007

[179] S Choudhary P Kumar and J Malik ldquoPlants and phytochem-icals for Huntington1015840s diseaserdquo Pharmacognosy Reviews vol 7no 14 pp 81ndash91 2013

[180] M Gu M T Gash V M Mann F Javoy-Agid J M Cooperand A H V Schapira ldquoMitochondrial defect in Huntingtonrsquosdisease caudate nucleusrdquo Annals of Neurology vol 39 no 3 pp385ndash389 1996

[181] I Tunez F Sanchez-Lopez E Aguera R Fernandez-Bolanos FM Sanchez and I Tasset-Cuevas ldquoImportant role of oxidativestress biomarkers in Huntingtonrsquos diseaserdquo Journal of MedicinalChemistry vol 54 no 15 pp 5602ndash5606 2011

[182] N Klepac M Relja R Klepac S Hecimovic T Babic and VTrkulja ldquoOxidative stress parameters in plasma of Huntingtonrsquosdisease patients asymptomatic Huntingtonrsquos disease gene car-riers and healthy subjects a cross-sectional studyrdquo Journal ofNeurology vol 254 no 12 pp 1676ndash1683 2007

[183] A-V Goula B R Berquist D M Wilson III V C WheelerY Trottier and K Merienne ldquoStoichiometry of base exci-sion repair proteins correlates with increased somatic CAG

instability in striatum over cerebellum in Huntingtonrsquos diseasetransgenic micerdquo PLoS Genetics vol 5 no 12 Article IDe1000749 2009

[184] S E Browne A C Bowling U MacGarvey et al ldquoOxidativedamage and metabolic dysfunction in huntingtonrsquos diseaseselective vulnerability of the basal gangliardquoAnnals of Neurologyvol 41 no 5 pp 646ndash653 1997

[185] M Ribeiro T R Rosenstock T Cunha-Oliveira I L FerreiraC R Oliveira and A C Rego ldquoGlutathione redox cycledysregulation in Huntingtonrsquos disease knock-in striatal cellsrdquoFree Radical Biology and Medicine vol 53 no 10 pp 1857ndash18672012

[186] N Stoy G M Mackay C M Forrest et al ldquoTryptophanmetabolism and oxidative stress in patients with Huntingtonrsquosdiseaserdquo Journal of Neurochemistry vol 93 no 3 pp 611ndash6232005

[187] R Duran F J Barrero B Morales J D Luna M Ramirez andF Vives ldquoOxidative stress and plasma aminopeptidase activityinHuntingtonrsquos diseaserdquo Journal of Neural Transmission vol 117no 3 pp 325ndash332 2010

[188] A M Oliveira S M Cardoso M Ribeiro R S G R Seixas AM S Silva and A C Rego ldquoProtective effects of 3-alkyl luteolinderivatives are mediated by Nrf2 transcriptional activity anddecreased oxidative stress inHuntingtonrsquos diseasemouse striatalcellsrdquo Neurochemistry International vol 91 pp 1ndash12 2015

[189] B D Shivasharan P Nagakannan B S Thippeswamy V PVeerapur P Bansal and M K Unnikrishnan ldquoProtective effectof Calendula officinalis Linn flowers against 3-nitropropionicacid induced experimental Huntingtonrsquos disease in ratsrdquo Drugand Chemical Toxicology vol 36 no 4 pp 466ndash473 2013

[190] H M Mahdy M G Tadros M R Mohamed A M Karimand A E Khalifa ldquoThe effect of Ginkgo biloba extract on 3-nitropropionic acid-induced neurotoxicity in ratsrdquoNeurochem-istry International vol 59 no 6 pp 770ndash778 2011

[191] I Tasset A J Pontes A J Hinojosa R de la Torre and I TunezldquoOlive oil reduces oxidative damage in a 3-nitropropionicacid-induced huntingtonrsquos disease-like rat modelrdquo NutritionalNeuroscience vol 14 no 3 pp 106ndash111 2011

[192] O Sagredo M R Pazos V Satta J A Ramos R GPertwee and J Fernandez-Ruiz ldquoNeuroprotective effects ofphytocannabinoid-based medicines in experimental models ofHuntingtonrsquos diseaserdquo Journal of Neuroscience Research vol 89no 9 pp 1509ndash1518 2011

[193] Y Gao S-F Chu J-P Li et al ldquoProtopanaxtriol protects against3-nitropropionic acid-induced oxidative stress in a rat model ofHuntingtonrsquos diseaserdquo Acta Pharmacologica Sinica vol 36 no3 pp 311ndash322 2015

[194] I Tunez P Montilla M Del Carmen Munoz M Feijoo andM Salcedo ldquoProtective effect of melatonin on 3-nitropropionicacid-induced oxidative stress in synaptosomes in an animalmodel of Huntingtonrsquos diseaserdquo Journal of Pineal Research vol37 no 4 pp 252ndash256 2004

[195] H I Rocha-Gonzalez M Ambriz-Tututi and V Granados-Soto ldquoResveratrol a natural compound with pharmacologicalpotential in neurodegenerative diseasesrdquoCNSNeuroscience andTherapeutics vol 14 no 3 pp 234ndash247 2008

[196] O A Andreassen R J Ferrante A Dedeoglu and M F BealldquoLipoic acid improves survival in transgenic mouse models ofHuntingtonrsquos diseaserdquo NeuroReport vol 12 no 15 pp 3371ndash3373 2001


[197] D E Ehrnhoefer M Duennwald P Markovic et al ldquoGreentea (-)-epigallocatechin-gallate modulates early events in hunt-ingtin misfolding and reduces toxicity in Huntingtonrsquos diseasemodelsrdquo Human Molecular Genetics vol 15 no 18 pp 2743ndash2751 2006

[198] K M Denny Joseph and Muralidhara ldquoEnhanced neuro-protective effect of fish oil in combination with quercetinagainst 3-nitropropionic acid induced oxidative stress in ratbrainrdquo Progress in Neuro-Psychopharmacology and BiologicalPsychiatry vol 40 no 1 pp 83ndash92 2013

[199] J Fu J Jin R H Cichewicz et al ldquoTrans-(-)-120576-viniferinincreases mitochondrial sirtuin 3 (SIRT3) activates AMP-activated protein kinase (AMPK) and protects cells in modelsof huntington diseaserdquo Journal of Biological Chemistry vol 287no 29 pp 24460ndash24472 2012

[200] N Huang J Lin J Lin et al ldquoA new drug design targeting theadenosinergic system for Huntingtonrsquos diseaserdquo PLoS ONE vol6 no 6 Article ID 20934 2011


[202] P Kumar and A Kumar ldquoPossible neuroprotective effect ofwithania somnifera root extract against 3-Nitropropionic acid-induced behavioral biochemical and mitochondrial dysfunc-tion in an animal model of huntingtonrsquos diseaserdquo Journal ofMedicinal Food vol 12 no 3 pp 591ndash600 2009

[203] G K Shinomol and Muralidhara ldquoProphylactic neuroprotec-tive property of Centella asiatica against 3-nitropropionic acidinduced oxidative stress and mitochondrial dysfunctions inbrain regions of prepubertal micerdquoNeuroToxicology vol 29 no6 pp 948ndash957 2008

[204] M Kaur A Prakash and A N Kalia ldquoNeuroprotective poten-tial of antioxidant potent fractions fromConvolvulus pluricaulisChois in 3-nitropropionic acid challenged ratsrdquo NutritionalNeuroscience vol 19 no 2 pp 70ndash78 2016

[205] B N Al-Sabahi M O Fatope M M Essa et al ldquoPomegranateseed oil effect on 3-nitropropionic acid-induced neurotoxicityin PC12 cells and elucidation of unsaturated fatty acids compo-sitionrdquo Nutritional Neuroscience vol 20 no 1 pp 40ndash48 2017

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Other signs of AD include finding the right words visionspatial issues and impaired reasoning or judgment [6]Worldwide around 16million peoples are affected by AD andover four million Americans are currently affected a figurethat may rise further due to the increase in the life span[7]This age-related progressive neurodegenerative disorderis the fourth leading cause of death in developed nationsand accounts for 70 of dementia in the elderly population[8] It has been suggested the incidence of AD could doubleevery five years beyond the age of 65 [9] Currently availablemedications only treat the symptoms of neurodegenerativediseases

3 Oxidative Stress and Alzheimerrsquos Disease

The etiology of AD is multifactorial Both genetic and envi-ronmental factors are regarded as a risk factor of AD [9 10]Free radicals are chemical species with an unpaired electronand are formed during both physiological and pathologicalprocesses Although reactive oxygen species (ROS) play apivotal role in several cellular and signaling pathways atphysiological concentrations (cell cycle regulation phagocy-tosis and enzyme activation) excessive generation of ROSleads to several harmful effects including DNA lipid andprotein damage [11ndash14] ROS are however scavenged bydefencemechanisms known as enzymatic and nonenzymaticantioxidants An imbalance in this oxidant-antioxidant statuscould determine the extent of cell damage Oxidative damagedue to ROS has been implicated in the pathogenesis ofneurodegenerative diseases cancer diabetes and aging [15]

Mitochondrial dysfunction and enhanced apoptosisaccompanied by a poor antioxidant status are the mecha-nisms for AD pathogenesis Extensive studies pointed outthe role of superoxide anion hydroxyl radical hydrogenperoxide and nitric oxide in the oxidative stress mediatedneurodegeneration in AD [16 17]Microglia activation due toneuronal lesions generates excessive superoxide radicals [18]Higher metabolic demand and the postmitotic nature of glialcells and neurons make them more susceptible to oxidativestress The low rate of brain regeneration and insufficientantioxidant potential in the brain further favors oxidativestress [19] Mitochondrial autophagy serves as a major sourceof ROS production [20]

A120573(1-42) has been recognized as a key factor in the neuro-degeneration inADpatients and itmediates its harmful effectvia inducing oxidative stress in the brain [21ndash23] A positiveassociation has been shown between the amyloid plaque andthe lipid peroxidation markers such as 4-hydroxynonenaland malondialdehyde [24] Elevated lipid peroxidation andinsufficient enzymatic and nonenzymatic antioxidants wereshown in the peripheral tissues of AD patients [25 26] Alarge number of studies have shown an elevated level of lipidperoxidation marker in the brain of AD patients especiallyin the region of the temporal lobe [27ndash29] An increasedlevel of 4-hydroxynonenal the byproduct of oxidative stresshas been reported as well [30 31] Iron-induced oxidativestress as evidenced by iron accumulation in the brain of ADis responsible for neurodegeneration in patients diagnosedwith AD [32] Profound studies explored iron accumulation

in the brain of AD patients and found that as a transitionmetal it is capable of generating hydroxyl radical through theFenton reaction [33 34] 120573-Amyloid could elevate oxidativestress mainly by binding with iron [35] The neuronal deathoccurs due to reactive oxygen species mediated changes inthe neuronal lipid molecules which includes alterations inthe membrane fluidity rigidity permeability and transport[36] It has been noticed that the entorhinal cortex and CAIregion of the hippocampus are the two major susceptiblecerebral regions to oxidative stress [37] Mitochondrial dam-age in AD could lead to excessive generation of ROS andlowered ATP production [38 39] Vitamin E the major lipid-soluble nonenzymatic antioxidant inhibits oxidative damageinduced by A120573(1-42) [40] Diminished levels of reducedglutathione in astrocytes have been reported [41] Melo etal [42] suggested that addition of antioxidants inhibited theactivity of acetylcholine esterase in the neuronal culture Alsosuperoxide dismutase activity was shown to have increasedin the CAI regions of hippocampus and amygdale [43] Thecauses of oxidative stress in AD are given in Figure 1

4 Natural Products and Alzheimerrsquos Disease

Medicinal plants serve as a good source for the treatmentof several illnesses including neurodegenerative diseasesdiabetes mellitus and cancer [44 45] A large number oftherapeutic medicines recommended worldwide for severaldiseases have been identified from medicinal plants Indiantraditional medicine has recommended several medicinalplants for the treatment of neurodegenerative diseases Intraditional medicine several plants have been used to treatthe symptoms of neurodegenerative diseases A large numberof studies scientifically validated the beneficial effects ofnatural products in the treatment of ADusing suitable animalmodels [46 47]

Veerendra Kumar and Gupta [48] explored the neu-roprotective effect of aqueous extract of Centella asiaticain a streptozotocin model of AD in rats They suggestedthat Centella asiatica reduced the oxidative stress as wellDhanasekaran et al [49] pointed out the neuroprotective roleof Centella asiatica in B6C3-Tg(APPswe PSEN1dE9)85 DboJ(PSAPP) mice They concluded that the antioxidant role ofCentella asiaticamodulated the amyloid pathology in PSAPPmice Clementi et al [50] suggested that Aloe arborescensexerted a significant neuroprotective effect in IMR-32 cellsvia reducing the oxidative stress in the cells Gong et al[51] suggested the lotus seed pod Proanthocyanidins was apromising candidate for the treatment of AD as it exhibited asignificant protective effect against cognitive impairment andbrain aging induced by D-galactose Turgut et al [52] pro-posed oxidative stress reduction as amajormechanism for theneuroprotective effect of Capparis spinosa L in D-galactose-induced cognitive impairment Yu et al [53] demonstratedthe neuroprotective role of rutin against amylin-inducedneurocytotoxicity in neuronal cells and concluded that theantioxidant property of rutin might have played a role in theprotection of neuronal cells Mairuae et al [54] showed thein vitro neuroprotective effect of okra in SH-SY5Y cells andsuggested that the antioxidant effect of okra was responsible



Oxidative stress



























Oxidative stress













































11 Conclusion









Competing Interests


References





























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Oxidative stress



























Oxidative stress













































11 Conclusion









Competing Interests


References





























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Oxidative stress













































11 Conclusion









Competing Interests


References





























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































11 Conclusion









Competing Interests


References





























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































11 Conclusion









Competing Interests


References





























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























11 Conclusion









Competing Interests


References





























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Competing Interests


References





























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article The Role of Reactive Oxygen Species in the ...downloads.hindawi.com/journals/omcl/2016/8590578.pdf · Review Article The Role of Reactive Oxygen Species in the Pathogenesis