protective effect of antioxidants on neuronal dysfunction

Review ArticleProtective Effect of Antioxidants on Neuronal Dysfunctionand Plasticity in Huntingtonrsquos Disease

Thirunavukkarasu Velusamy12 Archana S Panneerselvam3

Meera Purushottam4 Muthuswamy Anusuyadevi5 Pramod Kumar Pal6 Sanjeev Jain4

Musthafa Mohamed Essa7 Gilles J Guillemin8 and Mahesh Kandasamy39

1Department of Biotechnology Bharathiar University Coimbatore Tamil Nadu India2DBT Ramalingaswami Re-Entry Fellowship Programme Department of Biotechnology (DBT) New Delhi India3Laboratory of Stem Cells and Neuroregeneration Department of Animal Science School of Life Sciences Bharathidasan UniversityTiruchirappalli Tamil Nadu India4Department of Psychiatry National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore Karnataka India5Molecular Gerontology Laboratory Department of Biochemistry School of Life Sciences Bharathidasan UniversityTiruchirappalli Tamil Nadu India6Department of Neurology National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore Karnataka India7Department of Food Science and Nutrition CAMS Sultan Qaboos University Muscat Oman8Neuroinflammation Group Faculty of Medicine and Health Sciences Macquarie University Sydney NSW Australia9UGC-Faculty Recharge Program (UGC-FRP) University Grant Commission New Delhi India

Correspondence should be addressed to Gilles J Guillemin gillesguilleminmqeduauand Mahesh Kandasamy pkmahesh5gmailcom

Received 29 July 2016 Revised 9 November 2016 Accepted 5 December 2016 Published 12 January 2017

Academic Editor Vladimir Jakovljevic

Copyright copy 2017 Thirunavukkarasu Velusamy et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Huntingtonrsquos disease (HD) is characterised bymovement disorders cognitive impairments andpsychiatric problemsTheabnormalgeneration of reactive oxygen species and the resulting oxidative stress-induced mitochondrial damage in neurons upon CAGmutations in the HTT gene have been hypothesized as the contributing factors of neurodegeneration in HD The potential use ofantioxidants against free radical toxicity has been an emerging field in the management of ageing and many neurodegenerativedisorders Neural stem cells derived adult neurogenesis represents the regenerative capacity of the adult brainThe process of adultneurogenesis has been implicated in the cognitive functions of the brain and is highly modulated positively by different factorsincluding antioxidantsThe supportive role of antioxidants to reduce the severity of HD via promoting the functional neurogenesisand neuroprotection in the pathological adult brain has great promise This review comprehends the recent studies describing thetherapeutic roles of antioxidants in HD and other neurologic disorders and highlights the scope of using antioxidants to promoteadult neurogenesis in HD It also advocates a new line of research to delineate themechanisms by which antioxidants promote adultneurogenesis in HD

1 Introduction

Huntingtonrsquos disease (HD) is an autosomal dominant neu-rodegenerative syndrome associated with abnormal CAGexpansions in the Huntington (HTT) gene [1ndash3] The mutantHTT contains polymorphic CAG repeats in excess of 39in exon 1 of the gene present in the short arm of the

chromosome 4 [3ndash5] The CAG mutations ultimately resultin the abnormal expansion of polyglutamine (polyQ) tractsin the HTT protein which leads to misfolding and lossof protein function [6 7] The polyQ expansion has beenidentified to be the primary inducer of degeneration ofmedium spiny neurons (MSNs) in the striatum and leadsto neurodegeneration to other regions of brain including

HindawiOxidative Medicine and Cellular LongevityVolume 2017 Article ID 3279061 15 pageshttpsdoiorg10115520173279061

2 Oxidative Medicine and Cellular Longevity

the cortex hippocampus hypothalamus and brain stem in aprogressive manner [7ndash9] The epidemiology of HD suggeststhat the disease occurs worldwide but its prevalence variesdepending upon genetic diversity and geographical regions[9 10] The rate of incidence of HD is considerably higher inthe Caucasian population than the Asian population Whilean estimate shows the prevalence and increasing trend ofHD in Western Europe Australia North America and theUnitedKingdom India represents a large number of total HDcases in Asia [11 12] Single nucleotide polymorphism (SNP)at the HTT locus in association with the genetic diversitylifestyle food and environmental factors is presumed to bethe reasons for the variations in the frequency of HD amongthe human population [13] HD has been characterisedby choreiform movements dystonia cognitive deficits andpsychiatric problems [14]These symptoms have been accom-panied by neurodegeneration alongwith an abnormal level ofneurotransmittersmicroglial activation reactive astrogliosisand impaired neurogenesis [15] Recently HD patients havealso been characterised with different types of behaviouralmotor and aggressive symptoms [16 17]

All the abovementioned problems aggravate the develop-ment of HD and contribute to gradual deterioration of thephysical abilities and mental processes Importantly peoplewith HD have problems in taking care of their daily routinesuch as food consumption due to difficulty in swallowing(dysphagia) which may occur during the later stages ofthe disease Further abnormalities in energy metabolismcaused by mitochondrial dysfunctions add to severity ofthe disease The loss of muscle function in the mandibularregions pharynx and oesophagus could lead to disorderslike bruxism (grinding the teeth) failure to intake of foodand choking which could ultimately lead to death [16 18]Currently there are no available treatments that can delaythe onset or arrest the progression of the disease while thefocus of medical care is limited to merely managing theneurological symptoms of HD This is mainly due to lack ofknowledge about the underlying biology of the disease

Of the few therapeutic options available for the treat-ment of HD tetrabenazine has been an approved drug bythe Food and Drug Administration (FDA) for minimisingthe clinical symptoms of involuntary movements [19ndash23]Other treatment strategies for HD include administrationof antipsychotic and antidepressant drugs [21 22] Antipsy-chotic drugs like haloperidol [23] fluphenazine [24] clon-azepam [25] amantadine [26] and levetiracetam [27] mighthelp in controlling panic attacks aggression and choreiformmovements while antidepressants like fluoxetine [28] ser-traline [29 30] nortriptyline [31] and lithium [32] are usedto stabilize depression anxiety associated mood swings andnegative thoughts In addition riluzole is frequently used asa neuroprotective drug to control glutamatergic neurotrans-mission in HD [33 34] Deep brain stimulation (DBS) hasbeen proposed as a technique to manage chorea and othermotor symptoms like dystonia and cognitive deficits in HD[35] Alternatively using recombinant antibody fragmentsto neutralise the HTT aggregates [36] and stem cell trans-plantation [37] have also been tried with limited success Inaddition adapting to the aforementioned treatment strategies

warrants a very careful approach andhighly vigilant individu-als to carry out the procedures as most of these strategies androutes of administration have side effects including nauseafatigue abnormal neuroexcitability and tissue disruption[38] that could exacerbate the severity of HD symptoms[39] Thus developing novel and noninvasive therapeuticstrategies that are efficient but have no orminimal side effectsare important for the successful treatment of HD and willhave a promising therapeutic appeal Meanwhile the benefitsof physical activities an enriched environment with the aidof dietary supplements and palliative care therapies havebeen considered in conjunction with the drug treatment asnoninvasive and relatively affordable management strategiesfor HD

2 Detrimental Roles of Oxidative Stress inHuntingtonrsquos Disease

There have been many hypotheses proposed for the mani-festation of neurodegeneration associated clinical symptomsin HD Among them polyQ expansion associated oxidativestress that leads to caspase mediated neuronal cell death isconsidered as a potential cause of neuropathological changesin HD [9] Free radicals are highly reactive molecules thatfeature unpaired electrons on their valence orbital with theability to render variousmolecular and cellular vulnerabilitiesdue to their unstable reactive nature [40 41] The mostcommon biologically relevant free radicals are superoxide(Ominus) hydroxyl (OHminus) and nitricmonoxide (NO) species andare referred to as reactive oxygen species (ROS) and reactivenitrogen species (RNS) [41 42] Free radicals are provoked incells by enzymatic and nonenzymatic mechanisms throughabnormal metabolic genetic and cell cycle events that occuras a consequence of electromagnetic radiation ageing infec-tions immunological alteration intoxication abnormal dietmalnutrition and deficiency in vitamins and trace elements[43] Besides defects or mutations in the free radicals scav-enging metabolic enzymes such as glutathione peroxidasesnitric oxide synthase peroxiredoxins and superoxide dismu-tases are responsible for the accumulation of free radicals[44 45] The expressions of these detoxifying enzymesare controlled by the Nrf2-ARE complex pathway [46] Ingeneral highly regulated free radicals generated in the bodycan be of potential use in development and maintenanceof the tissues associated with improvement of the longevityof organisms As per the free radical theory of ageing theabnormally fabricated free radicals are harmful to the normalstructure and functioning of cells and tissues [46ndash48] Inorder to combat the negative impact of free radicals cellsdeploy defense mechanisms such as free radical scavengingactivity by antioxidants as a normal physiological process[49] The imbalance between the production of free radicalsand the ability of cells to counteract or detoxify free radicalscan eventually lead to DNA oxidation protein nitrationand lipid peroxidation culminating in cellular oxidativestress [50 51] Prolonged oxidative stress and failure indefense mechanisms could ultimately result in ageing relatedchronic diseases such as atherosclerosis [52] cancer [53]

Oxidative Medicine and Cellular Longevity 3

diabetes [54] rheumatoid arthritis [55] ischemic stroke [56]cardiovascular diseases [57] chronic inflammation [58] andneurodegenerative diseases including Alzheimerrsquos disease(AD) [59] and Parkinsonrsquos disease (PD) [60] in addition toHD [61 62]

The brain is highly susceptible to free radical mediatedoxidative damage which is largely due to its high metabolicrate and oxygen and energy consumption under the protec-tive isolation by the blood brain barrier from the circulation[62] ROS target neuronal cells by promoting formationof DNA-protein cross-linked harmful adducts through oxi-dation of both the backbone and the side chain of theprotein and DNA molecules [62 63] Various indices of freeradical mediated damage have been identified as aetiologiesof several neurodegenerative conditions including HD [61]While a reciprocal relationship exists between the length ofCAG repeats and the phenotype severity of HD recent datagathered from the experiments on theHD specific embryonicstem cells (ESC) and induced pluripotent stem cell (iPSC)models indicate the deleterious effects of oxidative damage onthe expansion of CAG triplets in the HTT gene [64ndash68] ThepolyQ mechanisms that account for the selective neuronalloss in the brain affected by HD are multifaceted in nature[67] Biomarkers for oxidative damage like heme oxygenase3-nitrotyrosine and malondialdehyde (MDA) are found tobe elevated in the striatum cortex and serum of human HDsubjects [69ndash71] The number of polyQ repeats in the HTTprotein is found to be responsible for oxidative damage to thecell membrane DNA and enzymes responsible for the ATPproduction ofmitochondria inHD [70 71] Besides Lim et alreported the disruption of mitochondrial Ca2+ homeostasisby free radicals in the striatal neurons of postmortem humanHD brains [72] Thus free radical induced mitochondrialdamage followed by decreased ATP production providesa strong mechanism for provoking the apoptotic pathwaysin HD brains [73] The interactions between free radicalinduced oxidative stress defects in mitochondrial energymetabolism and excitotoxicity have widely been implicatedin the neuropathogenicity of HD Evidence of the role ofoxidative stress in priming the pathogenesis of HD has beenidentified by higher plasma levels of lipid peroxidation inpresymptomatic HD patients [74ndash76] In addition the mito-chondrial permeability transition pore (mPTP) a nonspecificchannel is highly susceptible to the fluctuation of calciumhomeostasis and oxidative stress which in turn are consid-ered to be major contributors to mitochondrial dysfunctionin HD [77] Store-operated calcium entry (SOCE) a processcaused by lower of Ca2+ from the endoplasmic reticulum(ER) induces the influx of Ca2 from the extracellular spaceThe activity of SOC channels in medium spiny neurons(MSNs) was found to be high in transgenic YAC128 micemodel of HD [78] Recently the PPAR-120574 pathway has beenlinked to the induction of superoxideROS in HD [79] Thissuggests that the oxidative damage induced molecular andcellular changes in the circulation appear to be the initiator ofthe early pathogenic events in HD Taken together oxidativestress plays a crucial role in the neuropathology of HD and

is a potential target for the development of novel therapeuticinterventions for the neuroprotective management of HD

3 Neuroprotective Roles ofAntioxidants against OxidativeStress-Induced Complications inNeurodegenerative Disorders

Free radicals when overproduced need to be biologicallyscavenged or quenched by converting them into metabol-ically nondestructive cellular molecules This protectivemechanism called the antioxidant defense system preventsfree radical mediated damage of cells which lead to var-ious diseases and ageing [49 80ndash82] When endogenousantioxidant defenses are inadequate to scavenge the freeradicals completely diet or drug-derived antioxidants maybe particularly important in protecting against a numberof human diseases [76] Antioxidant defense mechanismsinvolve both enzymatic (superoxide dismutase catalase glu-tathione peroxidase and glutathione reductase) and nonen-zymatic (vitamins A C and E glutathione) strategies Otherantioxidants include albumin bilirubin ferritin ceruloplas-min melatonin uric acid lipoic acid mixed carotenoidscoenzyme Q10 bioflavonoids antioxidant minerals (copperzinc manganese and selenium) and the cofactors (folic acidvitamins B1 B2 B6 and B12) [80 81] Specific quenching ofthe free radicals and chelating redox metals by antioxidantscould possibly influence the gene expression profile of thetissue The toxic metal induced lipid peroxidation and DNAfragmentation can be controlled by metal-binding proteinslike ferritin transferrin ceruloplasmin and others such asmetallothionein [49] Glutathione S transferases are oneof the many enzymatic entities in cells and body fluidsthat reduce the level of ROS [82] Protective effects ofexogenously administered antioxidants have been extensivelystudied using experimental animal models and cell linesand have provided a strong insight into the relationshipbetween free radicals and associated disease complications[83 84] The study carried out by Chanvitayapongs et aldemonstrated the antioxidant property of resveratrol whichwhen combined with vitamin C andor E has a greaterprotective effect by reducing cell death in neurodegenerativediseases including AD [85]The amyloidal beta (A120573) inducedneurotoxicity and the underlying molecular pathologicalmechanisms in AD are found to be inhibited by naturalantioxidants such as Ginkgo biloba flavonoids soybeanisoflavones theanine and nicotine in cellular models as wellas transgenic animal models of AD [86] Long-term dietarysupplementation of pomegranates figs and dates reducedthe inflammatory cytokines during ageing in APPswTg2576transgenic mouse model of AD [87] Essa et al identifiedthat a diet rich in walnut helps to reduce the risk ofdeveloping PD and delay its onset due to the cumulativeantioxidant and mitochondrial protective effects exerted bywalnut constituents [88] The pomegranate oil on 3-nitropropionic acid (3-NP) induced cytotoxicity in rat pheochro-mocytoma (PC-12) neuronal cells enhanced the levels ofenzymatic and nonenzymatic antioxidants by neutralising


ROS or enhancing the expression of the antioxidant genes[89] Rezai-Zadeh et al demonstrated that epigallocatechin-3-gallate (EGCG) the main polyphenolic constituent ofgreen tea through its beta-secretase activity reduced A120573aggregation in neuron-like cells (N2a) transfected with thehuman ldquoSwedishrdquo mutant amyloid precursor protein (APP)and in primary neurons derived from Swedish mutant APP-overexpressing Tg APPSW transgenic micemodel of AD [90]L-Dihydroxyphenylalanine (L-dopa) used in the treatmentof PD produced free radicals during its normal metabolismand this side effect was shown to be reduced by antioxidantsin order to improve the efficacy of L-dopa therapy [91] Aseries of orally bioavailable antioxidants including MitoQMitoVitE and Mito TEMPOL are known to bypass thebiological membranes accumulate withinmitochondria andeffectively protect against mitochondrial oxidative damageand are useful in treating neurodegenerative disease like PD[92]

In relation to the effects of antioxidants onHD pathologya number of biomolecules have been tested and characterisedusing preclinical animal models of HD and cell lines express-ing different length of CAG repeats Among them transgenicmodels of HD R6-lines (R61 and R62) [93 94] knock-in YAC128 mouse model [95] and rats or mouse injectedwith acute and toxic quinolinic acid [96] and 3-NP [97] haveextensively been validated In various paradigms R62 micethat are supplemented with creatine vitamin C coenzymeQ tauroursodeoxycholic acid (TUDCA) docosahexenoicacid (DHA) and eicosapentenoic acid showed increasedlife span and motor performance in association with eitherreduced free radicals or reduced polyQ aggregates in thebrain [98 99] Chronic administration of JM6 an inhibitorof kynurenine-3-monooxygenase extended the life spanprevented synaptic loss and decreased microglial activationin the R62 transgenic mouse and drosophila models ofHD [100 101] A recent study indicated the significance ofanthocyanin-treatment on CAG repeat instability in R61transgenic mouse model of HD [102] Treatment of experi-mental rats with 5-diethoxyphosphoryl-5-methyl-1-pyrrolineN-oxide (DEPMPO) or with N-acetylcysteine (NAC) pro-tects against oxidative damage induced by 3-NP and thereforeacts against HD [103] Besides fumaric acid ester dimethyl-fumarate has been shown to provide neuroprotection andto suppress the dyskinetic movements through the activationof Nrf2 pathway in knock-in YAC-128 and transgenic R62models of HD [104] Van Raamsdonk et al demonstrated theattenuation of striatal neuroprotection by antioxidant effectsof cystamine YAC-128 model [105] Further treatment ofmelatonin significantly ameliorated the increased lipid per-oxidation within the striatum of brain in the 3-NP model ofHD [106] In the same line of evidence treatment of curcuminand carvedilol in 3-NP injected rats reduced the severity ofmotor and cognitive impairments [107 108]The treatment ofresveratrol naringin sertraline protopanaxatriol embelinpuerarin and olive oil was known to protect the experi-mental animal models against 3-NP induced oxidative stressand neurotoxicity [109] Neurodegeneration in the striatumwas prevented by TUDCA a hydrophilic bile acid with

antioxidant properties which ameliorated the locomotor andcognitive deficits in a 3-NP injected rat model of HD [110]Lycopene a carotenoid pigment and phytochemical naturallyfound in fruits and vegetables has the ability to reduce oxida-tive stress markers and improved behaviour in a 3-NP modelof HD [111] Low levels of cystathionine-c-lyase required forproduction of cysteine have been reported in HD pathologywhich is mainly responsible for glutamate excitotoxicityN-Acetylcysteine (NAC) an antioxidant supplement richin cysteine normalised the glutamate level mitochondrialdysfunction and oxidative stress when administered to R61model [112]

The ameliorative effects of s-allylcysteine copper cur-cumin safranal ksheerabala quercetin and tert-butylhydro-quinone against neurotoxicity have been described in quino-linic acid (QA) induced rat model of HD [113] Antioxi-dant selenium an essential element required by glutathioneperoxidase has been reported to reduce the lipid perox-idation within the striatum of QA rat model in a dosedependent manner [114] Metal-containing catalytic antiox-idant metalloporphyrins have emerged as a novel class ofpotential therapeutic agents that quench ROS in an effectivemanner The dietary supplementation of lipoic acid hassupported the longevity and delaying the weight loss in boththe R62 and N171-82Q transgenic lines [115] In additionadministration of L-carnitine dramatically extended the sur-vival ameliorated the motor performance and decreasedthe number of intranuclear polyQ aggregates in the N171-82Q mice [116] Another potent antioxidant 120572-tocopherol(vitamin E) along with idebenone attenuated glutamate-induced neuronal death in HD cell lines like N18-RE-105[117] CDDO-MA (2-cyano-N-methyl-312-dioxooleana-19(11)-dien-28 amide) treatment significantly attenuated 3-NP-induced loss of striatal neuronal nuclear antigen (NeuN)positive neurons [118] Grape seed phenolic extract (GSPE)is a good metal chelator that inhibited polyQ aggregationand reduced the carbonyl levels in PC-12 cells expressing103 glutamines fused with anEGFP reporter (HTT103Q-EGFP) [119] However the adverse effects of prolonged intakeof antioxidants and their overdosages cannot be entirelyexcluded Taken together further investigation needs to becarried out to understand the mechanism and molecularpathways behind the above-discussed biological effects ofantioxidants

Recently the benefits of flavonoid-rich dietary supple-ments have clearly been recognized in improving cognitionby protecting degenerating neurons by enhancing existingneuronal function or by stimulating neuronal regeneration[120] While neuroprotective natures of antioxidants againstfree radical damage have been extensively characterisedthe neuroregenerative potential of antioxidants has recentlyevolved due to the neural plastic roles of adult stem cellsof the brain As a result a number of naturally occurringdietary antioxidants have been identified with propertiesthat support neurogenesis The role of antioxidants hasalso been implicated in the functional outcomes in ageingand neurodegenerative disorders and their protective roleis clearly linked to such outcomes in the abovementionedstudies


In addition the neuroprotective effects of various naturalsynthetic and endogenous cannabinoids have been demon-strated in several in vitro and in vivo neurotoxicity models[121] Peroxynitrite is involved in METH-induced dopamin-ergic neurotoxicity and the neurons can be protected againstMETH-induced neurotoxicity and striatal dopamine deple-tion by use of selective antioxidants NOS inhibitors and per-oxynitrite decomposition catalysts [122] Supplementation ofselenium and antioxidants protect against METH-induceddopaminergic toxicity and the generation of OONOminus in PC-12 cell line and in mouse striatum [122] Ascorbate is presentas one among the few antioxidants in extracellular fluid andis homeostatically regulated but modulated by glutamate-mediated activity [123] Colle et al demonstrated that met-allothioneins and metallothionein-like proteins which areisolated from mouse brain act as neuroprotective agents byreducing oxidative stress Probucol (PB) a phenolic lipid-lowering agent possesses antioxidant property of scavengingfree radicals and acts as aNMDA receptor antagonist therebypromoting neuroprotection [124] However none of theabovementioned studies could suggest effective treatmentstrategies that could completely reverse the disease pathologyEffective management of degenerative diseases cannot beachieved by strategies that focus only on neuroprotectionwhereas neuroregeneration through stem cell mediated adultneurogenesis needs to be promoted in order to compensatefor the functional deficits that occur due to neuronal loss

4 Functional Significance and Regulation ofAdult Neurogenesis

The adult brain retains the capacity to generate new neuronsby the process called neurogenesis in specific regions ofthe organ [125ndash128] The actively occurring neurogenesis isrestricted to three defined neurogenic regions in the adultbrain under normal conditions namely (1) the subgranularzone (SGZ) in the dentate gyrus (DG) of the hippocampus[126 127] (2) the subventricular zone (SVZ) of the lateralventricles [129] and (3) third ventricles of the hypothalamus[130] In the hippocampal SGZ proliferating NSCs developinto intermediate progenitors which generate neuroblastsor immature neurons These newly generated immatureneurons migrate into the inner granule cell layer (GCL) anddifferentiate into new granule neurons of the hippocampus[128] Further these newborn neurons extend dendrites fromDG towards the molecular layer (ML) and project axonsthat form the mossy fibber tract in the hilus region In theSVZ proliferating radial glia-like cells give rise to transientamplifying cells that generate migrating neuroblasts [128131] Through the rostral migratory system (RMS) neurob-lasts migrate towards the olfactory bulb (OB) [131] In theOB immature neurons differentiate into different subtypes ofinterneurons in granule cell layer (GCL) and glomerular layer(GLOM) Neural progenitor cells identified in the ependymallayer of the third ventricle of the adult brain migrate anddifferentiate into mature neurons in the hypothalamus [130](Figure 1)

The potential roles of adult neurogenesis in variousneurophysiological processes like motor functions learn-ing and memory process olfaction and the regulation ofhypothalamus-pituitary-adrenal (HPA) axis have been exten-sively characterised [130 132] Adult neurogenesis has beenknown to be an integral component in neural plasticitybrain homeostasis maintenance and tissue remodelling[130] Adult neurogenesis is a multistep process that includesstem cell proliferation cell cycle exit and fate determina-tion of adult neural progenitors followed by differentiationmaturation and integration of mature neurons into theneural circuits [130 133] This process has been shown to bemodulated by many positive and negative factors [128 130ndash134]

The ageing process exposure to prolonged stress abnor-mal levels of glucocorticoids radiation prolonged drugabuse and chronic neuroinflammation are known to nega-tively influence adult hippocampal neurogenesis by inhibit-ing the proliferation and differentiation of NSCs or promot-ing the cell death of newborn granule cells [130 135 136]Thiscould lead to cognitive decline and loss of control of the HPAaxis and may render the susceptibilities to neuropsychiatricand neurodegenerative disorders leading to cognitive impair-ments [137 138] Moreover many of neuropsychiatric andneurodegenerative disorders are characterised with impairedadult neurogenesis It has been shown that neurogenesis isimpaired in the hippocampus of transgenic R6 mouse lines[139ndash141] transgenic rat model of HD [142] and knock-inYAC128 model [143] However in chemically induced acuteneurodegenerative models and HD patients neurogenesisis increased in the SEL and SVZ respectively [144 145]The increased neurogenesis in the SVZ in combination withabnormal migration of neuroblasts in the striatum is alsoobserved in a toxic ratmodel ofHD [145]Thus the abnormalreactive neurogenesis in the striatum has been observedas a common hallmark in HD [146] Acute neurologicalconditions like stroke epilepsy and traumatic brain injurieshave also been associated with increased adult neurogenesis[147 148] In HD the reactive neurogenesis in striatum hasbeen speculated to be an attempt of stem cell mediatedregeneration to overcome neuronal dysfunctions and neu-ronal loss Thus the endogenous self-regenerative measuresadapted by HD brain through neurogenesis to overcomeneurodegeneration highlight the possibility of exploitingpromotion of antioxidant-mediated neural regeneration as amanagement strategy for HD

The positive regulators of neurogenesis comprise physi-cal activity environmental enrichment growth factors andantioxidants derived from diet It is evident that physicalactivity such as running promotes neurogenesis by increasingthe proliferation of NSCs in the SGZ of the dentate gyrusthereby expanding the pool of progenitor cells available forfurther neuronal differentiation in the hippocampus [149]Spontaneous physical activity and task-based learning are thetwo important components of an enriched environment thatpromotes hippocampal neurogenesis [150] Neurotrophicfactors cytokines and growth factors regulate the adultneurogenesis by controlling proliferation maturation differ-entiation and survival of neuronal cells Systemic infusion of


NSC

NSC

Oligodendrocyte

Microglia

Astrocyte

Neuron

Neuroblasts

Bloo

d ve

ssel Self-

renew

al

(a)

NSC

NSC

Oligodendrocyte

Microglia

AstrocyteNeuron

Neuroblasts

Exogenous antioxidants

Proliferation

Diff

eren

tiatio

n

Neu

ropr

otec

tion

Bloo

d ve

ssel

Self-

renew

al

+

+

+

(b)

Reactive microgliosis

Astrogliosis

Reactive neuroblastosisNSC

Induced stem cellquiescence

Oligodendrocyte

Demyelination

Neurodegeneration

Impaired differentiation


Bloo

d ve

ssel

(c)

Figure 1 Illustration of neurogenic niche of the adult brain in various conditions (a) In normal brain (b) under antioxidant supplement (c)neuropathology and neurogenesis in HD

insulin growth factor-1 (IGF-I) increased the proliferation ofNSCs frequency of neuronal differentiation and survival inthe adult rat hippocampus [151] Jin et al demonstrated thatthe angiogenic protein vascular endothelial growth factor(VEGF) stimulates the proliferation of NSCs in murine cere-bral cortical cultures and in adult rat brains thus promotingneurogenesis apart from angiogenesis [152] Intracerebroven-tricular infusion of epidermal growth factor-1 (EGF-1) andfibroblast growth factor-2 (FGF-2) increased proliferationof NSCs in the SVZ of the adult rat brain [153] Ciliaryneurotrophic factor (CNTF) supported adult neurogenesis asCNTF knockout mice showed reduced neurogenesis [154]

Cotman and Berchtold reported that voluntary exerciseincreased the levels of brain-derived neurotrophic factor(BDNF) and other growth factors which in turn stimulatedneurogenesis [155] Nonsteroidal anti-inflammatory drugs(NSAIDs) are recognized to increase adult neurogenesis andthus aid in the process of neuroprotection [156] Chronictreatment with various antidepressants like tranylcyprominereboxetine fluoxetine and haloperidol is reported to increaseneurogenesis in early adulthood and experimental models ofstress [157] It has been reported that neuronal differentiationand survival are associated with TGF-beta signaling and

thus TGF-beta signaling remains as a crucial regulator ofadult neurogenesis [15 142 158] Moreover it has also beenreported that adult neurogenesis is positively regulated bydiet and it could prevent cognitive decline during ageingas well as to counteract the effect of stress and depression[159] It was shown recently that a reduction in calorie intakeincreases hippocampal neurogenesis in adult rodents andthat this effect is partly mediated by BDNF [160] Takentogether the decline in brain plasticity and mental processcan possibly be reestablished by the activation of NSCs thathave the ability to self-renew anddevelop into neurons or glialcells As no specific treatments are available as a cure to HDneuronal stem cell (NSC) mediated neurogenesis provides aregenerative strategy to replace the neuronal loss and neuralplasticity including motor impairments cognitive functionsand mood that are affected in HD

5 Role of Oxidative Stress on the Regulationof Adult Neurogenesis

The functional impairments of NSC particularly neurogene-sis represent an increasingly prominent contributor tomulti-ple CNS diseases and the process is highly altered by elevated


levels of oxidative stress Oxidative stress caused by increasedROS has been considered to affect neurogenesis and cognitivefunctions [161] Acute exposure of NSCs to ketamine leadsto increased cell proliferation whereas the chronic incubationresults in cellular damage via altered mitochondria pathwaysand induces cellular apoptosis [162] Superoxide dismutases(SODs) scavenge the superoxide radicals by converting themto hydrogen peroxide and oxygen molecule thus acting asfirst-line defense to protect cells [163] The SOD deficientmouse model showed reduction in the generation of newneurons in the hippocampus upon cranial irradiation [164]Cranial irradiation an effective treatment for brain tumorsleads to persistent elevation of oxidative stress and suppres-sion of hippocampal neurogenesis [165] Increased oxidativestress following irradiation is expected to play a major rolein the suppression of hippocampal neurogenesis and theassociated cognitive deficits Walton et al suggested that theproduction of ROS is a part of the routine maintenance ofphysiological neurogenesis but chronic oxidative stress mayplay a role in loss of function in ageing and progressiveCNS diseases [165] Accelerated age-dependent decline inadult neurogenesis is a consequence of oxidative stressConditional deletion of the clock gene Bmal1 (Bmal1minusminus) inmice accelerated ageing neurodegeneration and cognitivedeficits through oxidative damage [166] Moreover oxidativestress promotes aneuploidy and formation of neurofibrillarytangles in the neurogenic regions of the brain contributingto neurodegeneration in AD Sirtuin protein family members(eg Sirt1 Sirt2) are considered to be important in determin-ing the redox state in NSCs and also provide potential targetsfor modulating adult neurogenesis [167] Taken togetherincreased levels of oxidative stress by high accumulation ofROS have negative effect on adult neurogenesis during age-ing neuroinflammation and neurodegeneration [168]Thustargeting oxidative stress represent a novel way to regulateadult neurogenesis This in turn will help in decreasing thepathogenesis of neurocognitive disorders including HD bypromoting neurogenesis in order to compensate the neuronalloss which could pave a path for supporting the cognitivefunctions (Figure 2)

6 Supportive Role of Antioxidants inPromoting and Regulating Adult BrainNeurogenesis

The cognitive health of an organism is maintained bythe capacity of hippocampal neurogenesis Recently ben-efits of antioxidants have emerged as a potent strategy tosupport the cognitive function through the regulation ofadult neurogenesis Consumption of potent antioxidants forexample melatonin and polyunsaturated fatty acids has asignificant effect in lowering the decline of neurogenesis andattenuating the impairment of cognitive function [169ndash171]Impairment of hippocampal neurogenesis in rat models ofchronic alcoholism by elevation of oxidative stress can bereversed by treating with ebselen a drug with antioxidantproperty [152] Curcumin has been shown to increase adultneurogenesis in the hippocampus of adult rodents An

antioxidant-fortified food in an enrichment plan affectedthe survival of new neurons in the aged canine brain andis associated with improvement in cognitive performance[170] Administration of flavonoids like 31015840-methylated epi-catechin and 41015840-methylated epicatechin to animal modelsimproved cognitive performance by promoting neurogenesis[171] Qu et al demonstrated that Rhodiola crenulata extract(RCE) containing a potent antioxidant salidroside promotesneurogenesis in the hippocampus of intracerebroventricularinjected streptozotocin model of AD [172] Polyphenols areabundant micronutrients present in plant-derived foodsfruits and beverages such as tea red wine cocoa andcoffee and also act as powerful antioxidants [173] In ratspolyphenols increased hippocampal plasticity and improvedlearning andmemory performance while protecting neuronsagainst injury induced by neurotoxins suppress neuroinflam-mation and the potential to promote cognitive function Ingeneral dietary polyphenols seem to exert positive effects onanxiety and depression via regulation of adult hippocampalneurogenesis [174] Flavonoids protect the brain in manyways through enhancement of existing neuronal functionor by stimulating neuronal regeneration [175] Polyphenol-rich Ginkgo biloba extracts and other flavanoids have beenshown to protect hippocampal neurons from oxidative stressnitric oxide and beta-amyloid-induced neurotoxicity [176]An et al reported that the supplementation of flavanoids(XBXT-2) in rats subjected to chronic stress shows increasedneurogenesis and increase in BDNF levels [177] Differentpolyphenols are shown to exert their effects on adult hip-pocampal neurogenesis via different mechanisms of actionsuch as by activating the MAP kinase pathway or stimulatingthe expression and release of neurotrophic factors [178]Cocoa powder and chocolate contain a large percentage offlavonoids mainly epicatechin that interacts through sig-naling cascade proteins and lipid kinases thereby inhibitingneuronal death by apoptosis induced by oxygen radicals andpromoting neuronal survival and synaptic plasticity [179]In addition flavonoids preserve cognitive abilities in ratsduring ageing and lower the risk of AD stress and stroke inhumans [179] Thus neurogenic properties of antioxidantshave great significance in therapeutic interventions for braindiseases However reports on the effect of antioxidants inregulating adult neurogenesis in HD are limited While R62R61 YAC128 mice and TgHD rats have been characterisedwith induced NSCs quiescence and impaired neurogenesisthe elevated level of neuroinflammation related factors likeTGF-beta appears to inhibit the regenerative ability of theHDbrain [15] Free radicals involved oxidative damage observedin HDmight also act synergistically with neuroinflammationto impede the proneurogenic signals in HD Indeed combi-nations of antioxidant therapy along with physical exercisemay exert beneficial effect to promote neuroregeneration inHD

HD is accompanied by both cognitive and motor defectwhich is caused by progressive loss of striatal neuronsIncreased neuronal cell death has also been described in thecortex and the hippocampus of HD brains in addition to thestriatum [9] Recently adult neurogenesis has been identifiedin regions other than hippocampus and SVZ-OB such as


Neuroprotection

TranscriptionBDNFCREB

Synaptogenesis

Intactubiquitin proteasome

system

WTHTT

Neurogenesis

Development

Vesiclestransport

Antioxidants

Mitochondria

Free radicals

Equilibrium

(a)

Neurodegeneration

MutantHTT

Oxidative damage

Antioxidants

Free radicals

Imbalance

Lipid

ER stress

Impairedautophagy

Excitotoxicity

Transcriptionaldysregulation

Induced apoptoticpathways

Impaired ubiquitinproteasome system

Axonaldysregulation

Abnormal level ofneurotransmitters

Mitochondrialdysfunctions

peroxidation

(b)

Neurodegeneration

Antioxidants

Free radicals


Tetrabenazine

HaloperidolChlorpromazine RisperidoneQuetiapineAmantadineLevetiracetamClonazepam

Antipsychotics Mood-stabilizersLithiumValproateCarbamazepineLamotrigine

AntidepressantsCitalopram FluoxetineSertraline

Physical therapyOccupational therapy

Speech therapy

RxRx

Imbalance

+

minus

MutantHTT

Oxidative damage

Lipid

ER stress

Impairedautophagy

Excitotoxicity




Axonaldysregulation



peroxidation

(c)

Figure 2 Graphical representation for the possible roles of free radicals and antioxidants on neuronal functions in control andHDconditions(a) A balance is maintained between the amount of free radicals generated and the antioxidant defense mechanism which aid in normalphysiological functions of the neuron in normal brain (b) In HD brain the free radicals generated are higher and the antioxidant defensemechanism is impaired resulting in oxidative damage (c) Various therapeutic options to overcome the disruption caused by oxidative stresson cellular functions of neuron in HD

amygdala and hypothalamus which are responsible for fearmemory and the regulation of neuroendocrine functionsrespectively [180 181] Interestingly it has also been reportedthat neurogenesis occurs in the cortex of the adult monkey[181 182] and normal rat [183] suggesting that neurogenesisof adult brain is widespread Induction of adult neurogenesisin response to many CNS trauma and neurological diseaseshas been reported by several studies in the past decade [184185] It has been demonstrated that ischemia is a well-knownfactor to contribute to reactive neurogenesis in the cortex[147 148 186 187] The abnormal cortical neurogenesis hasalso been reported in multiple sclerosis [188] and ALS [189]Considering these facts it can be speculated that regenerationof damaged brain through cortical neurogenesis can occur

in the brains of HD subjects However reports on adultcortical neurogenesis remains a subject of ongoing debate[190] Hence these findings need to be reconfirmed and vali-dated with better experimental models Future studies shouldfocus on confirming the occurrence of neurogenesis in thecortex of damaged adult brains since cortical neurogenesisis important for compensating the loss of motor functions inHD cases

While a new line of research focusing on cortical neuro-genesis is necessary to implicate its role in brain regenerationreactive neurogenesis in the striatum of both normal andpathogenic adult brain including HD subjects has recentlybeen well established [143 145 191] As the striatum plays animportant role in the planning andmodulation ofmovement


it raises a question whether striatal neurogenesis is requiredfor compensating loss of motor tasks in HD Abnormal cellproliferation and reactive neuroblastosis in the striatum havebeen observed in several cases of HD brains [146] as amechanism to replenish the loss of neurons in the striatumHowever in many such cases the migrating and residentneuroblasts undergo apoptosis before maturing into neuronsin the striatum Hence survival of neurons does not occur inthe striatum of HD [143 191 192] As a part of compensatorymechanism against QA striatal lesion-induced neuronal lossthe brain promotes neurogenesis in the SVZ fromwhere neu-roblasts migrate to the damaged areas of the striatum [144]Ernst and Frisen demonstrated the presence of neuroblasts inthe striatum of the human brain using doublecortin (DCX)and polysialylated neuronal cell adhesion molecule (PSA-NCAM) immunostainings and confirmed the occurrence ofneurogenesis in the striatum [191 192] However they didnot observe the survival of newborn neurons in the normalstriatum as well as in HD cases confirming the prematuredepletion of neuroblasts before their integration into thestriatal tissue The failure of neuronal differentiation in thestriatum and reactive striatal neuroblastosis has been reca-pitulated in the rodent models of HD [143 144 146] Takentogether it can be hypothesized that the migrating SVZ bornneuroblasts andor neuroblasts generated by the striatummight provide the neurophysiological support to the striatumto overcome the motor deficits to certain extent In thisrespect it will be very interesting to see if antioxidants cancontribute to the terminal differentiation integration andsurvival of reactive neuroblasts in the degenerated striatumofHD It is possible that antioxidants may provide substratumand trophic support in addition to mitigating ROS generatedby striatal gliosis and neurodegeneration in HD

7 Conclusion

HD is a progressive neurodegenerative disease that has beenrefractory to treatment Despite the enormous research focuson HD no valid treatment that can alleviate the symptomsof HD has been developed This could be attributed tothe complex nature of the disease and lack of evidenceon a precise molecular target for therapeutic interventionGeneration of free radicals leading to oxidative stress (OS)damage contributes to neuronal loss in HD and the oxida-tive stress could be reduced by supplementation of naturalantioxidants Adult neurogenesis can act as an important toolfor regenerative therapy of HD brains as it contributes tothe cognitive functions of the adult brain Neurogenesis hasbeen shown to be upregulated by numerous antioxidantsImpaired hippocampal neurogenesis and reactive striatalneurogenesis have been the characteristics of HD brainsNaturally occurring antioxidants might therefore provideneurotropic as wells as proneurogenic and neuroprotectivesupport for theHDbrain in order to overcome themotor andcognitive impairments However the complete relationshipbetween oxidative stress and neuroregeneration and themolecular mechanism by which antioxidants support the

process of adult neurogenesis by triggering various signalingcascades needs further diligent investigation

Abbreviations

HD Huntingtonrsquos diseaseCAG Cytosine-Adenine-GuaninePolyQ PolyglutamineROS Reactive oxygen speciesRNS Reactive nitrogen speciesMSN Medium spiny neuronsDG Dentate gyrusSGZ Subgranular zoneSVZ Subventricular zoneOB Olfactory bulbSNP Single nucleotide polymorphismFDA Food and Drug AdministrationNrf2 Nuclear factor (erythroid-derived 2)-like 2AD Alzheimerrsquos diseasePD Parkinsonrsquos diseaseESC Embryonic stem cellsIPSC Induced pluripotent stem cellsMDA MalondialdehydeHO Heme oxygenaseATP Adenosine triphosphateMTA Mitochondria-targeted antioxidantmHTT Mutant huntingtin proteinDHA Docosahexenoic acidTUDCA Tauroursodeoxycholic acidNSC Neuronal stem cellGCL Granule cell layerRMS Rostral migratory systemGLOM Glomerular layerHPA Hypothalamus-pituitary-adrenalIGF-I Insulin growth factor-1VEGF Vascular endothelial growth factorEGF-1 Epidermal growth factor-1FGF-2 Fibroblast growth factor-2CNTF Ciliary neurotrophic factorBDNF Brain-derived neurotrophic factorNSAIDs Nonsteroidal anti-inflammatory drugsCNS Central nervous systemSODs Superoxide dismutasesRCE Rhodiola crenulata extractAPP Amyloid precursor proteinA120573 Amyloid beta

Competing Interests

The authors have declared that no competing interests exist

Acknowledgments

The work was supported by the Faculty Recharge Pro-gramme University Grants Commission (UGC-FRP) NewDelhi India (Mahesh Kandasamy) Ramalingaswami Re-Entry Fellowship Programme Department of BiotechnologyNew Delhi India (Thirunavukkarasu Velusamy) and anInternal Grant (IGAGRFOOD1401) from CAMS SQU


Oman (MusthafaMohamed Essa)This work was profession-ally edited by Red Fern Communication The authors alsoacknowledge theUGC-SAP andDST-FIST for the infrastruc-ture of the Department of Animal Science BharathidasanUniversity

References

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[2] E Bonilla ldquoHuntington disease A reviewrdquo InvestigacionClinicavol 41 no 2 pp 117ndash141 2000

[3] The Huntingtonrsquos Disease Collaborative Research Group ldquoAnovel gene containing a trinucleotide repeat that is expandedand unstable on Huntingtonrsquos disease chromosomesrdquo Cell vol72 no 6 pp 971ndash983 1993

[4] ACMGASHG Statement ldquoLaboratory guidelines for Hunting-ton disease genetic testingrdquo The American Journal of HumanGenetics vol 62 no 5 pp 1243ndash1247 1998

[5] J F Gusella KGibbonsWHobbs et al ldquoTheG8 locus linked toHuntingtonrsquos diseaserdquoTheAmerican Journal ofHumanGeneticsvol 36 p 139S 1984

[6] T Gidalevitz A Ben-Zvi K H Ho H R Brignull and R IMorimoto ldquoProgressive disruption of cellular protein folding inmodels of polyglutamine diseasesrdquo Science vol 311 no 5766 pp1471ndash1474 2006

[7] M DiFiglia E Sapp K O Chase et al ldquoAggregation ofhuntingtin in neuronal intranuclear inclusions and dystrophicneurites in brainrdquo Science vol 277 no 5334 pp 1990ndash1993 1997

[8] J S Paulsen V A Magnotta A E Mikos et al ldquoBrain structurein preclinical Huntingtonrsquos diseaserdquo Biological Psychiatry vol59 no 1 pp 57ndash63 2006

[9] F O Walker ldquoHuntingtonrsquos diseaserdquo The Lancet vol 369 no9557 pp 218ndash228 2007

[10] S C Warby H Visscher J A Collins et al ldquoHTT haplotypescontribute to differences in Huntington disease prevalencebetween Europe and East Asiardquo European Journal of HumanGenetics vol 19 no 5 pp 561ndash566 2011

[11] M D Rawlins N SWexler A RWexler et al ldquoThe prevalenceof Huntingtonrsquos diseaserdquo Neuroepidemiology vol 46 no 2 pp144ndash153 2016

[12] N S Moily L N Kota R M Anjanappa et al ldquoTrinucleotiderepeats and haplotypes at the huntingtin locus in an Indiansample overlaps with European haplogroup Ardquo PLoS CurrentsHuntington Disease vol 6 2014

[13] W Liu L A Kennington H D Rosas et al ldquoLinking SNPsto CAG repeat length in Huntingtonrsquos disease patientsrdquo NatureMethods vol 5 no 11 pp 951ndash953 2008

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[19] O R Adam and J Jankovic ldquoSymptomatic treatment of Hunt-ington diseaserdquo Neurotherapeutics vol 5 no 2 pp 181ndash1972008

[20] J U Toglia M McGlamery and R R Sambandham ldquoTetra-benazine in the treatment of Huntingtonrsquos chorea and otherhyperkinetic movement disordersrdquo The Journal of ClinicalPsychiatry vol 39 no 1 pp 81ndash87 1978

[21] D Paleacu ldquoTetrabenazine in the treatment of Huntingtonrsquosdiseaserdquo Neuropsychiatric Disease and Treatment vol 3 no 5pp 545ndash551 2007

[22] E C Lauterbach ldquoNeuroprotective effects of psychotropicdrugs in Huntingtonrsquos diseaserdquo International Journal of Molec-ular Sciences vol 14 no 11 pp 22558ndash22603 2013

[23] S Gimenez-Roldan and D Mateo ldquoHuntington disease tetra-benazine compared to haloperidol in the reduction of involun-tary movementsrdquo Neurologia vol 4 pp 282ndash287 1989

[24] C Korenyi and J R Whittier ldquoDrug treatment in 117 casesof Huntingtonrsquos disease with special reference to fluphenazine(prolixin)rdquoThe Psychiatric Quarterly vol 41 no 2 pp 203ndash2101967

[25] J B Peiris H Boralessa and N D Lionel ldquoClonazepam inthe treatment of choreiform activityrdquo The Medical Journal ofAustralia vol 1 no 8 pp 225ndash227 1976

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[31] H Wang Y Guan X Wang et al ldquoNortriptyline delays diseaseonset in models of chronic neurodegenerationrdquo EuropeanJournal of Neuroscience vol 26 no 3 pp 633ndash641 2007

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[34] G B Landwehrmeyer B Dubois J G De Yebenes et al ldquoRilu-zole in Huntingtonrsquos disease a 3-year randomized controlledstudyrdquo Annals of Neurology vol 62 no 3 pp 262ndash272 2007

[35] C Beste M Muckschel S Elben et al ldquoBehavioral and neuro-physiological evidence for the enhancement of cognitive controlunder dorsal pallidal deep brain stimulation in Huntingtonrsquosdiseaserdquo Brain Structure and Function vol 220 no 4 pp 2441ndash2448 2015


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[38] W C Koller and J Trimble ldquoThe gait abnormality of Hunting-tonrsquos diseaserdquo Neurology vol 35 no 10 pp 1450ndash1454 1985

[39] G O Abdulrahman Jr ldquoTherapeutic advances in the man-agement of Huntingtonrsquos diseaserdquo Yale Journal of Biology andMedicine vol 84 no 3 pp 311ndash319 2011

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

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[42] J Emerit M Edeas and F Bricaire ldquoNeurodegenerative dis-eases and oxidative stressrdquo Biomedicine and Pharmacotherapyvol 58 no 1 pp 39ndash46 2004

[43] T Finkel and N J Holbrook ldquoOxidants oxidative stress and thebiology of ageingrdquoNature vol 408 no 6809 pp 239ndash247 2000

[44] H Herken E Uz H Ozyurt S Sogut O Virit and OAkyol ldquoEvidence that the activities of erythrocyte free radicalscavenging enzymes and the products of lipid peroxidationare increased in different forms of schizophreniardquo MolecularPsychiatry vol 6 no 1 pp 66ndash73 2001

[45] J S Beckman and W H Koppenol ldquoNitric oxide superoxideand peroxynitrite the good the bad and uglyrdquo AmericanJournal of PhysiologymdashCell Physiology vol 271 no 5 pp C1424ndashC1437 1996

[46] A R Element ldquoAn important role of Nrf2-ARE pathwayin the cellular defense mechanismrdquo International Journal ofBiochemistry and Molecular Biology vol 37 no 2 pp 139ndash1432004

[47] D Harman ldquoFree radical theory of agingrdquo MutationResearchDNAging vol 275 no 3-6 pp 257ndash266 1992

[48] D Harman ldquoFree radical theory of aging effect of free radicalreaction inhibitors on the mortality rate of male LAF1 micerdquoJournals of Gerontology vol 23 no 4 pp 476ndash482 1968

[49] B Halliwell ldquoAntioxidants in human health and diseaserdquoAnnual Review of Nutrition vol 16 no 1 pp 33ndash50 1996

[50] H SiesOxidative Stress Introductory Remarks Oxidative Stress1985

[51] H Sies ldquoOxidative stress oxidants and antioxidantsrdquo Experi-mental Physiology vol 82 no 2 pp 291ndash295 1997

[52] D Harrison K K Griendling U Landmesser B Hornig andH Drexler ldquoRole of oxidative stress in atherosclerosisrdquo TheAmerican Journal of Cardiology vol 91 no 3 pp 7ndash11 2003

[53] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006

[54] J W Baynes ldquoRole of oxidative stress in development ofcomplications in diabetesrdquoDiabetes vol 40 no 4 pp 405ndash4121991

[55] P I Mapp M C Grootveld and D R Blake ldquoHypoxia oxida-tive stress and rheumatoid arthritisrdquo British Medical Bulletinvol 51 no 2 pp 419ndash436 1995

[56] S Love ldquoOxidative stress in brain ischemiardquo Brain Pathologyvol 9 no 1 pp 119ndash131 1999

[57] R J Hoeschen ldquoOxidative stress and cardiovascular diseaserdquoTheCanadian Journal of Cardiology vol 13 no 11 pp 1021ndash10251997

[58] N Khansari Y Shakiba and M Mahmoudi ldquoChronic inflam-mation and oxidative stress as a major cause of age-relateddiseases and cancerrdquo Recent Patents on Inflammation andAllergy Drug Discovery vol 3 no 1 pp 73ndash80 2009

[59] W R Markesbery ldquoOxidative stress hypothesis in Alzheimerrsquosdiseaserdquo Free Radical Biology and Medicine vol 23 no 1 pp134ndash147 1997

[60] P Jenner ldquoOxidative stress in Parkinsonrsquos diseaserdquo Annals ofNeurology vol 53 supplement 3 pp S26ndashS38 2003

[61] S E Browne R J Ferrante and M F Beal ldquoOxidative stress inHuntingtonrsquos diseaserdquo Brain Pathology vol 9 no 1 pp 147ndash1631999

[62] B Uttara A V Singh P Zamboni and R T Mahajan ldquoOxi-dative stress and neurodegenerative diseases a review ofupstream and downstream antioxidant therapeutic optionsrdquoCurrent Neuropharmacology vol 7 no 1 pp 65ndash74 2009

[63] R A Floyd and J M Carney ldquoFree radical damage to proteinand DNA mechanisms involved and relevant observations onbrain undergoing oxidative stressrdquo Annals of Neurology vol 32no 1 pp S22ndashS27 1992

[64] S Gandhi andA Y Abramov ldquoMechanism of oxidative stress inneurodegenerationrdquo Oxidative medicine and cellular longevityvol 2012 Article ID 428010 11 pages 2012

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[66] D M Cummings Y Alaghband M A Hickey et al ldquoA criticalwindow of CAG repeat-length correlates with phenotype sever-ity in the r62 mouse model of Huntingtonrsquos diseaserdquo Journal ofNeurophysiology vol 107 no 2 pp 677ndash691 2012

[67] I Jonson R Ougland A Klungland and E Larsen ldquoOxidativestress causes DNA triplet expansion in Huntingtonrsquos diseasemouse embryonic stem cellsrdquo Stem Cell Research vol 11 no 3pp 1264ndash1271 2013

[68] The HD iPSC Consortium ldquoInduced pluripotent stem cellsfrom patients with Huntingtonrsquos disease show CAG-repeat-expansion-associated phenotypesrdquo Cell Stem Cell vol 11 no 2pp 264ndash278 2012

[69] H L Paulson N M Bonini and K A Roth ldquoPolyglutaminedisease and neuronal cell deathrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no24 pp 12957ndash12958 2000

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[71] A Goswami P Dikshit A Mishra S Mulherkar N Nukinaand N R Jana ldquoOxidative stress promotes mutant huntingtinaggregation and mutant huntingtin-dependent cell death bymimicking proteasomal malfunctionrdquo Biochemical and Bio-physical Research Communications vol 342 no 1 pp 184ndash1902006

[72] D Lim L Fedrizzi M Tartari et al ldquoCalcium homeostasis andmitochondrial dysfunction in striatal neurons of Huntingtondiseaserdquo Journal of Biological Chemistry vol 283 no 9 pp5780ndash5789 2008


[73] M A Sorolla G Reverter-Branchat J Tamarit I Ferrer JRos and E Cabiscol ldquoProteomic and oxidative stress analysisin human brain samples of Huntington diseaserdquo Free RadicalBiology and Medicine vol 45 no 5 pp 667ndash678 2008

[74] 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

[75] V Shukla S K Mishra and H C Pant ldquoOxidative stress inneurodegenerationrdquo Advances in Pharmacological Sciences vol2011 Article ID 572634 13 pages 2011

[76] O I Aruoma ldquoFree radicals oxidative stress and antioxidantsin human health and diseaserdquo JAOCS Journal of the AmericanOil Chemistsrsquo Society vol 75 no 2 pp 199ndash212 1998

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[78] M Czeredys F Maciag A Methner and J Kuznicki ldquoTetrahy-drocarbazoles decrease elevated SOCE in medium spiny neu-rons from transgenicYAC128mice amodel ofHuntingtonrsquos dis-easerdquo Biochemical and Biophysical Research Communications2016

[79] J C Corona and M R Duchen ldquoPPAR120574 as a therapeutic targetto rescue mitochondrial function in neurological diseaserdquo FreeRadical Biology and Medicine vol 100 pp 153ndash163 2016

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[81] Y-Z Fang S Yang andGWu ldquoFree radicals antioxidants andnutritionrdquo Nutrition vol 18 no 10 pp 872ndash879 2002

[82] T Finkel ldquoOxidant signals and oxidative stressrdquo Current Opin-ion in Cell Biology vol 15 no 2 pp 247ndash254 2003

[83] J A Guest and R S Grant ldquoEffects of dietary derived antiox-idants on the central nervous systemrdquo International journal ofNutrition Pharmacology Neurological Diseases vol 2 no 3 pp185ndash197 2012

[84] O O Sunday M F Adekunle O T Temitope et al ldquoAlterationin antioxidants level and lipid peroxidation of patients withneurodegenerative diseases Alzheimerrsquos disease and Parkinsondiseaserdquo The International Journal of Nutrition PharmacologyNeurological Diseases vol 4 no 3 pp 146ndash152 2014

[85] S Chanvitayapongs B Draczynska-Lusiak and A Y SunldquoAmelioration of oxidative stress by antioxidants and resveratrolin PC12 cellsrdquo NeuroReport vol 8 no 6 pp 1499ndash1502 1997

[86] Y Zhao and B Zhao ldquoNatural antioxidants in prevention andmanagement of Alzheimerrsquos diseaserdquo Frontiers in BiosciencemdashElite Edition vol 4 pp 794ndash808 2012

[87] M M Essa S Subash M Akbar S Al-Adawi and G JGuillemin ldquoLong-Term dietary supplementation of pomegran-ates figs and dates alleviate neuroinflammation in a transgenicmouse model of alzheimerrsquos diseaserdquo PLOS ONE vol 10 no 32015

[88] 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

[89] B N Al-Sabahi M O Fatope M M Essa et al ldquoPomegranateseed oil effect on 3-nitropropionic acid-induced neurotoxicity

in PC12 cells and elucidation of unsaturated fatty acids compo-sitionrdquo Nutritional Neuroscience pp 1ndash9 2015

[90] K Rezai-Zadeh D Shytle N Sun et al ldquoGreen tea epigallo-catechin-3-gallate (EGCG) modulates amyloid precursor pro-tein cleavage and reduces cerebral amyloidosis in Alzheimertransgenic micerdquo Journal of Neuroscience vol 25 no 38 pp8807ndash8814 2005

[91] K N Prasad W C Cole and B Kumar ldquoMultiple antioxidantsin the prevention and treatment of Parkinsonrsquos diseaserdquo Journalof the American College of Nutrition vol 18 no 5 pp 413ndash4231999

[92] H Jin A Kanthasamy A Ghosh V Anantharam B Kalyanara-man and A G Kanthasamy ldquoMitochondria-targeted antiox-idants for treatment of Parkinsonrsquos disease Preclinical andclinical outcomesrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular Basis of Disease vol 1842 no 8 pp 1282ndash1294 2014

[93] D J Wright T Renoir Z M Smith et al ldquoN-Acetylcysteineimproves mitochondrial function and ameliorates behavioraldeficits in the R61 mouse model of Huntingtonrsquos diseaserdquoTranslational Psychiatry vol 5 no 1 article e492 2015

[94] J Y LiN Popovic andP Brundin ldquoTheuse of theR6 transgenicmouse models of Huntingtonrsquos disease in attempts to developnovel therapeutic strategiesrdquoNeuroRx vol 2 no 3 pp 447ndash4642005

[95] J Hamilton J J Pellman T Brustovetsky R A Harris and NBrustovetsky ldquoOxidative metabolism in YAC128 mouse modelof Huntingtonrsquos diseaserdquoHumanMolecular Genetics vol 24 no17 pp 4862ndash4878 2015

[96] A Santamarıa R Salvatierra-Sanchez B Vazquez-Roman etal ldquoProtective effects of the antioxidant selenium on quinolinicacid-induced neurotoxicity in rats in vitro and in vivo studiesrdquoJournal of Neurochemistry vol 86 no 2 pp 479ndash488 2003

[97] J Chakraborty D N Nthenge-Ngumbau U Rajamma andK P Mohanakumar ldquoMelatonin protects against behaviouraldysfunctions and dendritic spine damage in 3-nitropropionicacid-induced rat model of Huntingtonrsquos diseaserdquo BehaviouralBrain Research vol 264 pp 91ndash104 2014

[98] A V Rao and B Balachandran ldquoRole of oxidative stressand antioxidants in neurodegenerative diseasesrdquo NutritionalNeuroscience vol 5 no 5 pp 291ndash309 2002

[99] J Gil-Mohapel P S Brocardo and B R Christie ldquoThe role ofoxidative stress in Huntingtonrsquos disease are antioxidants goodtherapeutic candidatesrdquoCurrent Drug Targets vol 15 no 4 pp454ndash468 2014

[100] S Campesan E W Green C Breda et al ldquoThe kynureninepathway modulates neurodegeneration in a drosophila modelof Huntingtonrsquos diseaserdquo Current Biology vol 21 no 11 pp 961ndash966 2011

[101] D Zwilling S-Y Huang K V Sathyasaikumar et al ldquoKynure-nine 3-monooxygenase inhibition in blood ameliorates neu-rodegenerationrdquo Cell vol 145 no 6 pp 863ndash874 2011

[102] L Moslashllersen O Moldestad A D Rowe et al ldquoEffects of antho-cyanins on CAG repeat instability and behaviour in Hunting-tonrsquos disease R61 micerdquo PLoS Currents vol 8 2016

[103] M A La Fontaine J W Geddes A Banks and D AllanButterfield ldquoEffect of exogenous and endogenous antioxidantson 3-nitropionic acid-induced in vivo oxidative stress andstriatal lesionsrdquo Journal of Neurochemistry vol 75 no 4 pp1709ndash1715 2000

[104] G Ellrichmann E Petrasch-Parwez D-H Lee et al ldquoEfficacyof fumaric acid esters in the R62 and YAC128 models of


huntingtonrsquos diseaserdquo PLoS ONE vol 6 no 1 Article ID e161722011

[105] J M Van Raamsdonk J Pearson C D C Bailey et alldquoCystamine treatment is neuroprotective in the YAC128 mousemodel of Huntington diseaserdquo Journal of Neurochemistry vol95 no 1 pp 210ndash220 2005

[106] I Tunez I Tasset V Perez-De LaCruz and A Santamarıa ldquo3-Nitropropionic acid as a tool to study the mechanisms involvedinHuntingtonrsquos disease past present and futurerdquoMolecules vol15 no 2 pp 878ndash916 2010

[107] P Kumar and A Kumar ldquoProlonged pretreatment with carv-edilol prevents 3-nitropropionic acid-induced behavioral alter-ations and oxidative stress in ratsrdquo Pharmacological Reports vol60 no 5 pp 706ndash715 2008

[108] P Kumar S S V Padi P S Naidu and A Kumar ldquoPossibleneuroprotective mechanisms of curcumin in attenuating 3-nitropropionic acid-induced neurotoxicityrdquoMethods and Find-ings in Experimental and Clinical Pharmacology vol 29 no 12007

[109] J B Schulz D R Henshaw U Macgarvey and M F BealldquoInvolvement of oxidative stress in 3-nitropropionic acid neu-rotoxicityrdquoNeurochemistry International vol 29 no 2 pp 167ndash171 1996

[110] C D Keene C M P Rodrigues T Eich et al ldquoA bile acidprotects against motor and cognitive deficits and reducesstriatal degeneration in the 3-nitropropionic acid model ofHuntingtonrsquos diseaserdquo Experimental Neurology vol 171 no 2pp 351ndash360 2001

[111] P Kumar and A Kumar ldquoEffect of lycopene and epigallo-catechin-3-gallate against 3-nitropropionic acid induced cogni-tive dysfunction and glutathione depletion in rat a novel nitricoxide mechanismrdquo Food and Chemical Toxicology vol 47 no10 pp 2522ndash2530 2009

[112] D J Wright L J Gray D I Finkelstein et al ldquoN-acetylcysteinemodulates glutamatergic dysfunction and depressive behaviorinHuntingtonrsquos diseaserdquoHumanMolecular Genetics vol 25 no14 pp 2923ndash2933 2016

[113] A Johri and M F Beal ldquoAntioxidants in Huntingtonrsquos diseaserdquoBiochimica et Biophysica Acta (BBA)mdashMolecular Basis of Dis-ease vol 1822 no 5 pp 664ndash674 2012

[114] A Petersen R F Castilho O Hansson T Wieloch and PBrundin ldquoOxidative stress mitochondrial permeability transi-tion and activation of caspases in calcium ionophore A23187-induced death of cultured striatal neuronsrdquo Brain Research vol857 no 1-2 pp 20ndash29 2000

[115] 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

[116] E Vamos K Voros L Vecsei and P Klivenyi ldquoNeuroprotectiveeffects of L-carnitine in a transgenic animal model of Hunting-tonrsquos diseaserdquo Biomedicine and Pharmacotherapy vol 64 no 4pp 282ndash286 2010

[117] M Miyamoto and J T Coyle ldquoIdebenone attenuates neuronaldegeneration induced by intrastriatal injection of excitotoxinsrdquoExperimental Neurology vol 108 no 1 pp 38ndash45 1990

[118] L Yang N Y Calingasan B Thomas et al ldquoNeuroprotectiveeffects of the triterpenoid CDDO methyl amide a potentinducer of Nrf2-mediated transcriptionrdquo PLOS ONE vol 4 no6 Article ID e5757 2009

[119] J Wang L Ho W Zhao et al ldquoGrape-derived polyphenolicsprevent A120573 oligomerization and attenuate cognitive deteriora-tion in a mouse model of Alzheimerrsquos diseaserdquo The Journal ofNeuroscience vol 28 no 25 pp 6388ndash6392 2008

[120] K A Youdim and J A Joseph ldquoA possible emerging roleof phytochemicals in improving age-related neurological dys-functions a multiplicity of effectsrdquo Free Radical Biology andMedicine vol 30 no 6 pp 583ndash594 2001

[121] Y Sarne F Asaf M Fishbein M Gafni and O Keren ldquoThedual neuroprotective-neurotoxic profile of cannabinoid drugsrdquoBritish Journal of Pharmacology vol 163 no 7 pp 1391ndash14012011

[122] S Z Imam and S F Ali ldquoAging increases the susceptiblityto methamphetamine-induced dopaminergic neurotoxicity inrats correlation with peroxynitrite production and hyperther-miardquo Journal of Neurochemistry vol 78 no 5 pp 952ndash959 2001

[123] M E Rice ldquoAscorbate regulation and its neuroprotective role inthe brainrdquo Trends in Neurosciences vol 23 no 5 pp 209ndash2162000

[124] DColle JMHartwig F AA Soares andM Farina ldquoProbucolmodulates oxidative stress and excitotoxicity in Huntingtonrsquosdisease models in vitrordquo Brain Research Bulletin vol 87 no 4-5pp 397ndash405 2012

[125] P-M Lledo M Alonso and M S Grubb ldquoAdult neurogenesisand functional plasticity in neuronal circuitsrdquo Nature ReviewsNeuroscience vol 7 no 3 pp 179ndash193 2006

[126] J Altman and G D Das ldquoAutoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in ratsrdquo Jour-nal of Comparative Neurology vol 124 no 3 pp 319ndash335 1965

[127] P S Eriksson E Perfilieva T Bjork-Eriksson et al ldquoNeurogen-esis in the adult human hippocampusrdquo Nature Medicine vol 4no 11 pp 1313ndash1317 1998

[128] G-LMing andH Song ldquoAdult neurogenesis in themammaliancentral nervous systemrdquoAnnual Review of Neuroscience vol 28pp 223ndash250 2005

[129] V G Kukekov E D Laywell O Suslov et al ldquoMultipotentstemprogenitor cells with similar properties arise from twoneurogenic regions of adult human brainrdquo Experimental Neu-rology vol 156 no 2 pp 333ndash344 1999

[130] Y Xu N Tamamaki T Noda et al ldquoNeurogenesis in theependymal layer of the adult rat 3rd ventriclerdquo ExperimentalNeurology vol 192 no 2 pp 251ndash264 2005

[131] C Lois J-M Garcıa-Verdugo and A Alvarez-Buylla ldquoChainmigration of neuronal precursorsrdquo Science vol 271 no 5251 pp978ndash981 1996

[132] M Migaud M Batailler S Segura A Duittoz I Franceschiniand D Pillon ldquoEmerging new sites for adult neurogenesisin the mammalian brain a comparative study between thehypothalamus and the classical neurogenic zonesrdquo EuropeanJournal of Neuroscience vol 32 no 12 pp 2042ndash2052 2010

[133] G Kempermann LWiskott and FHGage ldquoFunctional signif-icance of adult neurogenesisrdquo Current Opinion in Neurobiologyvol 14 no 2 pp 186ndash191 2004

[134] G-LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011

[135] M Kandasamy R Reilmann J Winkler U Bogdahn andL Aigner ldquoTransforming growth factor-beta signaling in theneural stem cell niche a therapeutic target for Huntingtonrsquosdiseaserdquo Neurology Research International vol 2011 Article ID124256 13 pages 2011


[136] S Couillard-Despres C Wuertinger M Kandasamy et alldquoAgeing abolishes the effects of fluoxetine on neurogenesisrdquoMolecular Psychiatry vol 14 no 9 pp 856ndash864 2009

[137] S A Small S A Schobel R B Buxton M P Witter and C ABarnes ldquoA pathophysiological framework of hippocampal dys-function in ageing and diseaserdquo Nature Reviews Neurosciencevol 12 no 10 pp 585ndash601 2011

[138] M J Forster A Dubey K M Dawson W A Stutts H Lal andR S Sohal ldquoAge-related losses of cognitive function and motorskills in mice are associated with oxidative protein damage inthe brainrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 10 pp 4765ndash4769 1996

[139] S E Lazic H Grote R J E Armstrong et al ldquoDecreasedhippocampal cell proliferation in R6I Huntingtonrsquos micerdquoNeuroReport vol 15 no 5 pp 811ndash813 2004

[140] J M A C Gil P Mohapel I M Araujo et al ldquoReducedhippocampal neurogenesis in R62 transgenic Huntingtonrsquosdisease micerdquo Neurobiology of Disease vol 20 no 3 pp 744ndash751 2005

[141] Z Kohl M Kandasamy B Winner et al ldquoPhysical activity failsto rescue hippocampal neurogenesis deficits in the R62 mousemodel ofHuntingtonrsquos diseaserdquoBrain Research vol 1155 pp 24ndash33 2007

[142] M Kandasamy S Couillard-Despres K A Raber et al ldquoStemcell quiescence in the hippocampal neurogenic niche is associ-ated with elevated transforming growth factor-120573 signaling in ananimal model of Huntington diseaserdquo Journal of Neuropathol-ogy and Experimental Neurology vol 69 no 7 pp 717ndash728 2010

[143] J M Simpson J Gil-Mohapel M A Pouladi et al ldquoAlteredadult hippocampal neurogenesis in the YAC128 transgenicmouse model of Huntington diseaserdquo Neurobiology of Diseasevol 41 no 2 pp 249ndash260 2011

[144] M A Curtis E B Penney A G Pearson et al ldquoIncreased cellproliferation and neurogenesis in the adult humanHuntingtonrsquosdisease brainrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 100 no 15 pp 9023ndash90272003

[145] A S Tattersfield R J Croon YW Liu A P Kells R LM Faulland B Connor ldquoNeurogenesis in the striatum of the quinolinicacid lesion model of Huntingtonrsquos diseaserdquo Neuroscience vol127 no 2 pp 319ndash332 2004

[146] M Kandasamy M Rosskopf K Wagner et al ldquoReduction insubventricular zone-derived olfactory bulb neurogenesis in arat model of huntingtonrsquos disease is accompanied by striatalinvasion of neuroblastsrdquo PLOS ONE vol 10 no 2 Article IDe0116069 2015

[147] R J Felling and S W Levison ldquoEnhanced neurogenesis follow-ing strokerdquo Journal of Neuroscience Research vol 73 no 3 pp277ndash283 2003

[148] P K Dash S A Mach and A N Moore ldquoEnhanced neuroge-nesis in the rodent following traumatic brain injuryrdquo Journal ofNeuroscience Research vol 63 no 4 pp 313ndash319 2001

[149] H Van Praag G Kempermann and F H Gage ldquoRunningincreases cell proliferation and neurogenesis in the adult mousedentate gyrusrdquo Nature Neuroscience vol 2 no 3 pp 266ndash2701999

[150] J Brown C M Cooper-Kuhn G Kempermann et alldquoEnriched environment and physical activity stimulate hip-pocampal but not olfactory bulb neurogenesisrdquo European Jour-nal of Neuroscience vol 17 no 10 pp 2042ndash2046 2003

[151] M F Anderson M A I Aberg M Nilsson and P S ErikssonldquoInsulin-like growth factor-I and neurogenesis in the adult

mammalian brainrdquo Developmental Brain Research vol 134 no1-2 pp 115ndash122 2002

[152] K Jin Y Zhu Y Sun X O Mao L Xie and D A Green-berg ldquoVascular endothelial growth factor (VEGF) stimulatesneurogenesis in vitro and in vivordquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no18 pp 11946ndash11950 2002

[153] H G Kuhn J Winkler G Kempermann L J Thal and F HGage ldquoEpidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult ratbrainrdquoThe Journal of Neuroscience vol 17 no 15 pp 5820ndash58291997

[154] T Hagg ldquoFrom neurotransmitters to neurotrophic factors toneurogenesisrdquoThe Neuroscientist vol 15 no 1 pp 20ndash27 2009

[155] C W Cotman and N C Berchtold ldquoExercise a behavioralintervention to enhance brain health and plasticityrdquo Trends inNeurosciences vol 25 no 6 pp 295ndash301 2002

[156] A Klegeris and P LMcGeer ldquoNon-steroidal anti-inflammatorydrugs (NSAIDs) and other anti-inflammatory agents in thetreatment of neurodegenerative diseaserdquo Current AlzheimerResearch vol 2 no 3 pp 355ndash365 2005

[157] J E Malberg A J Eisch E J Nestler and R S DumanldquoChronic antidepressant treatment increases neurogenesis inadult rat hippocampusrdquo Journal of Neuroscience vol 20 no 24pp 9104ndash9110 2000

[158] L Aigner and U Bogdahn ldquoTGF-beta in neural stem cellsand in tumors of the central nervous systemrdquo Cell and TissueResearch vol 331 no 1 pp 225ndash241 2008

[159] D Stangl and S Thuret ldquoImpact of diet on adult hippocampalneurogenesisrdquo Genes and Nutrition vol 4 no 4 pp 271ndash2822009

[160] J Lee W Duan and M P Mattson ldquoEvidence that brain-derived neurotrophic factor is required for basal neurogenesisand mediates in part the enhancement of neurogenesis bydietary restriction in the hippocampus of adult micerdquo Journalof Neurochemistry vol 82 no 6 pp 1367ndash1375 2002

[161] J E Le Belle N M Orozco A A Paucar et al ldquoProliferativeneural stem cells have high endogenous ROS levels that regulateself-renewal and neurogenesis in a PI3KAkt-dependant man-nerrdquo Cell Stem Cell vol 8 no 1 pp 59ndash71 2011

[162] X Bai Y Yan S Canfield et al ldquoKetamine enhances humanneural stem cell proliferation and induces neuronal apoptosisvia reactive oxygen species-mediated mitochondrial pathwayrdquoAnesthesia and Analgesia vol 116 no 4 pp 869ndash880 2013

[163] T-F Yuan S Gu C Shan S Marchado and O Arias-CarrionldquoOxidative stress and adult neurogenesisrdquo StemCell Reviews andReports vol 11 no 5 pp 706ndash709 2015

[164] T-T Huang Y Zou and R Corniola ldquoOxidative stress andadult neurogenesismdashEffects of radiation and superoxide dismu-tase deficiencyrdquo Seminars in Cell and Developmental Biologyvol 23 no 7 pp 738ndash744 2012

[165] N M Walton R Shin K Tajinda et al ldquoAdult neurogenesistransiently generates oxidative stressrdquo PLOS ONE vol 7 no 4Article ID e35264 2012

[166] A A H Ali B Schwarz-Herzke A Stahr T Prozorovski OAktas and C von Gall ldquoPremature aging of the hippocampalneurogenic niche in adult Bmal1-deficient micerdquo Aging vol 7no 6 pp 435ndash449 2015

[167] T Prozorovski U Schulze-Topphoff R Glumm et al ldquoSirt1contributes critically to the redox-dependent fate of neuralprogenitorsrdquo Nature Cell Biology vol 10 no 4 pp 385ndash3942008


[168] S Rivas-Arancibia R Guevara-Guzman Y Lopez-Vidal et alldquoOxidative stress caused by ozone exposure induces loss of brainrepair in the hippocampus of adult ratsrdquo Toxicological Sciencesvol 113 no 1 Article ID kfp252 pp 187ndash197 2009

[169] T Valente J Hidalgo I Bolea et al ldquoA diet enriched inpolyphenols and polyunsaturated fatty acids LMNdiet inducesneurogenesis in the subventricular zone and hippocampus ofadult mouse brainrdquo Journal of Alzheimerrsquos Disease vol 18 no 4pp 849ndash865 2009

[170] D G Herrera A G Yague S Johnsen-Soriano et al ldquoSelectiveimpairment of hippocampal neurogenesis by chronic alco-holism protective effects of an antioxidantrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 100 no 13 pp 7919ndash7924 2003

[171] D Vauzour K Vafeiadou A Rodriguez-Mateos C Ren-deiro and J P E Spencer ldquoThe neuroprotective potential offlavonoids a multiplicity of effectsrdquo Genes and Nutrition vol3 no 3-4 pp 115ndash126 2008

[172] Z-Q Qu Y Zhou Y-S Zeng et al ldquoProtective effects ofa rhodiola crenulata extract and salidroside on hippocampalneurogenesis against streptozotocin-induced neural injury inthe ratrdquo PLoS ONE vol 7 no 1 Article ID e29641 2012

[173] C Manach A Scalbert C Morand C Remesy and L JimenezldquoPolyphenols food sources and bioavailabilityrdquo American Jour-nal of Clinical Nutrition vol 79 no 5 pp 727ndash747 2004

[174] D Vauzour A Rodriguez-Mateos G Corona M J Oruna-Concha and J P E Spencer ldquoPolyphenols and human healthprevention of disease andmechanisms of actionrdquoNutrients vol2 no 11 pp 1106ndash1131 2010

[175] D Vauzour K Vafeiadou C Rendeiro G Corona and J PE Spencer ldquoThe inhibitory effects of berry-derived flavonoidsagainst neurodegenerative processesrdquo Journal of Berry Researchvol 1 no 1 pp 45ndash52 2010

[176] S Bastianetto W-H Zheng and R Quirion ldquoThe Ginkgobiloba extract (EGb 761) protects and rescues hippocampal cellsagainst nitric oxide-induced toxicityrdquo Journal of Neurochem-istry vol 74 no 6 pp 2268ndash2277 2000

[177] L An Y-Z Zhang N-J Yu et al ldquoRole for serotonin in theantidepressant-like effect of a flavonoid extract of Xiaobuxin-Tangrdquo Pharmacology Biochemistry and Behavior vol 89 no 4pp 572ndash580 2008

[178] G P Dias N Cavegn A Nix et al ldquoThe role of dietarypolyphenols on adult hippocampal neurogenesis molecularmechanisms and behavioural effects on depression and anxietyrdquoOxidative Medicine and Cellular Longevity vol 2012 Article ID541971 18 pages 2012

[179] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[180] P J Bernier A Bedard J Vinet M Levesque and A ParentldquoNewly generated neurons in the amygdala and adjoiningcortex of adult primatesrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 17 pp11464ndash11469 2002

[181] A A Pierce and A W Xu ldquoDe novo neurogenesis in adulthypothalamus as a compensatorymechanism to regulate energybalancerdquoThe Journal of Neuroscience vol 30 no 2 pp 723ndash7302010

[182] E Gould A J Reeves M S A Graziano and C G GrossldquoNeurogenesis in the neocortex of adult primatesrdquo Science vol286 no 5439 pp 548ndash552 1999

[183] M S Kaplan ldquoNeurogenesis in the 3-month-old rat visualcortexrdquo Journal of Comparative Neurology vol 195 no 2 pp323ndash338 1981

[184] J M Parent Z S Vexler C Gong N Derugin and DM Ferriero ldquoRat forebrain neurogenesis and striatal neuronreplacement after focal strokerdquo Annals of Neurology vol 52 no6 pp 802ndash813 2002

[185] R Vandenbosch L Borgs P Beukelaers et al ldquoAdult neuroge-nesis and the diseased brainrdquo Current Medicinal Chemistry vol16 no 6 pp 652ndash666 2009

[186] A Arvidsson T Collin D Kirik Z Kokaia and O LindvallldquoNeuronal replacement from endogenous precursors in theadult brain after strokerdquo Nature Medicine vol 8 no 9 pp 963ndash970 2002

[187] Q-Q Li G-Q Qiao J Ma H-W Fan and Y-B Li ldquoCorticalneurogenesis in adult rats after ischemic brain injury most newneurons fail to maturerdquo Neural Regeneration Research vol 10no 2 pp 277ndash285 2015

[188] A Chang M C Smith X Yin R J Fox S M Staugaitis andB D Trapp ldquoNeurogenesis in the chronic lesions of multiplesclerosisrdquo Brain vol 131 no 9 pp 2366ndash2375 2008

[189] L Chi Y Ke C Luo et al ldquoMotor neuron degenerationpromotes neural progenitor cell proliferation migration andneurogenesis in the spinal cords of amyotrophic lateral sclerosismicerdquo STEM CELLS vol 24 no 1 pp 34ndash43 2006

[190] D R Kornack and P Rakic ldquoCell proliferation without neuro-genesis in adult primate neocortexrdquo Science vol 294 no 5549pp 2127ndash2130 2001

[191] A Ernst and J Frisen ldquoAdult neurogenesis in humansmdashcommon and unique traits in mammalsrdquo PLoS Biology vol 13no 1 2015

[192] A Ernst K Alkass S Bernard et al ldquoNeurogenesis in thestriatumof the adult human brainrdquoCell vol 156 no 5 pp 1072ndash1083 2014

Submit your manuscripts athttpswwwhindawicom

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


the cortex hippocampus hypothalamus and brain stem in aprogressive manner [7ndash9] The epidemiology of HD suggeststhat the disease occurs worldwide but its prevalence variesdepending upon genetic diversity and geographical regions[9 10] The rate of incidence of HD is considerably higher inthe Caucasian population than the Asian population Whilean estimate shows the prevalence and increasing trend ofHD in Western Europe Australia North America and theUnitedKingdom India represents a large number of total HDcases in Asia [11 12] Single nucleotide polymorphism (SNP)at the HTT locus in association with the genetic diversitylifestyle food and environmental factors is presumed to bethe reasons for the variations in the frequency of HD amongthe human population [13] HD has been characterisedby choreiform movements dystonia cognitive deficits andpsychiatric problems [14]These symptoms have been accom-panied by neurodegeneration alongwith an abnormal level ofneurotransmittersmicroglial activation reactive astrogliosisand impaired neurogenesis [15] Recently HD patients havealso been characterised with different types of behaviouralmotor and aggressive symptoms [16 17]

All the abovementioned problems aggravate the develop-ment of HD and contribute to gradual deterioration of thephysical abilities and mental processes Importantly peoplewith HD have problems in taking care of their daily routinesuch as food consumption due to difficulty in swallowing(dysphagia) which may occur during the later stages ofthe disease Further abnormalities in energy metabolismcaused by mitochondrial dysfunctions add to severity ofthe disease The loss of muscle function in the mandibularregions pharynx and oesophagus could lead to disorderslike bruxism (grinding the teeth) failure to intake of foodand choking which could ultimately lead to death [16 18]Currently there are no available treatments that can delaythe onset or arrest the progression of the disease while thefocus of medical care is limited to merely managing theneurological symptoms of HD This is mainly due to lack ofknowledge about the underlying biology of the disease

Of the few therapeutic options available for the treat-ment of HD tetrabenazine has been an approved drug bythe Food and Drug Administration (FDA) for minimisingthe clinical symptoms of involuntary movements [19ndash23]Other treatment strategies for HD include administrationof antipsychotic and antidepressant drugs [21 22] Antipsy-chotic drugs like haloperidol [23] fluphenazine [24] clon-azepam [25] amantadine [26] and levetiracetam [27] mighthelp in controlling panic attacks aggression and choreiformmovements while antidepressants like fluoxetine [28] ser-traline [29 30] nortriptyline [31] and lithium [32] are usedto stabilize depression anxiety associated mood swings andnegative thoughts In addition riluzole is frequently used asa neuroprotective drug to control glutamatergic neurotrans-mission in HD [33 34] Deep brain stimulation (DBS) hasbeen proposed as a technique to manage chorea and othermotor symptoms like dystonia and cognitive deficits in HD[35] Alternatively using recombinant antibody fragmentsto neutralise the HTT aggregates [36] and stem cell trans-plantation [37] have also been tried with limited success Inaddition adapting to the aforementioned treatment strategies

warrants a very careful approach andhighly vigilant individu-als to carry out the procedures as most of these strategies androutes of administration have side effects including nauseafatigue abnormal neuroexcitability and tissue disruption[38] that could exacerbate the severity of HD symptoms[39] Thus developing novel and noninvasive therapeuticstrategies that are efficient but have no orminimal side effectsare important for the successful treatment of HD and willhave a promising therapeutic appeal Meanwhile the benefitsof physical activities an enriched environment with the aidof dietary supplements and palliative care therapies havebeen considered in conjunction with the drug treatment asnoninvasive and relatively affordable management strategiesfor HD

2 Detrimental Roles of Oxidative Stress inHuntingtonrsquos Disease

There have been many hypotheses proposed for the mani-festation of neurodegeneration associated clinical symptomsin HD Among them polyQ expansion associated oxidativestress that leads to caspase mediated neuronal cell death isconsidered as a potential cause of neuropathological changesin HD [9] Free radicals are highly reactive molecules thatfeature unpaired electrons on their valence orbital with theability to render variousmolecular and cellular vulnerabilitiesdue to their unstable reactive nature [40 41] The mostcommon biologically relevant free radicals are superoxide(Ominus) hydroxyl (OHminus) and nitricmonoxide (NO) species andare referred to as reactive oxygen species (ROS) and reactivenitrogen species (RNS) [41 42] Free radicals are provoked incells by enzymatic and nonenzymatic mechanisms throughabnormal metabolic genetic and cell cycle events that occuras a consequence of electromagnetic radiation ageing infec-tions immunological alteration intoxication abnormal dietmalnutrition and deficiency in vitamins and trace elements[43] Besides defects or mutations in the free radicals scav-enging metabolic enzymes such as glutathione peroxidasesnitric oxide synthase peroxiredoxins and superoxide dismu-tases are responsible for the accumulation of free radicals[44 45] The expressions of these detoxifying enzymesare controlled by the Nrf2-ARE complex pathway [46] Ingeneral highly regulated free radicals generated in the bodycan be of potential use in development and maintenanceof the tissues associated with improvement of the longevityof organisms As per the free radical theory of ageing theabnormally fabricated free radicals are harmful to the normalstructure and functioning of cells and tissues [46ndash48] Inorder to combat the negative impact of free radicals cellsdeploy defense mechanisms such as free radical scavengingactivity by antioxidants as a normal physiological process[49] The imbalance between the production of free radicalsand the ability of cells to counteract or detoxify free radicalscan eventually lead to DNA oxidation protein nitrationand lipid peroxidation culminating in cellular oxidativestress [50 51] Prolonged oxidative stress and failure indefense mechanisms could ultimately result in ageing relatedchronic diseases such as atherosclerosis [52] cancer [53]





















NSC

NSC

Oligodendrocyte

Microglia

Astrocyte

Neuron

Neuroblasts

Bloo

d ve

ssel Self-

renew

al

(a)

NSC

NSC

Oligodendrocyte

Microglia

AstrocyteNeuron

Neuroblasts


Proliferation

Diff

eren

tiatio

n

Neu

ropr

otec

tion

Bloo

d ve

ssel

Self-

renew

al

+

+

+

(b)


Astrogliosis



Oligodendrocyte

Demyelination

Neurodegeneration



Bloo

d ve

ssel

(c)














Neuroprotection


Synaptogenesis


system

WTHTT

Neurogenesis

Development

Vesiclestransport

Antioxidants

Mitochondria

Free radicals

Equilibrium

(a)

Neurodegeneration

MutantHTT

Oxidative damage

Antioxidants

Free radicals

Imbalance

Lipid

ER stress

Impairedautophagy

Excitotoxicity




Axonaldysregulation



peroxidation

(b)

Neurodegeneration

Antioxidants

Free radicals


Tetrabenazine





Speech therapy

RxRx

Imbalance

+

minus

MutantHTT

Oxidative damage

Lipid

ER stress

Impairedautophagy

Excitotoxicity




Axonaldysregulation



peroxidation

(c)







7 Conclusion



Abbreviations


Competing Interests


Acknowledgments




References















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































NSC

NSC

Oligodendrocyte

Microglia

Astrocyte

Neuron

Neuroblasts

Bloo

d ve

ssel Self-

renew

al

(a)

NSC

NSC

Oligodendrocyte

Microglia

AstrocyteNeuron

Neuroblasts


Proliferation

Diff

eren

tiatio

n

Neu

ropr

otec

tion

Bloo

d ve

ssel

Self-

renew

al

+

+

+

(b)


Astrogliosis



Oligodendrocyte

Demyelination

Neurodegeneration



Bloo

d ve

ssel

(c)














Neuroprotection


Synaptogenesis


system

WTHTT

Neurogenesis

Development

Vesiclestransport

Antioxidants

Mitochondria

Free radicals

Equilibrium

(a)

Neurodegeneration

MutantHTT

Oxidative damage

Antioxidants

Free radicals

Imbalance

Lipid

ER stress

Impairedautophagy

Excitotoxicity




Axonaldysregulation



peroxidation

(b)

Neurodegeneration

Antioxidants

Free radicals


Tetrabenazine





Speech therapy

RxRx

Imbalance

+

minus

MutantHTT

Oxidative damage

Lipid

ER stress

Impairedautophagy

Excitotoxicity




Axonaldysregulation



peroxidation

(c)







7 Conclusion



Abbreviations


Competing Interests


Acknowledgments




References















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Neuroprotection


Synaptogenesis


system

WTHTT

Neurogenesis

Development

Vesiclestransport

Antioxidants

Mitochondria

Free radicals

Equilibrium

(a)

Neurodegeneration

MutantHTT

Oxidative damage

Antioxidants

Free radicals

Imbalance

Lipid

ER stress

Impairedautophagy

Excitotoxicity




Axonaldysregulation



peroxidation

(b)

Neurodegeneration

Antioxidants

Free radicals


Tetrabenazine





Speech therapy

RxRx

Imbalance

+

minus

MutantHTT

Oxidative damage

Lipid

ER stress

Impairedautophagy

Excitotoxicity




Axonaldysregulation



peroxidation

(c)







7 Conclusion



Abbreviations


Competing Interests


Acknowledgments




References















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















7 Conclusion



Abbreviations


Competing Interests


Acknowledgments




References















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















References















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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