review article redox modulations, antioxidants, and neuropsychiatric...

Review ArticleRedox Modulations Antioxidants and NeuropsychiatricDisorders

Erik A Fraunberger12 Gustavo Scola13 Victoria L M Laliberteacute2

Angela Duong2 and Ana C Andreazza123

1Centre for Addiction and Mental Health 250 College Street Toronto ON Canada M5T 1R82Department of Pharmacology University of Toronto Medical Science Building 1 Kingrsquos College Circle Toronto ON CanadaM5S 1A83Department of Psychiatry University of Toronto 250 College Street Toronto ON Canada M5T 1R8

Correspondence should be addressed to Gustavo Scola gustavoscolautorontoca

Received 8 May 2015 Accepted 14 June 2015

Academic Editor Ioannis P Trougakos

Copyright copy 2016 Erik A Fraunberger et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Although antioxidants redoxmodulations and neuropsychiatric disorders have beenwidely studied formany years the fieldwouldbenefit from an integrative and corroborative review Our primary objective is to delineate the biological significance of compoundsthat modulate our redox status (ie reactive species and antioxidants) as well as outline their current role in brain health and theimpact of redoxmodulations on the severity of illnessesTherefore this reviewwill not enter into the debate regarding the perceivedmedical legitimacy of antioxidants but rather seek to clarify their abilities and limitations With this in mind antioxidants may beinterpreted as natural products with significant pharmacological actions in the body A renewed understanding of these oftenoverlooked compounds will allow us to critically appraise the current literature and provide an informed novel perspective onan important healthcare issue In this review we will introduce the complex topics of redox modulations and their role in thedevelopment of select neuropsychiatric disorders

1 What Are Redox Modulations

As a dynamic environment a variety of chemical reactionsare constantly occurring within our cells at all times Acommon type of reaction the reduction-oxidation (redox)reaction plays a vital role in maintaining cellular functions(Table 1) including metabolic cycles (eg NAD+ and NADHrecycling) and detoxification of harmful substances [1] Inthese reactions usually facilitated by an enzyme one reactantloses electrons (becomes oxidized) and another gains thosesame electrons (becomes reduced) [1 2] As a result ourcells must maintain a delicate electrical balance between thevarious macromolecules that comprise them This balancebetween oxidized and reduced compounds within the cell isknown as the redox status [1 2] In a healthy cell this balanceis maintained as a result of our natural endogenous antiox-idant defences counteracting the continuous production ofreactive species Under normal conditions reactive speciesare commonly produced as by-products of metabolism [3]

Over time however our bodies have evolved adaptations tonot only detoxify these reactive species but use them to fulfilluseful biological functions [4] (Table 1) In cases where thisbalance of antioxidants and reactive species is disrupted byan excess or deficiency of either one our body experiences astrong modulation of its redox status commonly referred toas oxidative stress [5]

Redoxmodulation is defined as an imbalance in the redoxstatus If this imbalance is a shift towards a drastically moreoxidized environment it is characterized by alterations incellular dynamics and varying degrees ofDNARNA proteinand lipid damage [6] While there are many compounds suchas reactive carbon and bromine species that can cause damageto our cells the focus of this reviewwill be on reactive oxygenspecies (ROS) and reactive nitrogen species (RNS) due totheir high prevalence within our body and the surroundingenvironment [7]

As shown in Figure 1 the majority of ROS and RNSspecies originate from the metabolism of oxygen in the

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 4729192 14 pageshttpdxdoiorg10115520164729192

2 Oxidative Medicine and Cellular Longevity

Table 1 Biological roles of reactive species

Neurological Cardiovascular Immune response Cell biology

Mediation of learning andmemoryInvolved in the regulation ofstriatal dopamine release viaglutamate

Regulation of cardiaccontractilityRegulation of vascular tone (egpenile erection) via NOproductionSignalling involving carotidbodies (monitor arterial oxygenlevels)

Response to foreign pathogens(oxidative burst)Production of cytokinesWound repair

EmbryogenesisPrevent overpopulation of cellsand destroys malfunctioningcellsCellular differentiation

MitochondriaSOD

GPx

CAT

Lipid

Domain of lipid peroxidation

Mitochondrial production of reactive species

4-HNE Cycli

satio

n pr

oces

ses

MDA

Oxidation of arachidonic acid produces8-isoprostane

Domain of protein oxidation Domain of DNA oxidation

|| |

| ||HN

Protein|

ProteaseAmino acids

peptides

2

1

3

4

56

Guanosine

8OhdG

Prx(R)

GSSG

GSHGR

NADPH

NADP+

NAD+

NADH Lactate

Pyruvate

Prx(O)

Trx(R) Trx(O)

Prx(R)

NO∙ O2∙minus

O2∙minusO2

O2

ONOOminus

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+

Fe3+

Fe3+

Fe3+

Cu1+

Cu2+

H2O + O2

H2O

H2O

H2O

H2OH2O

H2O2

H2O2

H2O2

2H2O

ProteinndashCH2

ProteinndashCH2

ProteinndashCH2

middot middot middot

OHminus

OHminus

NH3 Fe2+

H-C=O

H2NH2N

| |Fe3+



H2N

| |Fe3+

middot middot middotH2N

ProteinndashCH∙

ProteinndashCH∙

L∙

LO∙ + LOOH LOO∙

+OH∙

OH∙

O2 + H∙

O

O

N

N N

NH

OH HHH

HH

HO NH2

O

O

N

N N

NH

OH

OH

HHH

HH

HO NH2

Figure 1 Production of reactive species and the endogenous antioxidant system Red enzymes green other products purple cofactorsub-strate black reactive species

mitochondria [8] The primary reactive by-product thesuperoxide anion (O2

∙minus) is exported from the mitochondriainto the cytosol via an anion channel where it proceedsthrough numerous chemical reactions in our bodyrsquos attemptto reduce its toxicity Unfortunately at the same time andunder the correct environmental conditions the superoxideanion can be converted into additional reactive specieseither directly or indirectly through catalysis [9] A commonexample within the human body is the reduction of hydrogenperoxide into hydroxyl radicals via transition metals usually

iron (Fenton and Haber-Weiss reactions) [10] (followingequations)

Fe3+ + ∙O2minus

997888rarr Fe2+ +O2

(Reduction of ferric iron)(1)

Fe2+ +H2O2 997888rarr Fe3+ +OHminus + ∙OH(Fenton Reaction)

(2)

∙O2minus

+H2O2 997888rarr∙OH+OHminus +O2 (Net Reaction) (3)

Oxidative Medicine and Cellular Longevity 3

RS

Carbonylation Nitration

Protein alteration

Loss of function

Lipid peroxidation

4-HNE 8-iso

Loss of membrane integrityproduction of hydroxyl radical

cell death

DNA alterations

Silence of gene transcription

Activation of demethylation

Changes in gene expression

Mitochondria

Formation of 8OhdG

Formation of 5mC Formation of 5hmC

O2

NH3+ NH3

+

COOminus COOminus

NO2

OH OH

O C

R

R

NH2 NH2

O O

OH

N

N N

N

NH2NH2

O

OO

O

N

NN

NNN

NHNH

OHOH

OH

CH2OHCH2OHLH + OH∙ 997888rarr L∙ + H2OL∙ + O2 997888rarr LOO∙

LH + LOO∙ 997888rarr L∙ + LOOH

Figure 2 Examples of the effects of reactive species in the cell

2 Macromolecular Changes Caused byReactive Species

Once these toxic molecules are produced in the bodythey begin to interact with DNA lipids and proteins tocause damage leading to an alteration in cellular function(Figure 2) It is important to remember that although theeffects shown in Figure 2 are negative not all changes causedby reactive species are detrimental to the body [4] In factrecent evidence has provided support for the hypothesisthat posttranslational modifications such as carbonylationS-nitrosylation and nitration play a vital role in the degra-dation of unnecessary or damaged proteins maintainingcellular health [11 12] A second example is the regulationof cellular development by H

2O2 considered to be a key

component in mediating the cell cycle and the aging process[13] At different concentrations hydrogen peroxide influ-ences the cell to advance or halt the cell cycle For example atin vivo concentrations of 10minus8 10minus6 and 10minus4M H

2O2causes

the cell to proliferate cease its growth or initiate apoptosisrespectively [13]

An important issue to address is the point at which theoxidative damage that is initially beneficial becomes harmfulto the cell In order to differentiate between negative andpositive effects of reactive species on the body we must

analyze several determining factors including the concen-tration half-life and diffusibility of the reactive speciesproduced When the cell is utilizing these molecules forsignalling purposes they usually possess very short half-lives and very limited diffusibility or are present in lowconcentrations [14] For example monocytes and neutrophilsuse NADPH oxidase to produce the superoxide anion as adefence against bacterial or fungal infection [15] Consideringthat the superoxide anion has a very short half-life (10minus6 s)a very limited ability to diffuse throughout the cell and isgenerated in a small concentration onto a focused target (iebacteria or fungi) [14] it is generally viewed as beneficial inthis context Numerous other examples indeed derivativesfrom reactions involving the superoxide anion includingH2O2and hypochlorite also play an important role in the

neutralization of harmful pathogens and maintenance of ahealthy cell Similarly antioxidants also play an importantrole in maintaining cellular functions in the face of redoxmodulations through a variety of mechanisms

3 What Is an Antioxidant

As the name implies antioxidants are compounds thatneutralize reactive species by decreasing their reactivity in


Cytoplasm

Nuclear membrane

Nucleus

ROS RNS Glutamate

Nrf2

[O][N]

Nrf2

Gq

Nrf2

[P]

Nrf2

Keap1

DAG

Nrf2

Keap1

SH

Nrf2

Nrf2MafGST

HMOX

NQO1

GCL

ARE

Bach1

Keap1C273C288

C151

Keap1C273C288

C151

=

=

Keap1Cys

residues∟

Cys

residues∟

P

Nrf2

Nrf2

Keap1

Nrf2

Keap1 ProteasomeDegradationUb

UbUb

Ub

Stressor

Chemical modification of Keap1 (ROSRNS) and Nrf2 (glutamate)

Liberation of Nrf2

Nuclear translocation

Displacement of Bach1

Nrf2 binds to ARE

Increased expression of antioxidant enzyme genes

Keap1 binds with Nrf2

Polyubiquitination of Nrf2

Degradation

Keap1

PKC-120575

1205731120572512057311205725

12057311205725

O=NndashS

NO+

Figure 3 Mechanisms of Nrf2 activation and degradation ROS reactive oxygen species RNS reactive nitrogen species Nrf2 nuclearfactor- (erythroid-derived-2-) like 2 Keap1 Kelch-like ECH-associated protein 1 DAG diacylglycerol PKC protein kinase C Bach1transcription regulator protein BACH1 Maf transcription factor Maf ARE antioxidant response elements GCL glutamate-cysteine ligaseGST glutathione-S-transferase NQO1 NADPHquinone oxidoreductase 1 HMOX heme oxygenase Ub ubiquitin

the body [2] We can divide antioxidants into two broad cat-egories endogenous and exogenousThe antioxidants withinthe body are composed of antioxidant enzyme defenses(Table 2) and additional antioxidant compounds such asmelatonin and glutathione that are internally synthesized

Outside of the body antioxidants can be supplied by thediet with a wide variety of natural and synthetic compoundsfound in complex mixtures (such as chocolate or olive oil) orisolated to be taken as a supplement [16] The mechanism ofaction of each antioxidant will vary depending upon locationchemical structure and bioavailability within the body aswellas the degree of redox modulation experienced by the cell

4 The Endogenous AntioxidantResponse System

Under conditions of oxidativenitrosative stress the antiox-idant response system (ARS) becomes active in order toensure cellular survival and restoration of a balanced redoxstatus [17] In our body Nrf2 acts as a master control for most

of our antioxidant defenses including the ones in the brainAs shown in Figure 3 a stressor can act directly or indirectlyto influence the activation of the Nrf2 signal transductionpathway In fact Habas et al report that neuronal activityat the tripartite synapse regulates Nrf2 activity in astrocytes[18] Following an increase in neuronal activity signalledthrough neurotransmitters such as glutamate the astrocyticNrf2 signalling cascade is triggered via stimulation of groupI metabotropic glutamate receptors and Ca2+i Regardlessof the stressor in question the translocation of Nrf2 intothe nucleus can be accomplished in two primary wayschemical modification of cysteine residues on Keap1 andorphosphorylation of Nrf2 [19]

In the kinase-independent mechanism of Nrf2 dissocia-tion reactive species directly oxidize (C151 C273 and C288)[20] or nitrosylate [21] key cysteine residues on Keap1 aprotein bound to Nrf2 that facilitates its polyubiquitinationand subsequent degradation under normal conditions Thisprocess creates chemically modified cysteine residues (oxi-dized disulphide bridges or S-nitrosothiol groups) that allowfor Nrf2 to become free within the cytosol


Table2En

dogeno

ussyste

mof

antio

xidant

enzymes

Antioxidant

enzyme

Cofactorsubstrate

Reactio

ncatalyzed

Locatio

nBiochemicalfunctio

n

Cop

per-zinc-SOD(Cu

Zn-SODorS

OD1)[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2

Cytosolnu

cleus

mito

chon

dria

(interm

embrane

space)

Catalyzesthe

dism

utation

reactio

nof

superoxide

toH

2O2to

decrease

itsredu

ctionpo

tential

Manganese

SOD(M

nSOD

orSO

D2)

[93]

Manganeselowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Mito

chon

drialm

atrix

Samea

sabo

ve

ExtracellularS

OD(ecSOD

orSO

D3)

[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Isoform

secreted

extracellularly

Samea

sabo

ve

Glutathione

peroxidase

(GPx

)[93]

GSHlowastlowast

Seleniumlowast

(1)R

-SeminusH

++

ROOHO

NOOminus

rarr

ROHO

NOminus

+R-SeOH

(2)2

GSH

+R-SeOHrarr

GS-SG

+R-Seminus

H+

Throug

hout

theb

ody

Redu

celip

idhydrop

eroxides

toalcoho

lsandH

2O2to

water

Glutathione-S-tr

ansfe

rase

(GST

)[94]

GSHlowastlowast

GSH

+RXrarr

GSR

+HX

X=leavinggrou

pR=ele

ctroph

ilicg

roup

Cytosol

mito

chon

dria

peroxisome

Detoxificatio

nof

xeno

biotics

Glutathione

redu

ctase(GR)

[94]

FADlowast

NADPHlowastlowast

GS-SGlowastlowast

GSSG+NADPHrarr

2GSH

+NADP+

Cytosol

mito

chon

drialm

atrix

Maintenance

ofGSH

levels

Catalase

(CAT

)[93]

Fe2+andFe3+lowast

H2O

2rarr

H2O

+O

2Th

roug

hout

theb

ody

lowestintheb

rain

Redu

cesH

2O2to

water

and

oxygen

Peroxiredo

xins

(Prx)[95]

Thioredo

xin(Trx)lowastlowast

(1)P

rxred+H

2O2rarr

Prxo

x+

2H2O

(2)P

rxox+Trxr

edrarr

Prxr

ed+

Trxo

x

Throug

hout

theb

ody

(intracellular)

Redu

cesH

2O2to

water

Prxisredu

cedby

Trxto

beused

insubsequent

reactio

nslowastCofactorlowastlowastsubstrateSO

Dsup

eroxided

ismutase


In the kinase-dependentmechanism ofNrf2 dissociationa stressor such as glutamate activates the Gq pathwayleading to the phospholipase C (PLC) catalyzed breakdownof phosphatidylinositol 45-bisphosphate (PIP

2) into diacyl-

glycerol (DAG) and inositol 145-triphosphate (IP3) [22]The

membrane bound DAG acts as a physiological activator ofPKC which proceeds to subsequently phosphorylate S40 onNrf2 [23] According to recent studies although PKC-120573 is themost abundant isoform in astrocytes [24] the predominantPKC isoform that participates in the phosphorylation of Nrf2is PKC-120575 [25] Since the delta isoform of PKC is novel itonly requires DAG alone to become active [25] and as suchthe mechanism of increased [26] Ca2+i by IP

3is discussed

elsewhere [22]As a result of one or both of the mechanisms above

numerous importins including 1205725 and 1205731 bind to the newlyexposed NLS on Nrf2 to facilitate nuclear translocation [27]Once inside the nucleus Nrf2 displaces Bach1 a transcrip-tional repressor of antioxidant response elements (ARE) andheterodimerizes with transcription factor Maf to bind toARE on the DNA [28] Consequently increased expressionof endogenous antioxidant enzyme genes such as NQO1HMOX-1 GCL and GST occurs increasing cellular defensesagainst detrimental redox modulations [29]

Once the cell has effectively compensated for the redoxmodulation a deactivation cascade commences involving thephosphorylation of glycogen synthase kinase 3120573 (GSK3120573)via unknown tyrosine kinases [28] GSK3120573 proceeds tophosphorylate Fyn a nonreceptor protein-tyrosine kinaseto facilitate its translocation into the nucleus Once insidethe nucleus Fyn phosphorylates Y568 on Nrf2 to facilitatenuclear export which is immediately followed by Keap1association polyubiquitination and proteolysis

Considering that our endogenous antioxidant responsesystem is able to tightly regulate the amount of reactivespecies and minimize related cellular damage the role ofexogenous antioxidants seems on the surface superfluousHowever Kaspar et al [28] found that exogenous antioxi-dants have a priming effect on the antioxidant response sys-tem [19] Following approximately 05ndash1 hour after exposureantioxidants were found to induce the phosphorylation ofKeap1 (Y85) Fyn (Y213) and Bach1 (Y486) via unknowntyrosine kinases to facilitate their export out of the nucleusTheoverall effect of nuclear exportation of negative regulatorsof Nrf2 is reduced competition for ARE (with Bach1) anddecreased nuclear export and degradation ofNrf2 via Fyn andKeap1 Working together with our endogenous antioxidantresponse system exogenous antioxidants allow for a moreenhanced and efficient defense against detrimental redoxmodulations

5 Mechanisms of Action ofExogenous Antioxidants

Aside from enhancing the efficiency of antioxidant generegulation exogenous antioxidants also exert their effectsthrough additional mechanisms of action In cases such astocopherols and resveratrol 2 or 3 different actions can be

simultaneously carried out to counter the effects of detrimen-tal redox modulations [30 31] Shown in Figure 4 below areseveral examples of antioxidant reactions that take place inthe body In general there are several common antioxidantmechanisms of action as described in Figure 4

51 Hydrogen Atom Transfer Electron Donation and DirectRadical Scavenging In free radical scavenging there arethree known primary mechanisms of action hydrogen atomtransfer (Reaction 1A) electron donation (Reaction 1B)and direct radical scavenging (Reaction 1C) In H atomtransfer a reactive hydrogen-containing group on the antiox-idant compound undergoes homolytic fission generating ahydrogen radical and antioxidant radical [32] The hydrogenradical is then able to interact with the free radical creatinga less reactive species The antioxidant radical while stillreactive is relatively less dangerous and can bind withanother antioxidant radical to form a nonreactive dimerIn electron donation the antioxidant compound containinga conjugated system donates an electron to the reactivespecies producing an anion [32ndash35] Using its conjugatedsystem the antioxidant is able to electronically redistributethe positive charge throughout its chemical structure or adoptan alternative stable conformation as is the case for catecholcontaining compounds such as catechins [36] or caffeic acid[37] In the particular case of caffeic acid the compoundinitially undergoes deprotonation under physiological pHconditions allowing for electron donation to occur from thecatechol-like moiety effectively reducing the nitronium ion[37] In direct radical scavenging the antioxidant absorbsa radical into its structure producing a less reactive finalproduct that possesses reduced cytotoxicity [33 38 39]

52 Metal Chelation In order to chelate metals the antiox-idant must contain free electron pairs with which to formcoordinate or normal covalent bonds with the free metalion [40] Common examples of antioxidant ligands includepolyphenols [41] and various flavonoids [42] However itis also possible to have other antioxidants using sulfuror nitrogen atoms to chelate metal ions with or withouta resulting de-protonation [40] Once the metal ion andantioxidant interact the antioxidant donates electrons to themetal ion (the number is dependent upon the nature of thecovalent bond as described above) reducing it to its groundelectronic state and inhibiting its ability to participate in RSgenerating reactions

53 Restoration of Antioxidant Levels As our body works tomaintain the redox status our endogenous supply of antioxi-dants begins to diminish effectively reducing our capacity tofight excessive amounts of reactive species In order to supple-ment our antioxidant defenses we can ingest food or supple-ments containing natural or synthetic compounds that eitherget directly converted into the endogenous antioxidant or aidin its replenishment Two representative examples of lipoicacid and N-acetylcysteine and its amide are explained below

531 N-Acetylcysteine (NAC) and N-Acetylcysteine Amide(NACA) OnceNACorNACAreaches the cells it is absorbed


CAT

Mn-SOD

GPx CAT

Zn Cu-SOD

Oxidized tocopherol derivative

NACNACA

Dopamine

Resveratrol

(+)POH 1A

MOA-B

Selegiline4

5

MPO

MC

MC

Prx(R)

or

2

7

GRGPx(selenium)

GSH

GSSG(+)

3 6

Catechin

Caffeic acidquinone

nitrate+

Caffeic acid

Nitro-catechin1B

1C

H2O2

H2O + O2

H2O + O2

O2∙minus O2

∙minus

NO∙

Fe2+

Fe2+

NO2+

1O2

H2O2 + other products

H2O2


Fe2+ or Cu+

2H2O

PO∙ + H2O

OH∙

120572-tocopherol + 3O2

(eg 120572-tocopherol quinone)

120572-tocopherol

ONOOminus

Figure 4 Mechanisms of action of exogenous antioxidants Red enzymes green other products purple cofactorsubstrate black reactivespecies CAT catalase MC metal chelator POH polyphenol GSSG oxidized glutathione MPO myeloperoxidase Reaction legend 1A H-atom transfer 1B electron donation 1C direct scavenging 2 metal chelation 3 restoration of endogenous antioxidants 4 inhibition ofRS generating species and reactions 5 support of endogenous antioxidant enzymes 6 cofactor in antioxidant enzymes 7 singlet oxygenquenching

into the cytosol where it is hydrolyzed to release cysteinethe limiting reagent in the formation of GSH [43] Using120574-glutamylcysteine synthetase glutamine and cysteine arecombined into 120574-glutamylcysteine where a further additionof glutamine produces glutathione

532 Reduced Lipoic Acid In its reduced form dihydrolipoicacid (DHLA) can aid in the restoration of endogenousantioxidants including vitamin C vitamin E and GSH byacting as a reducing agent [44]

54 Inhibition of RS Generating Enzymes and ReactionsCommonly used as an adjunct therapy for Parkinsonrsquos disease(PD) selegiline acts as a selective irreversible inhibitor ofmonoamine oxidase B (MAO-B) [45] By doing so selegilineincreases dopamine availability and reduces the requireddosage of L-DOPA minimizing side effects A secondaryeffect of this drug is to reduce the amount of hydrogenperoxide a natural by-product of dopamine metabolism inthe neuron [45]

55 Promote Activities of Antioxidant Enzymes Certainantioxidants play an indirect role in the protection of cellsagainst oxidative stress bymodulating the expression of someendogenous antioxidant enzymes Two examples of such amechanism of action involve lipoic acid and resveratrol

551 Lipoic Acid This exogenous antioxidant has the abilityto alter the expression of phase II metabolic enzyme genes(conjugating enzymes such as UDP-glucosyltransferase sul-fotransferases and glutathione-S-transferases) through Nrf2dependent pathway [44]

552 Resveratrol Among its many other mechanisms ofaction resveratrol has been shown to induce sirtuin activity[46] leading to nuclear translocation of the FOXO transcrip-tion factor [47] an increase in FOXO3a transcription andupregulation of mitochondrial Mn-SOD [48]

56 Cofactor in Antioxidant Enzymes In order for theendogenous antioxidant enzymes to work properly they


require numerous cofactors from organic (heme and flavin)and inorganic (metal ions) sources A common enzymeparticipating in the detoxification of reactive species iscytosolic glutathione peroxidase which requires a seleniumcofactor bound to a cysteine residue to act as a catalyticsite for the enzymeThemechanism involves hydroperoxidesor peroxynitrites oxidizing the selenol on the selenocysteineactive site on GPx to create less reactive alcohols and nitritesrespectively [49] The oxidized selenocysteine is reduced viatwo units of GSH into its corresponding selenic acid It hasalso been proposed that thioredoxin reductase may reduceoxidized selenocompounds at the expense of NADPH [50]

57 Singlet Oxygen Quenching Certain antioxidants such asthe tocopherols (VitaminE) exhibit a potent quenching effectwhen reacting with singlet oxygen The two known methodsby which singlet oxygen is neutralized involve physical orchemical quenching of the excited electronic state Whileeach of these processes is not mutually exclusive in solution(or in our case in vivo) physical quenching is usually thepredominant mechanism [30]

In physical quenching a charge transfer occurs followingan electronic interaction between the singlet oxygen and thetocopherol that results in the singlet oxygen molecule beingdeactivated to its triplet configuration [30] It is hypothesizedbyGorman et al (1984) that this occurs via intersystem cross-ing induced by spin-orbit coupling [51] Chemical quenchinghas the same net effect as physical quenching resulting ina deactivation of a singlet oxygen molecule However thismechanism of quenching involves the incorporation of thesinglet oxygen molecule into the tocol structure to create aquinone andor quinone-epoxide as well as other oxidizedproducts [30]

Through our understanding of antioxidant mechanismsof action it becomes possible to hypothesize which com-pound would be best suited to counteract a neuropsychiatricdisease For example a hallmark of PD pathology is excessiron in the substantia nigra pars compacta that subsequentlygenerates reactive species via the Fenton and Haber-Weissreactions [52] Therefore a possible strategy to combat PDwould be to utilize a compoundwith iron chelation properties[53] such as flavonoids or DHLA However although antiox-idants possess many positive functions within our body likeany pharmacologically active compound they also have sideeffects and in some cases detrimental effects Some potentialproblems surrounding antioxidants will be covered in thefollowing section

6 Limitations of Antioxidants

At first glance antioxidants appear to be a panacea How-ever as with any pharmacologically active compound thereare limitations to their usage and effectiveness within thebody These limitations are mostly concerned with thedosageconcentration route of administration possible druginteractions and negative side effects of the antioxidants

61 DosageConcentration In order to demonstrate thispoint effectively we will examine the case of the amyloid-120573

peptide one of the major contributing factors in the patho-physiology of Alzheimerrsquos disease (AD) [54] In a patientthat is not exhibiting symptoms of AD there is a very smallconcentration (01ndash10 nM) of the amyloid-120573 peptide presentin the CSF and plasma [55] At these low physiologicalconcentrations amyloid-120573 exhibits antioxidant effects usinga hydrophilic moiety to chelate transition metals (Cu andFe ions) as well as a cysteine residue on Met35 as a freeradical scavenger to prevent lipoprotein oxidation [55] Infact in comparison to the well-known antioxidant ascorbateamyloid-120573 levels correlate better with oxidative resistance inthe CSF [56] However at higher physiological (amyloid-120573) usually in the 120583M range and in the presence of tran-sition metals the peptide demonstrates prooxidant activity[55] This general principle of toxicity in proportion to theadministered dose can be widely applied to almost everypharmaceutical including exogenous antioxidants

62 Route of Administration In the context of antioxidantsthe most common method of administration is oral due toits high compliance among patients Considering that oralintake of antioxidants is most relevant it is worth noting thatfirst-pass metabolism dietary intake and BBB permeabilityhave dramatic effects on the cerebral absorption and bioavail-ability of the ingested antioxidant [57] A prominent examplewould be the antioxidant selegiline When administered asan adjunct therapy with L-DOPA for the treatment of PD itis recommended that the patient ingests a high-fat meal toincrease the absorption of the drug due to its hydrophobicproperties [45]

63 Drug Interactions As a consequence of the combinationof aging populations and a rise in popularity of nutritionalsupplements interactions between antioxidants and pharma-ceuticals constitute an emerging area of research and inquiryFrom a pharmacodynamics perspective antioxidants couldact as competitive or noncompetitive antagonists (reversibleor irreversible) with medication effectively reducing thetherapeutic window of themedication A prominent exampleis the possible physiological antagonism of nifedipine anantihypertensive agent by melatonin [58] Melatonin is anendogenous antioxidant that plays an important role inprotecting against free radical-induced oxidative damage[59] While the exact mechanism is unknown melatonin isthought to interfere with nifedipinersquos mechanism of actionthrough directly interacting with several enzymes involved incalcium signalling including calmodulin or adenylate cyclase

From a pharmacokinetic perspective in contrast to apharmacodynamic interaction the antioxidant would affectthe concentration of the medication at several sites includ-ing the gastrointestinal tract binding to plasma proteinsmetabolism by CYP enzymes and renal clearance A pop-ular example involves the inhibitory interactions betweencomponents of certain fruits such as grapefruit known asfuranocoumarins and intestinal CYP3A4 [60] Upon inges-tion of the furanocoumarins intestinal CYP3A4 is inhibitedleading to increased oral bioavailability of a drug [60]Considering that the half-life of the drug is unchanged thiscan lead to an unsafe peak plasma concentration within


the patient A similar effect can be found following ingestionof curcumin an antioxidant component of turmeric [61] Ina study by Burgos-Moron et al curcumin has been shown toinhibit cytochrome P450 enzymes glutathione-S-transferaseand UDP-glucuronosyltransferase leading to a potentiallytoxic increase in the concentration of any medications thata patient may be taking

64 Negative Side Effects One of the most important issuesto address in this context is the false equivalency betweenldquonaturalrdquo and ldquosaferdquo often made by those who are waryof the side effects and sceptical of the efficacy of modernpharmaceuticals As mentioned earlier the dosage of anypharmacologically active compound must be carefully regu-lated in order to stay within the experimentally determinedtherapeutic window Once the given intake exceeds themedian toxic dose (TD

50) negative side effects can begin

to manifest themselves as distressing physical symptomsOne example of negative side effects can be seen in themechanism of action of a key ingredient in green and blackteas epigallocatechin gallate (EGCG) [62] Purported as astrong antioxidant EGCGalso displays cytotoxicity in vitro inboth cancerous and primary human cell lines Whether theseeffects can be translated into an in vivo context remains to beseen

Overall these examples highlight the desperate need formore peer-reviewed research into the efficacy and toxicity ofantioxidant compounds that are currently being ingested bythe public

7 How Are Oxidative Stress and AntioxidantsRelevant to Brain Health

Thus far we have considered oxidative stress in a cellularcontext However considering that the body is much morethan the sum of its parts it is important to apply ourmechanistic and cellular understanding of oxidative stress tothe general concept of brain health According to Halliwelland Emerit et al the brain possesses several key physiologicalfeatures that make it susceptible to oxidative stress (Figure 5)[7 63] (1) High O2 Utilization Relative to the rest ofthe body the brain accounts for a small fraction of bodyweight However since it uses a high supply (up to 20)of available oxygen toxic by-products such as hydrogenperoxide and superoxide are inevitably produced and beginto cause damage (2) High PUFA Content The neuronalmembrane consists of numerous polyunsaturated fatty acids(PUFA) notably docosahexaenoic acid (DHA) Vulnerableto oxidation by reactive species PUFA can be oxidizedinto radicals and 4-hydroxynonenal (4-HNE) a cytotoxiccompound that interferes with neuronal metabolism (3)Presence of Redox-Active Metals In the average adult brainthere is approximately 60mg of nonheme iron usually boundto ferritin and hemosiderin In a normal healthy brain themovement of iron into the brain is controlled via transferrinand its associated receptors However if there is damage tothe brain especially in areas with high iron content (sub-stantia nigra caudate nucleus putamen and globus pallidus)

iron is released from ferritin or diffuses through damagedmicrovasculature Once inside the brain this catalytic ironcauses extensive amounts of damage due to the negligibleiron-binding ability of the CSF (4) High Ca2+ Flux acrossNeuronal Membranes In the presence of reactive speciessuch asH

2O2 disruptions inmitochondrial and endoplasmic

reticulum function specifically to their calcium sequestrationabilities can cause a rise in intracellular Ca2+ This causes theproduction of reactive species by mitochondria to increaseand cause further damage It has additionally been reportedby Fonfria et al that in the presence of reactive species suchasH2O2 someneurons and glial cells allow forCa2+ influx via

specific cation channels initiating a detrimental cascade thatculminates in cytoskeletal damage [64] (5)Excitotoxic AminoAcids Once reactive species have induced a state of oxidativestress in neurons there is a release of glutamate following celldeath This excitatory neurotransmitter proceeds to bind toglutamate receptors on neighbouring neurons causing cation(Ca2+ and Na+) influx and eventually necrosis This initiatesan excitotoxic ldquochain reactionrdquo in which neurons continu-ally experience excessive extracellular glutamate levels Theproblem is further compounded by disruptions in glutamatetransporters and glutamine synthetase activity (6) Autoxi-dizable Neurotransmitters Catecholamine neurotransmitters(dopamine epinephrine and norepinephrine) can react withO2to produce superoxide and quinonessemiquinones that

readily bind to sulfhydryl side chains and deplete the alreadylow cerebral GSH reserves (7) Low Antioxidant DefensesThroughout the brain there are lower levels of antioxidantdefenses relative to the rest of the body The only substantialantioxidant enzyme in the brain is catalase which is verylimited in its ability to detoxify H

2O2since it is localized to

microperoxisomesAs a result various neuropsychiatric diseases manifest

themselves as exploitations of these substrates and cofactorsthat usually contribute to normal brain health The mainsources of reactive species in the brain are as in the rest ofthe body by-products of normal homeostatic functions suchas protein degradation and energy production (Table 3)

8 Antioxidants andNeuropsychiatric Disorders

Despite these theoretical and practical difficulties antioxi-dants have the potential to act as effective treatments for avariety of neuropsychiatric disorders It has been previouslyestablished in patients with these neuropsychiatric disordersthat there is an imbalance in the levels of antioxidants inthe brain and blood plasma as well as some elements ofmitochondrial dysfunction For example patients with ADwere found to have decreased plasma levels of well-knownantioxidants lycopene vitamin A vitamin C and vitaminE [65] Unfortunately clinical trials directly treating thedisorder with supplementation have not displayed positiveresults with some cases demonstrating a progressive declinein cognitive function in participants [66] While these resultsare negative and do not support antioxidant therapy a varietyof factors such as the prooxidant effects of antioxidants


Cerebralsusceptibilityto oxidative

damage

Highpolyunsaturatedfatty acid content

Presence of redox-active metals (Cu

Fe Mn)

Presence ofexcitotoxic amino

acids

Autoxidizableneurotransmitters

Low antioxidantdefenses

Redox modulations

Severity of illness

(20 of total supply)

High O2 utilization

across neuronalmembranes

High Ca2+ flux

minus

minus

+

+

Figure 5 Contributing factors to the cerebral susceptibility to oxidative damage

Table 3 Various biological sources of reactive species in the brain

Source of reactive species inthe brain Function in the brain General role in neuropathology

Organelle Mitochondria [7] Generates ATP Defect or reduction in mitochondrialcomplex IIIIIIIV activity

Enzyme

Monoamine oxidases(MOA-A and MOA-B) [96] Degrades neurotransmitters

Increased or decreased activity can leadto neurotransmitter imbalances as well asexcess reactive species

Nitric oxide synthase [97] Synthesis of nitric oxide Production of superoxide anion duringnormal NO∙ production

Xanthine oxidase [98] Catabolism of purines Produces superoxide anions duringnormal metabolism

Cytochrome P450 enzymes[99]

Drug metabolismBioactivation of neurosteroids such asdehydroepiandrosterone (DHEA)Metabolism of retinoic acid (regulatesgene expression)Cholesterol turnover in the brain

Reduced DHEA levels correlated withmemory impairmentAltered gene expressionReduced cholesterol turnover leading toaccumulation in the brain

Metabolism Arachidonic acid (AA)metabolism [97]

Maintains membrane fluidityAids in the growth and repair of neuronsParticipates in activation of enzymes tostore free fatty acids in the brain(prevents oxidative damage)

Elevated AA metabolism andoroverexpression of metabolizing enzymesIncreased amounts of free fatty acids


and timing of administration can influence the outcomeof the trial Considering that reduced antioxidant enzymeactivity specifically superoxide dismutase glutathione per-oxidase and glutathione reductase and increased levels of8-isoprostane were found in the CSF plasma and urineof patients with mild cognitive impairment (MCI) [65] acondition commonly seen in pre-AD patients it is likely thatthe failure of antioxidant therapy in the treatment of ADcan be ameliorated through earlier interventionThe conceptof early intervention with antioxidant therapy still showspromise and should be investigated further in different con-texts as the potential for an effective treatment acrossmultipleneuropsychiatric disorders is high considering their commonpathophysiological origins and mechanisms of progression

9 Redox Modulations andNeuropsychiatric Disorders

Redox modulations play a major role in the developmentand progression of neuropsychiatric disorders [67] Processessuch as lipid peroxidation protein and DNA oxidation andmitochondrial dysfunction in the brain and periphery areindicative of neuropsychiatric disease among other thingsFor example mitochondrial dysfunction in PD [68] specif-ically complex I dysfunction [69] is linked to increasedoxidative damage to the macromolecules and toxic productssuch as 4-hydroxynonenal (4HNE) found in PD Moreover4HNE is correlated to damages to the 2620S proteasomesystem [70] in PD

In response to these toxic insults and enzymatic dysregu-lation a broad-spectrum neuroprotective response is elicitedthat includes the increased expression of GSH peroxidasesuccinic semialdehyde reductase heme oxygenase-1 andNADPH dehydrogenase-1 enzymes Considering that thedegeneration of the SNpc is at least correlatedwith an increasein neuronal and astroglial NADPH dehydrogenase-1 expres-sion this constitutes a potential intervention point for thera-peutics including antioxidants Whether artificial or naturalinducers of endogenous antioxidant enzyme activity and theneuronal Nrf2 system could hypothetically lead to an ame-lioration of any neuropsychiatric pathology remains an openand challenging question for basic and translational research

Furthermore mitochondrial dysfunction leading tooxidative damage has long been linked with many neuropsy-chiatric disorders such as AD [71ndash75] bipolar disorder(BD) [76ndash81] major depressive disorder (MDD) [82ndash84]schizophrenia (SCZ) [85] Huntingtonrsquos disease (HD) [86ndash88] and amyotrophic lateral sclerosis (ALS) [89ndash91] In factthere are common pathophysiological points between theseneuropsychiatric disorders emphasizing the possibility ofcommon pharmacological intervention through synthetic ornatural antioxidant compounds

10 Future Directions

In light of the available evidence regarding antioxidants it isclear that more studies are needed to explore their potentialpharmacological properties While there are many published

and peer-reviewed studies regarding themechanismof actionand biological effects of antioxidants there are few thatseek to address the underlying issue of drug interactionsspecifically with respect to medication prescribed for neu-ropsychiatric disorders In order to supplement this growingbody of research clinical trials regarding the efficacy ofantioxidants as potential stand-alone or adjunctive treat-ments need to be conducted In addition more studies arerequired to assess the long-term safety of antioxidants inhealthy and nonhealthy individuals From here it becomespossible to closely examine the physicochemical propertiesof each antioxidant and use these as a basis for future drugdevelopment in the treatment of neuropsychiatric disordersand other various illnesses in accordance with previouslyestablished CNS drug characteristics [92]

AbbreviationsROS Reactive oxygen speciesRNS Reactive nitrogen speciesNrf2 Nuclear factor (erythroid-derived 2)-like 2Keap1 Kelch-like ECH-associated protein 1PLC Phospholipase CPIP2 Phosphatidylinositol 45-bisphosphateDAG DiacylglycerolIP3 Inositol triphosphatePKC Protein kinase CBach1 Transcription regulator protein BACH1Maf Transcription factor MafNQO1 NADH quinone oxidoreductase 1HMOX-1 Heme oxygenase 1GCL Glutamate cysteine ligaseGST Glutathione S-transferaseGSK3120573 Glycogen synthase kinase 3 betaGSH GlutathioneDHLA Dihydrolipoic acid

Conflict of Interests

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

Acknowledgments

This paper is supported by funding provided by the Centerfor Addiction and Mental Health (CAMH) and CanadianInstitutes of Health Research (CIHR)

References

[1] B Halliwell and JM C Gutteridge Free Radicals in Biology andMedicine Clarendon Press Oxford UK 4th edition 2007

[2] B Harwell ldquoBiochemistry of oxidative stressrdquo BiochemicalSociety Transactions vol 35 part 5 pp 1147ndash1150 2007

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

[4] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007


[5] H Sies ldquoBiochemistry of oxidative stressrdquo Angewandte ChemieInternational Edition in English vol 25 no 12 pp 1058ndash10711986

[6] L M Sayre M A Smith and G Perry ldquoChemistry andbiochemistry of oxidative stress in neurodegenerative diseaserdquoCurrent Medicinal Chemistry vol 8 no 7 pp 721ndash738 2001

[7] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006

[8] M T Lin and M F Beal ldquoMitochondrial dysfunction andoxidative stress in neurodegenerative diseasesrdquoNature vol 443no 7113 pp 787ndash795 2006

[9] K J Barnham C L Masters and A I Bush ldquoNeurodegen-erative diseases and oxidatives stressrdquo Nature Reviews DrugDiscovery vol 3 no 3 pp 205ndash214 2004

[10] K Jomova D Vondrakova M Lawson and M Valko ldquoMetalsoxidative stress and neurodegenerative disordersrdquo Molecularand Cellular Biochemistry vol 345 no 1-2 pp 91ndash104 2010

[11] CMWong LMarcocci L Liu andY J Suzuki ldquoCell signalingby protein carbonylation and decarbonylationrdquo Antioxidants ampRedox Signaling vol 12 no 3 pp 393ndash404 2010

[12] Y M W Janssen-Heininger B T Mossman N H Heintz etal ldquoRedox-based regulation of signal transduction principlespitfalls and promisesrdquo Free Radical Biology and Medicine vol45 no 1 pp 1ndash17 2008

[13] M Giorgio M Trinei E Migliaccio and P G Pelicci ldquoHydro-gen peroxide a metabolic by-product or a common mediatorof ageing signalsrdquo Nature Reviews Molecular Cell Biology vol8 no 9 pp 722ndash728 2007

[14] C C Winterbourn ldquoReconciling the chemistry and biology ofreactive oxygen speciesrdquo Nature Chemical Biology vol 4 no 5pp 278ndash286 2008

[15] W M Nauseef ldquoHow human neutrophils kill and degrademicrobes an integrated viewrdquo Immunological Reviews vol 219no 1 pp 88ndash102 2007

[16] J Bouayed and T Bohn ldquoExogenous antioxidantsmdashdouble-edged swords in cellular redox state health beneficial effectsat physiologic doses versus deleterious effects at high dosesrdquoOxidativeMedicine and Cellular Longevity vol 3 no 4 pp 228ndash237 2010

[17] T W Kensler N Wakabayashi and S Biswal ldquoCell survivalresponses to environmental stresses via the Keap1-Nrf2-AREpathwayrdquo Annual Review of Pharmacology and Toxicology vol47 pp 89ndash116 2007

[18] AHabas J Hahn XWang andMMargeta ldquoNeuronal activityregulates astrocytic Nrf2 signalingrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 110 no45 pp 18291ndash18296 2013

[19] S K Niture R Khatri and A K Jaiswal ldquoRegulation of Nrf2mdashan updaterdquo Free Radical Biology and Medicine vol 66 pp 36ndash44 2014

[20] K W Kang S J Lee and S G Kim ldquoMolecular mechanismof Nrf2 activation by oxidative stressrdquo Antioxidants and RedoxSignaling vol 7 no 11-12 pp 1664ndash1673 2005

[21] H-C Um J-H Jang D-H Kim C Lee and Y-J Surh ldquoNitricoxide activates Nrf2 through S-nitrosylation of Keap1 in PC12cellsrdquo Nitric Oxide vol 25 no 2 pp 161ndash168 2011

[22] N Mizuno and H Itoh ldquoFunctions and regulatory mechanismsof Gq-signaling pathwaysrdquo NeuroSignals vol 17 no 1 pp 42ndash54 2009

[23] W Li and A-N Kong ldquoMolecular mechanisms of Nrf2-mediated antioxidant responserdquo Molecular Carcinogenesis vol48 no 2 pp 91ndash104 2009

[24] A Pascale D L Alkon and M Grimaldi ldquoTranslocation ofprotein kinase C-120573II in astrocytes requires organized actincytoskeleton and is not accompanied by synchronous RACK1relocationrdquo Glia vol 46 no 2 pp 169ndash182 2004

[25] S K Niture A K Jain and A K Jaiswal ldquoAntioxidant-inducedmodification of INrf2 cysteine 151 and PKC-120575-mediated phos-phorylation of Nrf2 serine 40 are both required for stabilizationand nuclear translocation of Nrf2 and increased drug resis-tancerdquo Journal of Cell Science vol 122 part 24 pp 4452ndash44642009

[26] L Shao X Sun L Xu L T Young and J-F Wang ldquoMoodstabilizing drug lithium increases expression of endoplasmicreticulum stress proteins in primary cultured rat cerebralcortical cellsrdquo Life Sciences vol 78 no 12 pp 1317ndash1323 2006

[27] MTheodore Y Kawai J Yang et al ldquoMultiple nuclear localiza-tion signals function in the nuclear import of the transcriptionfactor Nrf2rdquoThe Journal of Biological Chemistry vol 283 no 14pp 8984ndash8994 2008

[28] JW Kaspar S K Niture and A K Jaiswal ldquoNrf2INrf2 (Keap1)signaling in oxidative stressrdquo Free Radical Biology andMedicinevol 47 no 9 pp 1304ndash1309 2009

[29] C Gorrini I S Harris and TWMak ldquoModulation of oxidativestress as an anticancer strategyrdquoNature Reviews DrugDiscoveryvol 12 no 12 pp 931ndash947 2013

[30] A Kamal-Eldin and L-A Appelqvist ldquoThe chemistry andantioxidant properties of tocopherols and tocotrienolsrdquo Lipidsvol 31 no 7 pp 671ndash701 1996

[31] C Alarcon de la Lastra and I Villegas ldquoResveratrol as anantioxidant and pro-oxidant agent mechanisms and clinicalimplicationsrdquo Biochemical Society Transactions vol 35 no 5pp 1156ndash1160 2007

[32] M Leopoldini T Marino N Russo and M Toscano ldquoAntiox-idant properties of phenolic compounds H-atom versus elec-tron transfer mechanismrdquoThe Journal of Physical Chemistry Avol 108 no 22 pp 4916ndash4922 2004

[33] B Poeggeler S Saarela R J Reiter et al ldquoMelatoninmdasha highlypotent endogenous radical scavenger and electron donor newaspects of the oxidation chemistry of this indole accessed invitrordquo Annals of the New York Academy of Sciences vol 738 pp419ndash420 1994

[34] J V Higdon and B Frei ldquoTea catechins and polyphenols healtheffectsmetabolism and antioxidant functionsrdquoCritical Reviewsin Food Science and Nutrition vol 43 no 1 pp 89ndash143 2003

[35] F Nanjo M Mori K Goto and Y Hara ldquoRadical scavengingactivity of tea catechins and their related compoundsrdquo Bio-science Biotechnology and Biochemistry vol 63 no 9 pp 1621ndash1623 1999

[36] P Janeiro and A M Oliveira Brett ldquoCatechin electrochemicaloxidation mechanismsrdquo Analytica Chimica Acta vol 518 no 1-2 pp 109ndash115 2004

[37] A Pannala R Razaq B Halliwell S Singh and C A Rice-Evans ldquoInhibition of peroxynitrite dependent tyrosine nitrationby hydroxycinnamates nitration or electron donationrdquo FreeRadical Biology and Medicine vol 24 no 4 pp 594ndash606 1998

[38] A S Pannala C A Rice-Evans B Halliwell and S SinghldquoInhibition of peroxynitrite-mediated tyrosine nitration bycatechin polyphenolsrdquo Biochemical and Biophysical ResearchCommunications vol 232 no 1 pp 164ndash168 1997


[39] G Scola D Conte P W D-S Spada et al ldquoFlavan-3-ol com-pounds from wine wastes with in vitro and in vivo antioxidantactivityrdquo Nutrients vol 2 no 10 pp 1048ndash1059 2010

[40] M B Chenoweth ldquoChelation as a mechanism of pharmacolog-ical actionrdquo Pharmacological Reviews vol 8 no 1 pp 57ndash871956

[41] R C Hider Z D Liu and H H Khodr ldquoMetal chelation ofpolyphenolsrdquo Methods in Enzymology vol 335 pp 190ndash2032001

[42] M P Corcoran D L McKay and J B Blumberg ldquoFlavonoidbasics chemistry sources mechanisms of action and safetyrdquoJournal of Nutrition in Gerontology and Geriatrics vol 31 no 3pp 176ndash189 2012

[43] R Bavarsad Shahripour M R Harrigan and A V AlexandrovldquoN-acetylcysteine (NAC) in neurological disorders mecha-nisms of action and therapeutic opportunitiesrdquo Brain andBehavior vol 4 no 2 pp 108ndash122 2014

[44] K P Shay R F Moreau E J Smith A R Smith and T MHagen ldquoAlpha-lipoic acid as a dietary supplement molecularmechanisms and therapeutic potentialrdquo Biochimica et Biophys-ica Acta vol 1790 no 10 pp 1149ndash1160 2009

[45] K Magyar ldquoThe pharmacology of selegilinerdquo InternationalReview of Neurobiology vol 100 pp 65ndash84 2011

[46] J M Denu ldquoFortifying the link between SIRT1 resveratrol andmitochondrial functionrdquoCellMetabolism vol 15 no 5 pp 566ndash567 2012

[47] M Stefani M A Markus R C Y Lin M Pinese I W Dawesand B J Morris ldquoThe effect of resveratrol on a cell model ofhuman agingrdquo Annals of the New York Academy of Sciences vol1114 pp 407ndash418 2007

[48] G J P L Kops T B Dansen P E Polderman et al ldquoForkheadtranscription factor FOXO3a protects quiescent cells fromoxidative stressrdquo Nature vol 419 no 6904 pp 316ndash321 2002

[49] L-O Klotz K-D Kroncke D P Buchczyk and H Sies ldquoRoleof copper zinc selenium and tellurium in the cellular defenseagainst oxidative and nitrosative stressrdquo Journal of Nutritionvol 133 no 5 pp 1448Sndash1451S 2003

[50] G E Arteel K Briviba and H Sies ldquoFunction of thioredoxinreductase as a peroxynitrite reductase using selenocystine orebselenrdquoChemical Research in Toxicology vol 12 no 3 pp 264ndash269 1999

[51] A A Gorman I R Gould I Hamblett and M C StandenldquoReversible exciplex formation between singlet oxygen 1Δ gand vitamin E Solvent and temperature effectsrdquo Journal of theAmerican Chemical Society vol 106 no 23 pp 6956ndash69591984

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

[53] R B Mounsey and P Teismann ldquoChelators in the treatment ofiron accumulation in Parkinsonrsquos diseaserdquo International Journalof Cell Biology vol 2012 Article ID 983245 12 pages 2012

[54] M P Murphy and H LeVine III ldquoAlzheimerrsquos disease and theamyloid-120573 peptiderdquo Journal of Alzheimerrsquos Disease vol 19 no 1pp 311ndash323 2010

[55] A Kontush C Berndt W Weber et al ldquoAmyloid-120573 is anantioxidant for lipoproteins in cerebrospinal fluid and plasmardquoFree Radical Biology and Medicine vol 30 no 1 pp 119ndash1282001

[56] A Kontush ldquoAmyloid-120573 an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimerrsquos diseaserdquo FreeRadical Biology and Medicine vol 31 no 9 pp 1120ndash1131 2001

[57] M S Alavijeh M Chishty M Z Qaiser and A M PalmerldquoDrug metabolism and pharmacokinetics the blood-brainbarrier and central nervous system drug discoveryrdquo NeuroRxvol 2 no 4 pp 554ndash571 2005

[58] P Lusardi E Piazza and R Fogari ldquoCardiovascular effects ofmelatonin in hypertensive patients well controlled by nifedip-ine a 24-hour studyrdquo British Journal of Clinical Pharmacologyvol 49 no 5 pp 423ndash427 2000

[59] H-M Zhang and Y Zhang ldquoMelatonin a well-documentedantioxidant with conditional pro-oxidant actionsrdquo Journal ofPineal Research vol 57 no 2 pp 131ndash146 2014

[60] D G Bailey G Dresser and J M O Arnold ldquoGrapefruit-medication interactions forbidden fruit or avoidable conse-quencesrdquo CMAJ vol 185 no 4 pp 309ndash316 2013

[61] E Burgos-Moron J M Calderon-Montano J Salvador ARobles and M Lopez-Lazaro ldquoThe dark side of curcuminrdquoInternational Journal of Cancer vol 126 no 7 pp 1771ndash17752010

[62] J HWeisburg D BWeissman T Sedaghat and H Babich ldquoInvitro cytotoxicity of epigallocatechin gallate and tea extracts tocancerous and normal cells from the human oral cavityrdquoBasicampClinical Pharmacology amp Toxicology vol 95 no 4 pp 191ndash2002004

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

[64] E Fonfria I C B Marshall I Boyfield et al ldquoAmyloidbeta-peptide(1-42) and hydrogen peroxide-induced toxicity aremediated by TRPM2 in rat primary striatal culturesrdquo Journal ofNeurochemistry vol 95 no 3 pp 715ndash723 2005

[65] X Wang W Wang L Li G Perry H-G Lee and X ZhuldquoOxidative stress andmitochondrial dysfunction in Alzheimerrsquosdiseaserdquo Biochimica et Biophysica ActamdashMolecular Basis ofDisease vol 1842 no 8 pp 1240ndash1247 2014

[66] T Persson B O Popescu and A Cedazo-Minguez ldquoOxidativestress in Alzheimerrsquos disease why did antioxidant therapy failrdquoOxidative Medicine and Cellular Longevity vol 2014 Article ID427318 11 pages 2014

[67] A Reynolds C Laurie R Lee Mosley and H E GendelmanldquoOxidative stress and the pathogenesis of neurodegenerativedisordersrdquo International Review of Neurobiology vol 82 pp297ndash325 2007

[68] A H K Tsang and K K K Chung ldquoOxidative and nitrosativestress in Parkinsonrsquos diseaserdquo Biochimica et Biophysica Acta vol1792 no 7 pp 643ndash650 2009

[69] C Henchcliffe and F M Beal ldquoMitochondrial biology andoxidative stress in Parkinson disease pathogenesisrdquo NatureClinical Practice Neurology vol 4 no 11 pp 600ndash609 2008

[70] K S P McNaught and C W Olanow ldquoProteolytic stressa unifying concept for the etiopathogenesis of Parkinsonrsquosdiseaserdquo Annals of Neurology vol 53 supplement 3 pp S73ndashS86 2003

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

[72] K Leuner K Schulz T Schutt et al ldquoPeripheral mitochondrialdysfunction in Alzheimerrsquos disease focus on lymphocytesrdquoMolecular Neurobiology vol 46 no 1 pp 194ndash204 2012

[73] J Choi H D Rees S T Weintraub A I Levey L-S Chinand L Li ldquoOxidative modifications and aggregation of CuZn-superoxide dismutase associated with alzheimer and Parkinson


diseasesrdquo The Journal of Biological Chemistry vol 280 no 12pp 11648ndash11655 2005

[74] J Wang S Xiong C Xie W R Markesbery and M A LovellldquoIncreased oxidative damage in nuclear and mitochondrialDNA inAlzheimerrsquos diseaserdquo Journal of Neurochemistry vol 93no 4 pp 953ndash962 2005

[75] R Sultana M Perluigi and D A Butterfield ldquoLipid peroxida-tion triggers neurodegeneration a redox proteomics view intotheAlzheimer disease brainrdquo Free Radical Biology andMedicinevol 62 pp 157ndash169 2013

[76] A C Andreazza L Shoo J-F Wang and L Trevor YoungldquoMitochondrial complex I activity and oxidative damage tomitochondrial proteins in the prefrontal cortex of patients withbipolar disorderrdquo Archives of General Psychiatry vol 67 no 4pp 360ndash368 2010

[77] C Gubert L Stertz B Pfaffenseller et al ldquoMitochondrial activ-ity and oxidative stress markers in peripheral blood mononu-clear cells of patients with bipolar disorder schizophrenia andhealthy subjectsrdquo Journal of Psychiatric Research vol 47 no 10pp 1396ndash1402 2013

[78] H K Kim A C Andreazza P Y Yeung C Isaacs-Trepanierand L T Young ldquoOxidation and nitration in dopaminergicareas of the prefrontal cortex from patients with bipolar disor-der and schizophreniardquo Journal of Psychiatry and Neurosciencevol 39 no 4 Article ID 130155 pp 276ndash285 2014

[79] M G Soeiro-de-Souza A C Andreazza A F Carvalho RMachado-Vieira L T Young and R A Moreno ldquoNumberof manic episodes is associated with elevated DNA oxidationin bipolar i disorderrdquo The International Journal of Neuropsy-chopharmacology vol 16 no 7 pp 1505ndash1512 2013

[80] A C Andreazza J-F Wang F Salmasi L Shao and L TYoung ldquoSpecific subcellular changes in oxidative stress inprefrontal cortex from patients with bipolar disorderrdquo Journalof Neurochemistry vol 127 no 4 pp 552ndash561 2013

[81] G Scola H K Kim L T Young and A C Andreazza ldquoA freshlook at complex i in microarray data clues to understandingdisease-specific mitochondrial alterations in bipolar disorderrdquoBiological Psychiatry vol 73 no 2 pp e4ndashe5 2013

[82] E H Tobe ldquoMitochondrial dysfunction oxidative stress andmajor depressive disorderrdquo Neuropsychiatric Disease and Treat-ment vol 9 pp 567ndash573 2013

[83] M Maes P Galecki Y S Chang and M Berk ldquoA reviewon the oxidative and nitrosative stress (OampNS) pathwaysin major depression and their possible contribution to the(neuro)degenerative processes in that illnessrdquo Progress inNeuro-Psychopharmacology and Biological Psychiatry vol 35no 3 pp 676ndash692 2011

[84] Y Milaneschi M Cesari E M Simonsick et al ldquoLipid peroxi-dation and depressed mood in community-dwelling older menand womenrdquo PLoS ONE vol 8 no 6 Article ID e65406 2013

[85] N Nishioka and S E Arnold ldquoEvidence for oxidative DNAdamage in the hippocampus of elderly patients with chronicschizophreniardquoAmerican Journal of Geriatric Psychiatry vol 12no 2 pp 167ndash175 2004

[86] 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

[87] M A Sorolla G Reverter-Branchat J Tamarit I Ferrer JRos and E Cabiscol ldquoProteomic and oxidative stress analysis

in human brain samples of Huntington diseaserdquo Free RadicalBiology and Medicine vol 45 no 5 pp 667ndash678 2008

[88] J M A Oliveira ldquoNature and cause of mitochondrial dysfunc-tion in Huntingtonrsquos disease focusing on huntingtin and thestriatumrdquo Journal of Neurochemistry vol 114 no 1 pp 1ndash122010

[89] A C Bowling J B Schulz R H Brown Jr and M FBeal ldquoSuperoxide dismutase activity oxidative damage andmitochondrial energy metabolism in familial and sporadicamyotrophic lateral sclerosisrdquo Journal ofNeurochemistry vol 61no 6 pp 2322ndash2325 1993

[90] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998

[91] P Shi J Gal D M Kwinter X Liu and H Zhu ldquoMitochondrialdysfunction in amyotrophic lateral sclerosisrdquo Biochimica etBiophysica Acta vol 1802 no 1 pp 45ndash51 2010

[92] H Pajouhesh andG R Lenz ldquoMedicinal chemical properties ofsuccessful central nervous system drugsrdquoNeuroRx vol 2 no 4pp 541ndash553 2005

[93] J M Mates C Perez-Gomez and I N De Castro ldquoAntioxidantenzymes and human diseasesrdquoClinical Biochemistry vol 32 no8 pp 595ndash603 1999

[94] M Deponte ldquoGlutathione catalysis and the reaction mecha-nisms of glutathione-dependent enzymesrdquo Biochimica et Bio-physica Acta vol 1830 no 5 pp 3217ndash3266 2013

[95] S G Rhee S W Kang T-S Chang W Jeong and K KimldquoPeroxiredoxin a novel family of peroxidasesrdquo IUBMB Life vol52 no 1-2 pp 35ndash41 2001

[96] S Gal H Zheng M Fridkin and M B H Youdim ldquoNovelmultifunctional neuroprotective iron chelator-monoamine oxi-dase inhibitor drugs for neurodegenerative diseases In vivoselective brain monoamine oxidase inhibition and preventionof MPTP-induced striatal dopamine depletionrdquo Journal ofNeurochemistry vol 95 no 1 pp 79ndash88 2005

[97] N A Simonian and J T Coyle ldquoOxidative stress in neu-rodegenerative diseasesrdquo Annual Review of Pharmacology andToxicology vol 36 pp 83ndash106 1996

[98] R Harrison ldquoStructure and function of xanthine oxidoreduc-tase where are we nowrdquo Free Radical Biology andMedicine vol33 no 6 pp 774ndash797 2002

[99] D F V Lewis ldquoOxidative stress the role of cytochromesP450 in oxygen activationrdquo Journal of Chemical Technology andBiotechnology vol 77 no 10 pp 1095ndash1100 2002

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Biological roles of reactive species

Neurological Cardiovascular Immune response Cell biology

Mediation of learning andmemoryInvolved in the regulation ofstriatal dopamine release viaglutamate

Regulation of cardiaccontractilityRegulation of vascular tone (egpenile erection) via NOproductionSignalling involving carotidbodies (monitor arterial oxygenlevels)

Response to foreign pathogens(oxidative burst)Production of cytokinesWound repair

EmbryogenesisPrevent overpopulation of cellsand destroys malfunctioningcellsCellular differentiation

MitochondriaSOD

GPx

CAT

Lipid

Domain of lipid peroxidation

Mitochondrial production of reactive species

4-HNE Cycli

satio

n pr

oces

ses

MDA

Oxidation of arachidonic acid produces8-isoprostane

Domain of protein oxidation Domain of DNA oxidation

|| |

| ||HN

Protein|

ProteaseAmino acids

peptides

2

1

3

4

56

Guanosine

8OhdG

Prx(R)

GSSG

GSHGR

NADPH

NADP+

NAD+

NADH Lactate

Pyruvate

Prx(O)

Trx(R) Trx(O)

Prx(R)

NO∙ O2∙minus

O2∙minusO2

O2

ONOOminus

Fe2+

Fe2+

Fe2+

Fe2+

Fe2+

Fe3+

Fe3+

Fe3+

Cu1+

Cu2+

H2O + O2

H2O

H2O

H2O

H2OH2O

H2O2

H2O2

H2O2

2H2O

ProteinndashCH2

ProteinndashCH2

ProteinndashCH2


OHminus

OHminus

NH3 Fe2+

H-C=O

H2NH2N

| |Fe3+



H2N

| |Fe3+

middot middot middotH2N

ProteinndashCH∙

ProteinndashCH∙

L∙

LO∙ + LOOH LOO∙

+OH∙

OH∙

O2 + H∙

O

O

N

N N

NH

OH HHH

HH

HO NH2

O

O

N

N N

NH

OH

OH

HHH

HH

HO NH2

Figure 1 Production of reactive species and the endogenous antioxidant system Red enzymes green other products purple cofactorsub-strate black reactive species

mitochondria [8] The primary reactive by-product thesuperoxide anion (O2

∙minus) is exported from the mitochondriainto the cytosol via an anion channel where it proceedsthrough numerous chemical reactions in our bodyrsquos attemptto reduce its toxicity Unfortunately at the same time andunder the correct environmental conditions the superoxideanion can be converted into additional reactive specieseither directly or indirectly through catalysis [9] A commonexample within the human body is the reduction of hydrogenperoxide into hydroxyl radicals via transition metals usually

iron (Fenton and Haber-Weiss reactions) [10] (followingequations)

Fe3+ + ∙O2minus

997888rarr Fe2+ +O2

(Reduction of ferric iron)(1)

Fe2+ +H2O2 997888rarr Fe3+ +OHminus + ∙OH(Fenton Reaction)

(2)

∙O2minus

+H2O2 997888rarr∙OH+OHminus +O2 (Net Reaction) (3)


RS


Protein alteration

Loss of function

Lipid peroxidation

4-HNE 8-iso


cell death

DNA alterations




Mitochondria

Formation of 8OhdG


O2

NH3+ NH3

+

COOminus COOminus

NO2

OH OH

O C

R

R

NH2 NH2

O O

OH

N

N N

N

NH2NH2

O

OO

O

N

NN

NNN

NHNH

OHOH

OH








2O2causes








Cytoplasm

Nuclear membrane

Nucleus

ROS RNS Glutamate

Nrf2

[O][N]

Nrf2

Gq

Nrf2

[P]

Nrf2

Keap1

DAG

Nrf2

Keap1

SH

Nrf2

Nrf2MafGST

HMOX

NQO1

GCL

ARE

Bach1

Keap1C273C288

C151

Keap1C273C288

C151

=

=

Keap1Cys

residues∟

Cys

residues∟

P

Nrf2

Nrf2

Keap1

Nrf2


UbUb

Ub

Stressor


Liberation of Nrf2



Nrf2 binds to ARE




Degradation

Keap1

PKC-120575

1205731120572512057311205725

12057311205725

O=NndashS

NO+









Table2En

dogeno

ussyste

mof

antio

xidant

enzymes

Antioxidant

enzyme

Cofactorsubstrate

Reactio

ncatalyzed

Locatio

nBiochemicalfunctio

n

Cop

per-zinc-SOD(Cu

Zn-SODorS

OD1)[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2

Cytosolnu

cleus

mito

chon

dria

(interm

embrane

space)

Catalyzesthe

dism

utation

reactio

nof

superoxide

toH

2O2to

decrease

itsredu

ctionpo

tential

Manganese

SOD(M

nSOD

orSO

D2)

[93]

Manganeselowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Mito

chon

drialm

atrix

Samea

sabo

ve

ExtracellularS

OD(ecSOD

orSO

D3)

[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Isoform

secreted

extracellularly

Samea

sabo

ve

Glutathione

peroxidase

(GPx

)[93]

GSHlowastlowast

Seleniumlowast

(1)R

-SeminusH

++

ROOHO

NOOminus

rarr

ROHO

NOminus

+R-SeOH

(2)2

GSH

+R-SeOHrarr

GS-SG

+R-Seminus

H+

Throug

hout

theb

ody

Redu

celip

idhydrop

eroxides

toalcoho

lsandH

2O2to

water

Glutathione-S-tr

ansfe

rase

(GST

)[94]

GSHlowastlowast

GSH

+RXrarr

GSR

+HX

X=leavinggrou

pR=ele

ctroph

ilicg

roup

Cytosol

mito

chon

dria

peroxisome

Detoxificatio

nof

xeno

biotics

Glutathione

redu

ctase(GR)

[94]

FADlowast

NADPHlowastlowast

GS-SGlowastlowast

GSSG+NADPHrarr

2GSH

+NADP+

Cytosol

mito

chon

drialm

atrix

Maintenance

ofGSH

levels

Catalase

(CAT

)[93]

Fe2+andFe3+lowast

H2O

2rarr

H2O

+O

2Th

roug

hout

theb

ody

lowestintheb

rain

Redu

cesH

2O2to

water

and

oxygen

Peroxiredo

xins

(Prx)[95]

Thioredo


(1)P

rxred+H

2O2rarr

Prxo

x+

2H2O

(2)P

rxox+Trxr

edrarr

Prxr

ed+

Trxo

x

Throug

hout

theb

ody

(intracellular)

Redu

cesH

2O2to

water

Prxisredu

cedby

Trxto

beused

insubsequent

reactio


Dsup

eroxided

ismutase



2) into diacyl-



3is discussed













CAT

Mn-SOD

GPx CAT

Zn Cu-SOD


NACNACA

Dopamine

Resveratrol

(+)POH 1A

MOA-B

Selegiline4

5

MPO

MC

MC

Prx(R)

or

2

7

GRGPx(selenium)

GSH

GSSG(+)

3 6

Catechin

Caffeic acidquinone

nitrate+

Caffeic acid

Nitro-catechin1B

1C

H2O2

H2O + O2

H2O + O2

O2∙minus O2

∙minus

NO∙

Fe2+

Fe2+

NO2+

1O2


H2O2


Fe2+ or Cu+

2H2O

PO∙ + H2O

OH∙



120572-tocopherol

ONOOminus









































damage



Fe Mn)


acids



Redox modulations

Severity of illness


High O2 utilization


High Ca2+ flux

minus

minus

+

+





Enzyme























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















RS


Protein alteration

Loss of function

Lipid peroxidation

4-HNE 8-iso


cell death

DNA alterations




Mitochondria

Formation of 8OhdG


O2

NH3+ NH3

+

COOminus COOminus

NO2

OH OH

O C

R

R

NH2 NH2

O O

OH

N

N N

N

NH2NH2

O

OO

O

N

NN

NNN

NHNH

OHOH

OH








2O2causes








Cytoplasm

Nuclear membrane

Nucleus

ROS RNS Glutamate

Nrf2

[O][N]

Nrf2

Gq

Nrf2

[P]

Nrf2

Keap1

DAG

Nrf2

Keap1

SH

Nrf2

Nrf2MafGST

HMOX

NQO1

GCL

ARE

Bach1

Keap1C273C288

C151

Keap1C273C288

C151

=

=

Keap1Cys

residues∟

Cys

residues∟

P

Nrf2

Nrf2

Keap1

Nrf2


UbUb

Ub

Stressor


Liberation of Nrf2



Nrf2 binds to ARE




Degradation

Keap1

PKC-120575

1205731120572512057311205725

12057311205725

O=NndashS

NO+









Table2En

dogeno

ussyste

mof

antio

xidant

enzymes

Antioxidant

enzyme

Cofactorsubstrate

Reactio

ncatalyzed

Locatio

nBiochemicalfunctio

n

Cop

per-zinc-SOD(Cu

Zn-SODorS

OD1)[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2

Cytosolnu

cleus

mito

chon

dria

(interm

embrane

space)

Catalyzesthe

dism

utation

reactio

nof

superoxide

toH

2O2to

decrease

itsredu

ctionpo

tential

Manganese

SOD(M

nSOD

orSO

D2)

[93]

Manganeselowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Mito

chon

drialm

atrix

Samea

sabo

ve

ExtracellularS

OD(ecSOD

orSO

D3)

[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Isoform

secreted

extracellularly

Samea

sabo

ve

Glutathione

peroxidase

(GPx

)[93]

GSHlowastlowast

Seleniumlowast

(1)R

-SeminusH

++

ROOHO

NOOminus

rarr

ROHO

NOminus

+R-SeOH

(2)2

GSH

+R-SeOHrarr

GS-SG

+R-Seminus

H+

Throug

hout

theb

ody

Redu

celip

idhydrop

eroxides

toalcoho

lsandH

2O2to

water

Glutathione-S-tr

ansfe

rase

(GST

)[94]

GSHlowastlowast

GSH

+RXrarr

GSR

+HX

X=leavinggrou

pR=ele

ctroph

ilicg

roup

Cytosol

mito

chon

dria

peroxisome

Detoxificatio

nof

xeno

biotics

Glutathione

redu

ctase(GR)

[94]

FADlowast

NADPHlowastlowast

GS-SGlowastlowast

GSSG+NADPHrarr

2GSH

+NADP+

Cytosol

mito

chon

drialm

atrix

Maintenance

ofGSH

levels

Catalase

(CAT

)[93]

Fe2+andFe3+lowast

H2O

2rarr

H2O

+O

2Th

roug

hout

theb

ody

lowestintheb

rain

Redu

cesH

2O2to

water

and

oxygen

Peroxiredo

xins

(Prx)[95]

Thioredo


(1)P

rxred+H

2O2rarr

Prxo

x+

2H2O

(2)P

rxox+Trxr

edrarr

Prxr

ed+

Trxo

x

Throug

hout

theb

ody

(intracellular)

Redu

cesH

2O2to

water

Prxisredu

cedby

Trxto

beused

insubsequent

reactio


Dsup

eroxided

ismutase



2) into diacyl-



3is discussed













CAT

Mn-SOD

GPx CAT

Zn Cu-SOD


NACNACA

Dopamine

Resveratrol

(+)POH 1A

MOA-B

Selegiline4

5

MPO

MC

MC

Prx(R)

or

2

7

GRGPx(selenium)

GSH

GSSG(+)

3 6

Catechin

Caffeic acidquinone

nitrate+

Caffeic acid

Nitro-catechin1B

1C

H2O2

H2O + O2

H2O + O2

O2∙minus O2

∙minus

NO∙

Fe2+

Fe2+

NO2+

1O2


H2O2


Fe2+ or Cu+

2H2O

PO∙ + H2O

OH∙



120572-tocopherol

ONOOminus









































damage



Fe Mn)


acids



Redox modulations

Severity of illness


High O2 utilization


High Ca2+ flux

minus

minus

+

+





Enzyme























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Cytoplasm

Nuclear membrane

Nucleus

ROS RNS Glutamate

Nrf2

[O][N]

Nrf2

Gq

Nrf2

[P]

Nrf2

Keap1

DAG

Nrf2

Keap1

SH

Nrf2

Nrf2MafGST

HMOX

NQO1

GCL

ARE

Bach1

Keap1C273C288

C151

Keap1C273C288

C151

=

=

Keap1Cys

residues∟

Cys

residues∟

P

Nrf2

Nrf2

Keap1

Nrf2


UbUb

Ub

Stressor


Liberation of Nrf2



Nrf2 binds to ARE




Degradation

Keap1

PKC-120575

1205731120572512057311205725

12057311205725

O=NndashS

NO+









Table2En

dogeno

ussyste

mof

antio

xidant

enzymes

Antioxidant

enzyme

Cofactorsubstrate

Reactio

ncatalyzed

Locatio

nBiochemicalfunctio

n

Cop

per-zinc-SOD(Cu

Zn-SODorS

OD1)[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2

Cytosolnu

cleus

mito

chon

dria

(interm

embrane

space)

Catalyzesthe

dism

utation

reactio

nof

superoxide

toH

2O2to

decrease

itsredu

ctionpo

tential

Manganese

SOD(M

nSOD

orSO

D2)

[93]

Manganeselowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Mito

chon

drialm

atrix

Samea

sabo

ve

ExtracellularS

OD(ecSOD

orSO

D3)

[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Isoform

secreted

extracellularly

Samea

sabo

ve

Glutathione

peroxidase

(GPx

)[93]

GSHlowastlowast

Seleniumlowast

(1)R

-SeminusH

++

ROOHO

NOOminus

rarr

ROHO

NOminus

+R-SeOH

(2)2

GSH

+R-SeOHrarr

GS-SG

+R-Seminus

H+

Throug

hout

theb

ody

Redu

celip

idhydrop

eroxides

toalcoho

lsandH

2O2to

water

Glutathione-S-tr

ansfe

rase

(GST

)[94]

GSHlowastlowast

GSH

+RXrarr

GSR

+HX

X=leavinggrou

pR=ele

ctroph

ilicg

roup

Cytosol

mito

chon

dria

peroxisome

Detoxificatio

nof

xeno

biotics

Glutathione

redu

ctase(GR)

[94]

FADlowast

NADPHlowastlowast

GS-SGlowastlowast

GSSG+NADPHrarr

2GSH

+NADP+

Cytosol

mito

chon

drialm

atrix

Maintenance

ofGSH

levels

Catalase

(CAT

)[93]

Fe2+andFe3+lowast

H2O

2rarr

H2O

+O

2Th

roug

hout

theb

ody

lowestintheb

rain

Redu

cesH

2O2to

water

and

oxygen

Peroxiredo

xins

(Prx)[95]

Thioredo


(1)P

rxred+H

2O2rarr

Prxo

x+

2H2O

(2)P

rxox+Trxr

edrarr

Prxr

ed+

Trxo

x

Throug

hout

theb

ody

(intracellular)

Redu

cesH

2O2to

water

Prxisredu

cedby

Trxto

beused

insubsequent

reactio


Dsup

eroxided

ismutase



2) into diacyl-



3is discussed













CAT

Mn-SOD

GPx CAT

Zn Cu-SOD


NACNACA

Dopamine

Resveratrol

(+)POH 1A

MOA-B

Selegiline4

5

MPO

MC

MC

Prx(R)

or

2

7

GRGPx(selenium)

GSH

GSSG(+)

3 6

Catechin

Caffeic acidquinone

nitrate+

Caffeic acid

Nitro-catechin1B

1C

H2O2

H2O + O2

H2O + O2

O2∙minus O2

∙minus

NO∙

Fe2+

Fe2+

NO2+

1O2


H2O2


Fe2+ or Cu+

2H2O

PO∙ + H2O

OH∙



120572-tocopherol

ONOOminus









































damage



Fe Mn)


acids



Redox modulations

Severity of illness


High O2 utilization


High Ca2+ flux

minus

minus

+

+





Enzyme























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2En

dogeno

ussyste

mof

antio

xidant

enzymes

Antioxidant

enzyme

Cofactorsubstrate

Reactio

ncatalyzed

Locatio

nBiochemicalfunctio

n

Cop

per-zinc-SOD(Cu

Zn-SODorS

OD1)[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2

Cytosolnu

cleus

mito

chon

dria

(interm

embrane

space)

Catalyzesthe

dism

utation

reactio

nof

superoxide

toH

2O2to

decrease

itsredu

ctionpo

tential

Manganese

SOD(M

nSOD

orSO

D2)

[93]

Manganeselowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Mito

chon

drialm

atrix

Samea

sabo

ve

ExtracellularS

OD(ecSOD

orSO

D3)

[93]

Cop

pera

ndzinclowast

∙

O2

minus

+∙

O2

minus

+2H

+rarr

H2O

2Isoform

secreted

extracellularly

Samea

sabo

ve

Glutathione

peroxidase

(GPx

)[93]

GSHlowastlowast

Seleniumlowast

(1)R

-SeminusH

++

ROOHO

NOOminus

rarr

ROHO

NOminus

+R-SeOH

(2)2

GSH

+R-SeOHrarr

GS-SG

+R-Seminus

H+

Throug

hout

theb

ody

Redu

celip

idhydrop

eroxides

toalcoho

lsandH

2O2to

water

Glutathione-S-tr

ansfe

rase

(GST

)[94]

GSHlowastlowast

GSH

+RXrarr

GSR

+HX

X=leavinggrou

pR=ele

ctroph

ilicg

roup

Cytosol

mito

chon

dria

peroxisome

Detoxificatio

nof

xeno

biotics

Glutathione

redu

ctase(GR)

[94]

FADlowast

NADPHlowastlowast

GS-SGlowastlowast

GSSG+NADPHrarr

2GSH

+NADP+

Cytosol

mito

chon

drialm

atrix

Maintenance

ofGSH

levels

Catalase

(CAT

)[93]

Fe2+andFe3+lowast

H2O

2rarr

H2O

+O

2Th

roug

hout

theb

ody

lowestintheb

rain

Redu

cesH

2O2to

water

and

oxygen

Peroxiredo

xins

(Prx)[95]

Thioredo


(1)P

rxred+H

2O2rarr

Prxo

x+

2H2O

(2)P

rxox+Trxr

edrarr

Prxr

ed+

Trxo

x

Throug

hout

theb

ody

(intracellular)

Redu

cesH

2O2to

water

Prxisredu

cedby

Trxto

beused

insubsequent

reactio


Dsup

eroxided

ismutase



2) into diacyl-



3is discussed













CAT

Mn-SOD

GPx CAT

Zn Cu-SOD


NACNACA

Dopamine

Resveratrol

(+)POH 1A

MOA-B

Selegiline4

5

MPO

MC

MC

Prx(R)

or

2

7

GRGPx(selenium)

GSH

GSSG(+)

3 6

Catechin

Caffeic acidquinone

nitrate+

Caffeic acid

Nitro-catechin1B

1C

H2O2

H2O + O2

H2O + O2

O2∙minus O2

∙minus

NO∙

Fe2+

Fe2+

NO2+

1O2


H2O2


Fe2+ or Cu+

2H2O

PO∙ + H2O

OH∙



120572-tocopherol

ONOOminus









































damage



Fe Mn)


acids



Redox modulations

Severity of illness


High O2 utilization


High Ca2+ flux

minus

minus

+

+





Enzyme























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















2) into diacyl-



3is discussed













CAT

Mn-SOD

GPx CAT

Zn Cu-SOD


NACNACA

Dopamine

Resveratrol

(+)POH 1A

MOA-B

Selegiline4

5

MPO

MC

MC

Prx(R)

or

2

7

GRGPx(selenium)

GSH

GSSG(+)

3 6

Catechin

Caffeic acidquinone

nitrate+

Caffeic acid

Nitro-catechin1B

1C

H2O2

H2O + O2

H2O + O2

O2∙minus O2

∙minus

NO∙

Fe2+

Fe2+

NO2+

1O2


H2O2


Fe2+ or Cu+

2H2O

PO∙ + H2O

OH∙



120572-tocopherol

ONOOminus









































damage



Fe Mn)


acids



Redox modulations

Severity of illness


High O2 utilization


High Ca2+ flux

minus

minus

+

+





Enzyme























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















CAT

Mn-SOD

GPx CAT

Zn Cu-SOD


NACNACA

Dopamine

Resveratrol

(+)POH 1A

MOA-B

Selegiline4

5

MPO

MC

MC

Prx(R)

or

2

7

GRGPx(selenium)

GSH

GSSG(+)

3 6

Catechin

Caffeic acidquinone

nitrate+

Caffeic acid

Nitro-catechin1B

1C

H2O2

H2O + O2

H2O + O2

O2∙minus O2

∙minus

NO∙

Fe2+

Fe2+

NO2+

1O2


H2O2


Fe2+ or Cu+

2H2O

PO∙ + H2O

OH∙



120572-tocopherol

ONOOminus









































damage



Fe Mn)


acids



Redox modulations

Severity of illness


High O2 utilization


High Ca2+ flux

minus

minus

+

+





Enzyme























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































damage



Fe Mn)


acids



Redox modulations

Severity of illness


High O2 utilization


High Ca2+ flux

minus

minus

+

+





Enzyme























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article redox modulations, antioxidants, and neuropsychiatric...

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