Review Article Isoprostanes and Neuroprostanes as ...downloads.hindawi.com/journals/omcl/2014/572491.pdf · Review Article Isoprostanes and Neuroprostanes as Biomarkers of Oxidative

Review ArticleIsoprostanes and Neuroprostanes as Biomarkers of OxidativeStress in Neurodegenerative Diseases

Elhbieta Miller12 Agnieszka Morel3 Luciano Saso4 and Joanna Saluk35

1 Department of Physical Medicine Medical University of Lodz Hallera 1 Lodz Poland2Neurorehabilitation Ward III General Hospital in Lodz Milionowa 14 Lodz Poland3Department of General Biochemistry Faculty of Biology and Environmental Protection University of LodzPomorska 141143 90-236 Lodz Poland

4Department of Physiology and Pharmacology ldquoVittorio Erspamerrdquo Sapienza University of Rome Rome Italy5 Department of Toxicology Faculty of Pharmacy with Division of Medical Analytics Wroclaw Medical UniversityBorowska 211 50-556 Wroclaw Poland

Correspondence should be addressed to Elzbieta Miller bettymillerinteriapl

Received 12 February 2014 Revised 28 March 2014 Accepted 31 March 2014 Published 29 April 2014

Academic Editor Kota V Ramana

Copyright copy 2014 Elzbieta Miller et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Accumulating data shows that oxidative stress plays a crucial role in neurodegenerative disorders The literature data indicate thatin vivo or postmortem cerebrospinal fluid and brain tissue levels of F

2-isoprostanes (F

2-IsoPs) especially F

4-neuroprotanes (F

4-

NPs) are significantly increased in some neurodegenerative diseases multiple sclerosis Alzheimerrsquos disease Huntingtonrsquos diseaseand Creutzfeldt-Jakob disease Central nervous system is the most metabolically active organ of the body characterized by highrequirement for oxygen and relatively low antioxidative activity what makes neurons and glia highly susceptible to destruction byreactive oxygennitrogen species and neurodegeneration The discovery of F

2-IsoPs and F

4-NPs as markers of lipid peroxidation

caused by the free radicals has opened up new areas of investigation regarding the role of oxidative stress in the pathogenesisof human neurodegenerative diseases This review focuses on the relationship between F

2-IsoPs and F

4-NPs as biomarkers of

oxidative stress and neurodegenerative diseases We summarize the knowledge of these novel biomarkers of oxidative stress andthe advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases

1 Introduction

The CNS (central nervous system) is very vulnerable tooxidative injury due to its high oxygen demand high level ofpolyunsaturated fatty acids (PUFAs) and weak antioxidantdefenses The vulnerability of the brain to oxidative damageincreases with the age due to reduced integrity of the blood-brain barrier (BBB) and increasedmitochondrial dysfunction[1ndash19] Brain aging and neurodegeneration are characterizedby chronic inflammation with persistent microglial activa-tion and higher level of proinflammatory cytokines [4] Inaddition it promotes oxidative stress and neuronal damageNeurons are particularly vulnerable to oxidative damagenot only due to excitotoxicity but also to mitochondrialdysfunction Moreover neuronal membranes have plenty ofunsaturated fatty acids At higher concentrations reactiveoxygennitrogen species (ROSRNS) cause neural membrane

damageTherefore it can change not only membrane fluiditybut also decreased activities of membrane-bound enzymesion channels and receptors The main sources of ROSRNSare the mitochondrial respiratory chain an uncontrolledarachidonic acid (AA) cascade and NADPH oxidase (nicoti-namide adenine dinucleotide phosphate-oxidase) [5 6]

It is known that both inflammation and oxidative stresscontribute to the development of various neuropatholo-gies including Alzheimerrsquos disease (AD) Parkinsonrsquos disease(PD) and multiple sclerosis (MS) [5 6 20] As discussed byGuest et al [7] the cerebrospinal fluid (CSF) of participantsaged over 45 years contained statistically higher amounts ofthe oxidative damage marker F

2-isoprostane (F

2-IsoPs) and

the inflammatory cytokine IL-6Brain response to oxidative stress-mediated neurodegen-

eration is very complex All brain structures are involved

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2014 Article ID 572491 10 pageshttpdxdoiorg1011552014572491

2 Oxidative Medicine and Cellular Longevity

in this multifactorial process Astrocytes constitute approx-imately 90 of human brain and protect neurons fromexcitotoxicity through glutamate uptake system and on theother side astrocytes contribute to the extracellular glu-tamate via reversed glutamate transporter [5] Moreoverthey may undergo astrocytosis after dopaminergic cell lossand are involved in the inflammatory processes In generalinflammation is a protective response The main mediatorsof neuroinflammation are microglial cells Microglial cellsconsistmainly ofmacrophages and react to oxidative stress bytransformation into activatedmicroglia that are characterizedby amoeboid morphology and rapid migration Chronicactivation of microglia may cause neuronal damage throughthe release of potentially toxic molecules such as proin-flammatory cytokines matrix metalloproteinases ROSRNSproteinases prostaglandin E

2 complement proteins and

growth factors and also leads to the DNA and RNA damage[5 21] These factors have neuroprotective properties but onthe other hand they can be responsible for acceleration ofoxidative stress and neurodegeneration

Markers of lipid peroxidation include different moleculessuch as 4-hydroxy-trans-2-nonenal (4-HNE) 4-oxo-trans-2-nonenal (4-ONE) acrolein isoprostanes and isofuransThese markers are derived from AA which is releasedfrom neural membrane glycerophospholipids through theactivation of cytosolic phospholipases A

2(cPLA

2) [22]

Lipid peroxidation is a hallmark of oxidative stress Highlevel of lipid peroxidation products is a characteristic formany human diseases especially neurodegenerative diseasesIt can cause damage to cellular membranes through changesof membrane organization and alteration of membraneintegrity fluidity and permeability [23]

2 Biomarkers

Biomarkers are defined as the indicators of normal biologicalprocesses or pathologic processes that can be objectivelymea-sured and evaluated [1] The well-characterized appropriatebiomarkers may be used for health examination diagnosisof pathologic processes at early stage assessment of treat-ment response and prognosis Noninvasivemeasurements ofcirculating levels of specific biomarker are useful along thewhole spectrum of the disease process and before diagnosisbiomarkers could be used for screening and risk assessmentof the diseases [2] Moreover biomarkers may be used forprecise measurement of oxidative stress status in vivo [3]Among the biological molecules lipids appear to be the mostsusceptible to the attack of ROSRNS [24 25] and lipid per-oxidation has been implicated in the neurodegeneration [11]Therefore the levels of lipid peroxidation products may beused as a biomarker for the measurement of oxidative stressstatus in vivo in neurodegenerative diseases [3] The levels oflipid peroxidation products in biological fluids and tissuesof human subjects have been measured extensively [26]Presently various lipid peroxidation products are applied forassessment of lipid peroxidation and oxidative stress status invivo

The measurement of F2-IsoPs is currently the best avail-

able biomarker of lipid peroxidation [8 10 22 24]

3 The Isoprostanes Pathways

In the mid-1970s it was shown that PG-like compoundscould be formed in vitro by the nonenzymatic peroxidationof purified PUFAs F

2-IsoPs have been discovered in 1990 by

Milne et al [27] and Roberts II and Morrow [28] and sincethen they collected a lot of evidence that these compoundsmight be biomarkers of lipid peroxidation and oxidativestress in vivo as well as in vitro

F2-IsoPs are a unique prostaglandin-like products which

are formed via nonenzymatic free radical-mediated per-oxidation of polyunsaturated fatty acidsmdashfor example AA[28 29] The oxidation of AA proceeds by many competingreactions to give numerous products IsoPs containing avariety of prostane ring structures are composed of variousisomers including F

2-IsoPs which are isomeric to PGF

2120572

[27 30 31] and D2E2-IsoPs which are isomers of PGD

2

and PGE2 respectively [32] The mechanism of F

2-IsoPs

formation involves several steps In the first stage ROS reactswith the arachidonic acid and undergoes abstraction of anbisallylic hydrogen atom to yield an arachidonyl carbon-centered radical What is more there is insertion of oxygenwhich leads to the formation of peroxyl radicals Fourdifferent peroxyl radical isomers are formed depending onsite of hydrogen abstraction and oxygen insertion Peroxylradicals isomers undergo 5-endocyclization and a secondmolecule of oxygen adds to the backbone of the compound toform four bicyclic endoperoxide intermediate regioisomersmdashPGH2-like compounds These unstable bicycloendoperoxide

intermediates are reduced to the F2-IsoPs and four F

2-IsoPs

regioisomers are formed [30 33 34] This regioisomers arereduced to four series of F-ring regioisomers (15- 8- 12-5-series) each consisting of eight racemic diastereoisomersThese regioisomers are depending on the carbon atom towhich the side chain hydroxyl is attached [8]

To sum up the biosynthetic steps of IsoPs includeformation of the following

(i) three arachidonyl radicals(ii) four peroxyl radical isomers with subsequent endo-

cyclization finally formation of bicycloendoperoxideregioisomers which are reduced to F

2-IsoPs IsoPs are

compounds that have F-type prostane rings isomericto PGF

2120572

The alternative ring structures DE-type and AJ-typeprostane are formed by the same mechanisms [32 34]So that E- or D-ring and thromboxane-ring compounds ofIsoPs are formed during the rearrangement of isoprostaneendoperoxides in vivo E

2- and D

2-IsoPs are not terminal

products of the IsoP pathwayThese compounds are unstableand readily undergo dehydration in vivo to yield A

2J2-IsoPs

The cyclopentenone IsoPs might be neurotoxic products ofthe IsoPs pathway and might contribute to the pathogenesisof oxidative neurodegeneration A

2-J2-IsoPs contain 120572120573-

unsaturated carbonyls which rapidly adduct cellular thiolsand these cyclopentenone IsoPs induce neuronal apoptosisand promote neurodegeneration [27]

The other electrophilic lipid peroxidation products canalso damage neurons The 120574-ketoaldehydes (eg isoketals

Oxidative Medicine and Cellular Longevity 3

isolevuglandins) highly reactive acyclic compounds mightbe formed as a products of IsoPs endoperoxide rearrange-ment [35]

PUFAs are the most susceptible to free radical attackand in general oxidizability increases as the number ofdouble bonds increases So the oxidizability of PUFAs can beestimated by the linear increase in the rate of oxidation withthe increasing number of active methylene groups locatedbetween two bonds From such correlation the oxidizabilityof each PUFA is increased for about twofold for each activemethylene group Thus the oxidizability of common fattyacids is as follows linoleic acid (18 2) lt arachidonic acid(20 4 119899 minus 6) lt eicosapentaenoic acid (EPA 20 5 119899 minus 3) ltdocosahexaenoic acid (DHA 22 6 119899 minus 3) [27 36]

The oxidation mechanisms of IsoPs are well known butthey are not the only substrate for the IsoPs pathway Thepresence of at least three double bonds in fatty acid moleculeallows the cyclization

F2-dihomo-isoprostanes (F2-dihomo-IsoPs) are the per-oxidation products from adrenic acid which is the maincomponent of myelin The great amount of DHA is observedin brain but primarily found in white matter and is asso-ciated with myelin White matter is commonly damagedby ischemic stroke and is uniformly damaged in MS F2-dihomo-IsoPs are generated in significant amounts fromadrenic acid and their levels are greatly increased in settingsof oxidative stress occurring in the white matter portion ofthe human brains Roberts II andMilne [8] demonstrate thatproportionally levels of F2-dihomo-IsoPs in white matterundergoing oxidative injury increase to a greater extent thanIsoPs and NeuroPs derived from AA and DHA respectivelyTheir studies suggest that the quantification of F2-dihomo-IsoPs might be a selective marker of white matter injury invivo [8]

F2-dihomo-IsoPs are also present in kidney adrenalglands and tissues and might be regarded as an earlymarker of lipid peroxidation in Rett syndromemdasha disorderof the nervous system that leads to developmental reversalsespecially in the areas of expressive language and hand use[37]

31 AA Is Not the Only One PUFA That Can Be Oxidizedto Form IsoPs By the peroxidation of the 120596-3 PUFA EPAand DHA F-ring IsoPs have been generated The IsoPs-likecompounds generated from this acid are named NeuroPs [8]

F3-IsoPs are formed in abundance in vitro and in vivo

from EPA nonenzymatically peroxidation [38ndash40] whileDHA may be oxidized nonenzymatically into F

4- D4- E4-

A4- and J

4-neuroprostanes (F

4- D4- E4- A4- and J

4-

NeuroPs) [38 39] AA is relatively evenly distributed inbrain with similar concentrations in gray matter and whitematter and within glia and neurons Unlike AA DHA ishighly concentrated in neuronal membranes to the exclusionof other cell types Moreover F

4-NeuroPs are by far the

most abundant products of this pathway in the brain [32]The quantification of F

4-NeuroPs provides a highly selective

quantitative window for neuronal oxidative damage in vivoThus F

2-IsoPs quantification is a reflection of oxidative

damage to the brain in general and F4-NeuroPs in par-

ticular [40 41] Roberts II and Milne [8] have found that

the level of IsoPs produced from the oxidation of EPAsignificantly exceeds those of the F

2-IsoPs generated from

AA This is because EPA contains more double bonds andtherefore it is more easily oxidizable The authors have alsoobserved that EPA supplementation markedly reduced levelsof arachidonate-delivered F

2-IsoPs mouse heart tissues by

over 60 Such observations are crucial because F2-IsoPs

are generally considered as a proinflammatory moleculesassociated with the pathophysiological sequelae of oxidantstress It is thus surprising to propose that the part ofmechanism by which EPA prevents certain diseases is itsability to decrease F

2-IsoP generation [8]

32 IsoPs As Biomarkers of Lipid Peroxidation in Neurodegen-erative Diseases Oxidative stress is caused by an imbalancebetween free radicals production and antioxidant defensesin favor of the oxidation and leads to lipid peroxidationmembrane protein and DNA damage and is thought tobe important in the pathogenesis of a variety of neuro-logical disorders especially neurodegenerative diseases oratherosclerosis cancer and aging [42] Lipid peroxidation isthe most important source of free radical-mediated injurythat directly damages neuronal membranes and yields anumber of secondary products responsible for extensivecellular damage Any specific repair process of lipid perox-idation does not exist as it does for proteins and DNA andthis may explain why moderate levels of lipid peroxidationcould have physiological significance for cell signaling andmembrane remodeling [7] One of the major targets of thelipid peroxidation process is the CNS The brain is the mostsusceptible to oxidative damage because of the high oxygenconsumption the low levels of antioxidant enzymes (catalaseand glutathione peroxidase) the elevated levels of iron (apotent catalyst for oxidant formation) and the ability tooxidize different substrates (eg membrane polyunsaturatedfatty acids) Despite the fact that free radicals can attackmanyvarious critical biological molecules such as DNA and cel-lular proteins the high content of unsaturated lipids renderslipid peroxidation the central feature of oxidant injury in thebrain [43] Peroxidation of membrane lipids affects neuronalhomeostasis resulting in augmented membrane inflexibil-ity diminished activity of membrane-bound enzymes (egsodium pump) destruction of membrane receptors andchanged permeability [44 45] One leading hypothesis isthat the free radical-mediated oxidation of lipids contributesto the main pathological effects of oxidative stress in thebrain In support of this theory increased levels of bioactivelipid peroxidation products have been identified in affectedbrain regions from humans with various neurodegenerativediseases [46 47] as well as in corresponding animal models[48]

Due to the fact that free radicals are unstable and highlyreactive there are difficulties in direct measurement of theirlevel That is why elucidation of the importance of oxidativedamage in neurological diseases is very hard Because of theirstability the measurement of F

2-IsoPs by mass spectrometry

has been extensively employed as a marker of oxidant stressand iswidely considered to be the gold-standard index of lipidperoxidation in vivo [49 50] IsoPs can be relatively easily


Table 1 Isoprostanes as markers of oxidative stress in neurodegenerative diseases

Classes of isoprostanes Material Disease Study Versus control Reference

F2-IsoPsCSFlowast post

mortem braintissue plasma urinary

Alzheimer disease vivo High [10ndash13 32]Creutzfeldt-Jakob vivovitro High [17 18 53]Huntington disease vivo High [54]

8-iso PGF 2alfaUrine SPMSlowastlowast vivo 6-fold [55]

CSF RRMSlowastlowastlowast vivo Higher [9 53 56 57]ALSlowastlowastlowastlowast vivo Higher [5 19 58]

CSFlowast cerebrospinal fluid SPMSlowastlowast secondary-progressive type of multiple sclerosis RRMSlowastlowastlowast relapsing-remitting type of multiple sclerosis ALSlowastlowastlowastlowastamyotrophic lateral sclerosis

quantified in body fluids because they are commonly found inurine blood and CSF and are also present in the exhaled air(Table 1) Their formation in vivo can be reliably monitoredin every biological fluid by the noninvasive measurementsof specific signals of lipid peroxidation which tend to besensitive and specific [51] The measurement of F

2-IsoPs has

emerged as one of the most reliable approaches to assessoxidative stress status in vivo providing an important toolto explore the role of oxidative stress in the pathogenesisof human disease In the oxidative tissue injury the level ofF2-IsoP is significantly increasing The rapid development

of analytical methods for IsoPs measurement helped clarifythe role of the free radicals in human physiology andpathophysiology [52]

Measurement of F4-NPs the stable product of free radical

damage to DHA also provides valuable data in exploringthe role of oxidative stress in neurodegenerative diseasesThe products of the IsoP pathway were found to havestrong biological actions and therefore may participate asphysiological mediators of the disease [59] Research onbrain-derived IsoPs has begun only a few years ago but it hasalready provided convincing evidence on the usefulness ofthese markers in understanding the role of oxidative damagein brain diseases [60] IsoPs as active products of free-radical-mediated peroxidation of AA contained in phospholipids ofcell membranes and lipoproteins have a potential relevance tohuman neurodegenerative and demyelinating diseases Therole of free radical-induced oxidative damage in the patho-genesis of neurodegenerative disorders has been definitelyestablished [61ndash65] The elevated formation of F

2-IsoPs has

been observed in brain tissues and body fluids in numerousneurodegenerative diseases including Alzheimerrsquos disease[32] Parkinsonrsquos disease [6] Huntingtonrsquos disease (HD) [66]Creutzfeldt-Jakob disease (CJD) [66] multiple sclerosis [55]and amyotrophic lateral sclerosis (ALS) [43]

The measurement of free F2-IsoPs in plasma or urine can

be utilized to assess the endogenous formation of IsoPs butnot to reveal the organ in which they are formed Determin-ing the levels of IsoPs in the unique fluid compartmentmdashCSF which reflects the ongoing metabolic activity of thebrain provides a great opportunity to reveal the occurrenceof oxidative stress and lipid peroxidation in the brain [10 44]

4 Multiple Sclerosis

Multiple sclerosis is a multifactorial heterogeneous diseasewith several pathophysiological components inflammation

demyelination redox axonal damage and repair processesThese components are not uniformly contributed in patientpopulations but can individually predominate [67 68] MSis a leading cause of neurological disabilities in youngadults and affects up to 24permil of population in USA andCanada and up to 19permil in some European countries It isconsidered to be autoimmune or at least its etiopathogenesisinvolves intensive autoaggressive immune response [69] MSis heterogeneous disease on several groundsThere are severaldifferent clinical courses of this disorder The most usual(over 80) is relapsing-remitting course (RRMS) in whichrelapse occurs from time to time followed up by completeor partial recovery [67] This stage of disease is character-ized with multifocal inflammation oedema and cytokinesactions About half of RRMS patients after 10ndash20 years ofdisease lasting accumulate irreversible neurological deficits[67 70] This type of MS is known as secondary progressive(SPMS) that is dominated by neurodegeneration processesand progression of clinical symptoms [71] The next 20 ofMS patients with progressive symptoms from the onset haveprimary-progressive (PPMS) type For the transition fromRRMS to progressive stage axonal injury is responsible [67]Neurodegeneration of demyelinated axons is a major causeof irreversible neurological disability in MS Disability levelsin progressive forms of MS patients often worsen despite astable MRI T(2) (magnetic resonance) lesion burden [67]The presence of oxidative stress in the absence of measurableinflammation could help explain this phenomenon [3 47]

Currently classifications of biomarkers of MS are con-nected with the pathophysiological processes It has beendivided into seven categories

(1) alteration of the immune system (interleukins IL-1120573IL-2 IL-4 IL-6 IL-10 IL-12 IL-23 interferon (IFN120574)tumor necrosis factor (TNF120572) transforming growthfactor (TGF120573) cytokines CXCR3CXCL10mdashmarkeractivated T cells E-selectin L-selectin ICAM-1VCAM-1 CD31 surface expression of LFA-1 andVLA-4 (adhesion molecules) CD40CD40L CD80CD86 and heat shock proteins (hsp))

(2) axonalneuronal damage (Tau protein 24S-hydroxyc-holesterol N-acetylaspartic acid)

(3) blood-brain barrier disruption (matrix metallopr-oteinases (MMPs) MMP-9 and their inhibitors(TIMP) platelet activating factor (PAF) and throm-bomodulin)


(4) demyelination (MBP and MBP-like material prote-olytic enzymes)

(5) oxidative stress and excitotoxicity (nitric oxide deriv-atives F

2-IsoPs and uric acid)

(6) gliosis (glial fibrillary acid protein (GFAP) S-100 pro-tein)

(7) remyelination and repair (NCAM (neural cell adhe-sion molecule) CNTF (ciliary neurotrophic factor)MAP-2 + 13 (microtubule-associated protein-2 exon13) and CPK-BB (creatine phosphatase BB) [67]

IsoPs are the candidate biomarkers of lipid peroxidationin MS In diseases with a complex pathogenesis an indi-vidual biomarker is reflected in only one of many ongoingpathogenic processes [5 67] The data presented in ourstudies indicate that lipid peroxidation and oxidative stressin patients with MS may occur It was found that the urineIsoPs level was over 6-fold elevated in patients with SPMSthan in control [3] The increased level of 15-F

2119905-IsoPs in CSF

of MS patients has been described by Mattsson et al [9]To investigate the possible correlation between F

2-IsoPs and

the disease inflammatory activity it has been observed thatthe CSF levels of 15-F

2119905-IsoPs in patients with RRMS were

not correlated with the clinical signs of the disease Theseobservations suggest that high levels of F

2-IsoPs (about 9-

fold higher than control subjects) may represent an indexof degenerative phenomena which persist also in the lackof an ongoing inflammatory activity In other researchesMinghetti et al [10] have found that the CSF level of thereliable marker of oxidative stress in vivo 15-F

2119905-IsoP is 3

times higher in patients with MS than in a benchmark groupof subjects with other neurologic diseases This increase wasnot correlated with the 15-F

2119905-IsoP levels andwasmuch lower

in steroid-treated patients Clearly the levels of 15-F2119905-IsoP

were associated with the degree of disability What is morein the spinal cord of mice during early progressive stagesof experimental autoimmune encephalomyelitis (EAE) theelevated levels of F

2-IsoPs and F

4-NPs were observed [72 73]

In white matter and myelin-forming oligodendrocytes theDHA levels are relatively low which are affected in MS SoF2-IsoPs might be preferable to F

4-NPs as lipid peroxidation

biomarkers in this demyelinating disease [66] There aresome studies which examine the correlation between levelsof F2-IsoPs in CSF of MS patients their healthy siblings

and unrelated controls The CSF concentrations of F2-IsoPs

in siblings of MS patients were significantly higher than inhealthy controls The F

2-IsoPs levels in patients suffering

from MS were intermediate between siblings as well ascontrols In patients with MS and siblings the levels of F

2-

IsoPs were significantly correlated These researches havebeen proved that siblings of MS patients have an increasedoxidative stress response to the environmental and geneticfactors that might be involved in MS pathogenesis [9]

5 Alzheimerrsquos Disease

Alzheimerrsquos disease (AD) is one of the major causes ofdementia which is characterized by the deposition of the

amyloid 120573 (A120573) peptide and microtubule-associated proteintau in the brain [74 75] The critical role in the ADpathogenesis plays an abnormal tau phosphorylation It hasbeen proved that A120573 has capacity to interact with transitionmetals generating redox active ions which precipitate inlipid peroxidation and cellular oxidative stress [76] In otherwords A120573 promotes cellular oxyradicals accumulation inneurons and glial cells in vulnerable regions of AD brainSuch oxidative stress may lead to many of the metabolicand neurodegenerative alterations observed in this disease[77] Moreover in tau phosphorylation the mediation ofoxidant toxicity by A120573 has been also implicated Besidesthe oxidative stress the mitochondrial dysfunction has beenobserved in AD [78] A variety of markers of oxidative stressare increased with a clear relationship with A120573 depositionand neurofibrillary degeneration has been observed in post-mortem brain tissues from AD patients [79] It has beenreported that the activity andor protein levels of severalantioxidant enzymes were altered in AD brain regionsconsistent with ongoing oxidative stress [11] Increased F

2-

IsoPs and F4-NPs levels in the postmortem ventricular fluid

from definite AD patients had been firstly demonstrated byMontine et al [11] The authors given the partial overlapbetween CSF concentrations of F

2-IsoPs in AD patients

and healthy subjects suggested that the quantification ofCSF F

2-IsoPs could not be utilized as an early marker of

dementia There was no correlation between CSF F2-IsoPs

and age or duration of disease This study concerns therelative small group of AD patients and probably may notbe fully representative of the AD population [11] In anindependent studyMusiek and colleagues [80] demonstratedthe formation of F

4-NPs during peroxidation of DHA in

vitro F4-NPs may be used as a marker of lipid peroxidation

in the pathogenesis of neurodegenerative diseases becausein these diseases the elevated levels of F

4-NPs is observed

Subsequently they proved the presence of esterified F4-NPs

in the human brain and showed abnormally high levels inoccipital and temporal lobes ofADbrains Interestingly whilein vitro oxidation of DHA yields 34-fold higher levels of F

4-

NPs compared with F2-IsoPs the CSF levels of these two

classes of compounds showed a very close correlation in asmall number of AD patients [66]

In Yao et alrsquos [12] and Pratico et alrsquos [13] researchesfound that the contents of 15-F

2119905-IsoPs and IPF

2alpha-VI

were markedly elevated in the frontal and temporal lobesof AD brains compared to the corresponding cerebella andto the same regions of control brains Moreover there wasalso a significant correlation between the levels of the twoIsoPsmeasured in each AD brain In postmortem ventricularCSF IPF

2alpha-VI levels were higher in AD patients than in

healthy people In contrast brains levels of 6-keto PGF1alpha

an index of prostaglandin production and ventricular CSF15-F2119905-IsoP levels did not differ in AD and control subjects

F2-IsoPs were measured also in plasma and in urine of

ADpatients It has been shown that plasma and urinary levelswere higher than controls but only in the case of plasmathe difference was statistically significant So plasma or urinecontent of IsoP in patients with AD reflects a specific increasein oxidative stress within the brain or a more generalized


systemic oxidative stress remains to be determined Theauthors also found that in the control group F

2-IsoPs levels

in females were higher than in males and suggested that thiscould be related to an increase in oxidative stress associatedwith the loss of estrogens in the postmenopausal period[81] Indeed estrogens can be antioxidants because of theirphenolic structure [82] or may upregulate apolipoprotein Efavoring the formation of the apolipoprotein EA-complexand thus the sequestration of A120573 Consistent with thishypothesis Pratico et al [13] demonstratedmarkedly elevatedF2-IsoPs in the brains of aged apolipoprotein E-deficientmice

compared with wild-type C5 [83]

6 Huntingtonrsquos Disease

The abnormal expansions of an unstable cytosine-adenine-guanine repeat region at the 51015840-end of a gene on chromosome4 are the main cause of this disease This genetic abnormalityresults in the expression of an expanded polyglutamine tractin huntingtin protein which can aggregate in neuronal nucleiand dystrophic neuritis in Huntingtonrsquos disease brains TheHD gene defect causing the death of specific populationsof striatal neurons is still unknown The elevated oxidativedamage observed in areas of degeneration in patientsrsquo brainswith HD and the increased free radical production in animalmodels indicate the involvement of oxidative stress either asa cause or as a consequence of the cell death cascade in thedisease [66 84] There are a lot of studies suggesting thatoxidative stress is prominent in the neostriatum of HD brains[85] and contributes to degeneration of the neostriatum Inpatients suffering from HD the mitochondrial dysfunctionresults in overproduction of ROS leading to oxidative andnitrosative stress [54 86ndash88] Such stress contributes toneuronal dysfunction by damaging the main structuresDNA proteins and lipids It has been shown that the highlyreactive product of nitric oxide and superoxide free radicalsmdashperoxynitrite which inhibits mitochondrial respiration andreduce antioxidant defenses in cells is marked by increasedof 3-nitrotyrosine (3-NT) levels [54 87 89] The immunore-activity of 3-NT is increased in postmortem HD brain tissue[85] Also increased levels of protein carbonyls in HDstriatum and cerebral cortex have been observed [85] It hasbeen observed that 4-hydroxynonenal andmalondialdehydelipid peroxidation products are increased eightfold in HDhuman plasma [90] and also in postmortem brain tissue [84]

The measurement of the levels of F2-IsoPs in the CSF of

HD patients indicates the contribution of oxidative stress tothe pathogenesis of HD The level of F

2-IsoP in HD patients

was significantly higher than in the control group Howeverthe overlap of levels between these groups suggested that theoxidative damage to the brain may not occur uniformly inthe early phase of the disease But like in AD correlationbetween F

2-IsoPs and age or disease duration there was not

found moreover no difference betweenmen and women wasobserved [66]

In addition in HD plasma the glutathione levels aresignificantly reduced [91] Browne and Beal [14] suggest thatin transgenic HD mice there are increased immunostainingfor malondialdehyde 4-hydroxynonenal and 15-F

2119905-IsoPs

[54]

7 Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is one of the most knownhuman transmissible spongiform encephalopathies (TSEs) orprion diseases a heterogeneous group of infectious sporadicand genetic disorders characterized by rapidly progressivedementia The characteristic neuropathological hallmark ofthe disease is the amyloid deposition of the pathological formof a cellular protein (like in ADmdashA120573 or HDmdashhuntingtin)The accumulation of the pathological prion protein is con-sidered as a central event and is thought to trigger severalpathogenetic mechanisms eventually culminating in thetypical spongiform degeneration [66]

The physiological functions of cellular prion protein arestill unknown however due to its cooper binding ability itmight play an important role in the oxidative homeostasis ofthe brain and could act as an antioxidant These antioxidantproperties may be related to its superoxide dismutase- (SOD-) like activity [15 16] Kralovicova et al [15] have proved thatthese cells which express higher levels of prion protein aremore resistant to oxidative stress Wong et al suggest [16]that the levels of several oxidative stress markers proteincarbonyl groups and products of lipid peroxidation wereincreased in brain tissues of prion protein knockout mice[92] In brains of mice infected with scrapie the elevatedlevels of nitrotyrosine and heme oxygenase-1 had been found[93] It has been suggested that the level of lipid peroxidationproducts is increased in brains of scrapie-infected mice andalso prion proteins purified from brains of these animalspossess a reduced SOD-like activity [94]

The increased levels of F2-IsoP in CSF of Creutzfeldt-

Jakob patients have been observed in Minghetti et alrsquos [17]researches Also another product of lipid peroxidation hasbeen found to be unchanged in CSF from patients sufferingfrom CJD in comparison to controls [95] Arlt et al [18]found that CSF lipids from patients suffering from CJDwere more susceptible to oxidation process than those fromnondemented controls Thus they observed that in the CJDpatients the levels of antioxidants and the amount of PUFAswere reduced Their researches indicate that oxidative stressis elevated in CJD patients and the oxidative mechanisms arecorrelated with pathogenesis of this disease

It has been observed that in patients with sporadic andfamilial CJD CSF levels of 15-F

2119905-IsoP were about 25-fold

higher than in patients with noninflammatory disorders Nocorrelation was found between 15-F

2119905-IsoPs and PGE

2and

also 15-F2119905-IsoP levels and age of patients nor polymorphism

at codon 129 of the prion protein gene indicating that lipidperoxidation and prostaglandin synthesis are unrelated phe-nomena in this disease PGE

2concentrations that were about

65-fold higher than in controls were inversely correlatedwith patient survival meanwhile the levels of 15-F

2119905-IsoP

were not correlated with the clinical duration of the diseaseIt has been suggested that the inflammation might be morerelevant than oxidative stress to the pathogenesis of thisparticular disease [53 66]

In other studies it has been proved that the increasedlevel of PGE

2in hippocampal is associated with a strong

induction of COX-2 expression which was elevated with


progression of disease and is localized tomicroglial cells [56]In sporadic CJD patients the shorter survival was associatedwith higher levels of PGE

2in CSF patients PGE

2may be

an index of disease severity rather than progression becausePGE2levels were not dependent on the time of CSF sampling

during the course of the disease [10] PGE2can be associated

with neuronal death because in neuroblastoma cells prionproteins peptides increase PGE

2levels and COX-1 inhibitors

protect against prion proteins toxicity [57] Whether PGE2

contributes to neuronal death in CJD is a consequence ofneuronal apoptosis or is just an index of the disease stateremains to be established

8 Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a multifactorial andcomplex disease inwhich genetic environmental or genetic-environmental interactions lead to motor neuronal degener-ation The deposition of a misfolded protein in neural tissuein this instance copperzinc SOD is characteristic for theALS and other neurodegenerative diseases [96 97] Severalneuroinflammatory changes such as increased levels ofproinflammatory molecules astrogliosis and also microglialactivation which are characteristic for many neurodegen-erative diseases have been also found in spinal cord tissuefrom patients who died of ALS These processes suggestthat inflammation might promote motor neuron death Inaddition in ALS high CSF levels of glutamate and excito-toxicity have been reported [98] It has been proved that inALS oxidative stress is closely associated with motor neurondegeneration Several recent clinical researches suggest thatthere exist a number of biomarkers for oxidative stress inALS Mitsumoto et al [19] have observed that the level ofurinary 15-F

2119905-IsoP and urinary 8-oxodG was higher among

ALS patients than in control No correlation has been foundbetween age and urinary IsoPs Protein carbonyl levels didnot differ between patients suffering from ALS and controlsin contrast to urinary levels of IsoPs and urinary 8-oxodGwhich are strongly correlated This suggests that 15-F

2119905-IsoPs

and 8-oxodG are biomarkers of oxidative stress in patientswith ALS [58 99]

What is more it has been proved that the well-establishedrole of COX-2 in inflammation and in glutamate-dependentneurotoxicity is a basic hypothesis of COX-2 involvementin ALS pathogenesis The increased COX-2 mRNA andprotein were found in postmortem spinal cord of ALSpatients Together with the increase of PGE

2tissue levels

the elevated expression of COX-2 has been observed [100]COX-2 is expressed in neurons in the spinal cord dorsal andventral horns and also in dorsal root ganglia under normalconditions The COX-2 expression was markedly evaluatedand localized to both neurons and glial cells in postmortemspinal cord of ALS patients It has been proved that COX-2is associated with astrocytes andmuch lesser extent with glialcells [101] Some studies suggest that inhibition of COX-2mayhave therapeutic benefits by altering the cascade of eventsleading to the progressive neuronal death in ALS patientsBut the efficacy of COX-2 inhibition in the presence of overtclinical signs of disease still remains unknown

In addition in spinal cords of sporadic ALS patientsthe immunoreactivity of 15-deoxy-D12-14-PGJ

2(15d-PGJ

2)

has been found 15d-PGJ2 this bioactive prostanoid pro-

duced by dehydration and isomerization of PGD2 activates

the nuclear peroxisome proliferatormdashactivated receptor 120574(PPARy) PPARy is a critical transcription factor involved inadipocyte and monocyte differentiation

This receptor can be considered as a potential therapeuticbenefit of its activation in several inflammatory neurologicaldiseases [31]

Conflict of Interests

The authors declare that there is no conflict of interests regar-ding the publication of this paper

References

[1] A M Enciu M Gherghiceanu and B O Popescu ldquoTriggersand effectors of oxidative stress at blood-brain barrier levelrelevance for brain ageing and neurodegenerationrdquo OxidativeMedicine and Cellular Longevity vol 2013 Article ID 297512 12pages 2013

[2] E Niki ldquoLipid peroxidation products as oxidative stress biom-arkersrdquo BioFactors vol 34 no 2 pp 171ndash180 2008

[3] R Santos C R Almodovar A L Bulteau and C M GomesldquoNeurodegeneration neurogenesis and oxidative stressrdquoOxidative Medicine and Cellular Longevity vol 2013 Article ID730581 2 pages 2013

[4] G Cappellano M Carecchio T Fleetwood et al ldquoImmunityand inflammation in neurodegenerative diseasesrdquo AmericanJournal of Neurodegenerative Disease vol 2 no 2 pp 89ndash1072013

[5] G Almer P Teismann Z Stevic et al ldquoIncreased levels of thepro-inflammatory prostaglandin PGE2 in CSF from ALS pat-ientsrdquo Neurology vol 58 no 8 pp 1277ndash1279 2002

[6] T Farooqui and A A Farooqui ldquoLipid-mediated oxidativestress and inflammation in the pathogenesis of Parkinsonrsquosdiseaserdquo Parkinsonrsquos Disease vol 2011 Article ID 247467 9pages 2011

[7] J Guest R Grant T A Mori and K D Croft ldquoChanges in oxi-dative damage inflammation and [NAD(H)] with age in cere-brospinal fluidrdquo PLoS ONE vol 9 no 1 Article ID e85335 2014

[8] L J Roberts II and G L Milne ldquoIsoprostanesrdquo Journal of LipidResearch vol 50 pp S219ndashS223 2009

[9] NMattsson S Haghighi O Andersen et al ldquoElevated cerebro-spinal fluid F

2-isoprostane levels indicating oxidative stress in

healthy siblings of multiple sclerosis patientsrdquo NeuroscienceLetters vol 414 no 3 pp 233ndash236 2007

[10] L Minghetti A Greco F Cardone et al ldquoIncreased brain synt-hesis of prostaglandin E

2and F

2-isoprostane in human and

experimental transmissible spongiform encephalopathiesrdquo Jou-rnal of Neuropathology and Experimental Neurology vol 59 no10 pp 866ndash871 2000

[11] T J Montine J F Quinn D Milatovic et al ldquoPeripheral F2-iso-

prostanes and F4-neuroprostanes are not increased in Alzh-

eimerrsquos diseaserdquo Annals of Neurology vol 52 no 2 pp 175ndash1792002

[12] Y Yao V Zhukareva S Sung et al ldquoEnhanced brain levels of812-iso-iPF2120572-VI differentiate AD from frontotemporal dem-entiardquo Neurology vol 61 no 4 pp 475ndash478 2003


[13] D Pratico V M Y Lee J Q Trojanowski J Rokach and G AFitzgerald ldquoIncreased F

2-isoprostanes in Alzheimerrsquos disease

evidence for enhanced lipid peroxidation in vivordquo FASEBJournal vol 12 no 15 pp 1777ndash1783 1998

[14] S E Browne andM F Beal ldquoOxidative damage in Huntingtonrsquosdisease pathogenesisrdquo Antioxidants and Redox Signaling vol 8no 11-12 pp 2061ndash2073 2006

[15] S Kralovicova S N Fontaine A Alderton et al ldquoThe effects ofprion protein expression on metal metabolismrdquoMolecular andCellular Neuroscience vol 41 no 2 pp 135ndash147 2009

[16] B S Wong T Pan T Liu et al ldquoPrion disease a loss of ant-ioxidant functionrdquo Biochemical and Biophysical Research Com-munications vol 275 no 2 pp 249ndash252 2000

[17] L Minghetti F Cardone A Greco et al ldquoIncreased CSF levelsof prostaglandin E

2in variant Creutzfeldt-Jakob diseaserdquo Neu-

rology vol 58 no 1 pp 127ndash129 2002[18] S Arlt A Kontush I Zerr et al ldquoIncreased lipid peroxidation in

cerebrospinal fluid and plasma from patients with creutzfeldt-jakob diseaserdquo Neurobiology of Disease vol 10 no 2 pp 150ndash156 2002

[19] H Mitsumoto R Santella X Liu et al ldquoOxidative stressbiomarkers in sporadic ALSrdquoAmyotrophic Lateral Sclerosis vol9 no 3 pp 177ndash183 2008

[20] R Zhang Q Zhang J Niu et al ldquoScreening of microRNAsassociated with Alzheimerrsquos disease using oxidative stress cellmodel and different strains of senescence accelerated micerdquoJournal of the Neurological Sciences vol 338 pp 57ndash64 2014

[21] K D Jacob N Noren N Hooten A R Trzeciak and M KEvans ldquoMarkers of oxidant stress that are clinically relevant inaging and age-related diseaserdquo Mech Ageing vol 134 pp 139ndash157 2013

[22] A A Farooqui L A Horrocks and T Farooqui ldquoInteractionsbetween neural membrane glycerophospholipid and sphin-golipid mediators a recipe for neural cell survival or suiciderdquoJournal of Neuroscience Research vol 85 no 9 pp 1834ndash18502007

[23] R E Gonsette ldquoNeurodegeneration in multiple sclerosis therole of oxidative stress and excitotoxicityrdquo Journal of the Neu-rological Sciences vol 274 no 1-2 pp 48ndash53 2008

[24] B Halliwell and C Y J Lee ldquoUsing isoprostanes as biomarkersof oxidative stress some rarely considered issuesrdquo Antioxidantsand Redox Signaling vol 13 no 2 pp 145ndash156 2010

[25] G Barrera ldquoOxidative stress and lipid peroxidation productsin cancer progression and therapyrdquo ISRN Oncology vol 2012Article ID 137289 21 pages 2012

[26] Y Dotan D Lichtenberg and I Pinchuk ldquoLipid peroxidationcannot be used as a universal criterion of oxidative stressrdquoProgress in Lipid Research vol 43 no 3 pp 200ndash227 2004

[27] G L Milne H Yin K D Hardy S S Davies and L J RobertsldquoIsoprostane generation and functionrdquo Chemical Reviews vol111 no 10 pp 5973ndash5996 2011

[28] L J Roberts II and J D Morrow ldquoProducts of the isoprostanepathway unique bioactive compounds and markers of lipidperoxidationrdquo Cellular and Molecular Life Sciences vol 59 no5 pp 808ndash820 2002

[29] K D Hardy B E Cox G L Milne H Yin and L JRoberts II ldquoNonenzymatic free radical-catalyzed generation of15-deoxy-Δ1214 J

2-like compounds (deoxy-J

2-isoprostanes) in

vivo1rdquo Journal of Lipid Research vol 52 no 1 pp 113ndash124 2011[30] R C Murphy and E Fahy ldquoIsoprostane nomenclature more

suggestionsrdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 82 no 2-3 pp 69ndash70 2010

[31] S G Harris J Padilla L Koumas D Ray and R P PhippsldquoProstaglandins as modulators of immunityrdquo Trends in Imm-unology vol 23 no 3 pp 144ndash150 2002

[32] E E Reich W R Markesbery L J Roberts II L L Swift JD Morrow and T J Montine ldquoBrain regional quantificationof F-ring and D-E-ring isoprostanes and neuroprostanes inAlzheimerrsquos diseaserdquoAmerican Journal of Pathology vol 158 no1 pp 293ndash297 2001

[33] E L Streck G A Czapski and C Goncalves da Silva ldquoNeur-odegeneration mitochondrial dysfunction and oxidative str-essrdquo Oxidative Medicine and Cellular Longevity vol 2013Article ID 826046 2 pages 2013

[34] Y Chen J D Morrow and L J Roberts II ldquoFormation of rea-ctive cyclopentenone compounds in vivo as products of theisoprostane pathwayrdquo Journal of Biological Chemistry vol 274no 16 pp 10863ndash10868 1999

[35] Y Chen W E Zackert L J Roberts II and J D MorrowldquoEvidence for the formation of a novel cyclopentenone iso-prostane 15-A(2t)-isoprostane (8-iso-prostaglandin A2) invivordquo Biochimica et Biophysica Acta Molecular and Cell Biologyof Lipids vol 1436 no 3 pp 550ndash556 1999

[36] R D OrsquoBrien ldquoFats and oils analysisrdquo in Fats and OilsFormulating and Processing for Applications pp 197ndash260 CRCPress Boca Raton Fla USA 3rd edition 2009

[37] C de Felice C Signorini T Durand et al ldquoF2-dihomo-isop-

rostanes as potential early biomarkers of lipid oxidative damagein Rett syndromerdquo Journal of Lipid Research vol 52 no 12 pp2287ndash2297 2011

[38] A E Barden T B Corcoran E Mas et al ldquoIs there a role forisofurans and neuroprostanes in pre-eclampsia and normal pre-gnancyrdquo Antioxidants and Redox Signaling vol 16 no 2 pp165ndash169 2012

[39] J D Brooks G L Milne H Yin S C Sanchez N A Porterand J DMorrow ldquoFormation of highly reactive cyclopentenoneisoprostane compounds (A 3J3-isoprostanes) in vivo fromeicosapentaenoic acidrdquo Journal of Biological Chemistry vol 283no 18 pp 12043ndash12055 2008

[40] M Comporti C Signorini B Arezzini D Vecchio B Monacoand C Gardi ldquoF

2-isoprostanes are not just markers of oxidative

stressrdquo Free Radical Biology andMedicine vol 44 no 3 pp 247ndash256 2008

[41] S Zaja-Milatovic R C Gupta M Aschner and D MilatovicldquoProtection of DFP-induced oxidative damage and neurode-generation by antioxidants and NMDA receptor antagonistrdquoToxicology and Applied Pharmacology vol 240 no 2 pp 124ndash131 2009

[42] D Milatovic T J Montine and M Aschner ldquoMeasurement ofisoprostanes as markers of oxidative stressrdquo Methods in Molec-ular Biology vol 758 pp 195ndash204 2011

[43] E D rsquoAmico P Factor-Litvak R M Santella and H Mitsum-oto ldquoClinical perspective on oxidative stress in sporadic amyot-rophic lateral sclerosisrdquo Free Radical BiologyampMedicine vol 65pp 509ndash527 2013

[44] JWong-Ekkabut Z XuW Triampo IM Tang D P Tielemanand LMonticelli ldquoEffect of lipid peroxidation on the propertiesof lipid bilayers a molecular dynamics studyrdquo BiophysicalJournal vol 93 no 12 pp 4225ndash4236 2007

[45] S Yehuda S Rabinovitz R L Carasso and D I MostofskyldquoThe role of polyunsaturated fatty acids in restoring the agingneuronal membranerdquo Neurobiology of Aging vol 23 no 5 pp843ndash853 2002


[46] T J Montine M D Neely J F Quinn et al ldquoLipid peroxidationin aging brain andAlzheimerrsquos diseaserdquoFree Radical Biology andMedicine vol 33 no 5 pp 620ndash626 2002

[47] E Miller A Walczak J Saluk M B Ponczek and I MajsterekldquoOxidative modification of patientrsquos plasma proteins and its rolein pathogenesis of multiple sclerosisrdquoClinical Biochemistry vol45 no 1-2 pp 26ndash30 2012

[48] Z Korade L Xu K Mirnics and N A Porter ldquoLipid biomark-ers of oxidative stress in a geneticmousemodel of Smith-Lemli-Opitz syndromerdquo Journal of InheritedMetabolic Disease vol 36no 1 pp 113ndash122 2013

[49] G L Milne B Gao E S Terry W E Zackert and S C San-chez ldquoMeasurement of F

2-isoprostanes and isofurans using gas

chromatography-mass spectrometryrdquo Free Radical Biology ampMedicine vol 59 pp 36ndash44 2013

[50] B CasettaM Longini F Proietti S Perrone andG BuonocoreldquoDevelopment of a fast and simple LC-MSMSmethod formea-suring the F

2-isoprostanes in newbornsrdquo Journal of Maternal-

Fetal and Neonatal Medicine vol 25 no 1 pp 114ndash118 2012[51] G L Milne H Yin and J D Morrow ldquoHuman biochemistry of

the isoprostane pathwayrdquo Journal of Biological Chemistry vol283 no 23 pp 15533ndash15537 2008

[52] G L Milne H Yin K D Hardy S S Davies and L J RobertsldquoIsoprostane generation andfunctionrdquo Chemical Reviews vol111 no 10 pp 5973ndash5996 2011

[53] S Bleich S Kropp D Degner et al ldquoCreutzfeldt-Jakob diseaseand oxidative stressrdquo Acta Neurologica Scandinavica vol 101no 5 pp 332ndash334 2000

[54] T J Montine M F Beal D Robertson et al ldquoCerebrospinalfluid F

2-isoprostanes are elevated in Huntingtonrsquos diseaserdquo

Neurology vol 52 no 5 pp 1104ndash1105 1999[55] E Miller M Mrowicka J Saluk-Juszczak and M Ireneusz

ldquoThe level of isoprostanes as a non-invasive marker for in vivolipid peroxidation in secondary progressive multiple sclerosisrdquoNeurochemical Research vol 36 no 6 pp 1012ndash1016 2011



rology vol 58 no 1 pp 127ndash129 2002[57] D T Walsh V H Perry and L Minghetti ldquoCyclooxygenase-2

is highly expressed in microglial-like cells in a murine model ofprion diseaserdquo Glia vol 29 pp 392ndash396 2000

[58] C Consilvio A M Vincent and E L Feldman ldquoNeuroinflam-mation COX-2 and ALSmdasha dual rolerdquo Experimental Neurol-ogy vol 187 no 1 pp 1ndash10 2004

[59] L J Roberts II J P Fessel and S S Davies ldquoThe biochemistry ofthe isoprostane neuroprostane and isofuran pathways of lipidperoxidationrdquo Brain Pathology vol 15 no 2 pp 143ndash148 2005

[60] D Milatovic and M Aschner ldquoMeasurement of isoprostanesas markers of oxidative stress in neuronal tissuerdquo in CurrentProtocols in Toxicology unit 1214 pp 1ndash12 2009

[61] A Melo L Monteiro R M F Lima D M de Oliveira MD de Cerqueira and R S El-Bacha ldquoOxidative stress in neur-odegenerative diseases mechanisms and therapeutic perspec-tivesrdquo Oxidative Medicine and Cellular Longevity vol 2011Article ID 467180 14 pages 2011

[62] G G Ortiz F P Pacheco-Moises O K Bitzer-Quintero et alldquoImmunology and oxidative stress in multiple sclerosis clin-ical and basic approachrdquo Journal of Cerebral Blood Flow ampMetabolism vol 34 pp 34ndash42 2014

[63] R Sultana and D A Butterfield ldquoRole of oxidative stress inthe progression of Alzheimerrsquos diseaserdquo Journal of AlzheimerrsquosDisease vol 19 no 1 pp 341ndash353 2010

[64] S Ayala-Pena ldquoRole of oxidative DNA damage in mitochon-drial dysfunction and Huntingtonrsquos disease pathogenesisrdquo FreeRadical Biology amp Medicine vol 62 pp 102ndash110 2013

[65] D A Butterfield M L Bader Lange and R Sultana ldquoInvolve-ments of the lipid peroxidation product HNE in the patho-genesis and progression of Alzheimerrsquos diseaserdquo Biochimica etBiophysica Acta Molecular and Cell Biology of Lipids vol 1801no 8 pp 924ndash929 2010

[66] A Greco L Minghetti and G Levi ldquoIsoprostanes novel mark-ers of oxidative injury help understanding the pathogenesis ofneurodegenerative diseasesrdquo Neurochemical Research vol 25no 9-10 pp 1357ndash1364 2000

[67] E Miller ldquoNeurodegenerative diseasesrdquo Advances in Experi-mental Medicine and Biology vol 724 pp 228ndash238 2012

[68] D Karussis ldquoThe diagnosis of multiple sclerosis and the variousrelated demyelinating syndromes a critical reviewrdquo Journal ofAutoimmunity vol 48-49 pp 134ndash142 2014

[69] S Gandhi andA Y Abramov ldquoMechanism of oxidative stress inneurodegenerationrdquoOxidativeMedicine and Cellular Longevityvol 2012 Article ID 428010 11 pages 2012

[70] L K Peterson and R S Fujinami ldquoInflammation demyelina-tion neurodegeneration and neuroprotection in the pathogen-esis of multiple sclerosisrdquo Journal of Neuroimmunology vol 184no 1-2 pp 37ndash44 2007

[71] E Miller M Mrowicka K Malinowska J Mrowicki J Saluk-Juszczak and J Kedziora ldquoEffects of whole-body cryotherapyon a total antioxidative status and activities of antioxidativeenzymes in blood of depressive multiple sclerosis patientsrdquoWorld Journal of Biological Psychiatry vol 12 no 3 pp 223ndash2272011

[72] S Ljubisavljevic I Stojanovic D Pavlovic et al ldquoSuppressionof the lipid peroxidation process in the CNS reduces neu-rological expression of experimentally induced autoimmuneencephalomyelitisrdquo Folia Neuropathologica vol 51 pp 51ndash572013

[73] A Greco and L Minghetti ldquoIsoprostanes as biomarkers andmediators of oxidative injury in infant and adult central nervoussystem diseasesrdquo Current Neurovascular Research vol 1 no 4pp 341ndash354 2004

[74] S Mondragon-Rodrıguez G Perry X Zhu and J BoehmldquoAmyloid beta and tau proteins as therapeutic targets forAlzheimerrsquos disease treatment rethinking the current strategyrdquoInternational Journal of Alzheimerrsquos Disease vol 2012 Article ID630182 7 pages 2012

[75] M G Savelieff S Lee Y Liu andM H Lim ldquoUntangling amy-loid-120573 tau and metals in Alzheimerrsquos diseaserdquo ACS ChemicalBiology vol 8 pp 856ndash865 2013

[76] G Ellis E Fang M Maheshwari et al ldquoLipid oxidation andmodification of amyloid-120573 (A120573) in vitro and in vivordquo Journalof Alzheimerrsquos Disease vol 22 no 2 pp 593ndash607 2010

[77] R Sultana M Perluigi and A D Butterfield ldquoLipid peroxida-tion triggers neurodegeneration a redox proteomics view intothe Alzheimer disease brainrdquo Free Radical Biology amp Medicinevol 62 pp 157ndash169 2013

[78] S M Pritchard P J Dolan A Vitkus and G V W JohnsonldquoThe toxicity of tau in Alzheimer disease turnover targetsand potential therapeuticsrdquo Journal of Cellular and MolecularMedicine vol 15 no 8 pp 1621ndash1635 2011

[79] Y Zhao and B Zhao ldquoOxidative stress and the pathogenesis ofAlzheimerrsquos diseaserdquoOxidativeMedicine andCellular Longevityvol 2013 Article ID 316523 10 pages 2013


[80] E S Musiek J K Cha H Yin et al ldquoQuantification of F-ringisoprostane-like compounds (F

4-neuroprostanes) derived from

docosahexaenoic acid in vivo in humans by a stable isotopedilution mass spectrometric assayrdquo Journal of ChromatographyB Analytical Technologies in the Biomedical and Life Sciencesvol 799 no 1 pp 95ndash102 2004

[81] J Long P He Y Shen and R Li ldquoNew evidence of mitochon-dria dysfunction in the female Alzheimerrsquos disease brain defi-ciency of estrogen receptor-120573rdquo Journal of Alzheimerrsquos Diseasevol 30 pp 545ndash558 2012

[82] A Mancini S Raimondo M Persano et al ldquoEstrogens as ant-ioxidant modulators in human fertilityrdquo International Journal ofEndocrinology vol 2013 Article ID 607939 6 pages 2013

[83] D Pratico J Rokach and R K Tangirala ldquoBrains of aged apoli-poprotein E-deficient mice have increased levels of F

2-isop-

rostanes in vivomarkers of lipid peroxidationrdquo Journal of Neu-rochemistry vol 73 no 2 pp 736ndash741 1999

[84] F Sanchez-Lopez I Tasset E Aguera et al ldquoOxidative stressand inflammation biomarkers in the blood of patients withHuntingtonrsquos diseaserdquo Neurological Research vol 34 pp 721ndash724 2012

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


[87] F Haun T Nakamura and S A Lipton ldquoDysfunctional mito-chondrial dynamics in the pathophysiology of neurodegenera-tive diseasesrdquo Journal of Cell Death vol 6 pp 27ndash35 2013

[88] E C Stack W R Matson and R J Ferrante ldquoEvidence of oxi-dant damage in Huntingtonrsquos disease translational strategiesusing antioxidantsrdquoAnnals of theNewYorkAcademy of Sciencesvol 1147 pp 79ndash92 2008

[89] L Gan and J A Johnson ldquoOxidative damage and the Nrf2-AREpathway in neurodegenerative diseasesrdquo Biochimica et Biophys-ica Acta 2013

[90] A Carrizzo A Di Pardo V Maglione et al ldquoNitric oxide dys-regulation in platelets from patients with advanced huntingtondiseaserdquo PLoS ONE vol 9 no 2 Article ID e89745 2014

[91] N Stoy G M Mackay C M Forrest et al ldquoTryptophan meta-bolism and oxidative stress in patients with Huntingtonrsquos dis-easerdquo Journal of Neurochemistry vol 93 no 3 pp 611ndash623 2005

[92] 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

[93] B SWong T Liu R Li et al ldquoIncreased levels of oxidative stressmarkers detected in the brains of mice devoid of prion proteinrdquoJournal of Neurochemistry vol 76 no 2 pp 565ndash572 2001

[94] MGuentchev T Voigtlander CHaberlerMHGroschup andH Budka ldquoEvidence for oxidative stress in experimental priondiseaserdquoNeurobiology of Disease vol 7 no 4 pp 270ndash273 2000

[95] B S Wong D R Brown T Pan et al ldquoOxidative impairmentin scrapie-infected mice is associated with brain metals per-turbations and altered antioxidant activitiesrdquo Journal of Neuro-chemistry vol 79 no 3 pp 689ndash698 2001

[96] C Bate S Rutherford M Gravenor S Reid and A WilliamsldquoCyclo-oxygenase inhibitors protect against prion-induced

neurotoxicity in vitrordquo NeuroReport vol 13 no 15 pp 1933ndash1938 2002

[97] S Boillee C Vande Velde and D Cleveland ldquoALS a disease ofmotor neurons and their nonneuronal neighborsrdquo Neuron vol52 no 1 pp 39ndash59 2006

[98] P F Pradat S Attarian J P Camdessanche et al ldquoResearch inamyotrophic lateral sclerosis what is new in 2009rdquo Revue Neu-rologique vol 166 no 8-9 pp 683ndash698 2010


[100] S C Barber and P J Shaw ldquoOxidative stress in ALS key role inmotor neuron injury and therapeutic targetrdquo Free Radical Bio-logy and Medicine vol 48 no 5 pp 629ndash641 2010

[101] G Almer C Guegan P Teismann et al ldquoIncreased expressionof the pro-inflammatory enzyme cyclooxygenase-2 in amy-otrophic lateral sclerosisrdquo Annals of Neurology vol 49 no 2pp 176ndash185 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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EndocrinologyInternational Journal of



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Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


in this multifactorial process Astrocytes constitute approx-imately 90 of human brain and protect neurons fromexcitotoxicity through glutamate uptake system and on theother side astrocytes contribute to the extracellular glu-tamate via reversed glutamate transporter [5] Moreoverthey may undergo astrocytosis after dopaminergic cell lossand are involved in the inflammatory processes In generalinflammation is a protective response The main mediatorsof neuroinflammation are microglial cells Microglial cellsconsistmainly ofmacrophages and react to oxidative stress bytransformation into activatedmicroglia that are characterizedby amoeboid morphology and rapid migration Chronicactivation of microglia may cause neuronal damage throughthe release of potentially toxic molecules such as proin-flammatory cytokines matrix metalloproteinases ROSRNSproteinases prostaglandin E

2 complement proteins and

growth factors and also leads to the DNA and RNA damage[5 21] These factors have neuroprotective properties but onthe other hand they can be responsible for acceleration ofoxidative stress and neurodegeneration

Markers of lipid peroxidation include different moleculessuch as 4-hydroxy-trans-2-nonenal (4-HNE) 4-oxo-trans-2-nonenal (4-ONE) acrolein isoprostanes and isofuransThese markers are derived from AA which is releasedfrom neural membrane glycerophospholipids through theactivation of cytosolic phospholipases A

2(cPLA

2) [22]

Lipid peroxidation is a hallmark of oxidative stress Highlevel of lipid peroxidation products is a characteristic formany human diseases especially neurodegenerative diseasesIt can cause damage to cellular membranes through changesof membrane organization and alteration of membraneintegrity fluidity and permeability [23]

2 Biomarkers

Biomarkers are defined as the indicators of normal biologicalprocesses or pathologic processes that can be objectivelymea-sured and evaluated [1] The well-characterized appropriatebiomarkers may be used for health examination diagnosisof pathologic processes at early stage assessment of treat-ment response and prognosis Noninvasivemeasurements ofcirculating levels of specific biomarker are useful along thewhole spectrum of the disease process and before diagnosisbiomarkers could be used for screening and risk assessmentof the diseases [2] Moreover biomarkers may be used forprecise measurement of oxidative stress status in vivo [3]Among the biological molecules lipids appear to be the mostsusceptible to the attack of ROSRNS [24 25] and lipid per-oxidation has been implicated in the neurodegeneration [11]Therefore the levels of lipid peroxidation products may beused as a biomarker for the measurement of oxidative stressstatus in vivo in neurodegenerative diseases [3] The levels oflipid peroxidation products in biological fluids and tissuesof human subjects have been measured extensively [26]Presently various lipid peroxidation products are applied forassessment of lipid peroxidation and oxidative stress status invivo

The measurement of F2-IsoPs is currently the best avail-

able biomarker of lipid peroxidation [8 10 22 24]

3 The Isoprostanes Pathways

In the mid-1970s it was shown that PG-like compoundscould be formed in vitro by the nonenzymatic peroxidationof purified PUFAs F

2-IsoPs have been discovered in 1990 by

Milne et al [27] and Roberts II and Morrow [28] and sincethen they collected a lot of evidence that these compoundsmight be biomarkers of lipid peroxidation and oxidativestress in vivo as well as in vitro

F2-IsoPs are a unique prostaglandin-like products which

are formed via nonenzymatic free radical-mediated per-oxidation of polyunsaturated fatty acidsmdashfor example AA[28 29] The oxidation of AA proceeds by many competingreactions to give numerous products IsoPs containing avariety of prostane ring structures are composed of variousisomers including F

2-IsoPs which are isomeric to PGF

2120572

[27 30 31] and D2E2-IsoPs which are isomers of PGD

2

and PGE2 respectively [32] The mechanism of F

2-IsoPs

formation involves several steps In the first stage ROS reactswith the arachidonic acid and undergoes abstraction of anbisallylic hydrogen atom to yield an arachidonyl carbon-centered radical What is more there is insertion of oxygenwhich leads to the formation of peroxyl radicals Fourdifferent peroxyl radical isomers are formed depending onsite of hydrogen abstraction and oxygen insertion Peroxylradicals isomers undergo 5-endocyclization and a secondmolecule of oxygen adds to the backbone of the compound toform four bicyclic endoperoxide intermediate regioisomersmdashPGH2-like compounds These unstable bicycloendoperoxide

intermediates are reduced to the F2-IsoPs and four F

2-IsoPs

regioisomers are formed [30 33 34] This regioisomers arereduced to four series of F-ring regioisomers (15- 8- 12-5-series) each consisting of eight racemic diastereoisomersThese regioisomers are depending on the carbon atom towhich the side chain hydroxyl is attached [8]

To sum up the biosynthetic steps of IsoPs includeformation of the following

(i) three arachidonyl radicals(ii) four peroxyl radical isomers with subsequent endo-

cyclization finally formation of bicycloendoperoxideregioisomers which are reduced to F

2-IsoPs IsoPs are

compounds that have F-type prostane rings isomericto PGF

2120572

The alternative ring structures DE-type and AJ-typeprostane are formed by the same mechanisms [32 34]So that E- or D-ring and thromboxane-ring compounds ofIsoPs are formed during the rearrangement of isoprostaneendoperoxides in vivo E

2- and D

2-IsoPs are not terminal

products of the IsoP pathwayThese compounds are unstableand readily undergo dehydration in vivo to yield A

2J2-IsoPs

The cyclopentenone IsoPs might be neurotoxic products ofthe IsoPs pathway and might contribute to the pathogenesisof oxidative neurodegeneration A

2-J2-IsoPs contain 120572120573-

unsaturated carbonyls which rapidly adduct cellular thiolsand these cyclopentenone IsoPs induce neuronal apoptosisand promote neurodegeneration [27]

The other electrophilic lipid peroxidation products canalso damage neurons The 120574-ketoaldehydes (eg isoketals










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