review article role of oxidative stress in the

Review ArticleRole of Oxidative Stress in the Neurocognitive Dysfunction ofObstructive Sleep Apnea Syndrome

Li Zhou123 Ping Chen123 Yating Peng123 and Ruoyun Ouyang123

1Department of Respiratory Medicine The Second Xiangya Hospital Central South University 139 Renming Middle RoadChangsha Hunan 410011 China2Research Unit of Respiratory Disease Central South University 139 Renming Middle Road Changsha Hunan 410011 China3Treatment Center of Respiratory Disease Central South University 139 Renming Middle Road Changsha Hunan 410011 China

Correspondence should be addressed to Ruoyun Ouyang ruoyun001126com

Received 5 June 2016 Accepted 1 September 2016

Academic Editor Saeid Golbidi

Copyright copy 2016 Li Zhou et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Obstructive sleep apnea syndrome (OSAS) is characterized by chronic nocturnal intermittent hypoxia and sleep fragmentationsNeurocognitive dysfunction a significant and extraordinary complication of OSAS influences patientsrsquo career family and sociallife and reduces quality of life to some extent Previous researches revealed that repetitive hypoxia and reoxygenation causedmitochondria and endoplasmic reticulum dysfunction overactivated NADPH oxidase xanthine oxidase and uncoupling nitricoxide synthase induced an imbalance between prooxidants and antioxidants and then got rise to a series of oxidative stress (OS)responses such as protein oxidation lipid peroxidation and DNA oxidation along with inflammatory reaction OS in brain couldtrigger neuron injury especially in the hippocampus and cerebral cortex regionsThose two regions are fairly susceptible to hypoxiaand oxidative stress production which could consequently result in cognitive dysfunction Apart from continuous positive airwaypressure (CPAP) antioxidant may be a promising therapeutic method to improve partially reversible neurocognitive functionUnderstanding the role that OS played in the cognitive deficits is crucial for future research and therapeutic strategy developmentIn this paper recent important literature concerning the relationship between oxidative stress and cognitive impairment in OSASwill be summarized and the results can provide a rewarding overview for future breakthrough in this field

1 Introduction

Obstructive sleep apnea syndrome (OSAS) a clinical syn-drome manifesting as repetitive episodes of partial or com-plete collapse of the upper airway during sleep resultsin recurrent nocturnal apnea chronic intermittent hypoxia(CIH) transitory hypercapnia and sleep fragmentation Ithas been recognized as a paramount and growing prevalentpublic health problem affecting 22 of men and 17 ofwomen on average [1] Among the population with OSAScertain subgroups like middle-age adults and elderly standat a higher risk [2] which is also closely associated with aseries of adverse complications such as hyperlipemia [3 4]type 2 diabetes [5 6] cardiovascular disease [7ndash9] (systemichypertension [10] coronary disease [11] heart failure [12]and stroke [13]) pulmonary hypertension [14] and neu-rocognitive deficits [15 16] Cognitive impairment in OSAS

individuals is involved with various cognitive domains suchas attentionvigilancememory and global cognitive functionas well as executive function Substantial studies have provedthat oxidative stress (OS) a consequence of chronic recurrenthypoxia and reoxygenation and an extraordinary feature ofOSAS plays a significant role in cardiovascular disease asso-ciated with OSAS More importantly accumulating evidencehas demonstrated thatOS is also one of the importantmecha-nisms leading to neurocognitive dysfunctionThis reviewwillsummarize the current research conducted neurocognitiveimpairment and OSAS and the role of oxidative stress inneurocognitive impairment of OSAS

2 OS in OSAS

Oxidative stress (OS) is a state of prooxidantantioxidantimbalance resulting from a variety of exogenous or

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 9626831 15 pageshttpdxdoiorg10115520169626831

2 Oxidative Medicine and Cellular Longevity

endogenous stimulation or stress It could be induced byoverproduction of reactive oxygen species (ROS) and reactivenitrogen species (RNS) or a decreased capacity of antioxidantThere are two kinds of antioxidantsThe first one is enzymaticprocesses including superoxide dismutase (SOD) catalase(CAT) glutathione peroxidase (GSH-Px) peroxiredoxinglutathione reductase and thioredoxin reductase (TRXR)The other type of antioxidant includes ergothioneine vitaminC vitamin E glutathione melatonin alpha lipoic acidcarotenoid copper zinc and selenium Recent studies havesuggested that the recurrence of the process of hypoxiareox-ygenation in OSAS contributes to the imbalance betweenantioxidant defense system and oxidant system which couldlead to OS and then activate and accelerate peroxidationdamage and inflammation reaction A series of transcriptionfactors such as hypoxia inducible transcription factors-1120572(HIF-1120572) nuclear factor-like 2 (Nrf2) activator protein 1(AP1) and nuclear factor 120581120573 (NF120581120573) are activated in OSAS[17] Consequently damage to tissue and cells endothelialdysfunction [18] and metabolic disturbance occurred andother comorbidities such as type 2 diabetes dyslipidemiacardiovascular complications [19ndash23] and neurocognitiveimpairment followed [17 24]

21 Biomarkers of OS Levels OS is a result of imbalanceof oxidative system and antioxidative system The majorOS damage includes lipid peroxidation protein oxidationRNA and DNA damage protein nitration production ofROS and peroxide and change of total antioxidant capacityBiomarkers related to OS include protein oxidation (proteincarbonyl advanced oxidative protein production AGE glu-tathione [25] GSSG 3-nitrotyrosine) lipid peroxidation (8-hydroxyguanosine thiobarbituric acid reactive substancesox-LDL malondialdehyde (MDA) [26] 4-hydroxynonenaland LOOH) DNA damage (8-hydroxydeoxyguanosine [27]8-hydroxyguanosine and comet assay) antioxidation (SODCAT and GSH-Px) ROS nitrate nitrite NADPH oxidase(Nox) Cp paraoxonase arylesterase sulfhydryl group TASTOS and OSI In addition previous research suggeststhat CCAT-enhancer binding protein (CEBP) homologousbinding protein (CHOP) which is indispensable for pro-cesses like NADPH oxidase subtype 2 (Nox2) ROS andhypoxia inducible factor-1120572 activation (HIF-1120572) might bean upstream target to protect OSAS patients from oxidativedamage [28] Furthermore the concentration of ROS RNSand oxygen ion can be directly and accurately measured byan advanced method electron paramagnetic resonance withhigh sensitivity [29]

A multitude of studies have manifested the occurrenceof oxidative stress in obstructive sleep apnea (OSA) patients[30ndash33] A study by Lavie et al [34] has investigated 114OSA patients and 30 nonapneic controls Among the OSApatients 59 have cardiovascular disease (CVD) 55 have nocardiovascular disease (CVD) It was found that the levelof paraoxonase-1 (PON1) is lower and the concentrations ofthiobarbituric reactive substances (TBARS) and peroxides(PD) are higher in OSA patients group compared withcontrol subjects Besides a negative association betweenPON1 activity and respiratory disturbance index (RDI) was

observed while TBARS and PD were significantly positivelycorrelated with RDI After nCPAP treatment the levels ofTBARS and PD were significantly decreased Increased levelsof other lipid peroxidation biomarkers such as MDA and 8-isoprostane were also observed in OSAS patients in otherresearches and improved after CPAP treatment [18 35 36]

Mancuso et al [37] have assessed levels of advancedoxidation protein products (AOPP) ferric reducing antiox-idant power (FRAP) and total glutathione (GSH) in twogroups (41 OSA patients and 32 healthy control subjects)All the subjects are free of comorbidities and are non-smokers They found a significant increase in serum AOPPconcentration and a decrease in FRAP and GSH levels inOSA patients This study revealed that OSAS patients weresubjected to protein oxidation and antioxidative capacityimpairment CPAP treatment improved the abnormal FRAPlevel which suggests that FRAP is likely to be a potentialbiomarker to access OS level after CPAP treatment A cross-sectional study measuring urinary excretion of 8-hydroxy-21015840-deoxyguanosine (8-OHdG) as an indicator of DNA OSdamage also showed similar results [27]

Hopps et al [38] have measured concentration of TBARSand carbonyl between a group of 27 severe OSAS patients(AHI gt 30) and a group of 21 mild-to-moderate OSASpatients (AHI lt 30) Significantly higher levels of TBARSand carbonyl were found in severe OSAS group Besidesthese biomarkers were positively associated with neck andwaist circumference AHI value and oxygen desaturationindex respectively and negatively associated with the meanoxygen saturation Similarly Franco et al [39] have reportedsignificantly higher superoxide radical and lower levels ofserum nitrates and nitrites in OSAS patients compared tohealthy subjects in a severity-dependent manner They alsofound thatmoderate and severeOSAS patients had semblableOS profile and condition which were remarkably differentfrom mild patients That is a critical condition probablyexists in the triggering of oxidative stress metabolism andsymptoms between mild and moderate OSAS

22 Posttreatment OS Levels A number of studies havesuggested that treatment with CPAP could attenuate OSlevels in OSA patients [35 40ndash45] Carpagnano et al [46]have reported that serum and exhaled breath condensateconcentration of 8-isoprostane were progressively decreasedafter CPAP treatment Relevant conclusions in the populationof elderly OSAS were also reached by Yagihara et al [41] whoreported significantly reducedMDA levels after sixmonths ofCPAP therapy Similarly Oyama et al [43] found markedlyraised plasma levels of nitric oxide and declined TBARS andasymmetrical dimethylarginine levels after three months ofCPAP treatment In recent years the relationship betweenOS and pediatric OSA became a rising concern Similar toadults pediatric OSA is associated with an increased OSThe study conducted by Tauman found that OSA in childrenis associated with increased lipid peroxidation which waspositively correlated with disease severity and the degree ofintermittent hypoxia [31]

Oxidative Medicine and Cellular Longevity 3

23 Mechanism of OS in OSAS There are several subcellularcompartments involved in the production of ROS such asmitochondria endoplasmic reticulum cellular membranelysosomes peroxisomes and the enzymatic systems whichincludeNADPHoxidases (Nox2 andNox4) xanthine oxidase(XOD) phospholipase A2 lipoxygenases cyclooxygenaseand uncoupled nitric oxide synthases (NOSs) [27 47 48]The mitochondria which are main sources for the formationof ROS from electron transport chain (ETC) are suscepti-ble to hypoxia Recurrent ischemiareoxygenation in OSASpatients could lead to dysfunction of mitochondria andendoplasmic reticulum and activation of Nox which willcause overproduction of ROS and OS eventually [30] XODplays a crucial role in cellular oxidative status detoxificationof aldehydes and oxidative injury in ischemia-reperfusion[49] A case-control study including 43 OSAS patients and 43age- and sex-matched subjects showed that plasma concen-tration of xanthinehypoxanthine was significantly increasedinOSAS patients and positively associatedwith age AHI andseverity of the disease [50] In additionNtalapascha et al [25]evaluated OS levels extensively in a homogenous populationof severe OSAS patients (AHI gt 30) These patients haveundergone no treatment free of comorbidities or factorsknown to augment OS per se Their study demonstrated thatOSA may be related to elevated OS burden through proteinoxidation-GSHGSSG pathway

However it should be noted that the pathogenic role ofOSin OSAS is still controversial Some studies failed to demon-strate that OSAS is linked to increased oxidative stress [2651 52] An analysis by Simiakakis et al recruited a group of42 moderate to severe OSAS patients and 24 healthy controlsubjects and revealed that smoking obesity and gender playcrucial roles in determining OS levels of OSAS patients [53]Confounding factors such as age obesity smoking dietaryhabits hypertension diabetes hyperlipemia coronary heartdisease metabolic syndrome and other concurrent comor-bidities which might augment OS could cause experimentalerrors and bias if the researchers did not exclude these factorsDespite the argument the understanding that OS plays acrucial role in the development of OSAS has seemed tobe an emerging consensus [33] However more large-scalemulticenter randomized control trials with homogeneouspopulation are needed to be conducted and confirm whetherOS is involved in OSAS and its complications

3 Neurocognitive Dysfunction in OSAS

Cognitive function is an important component of humanadvanced nervous function It includes psychological processsuch as feeling consciousness reasoning language thoughtintelligence and learning The risk factors of cognitive disor-der consist of age gender smoking alcohol drinking obe-sity hypertension chronic heart disease diabetes metabolicsyndrome stroke hypothyroidism active psychiatric drugapolipoprotein E epsilon 4 (APOE 1205764) allele Down syn-drome abnormal maxillofacial anatomy family history andOSA [54] Neurocognitive impairment of OSAS involved inpatients of all age ranges [55] has an unfavorable impact

on the patientsrsquo work productivity quality of life and socialsafety

31 Classification of Neurocognitive Dysfunction in OSAS Asystematic meta-review has indicated that OSAS are asso-ciated with a broad range of neurocognitive deficits atten-tionvigilance executive function delayed long-term visualand verbal memory global cognitive function and visuospa-tialconstruction abilities [16 54] Generally attention is themost common impaired cognition in OSAS subjects and itcan be divided into three components sustained selectiveand divided attention [56] Several studies [57 58] havedemonstrated that drivers with OSA have decreased visualvigilancesustained attention which is closely associatedwithsleep fragmentationdisorder related daytime sleepiness andtiredness and they have a greater risk of motor vehiclecrashes compared to the healthy population In additionby using event-related-potentials (ERP) Gosselin et al [59]showed that OSA patients have involuntary attention switch-ing deficit And attentionvigilance damage has been shownto be positively associated with the severity of OSA [60]

Memory roughly includes two categories short-term andlong-term memory A number of studies have suggested thatOSAS patients were involved in short-term and workingmemory deficit whichwas probably correlatedwith hypoxia-related change in hippocampal impairment [61] The specificsubcomponent of memory impairment involved in OSA hasbeen controversial The research by Twigg et al [62] hasshown that verbal but not visual memory was impaired inOSA patients Yet it was found that OSA patients havemild visual cognitive dysfunction [63] And a recent meta-analysis which included 42 researches revealed that verbalepisodic memory and visuospatial episodic memory mainlyrepresenting the domain of immediate and delayed recallwere disturbed in OSA in comparison to healthy group [64]

Executive function including inhibition shifting updat-ing and generativity as well as fluid reasoning is the mostvulnerable part among the neurocognitive functions [65 66]Several meta-analyses demonstrated that all subdomains ofexecutive function especially working memory phonolog-ical fluency cognitive flexibility and planning have beenimpaired in OSA patients [67] Meanwhile CPAP treatmentcould improve some but not all executive functions indifferent degrees [67ndash70]

Nevertheless due to heterogeneity in methodology thereare controversial opinions about the impaired cognitivedomains in OSA Rather than intelligence attention mem-ory and executive function are the most reported cognitivedeficits Furthermore the current meta-analysis revealedthat treatment with CPAP improved cognitive dysfunctionespecially attention and executive function in patient withOSA [67 71] However it seems that impaired cognitioncould be partially reversed after CPAP treatment [71 72]

32 OSA and Brain Tissue Abnormality Using imagingtechnology previous researches found that in OSA patientsthere are different degree changes in extensive brains tissuesincluding cerebra grey white matter hippocampus fron-totemporal and occipital lobe thalamus and basal ganglion


as well as part of cerebellum [73ndash78] The preliminary studymanifested that the most obviously changed area of brainmorphology in OSA patients was hippocampus a part oflimbic system which edits learning and memory functionespecially the storage of short-termmemory [77] In additionthe cerebral grey is closely associated with executive functionBy diffusion tensor magnetic resonance imaging previousresearch demonstrated that extensive white matter impair-ment happened in OSA patients especially in axon-relatedbrain tissue such as limbic system pons and frontotemporaland parietal cerebral cortex [79] Joo et al [80] evaluatedthe structural differences in gray matter between newlydiagnosed male patients and healthy people using optimizedvoxel-based morphometry an automated processing tech-nique for MRI Their data showed that the gray-matterconcentrations of OSA patients were significantly reduced inextensive brain region such as the gyrus rectus frontal gyriprecentral gyrus frontomarginal gyri anterior cingulate gyriinsular gyrus caudate nuclei thalami amygdalohippocampaltemporal gyri and the cerebellum However the total volumeof brain is normal Chan et al [81] used high resolution3-dimensional magnetic resonance images of the brain toanalyze grey matter density and cerebral volume in childrenwith and without OSA Their results showed that significantnegative correlations were found between the visual-finemotor coordination score and the ratio of greymatter volumeto total brain volume However Algin et al [82] found signif-icantly lower NAACr ratios in the frontal cortex and frontalwhite matter of OSAS patients using magnetic resonancespectroscopy (MRS) and no neurochemical changes on T2relaxometry and diffusion weighted imaging (DWI) Besidescognitive impairments were related with focal reductions ofgray-matter volume in the hippocampus posterior parietalcortex and superior frontal gyrus Meanwhile cognitivefunction such as memory attention and executive functionwas significantly improved after treatment in parallel withincreased gray-matter volume in hippocampal and frontalstructures [83]

33TheMechanism Involved in Cognitive Dysfunction in OSAPatients It has been believed that the main mechanismsregulating the development of cognitive complaints werehypoxemia and sleep fragmentation A prospective cohortstudy by Shpirer et al [84] demonstrated that attention defectwas closely associated with intermittent hypoxemia not sleepfragmentation Executive function was not affected by thedegree of hypoxia In a study on population with matcheddegree of daytime sleepiness age gender and educationallevel Quan et al [85] found that motor speed and processingspeed performance were negatively correlated with oxygendesaturation but attention and executive function were notrelated to hypoxemia degree Besides a literature review bySateia presented that defects in general intellectual functionand executive function were strongly linked to the degreeof hypoxia [86] Yet disturbances in vigilance alertnessand memory seem to possibly have correlation with sleepdisruption In a rat CIH model study Kheirandish et al[87] proved that nocturnal hypoxemia could lead to theimpairment in the spatial working memory and the frontal

cortex Hippocampus regions of rats after exposures tochronic intermittent hypoxia were markedly injured

On the other hand nocturnal arousal sleep disorderand slow-wave and rapid-eye-movement sleep deprivation inOSAS patients lead to daytime somnolence There is a closeassociation between daytime sleepiness and cognitive dys-function including decline in attention memory and visu-ospatial ability [88] In a previous study OrsquoBrien et al inves-tigated children with primary snoring and discovered thatsnoring children showed poorer general cognitive functionlanguage and visual spatial ability compared with healthychildren [89] An international epidemiological survey in apopulation of 13057 subjects also reached a conclusion thatsleep arousal disturbance was closely related to neuropsycho-logical changes in OSA patients [90] In addition metabolicdisturbance of lipid and protein could also cause cognitiveimpairment Andhigher intelligence and younger age seem tohave a protective effect on OSA-associated cognitive defects[55] The concentration of serum insulin-like growth factor(IGF) was significantly decreased in the group of OSA chil-dren with cognitive complication compared to the group ofOSA childrenwith normal cognitive score [91] Notably stud-ies demonstrated that carrier rate of APOE 1205764 allele is obvi-ously increased in OSA patients with neurocognitive impair-ment compared to normal cognition people which indicatedthat cognitive decline in OSAwas probably linked to heredity[92] What is more beyond the influence of covariates andapnea severity the level of nocturnal cortisolwas also possiblyassociated with neuropsychological function [93]

4 The Role of Oxidative Stressin the Development of CognitiveDysfunction in OSA

It is generally recognized that oxidative stress is closely associ-ated with the formation and development of nervous systemdiseases such as Alzheimer disease Parkinsonrsquos disease andepilepsy as well as endothelial dysfunction and cardiovas-cular disease (CVD) in OSA Researches have indicatedthat OS also play a critical role in the intermittent hypoxiainduced nervous injury [17 30] Repeated processes of airwayobstruction and collapse during sleep of OSAS patientslead to nocturnal chronic intermittent hypoxia (IH) resultin mitochondria and endoplasmic reticulum dysfunctionexcessively activate NADPH oxidase and decline antioxidantcapacity which further trigger overproduction of ROS andconsequently initiate protein lipid and DNA peroxidationdamage and inflammatory response since the cerebral cortexand hippocampus are vulnerable to OS These changes couldmediate apoptosis and necrosis of nerve cells and thencontribute to neuropsychological alterations [17 94] Thelatest clinical meta-analysis showed that the mechanisminvolved in cognitive impairment in OSA patients could beas follows CIH and other risk factors promoted inflamma-tion endothelial dysfunction and oxidative stress of centralnervous system thus causing cerebral cortex brainstem orother brain region dysfunction and lead to neurocognitivedysfunction eventually (Figure 1) [95]


Chronic intermittent hypoxia

Mitochondriadysfunction

ER stress

Oxidative stress

Lipid peroxidation protein oxidationDNA oxidation protein carbonylation

ERO1L

Neurocognitive dysfunction

OSAS

Memory Executive function Attentionvigilance

Antioxidant PR

PGE2

EPOVEGFHO-1

PR

NO uarr

iNOS uarr COX-2 uarrPAF uarr

Nox uarr

HIF-1120572

CHOP uarr

ROS uarr RNS uarr antioxidant capacity darr

enzymes uarr

synaptic activity darr signal transduction within neurons darrNeuronal cells apoptosisneurosis uarr hippocampal long-term potentiation darr

TNF-120572 c-Fos c-Jun NF-120581120573 uarrInflammatory response uarr caspase-12 caspase-3

uarrIGF-1

Figure 1 Schematic demonstration of the important role played by oxidative stress in the development of cognitive dysfunction in OSASpatients chronic intermittent hypoxia (CIH) resulting from OSAS causes dysfunction of mitochondria and endoplasmic reticulum andoveractivation of Nox iNOS PAF and COX-2 All the above induce overproduction of ROS and RNS as well as attenuated antioxidantcapacity and consequently contribute to imbalance of oxidation-antioxidation and a state of oxidative stress which result in protein lipid andDNA peroxidation damage and a series of inflammatory responses Meanwhile ER stress could upregulate CHOP expression which couldexacerbate production of ROS further Substantial inflammatory cytokines and peroxidation lead to necrosis and apoptosis of nerve cell whicheventually results in gradual neurocognitive dysfunction of OSA patients PAF platelet-activating factor Nox NADPH oxidase ERO1Lendoplasmic reticulum oxidoreductin-1-like COX-2 cyclooxygenase-2 VEGF vascular endothelial growth factor HO-1 heme oxygenase-1ER endoplasmic reticulum IGF insulin-like growth factor iNOS inducible nitric oxide synthase CHOP CEBP-homologous protein PRprotective factor

41 Association within OS and Cognitive Dysfunction inOSAS Patients (Table 1) There are several researchers whoobserved the correlation between OS and cognitive dys-function in OSAS patients via measuring OS biomarkerslevels andneurocognitive test scores Anobservational cross-sectional study in a group of 14 OSA patients and 13 controlswas conducted by Sales et al [96] to explore the relationshipbetween cognitive dysfunction and oxidative stress Theyperformed the Toulouse-Pieron Attention Test WisconsinCard Sorting Test (WCST) the Digit Symbol Substitution

Test the Forward Digit Span the Similarities Test theLogical Memory Verbal Paired Association Tests and theRey-Osterrieth Complex Figure Test to evaluate varioussubcomponents of cognitive function The concentrations ofpotential biomarkers for OS such as serum SOD catalaseGSH and vitamins were also evaluated Their data revealeda positive correlation between vitamin E levels and perfor-mance in the Backward Digit Span task And after matchingage and body mass index the correlation also remained Theconcentrations of SOD correlated with the levels of executive


Table 1 Association between OS and cognitive dysfunction in OSAS patients

Reference E group C group OS biomarkerslever Cognitive test Cognitive

function Relevance

Sales et al 2013 [96] 14 male OSA 13 malesubjects

Lower level ofVitE SOD andVitB11 andhigher

homocysteineUnchanged

VitC catalaseglutathione andVitB12 level

WCST the DigitSymbol

SubstitutionTest Digit Spanthe SimilaritiesTest the LogicalMemory andVerbal PairedAssociationTests and theRey-OsterriethComplex Figure

Test

Worse attentionworking

memory andverbal memoryperformance

Showingcorrelation

between SODVitE andcognitivefunction

Li et al 2014 [9] 28 OSAS 16 healthy adults

Significantlyreduced serum

SODconcentrationand increased

MDAconcentration in

OSAHS

MoCA

Delay recallcalculation andlanguage wereimpaired in

OSAS

Serum SOD andMDA level werecorrelated with

impairedneurocognitive

function

Li and Qin 2007 [97] 18 OSAS 14 healthy adultsIncreased serum

NOconcentration

WMS-RCWAIS-RC

Impairedmemory (visualrecognition anddigit symbols)

The NOconcentrationwas negativelyrelated tocognitivefunction

Huang et al 2014 [98] 41 OSAHS 44 healthyadults

Higher Noxactivity and

serum 8-OHdGconcentration in

OSAHS

MMSE MoCA

Impaired delayrecall attentionlanguage visualspatial andexecutivefunction inOSAHS

Cognitivefunction wasnegatively

associated withthe Nox activity

and serum8-OHdG level

Yang et al 2013 [99] 67 OSAHS 20 healthyadults

Elevated AOPPMDA and

reduced SODlevel in OSApatients

MMSE ESSand CDT

Impairedattention

calculation andmemory

AOPP MDAand SOD

concentrationwere associatedwith the MMSEand CDT score

ESS Epworth sleepiness scale MMSE mini-mental state examination CDT clocking drawing test MoCA Montreal Cognitive Assessment WMS-RCWechsler memory scale-revised in China WAIS-RC Wechsler adult intelligence-revised in China MDA malondialdehyde SOD superoxide dismutaseAOPP advanced oxidation protein products

nonperseveration errors in the Wisconsin Card Sorting Testwhich suggested that an imbalance between antioxidantsand prooxidants might induce the cognitive dysfunction ofOSA patients Yu et al [9 97] compared the differencesin levels of serum MDA SOD and NO between OSAHSand healthy subject and analyzed the correlation betweenthosemarkers and hypoxia index apnea hypopnea index andcognitive function scores separatelyTheir results showed thatit is possible that hypoxemia and sleep fragmentation couldcause overproduction of MDA and NO as well as decreaseof antioxidation power to some degree consequently makingthe patient be in a state of OS and induce damage to nervoussystem which is the biochemical foundation of cognitive

dysfunction in OSA Moreover Huang et al [98] usedthe mini-mental state examination (MMSE) and MontrealCognitive Assessment (MoCA) to assess cognitive status andconcurrently measured Nox activity and 8-OHdG level inOSA patients and healthy people The correlation analysisshowed that OS was likely to be one of the pathogeneses ofcognitive complains inOSA In addition Yang et al [99]mea-sured the concentration of AOPP SOD and MDA in serumand analyzed their correlation with MMSE clock drawingtest AHI and the lowest SaO2 Their study revealed that thelevels of biomarkers of OS were associated with the MMSEscore and clock drawing test All those clinical trials provideus with an original prospect to perform further studies and


more randomized control trials to confirm our viewpointNevertheless on the other hand as we can see from all theclinical studies it is usually difficult for researchers to obtainpatientsrsquo brain tissue to observe or detect its damage directlyand distinctly Thus these clinical trials could not estab-lish a direct effect relationship between neuropsychologicaldysfunction and OS Because of limitation in obtaining thehuman body specimen how to detect the level of cerebral OSand analyze association with cognitive disturbance in OSASpatients is still a dilemma Some radiological technologiessuch as molecular imaging technology functional magneticresonance imaging (MRI) single photon emission computedtomography (SPECT) and optical imaging methods arepromising to evaluate OS extent

42 OS Leading to Cognitive Deficits in OSA Animal Model(Table 2) So far animalmodels have been used to explore therelation between OS and cognitive deficits in OSA Signifi-cantly elevated OS levels were detected in the hippocampusand cortex regions of chronic intermittent hypoxia (CIH)mice Wang et al [100] observed that there was obviousdifference in apoptosis of neurocyte andHIF-1120572 expression inrats under hypoxia and normoxia condition Three differentgroups of rats were included in the study normoxia intermit-tent hypoxia (IH) and continuous hypoxia (CH) The groupof IH rats showed the highest percentage of apoptotic neu-ronal cells andHIF-1120572 expression Besides apoptotic neuronsand HIF-1120572 expression mainly were distributed in the cere-bral cortex and hippocampus Similarly the study by Xu et al[101] showed that both ROS production and OS biomarkersin cortex and cortical neuronal cells of mouse brain weresignificantly increased upon exposure to CIH followed byincreased levels of protein oxidation lipid peroxidation andnucleic acid oxidation in mice brain cortex Moreover alower level of steady-state ROS production and reducednumber of neuronal apoptoses were detected in brain cortexof transgenic mice overexpressing Cu and Zn superoxidedismutase when exposed to CIH conditions compared tocontrol mice The increased ROS production and oxidativestress inducedCIH-mediated cortical neuronal apoptosis andneurocognitive dysfunction In addition Row et al [102]conducted a randomized controlled trial by two variable fac-tors oxygen concentration and injection of antioxidant PNU-101033E (PNU) Their experiment showed that CIH rat with-out PNU-101033E treatment had the worst cognitive functionand the highest levels of lipid peroxidation and oxidant stressin brain tissue and the antioxidant PNU-101033E attenuatesthe spatial learning dysfunction in the rats exposure to IHThese findings demonstrated that oxidative stress might playan important role in the neuron cell damage and consequentbehavioral impairments associated with CIH

Compared with other parts of body brain needs higherenergy consumption and oxygen so it is more sensitive tohypoxia After exposure toCIHmalfunction of self-adjustingmechanism to hypoxia in human body starts to develop fol-lowed by mitochondria dysfunction which leads to produc-tion of ROS Shan et al [103] analyzed the cellularmechanismof enhanced production of ROS during cortical neuronalcell damage and neurocognitive impairment using in vitro

cultured cells and CIH mice models Their data revealed thatthe neuronal cell loss and development of neurocognitivedefects in OSA are mediated in part by CIH-mediatedmito-chondrial oxidative stress In addition they found that over-expression of manganese superoxide dismutase (MnSOD)in mitochondrion could reduce CIH-mediated cortical neu-ronal apoptosis and attenuate spatial learning deficits

On the other hand excessively activated Nox is also likelyto play a vital role in the evolution of central nervous systemdysfunction Nox specifically located in the membranes ofphagocyte is one of the key enzymes to produce ROS Whenexceedingly activated Nox induces oxidative stress Nair et al[104] observed spatial learning capacity difference betweenmice lacking Nox activity (gp91phoxminusY) and wild-typelittermates exposed to IH Significantly increased expressionlevels and activity of Nox as well as MDA and 8-OHDG wereobserved in cortical and hippocampal lysates of wild-typemice following IH exposures while remarkable spatial learn-ing deficits were observed in thosemice Similarly Zhan et al[105] demonstrated that the gene and protein expression lev-els of Nox mediated by long-term hypoxiareoxygenation inwake-active brain regions were obviously higher in wild-typemice compared to the transgenic Nox-knockout mice andmice with pharmacologic inhibition of Nox activity Thesefindings provide evidence to the concept that oxidative stressresponses induced by overactive Nox play a crucial role in theneurobehavioral impairments induced by IH during sleep

Meanwhile thioredoxin (Trx) as an antioxidase couldreduce levels of ROS and concentration of protein thiolsYang et al [106] examined mRNA and protein expression ofTrx in the hippocampus tissue and the number of apoptoticcells in the hippocampus CA1 region They found declinedTrx mRNA and protein levels in the CIH-hippocampus ofrats exposed to CIH and an elevated apoptosis percentage inhippocampal neurons And apoptotic index (determined bycounting the percentage of TUNEL-positive cellshigh-powerfield (times100) in at least five high-power fields) of the neuronsin the hippocampus was negatively associated with mRNAlevels and protein expression of Trx They suggested thatlower level of Trx may play an important role in the impairedcognition in rats exposed to CIH through inducing apoptosisof neurons in the hippocampus It has also been confirmedthat cyclooxygenase-2 is upregulated in the neurologicaldisorder such as ischemic brain injury Alzheimer diseaseand stroke IH-induced OS and proinflammatory cytokinesmaymediate upregulation of the RNA and protein expressionlevels of COX-2 and substantial increase of prostaglandin E2(PGE2) thereby leading to spatial learning deficits in OSAAnd COX-2 inhibitor NS-398 attenuated neuron apoptosisand neurobehavioral disturbance in rodent CIH model [114]

CHOP a transcription factor and amajor mediator of ERstress-induced apoptosis signaling pathways regulates ROSformation [117] Moderate CHOP may protect neuron fromOS inOSA Chou et al [28] observed the association betweenCHOP and LTIH oxidative injury in the hippocampus andcortex via contrasting neuron oxidation and apoptosis inCHOP null and wild-type mice Their data revealed thatendogenous CHOP positively upregulated Nox2 and HIF-1120572


Table 2 The role of OS in the neurocognitive deficits of OSA animal model

Reference E group C group Detecting parameter Morris water mazetesting Outcome

Wang et al2010 [100]

Male Wistarmice + IH

Male Wistar mice+ RA male Wistar

mice + CH

Apoptotic neuronal cellHIF-1120572 protein and

RNANA

HIF-1120572uarr distributing withneuron apoptosis

consistently in brain cortexand hippocampus of E

group

Xu et al 2004[101]

Transgenic miceoverexpressingSOD + IH

C578L6J mice+ IH

Transgenic miceoverexpressingSOD + RA

C578L6J mice +RA

ROS production c-Fosc-Jun NF-120581120573 caspase-3carbonyl protein MDA8-hydroxyguanosineand neuronal cell

apoptosis

Spatial taskacquisitiondarr workingspatial memorydarr

All the parametersincreased in brain cortexupon CIH-C578L6J micetransgenic mice showinglower level compared with

NCM

Row et al 2003[102] V-IH PNU-IH V-RA PNU-RA MDA isoprostane and

oxo8dGoxo8G

The longest latenciesand path lengths tolocate the hiddenplatform in V-IH

The highest MDAisoprostane and

oxo8DGoxo8G in thecortex and hippocampalCA1 region of V-IH

PNU-101033E decreased OSlevel and improved

neurocognitive deficits

Shan et al 2007[103]

(1) Transgenicmice

overexpressingSOD + IH

C578L6J mice+ IH

(2) Corticalneurons + CIH

(1) Mice + RA(2) Corticalneurons + RA

ROS production incortical neurons MDAand protein oxidation

Reduced spatiallearning deficits in themice exposure to CIH

Elevated ROS productionin cortical neuronal cortexand apoptotic neuronal cellTransgenic mice showingreduced cortical neuron

apoptosis and ROSproduction

Nair et al 2011[104]

gp91phoxminusYmice + IH

C578L6J mice+ IH

gp91phoxminusY mice+RA C578L6Jmice + RA

NADPH oxidaseexpression and activityMDA and 8-OHDG

Spatial learning andmemory deficits

showing inIH-C57BL6J micenot in gp91phoxminusYmice exposed to IH

All the parameters weresignificantly increased inIH-C57BL6J mice in thecortex and hippocampus

Nox activities wereattenuated in gp91phoxminusY

mice

Zhan et al 2005[105]

gp91phoxminusminusmice + IH

C578L6J mice+ IH

Mice + sham LTIH(normal Sp02)

NADPH oxidase geneand protein responsesp67phox TNF-120572 iNOSCOX-2 gene protein

carbonyl F2isoprostanes

NA

All the parameters showingincrease in wide-type mice

exposed to LTIH inwake-active region of thebrain transgenic absenceand inhibiting NADPHoxidase activity showingdeclined OS damage

Yang et al 2012[106]

CIH + NSgroup

CIH + NACgroup

Sham CIH + NSgroup

sham CIH + NACgroup

Expression of TrxmRNA and protein cells

apoptosis in thehippocampus CA1

region

Impaired spatiallearning and memory

in CIH-rats

CIH rats showingdecreased Trx mRNA andprotein levels and elevated

apoptotic cells in thehippocampus

Chou et al 2013[28]

CHOP nulladult male mice

+ LTIHwild-type adultmale mice +

LTIH

CHOP null + shamLTIH wild-typeadult male mice +

sham LTIH

Nox2 CC-3 MAP-2ChAT and ERO1L inmotor nuclei CHOPprotein oxidationneuronal apoptosis

NA

Relative to wild-type miceCHOPminusminusmice prevent

oxidative stress (superoxideproductioncarbonylproteins) neuronal

apoptosis and upregulationof Nox and HIF-1120572 in brain

regions of cortexhippocampus and

brainstem motoneurons


Table 2 Continued


Kheirandish etal 2005[87 107]

ApoEminusminusmicewild-type

littermates in IH


littermates in RA

Prostaglandin E2 andMDA in hippocampal

region

Longer times(latency) and

distances (pathlength)to locate the hiddenplatform in IH mice

The highest PGE2 andMDA concentrations

presenting in hippocampalbrain tissues of ApoEminusminus

mice exposed to IH

Row et al 2004[108]

PAFRndashndash micewild-type

littermates in IH


littermates in RA

NOS activity PGE2COX-2 proteasomalactivity and CC-3

PAFRndashndashmice in CIHdisplaying normal

spatiallearning comparedwith wild-typelittermates

All the parameters showingincrease in prefrontal

cortex and thehippocampus CA1 regionof wide-type mice exposed

to IH PAFRminusminusmiceshowing attenuated OS

Dayyat et al2012 [109]

(1) V-IHEPO-IH

(2) Primaryneuronal cellcultures

(1) V-SH EPO-SH(2) V-RA EPO-RA

NADPH oxidase MDA8-OHDG and EPO

EPO-IH miceshowing normal

learning V-IH micedisplaying spatiallearning deficits

V-IH mice but notEPO-treated IH-exposedmice showing elevatedlevels of NADPH oxidaseexpression MDA and8-OHDG in cortical andhippocampal lysates

Nair et al 2013[110] V-IH JI-34-IH V-RA JI-34-RA

MDA 8-OHDG HIF-1120572DNA EPO and IGF-1

expression

JI-34 attenuatedspatial learning

performance deficitsin mice exposed to IH

V-IH mice showingincreased MDA and

8-OHDG in hippocampusand cortex JI-34 reducedOS and increased HIF-1120572

DNA binding andexpression of IGF-1 and

EPO

Li et al 2011[111]

V-IHGH-IH

(1) V-RA GH-RA(2) CH

EPO VEGF HO-1 andGLUT-1 mRNA

expression

GH attenuatedIH-induced

neurocognitivedeficits

GH increased mRNAexpression of IGF-1 EPO

and VEGF in thehippocampus

Yuan et al 2015[112]

V-IHtelmisartan-IH

V-RAtelmisartan-RA

MDA NOS activity NOcontent and apoptoticcells in hippocampusplasma CRP and IL-6

NA

Increased iNOS NOcontent MDA and

inflammatory reactionshowing in the

hippocampus of IH miceTelmisartan attenuatedabove response and

apoptosis in hippocampus

Goldbart et al2006 [113]

HFRC + IHLFCC + IH

HFRC + RALFCC + RA

CREB phosphorylationin the CA1 region of the

hippocampus

The worstplace-training

reference memorytask deficits occurringin HFRC + IH mice

Abundant reduced CREBphosphorylation showing

in CA1 of IH mice

Li et al 2003[114] V-IH NS398-IH

(1) V-RANS398-RA(2) V-CH

COX-1 gene COX-2genes and protein

expression and activityand PGE2 concentrationin cortical regions of rat

brain

Deficits in theacquisition and

retention of a spatialtask showing in IH

mice NS-398treatment attenuated

IH-inducedneurobehavioral

deficits

Increased COX-2 proteinand gene expression PGE2

levels and neuronalapoptosis in cortex


Table 2 Continued


Burckhardt etal 2008 [115] V-IH GTP-IH V-RA

GTP-RA

MDA PGE2 p47phoxmRNA GFAP RAGE

and the ratio ofRAGE120573-actin in the

cortical andhippocampal regions of

rat model

GTPs are capable ofattenuating

IH-induced spatiallearning deficits

All parameters showedincreases in the brain

cortex and hippocampus ofIH-exposed rats GTPsattenuated IH-inducedoxidative stress and

inflammatory reactiondamage in the rat brain

B AAbdel-Wahaband M MAbdel-Wahab2016 [116]

V-IHresveratrol-IH

V-RAresveratrol-RA

TBARS GSH glutamateGSH-Px activity

8-OHdG total proteinand p47phox mRNA in

the hippocampus

Resveratrol protectsanimals from

IH-induced spatialmemory deficits

Resveratrol preventedIH-induced increases ofglutamate TBARS and8-OHdG levels and

p47Phox expression in thehippocampus of IH rats

and decreases ofhippocampal GSH levelsand GSH-Px activity

8-OHDG 8-hydroxydeoxyguanosine MDA malondialdehyde PGE2 prostaglandin E2 NOS nitric oxide synthase MAP-2 microtubule associate protein-2ChAT choline acetyltransferase CC-3 cleaved caspase-3NoxNADPHoxidase ERO1L endoplasmic reticulumoxidoreductin-1-like COX-2 cyclooxygenase-2 VEGF vascular endothelial growth factor HO-1 heme oxygenase-1 CREB cyclic AMP response element binding protein PNU PNU-101033Eoxo8DGoxo8G 8-hydroxy-21015840-deoxyguanosine8-hydroxyguanosine COX cyclooxygenase Trx thioredoxin ApoE apolipoprotein E GFAP glial fibrillaryacidic protein RAGE receptor for advanced glycation end products TBARS thiobarbituric acid reactive substances GSH glutathione GSH-Px glutathioneperoxidase GTPs green tea catechin polyphenolsE group experiment group C group control group CIH + NS group CIH + normal saline (CIH + NAC) group N-acetylcysteine-treated CIH sham CIH+ NS a sham CIH group CIH + NAC group sham NAC-treated sham CIH EPO-IH exogenously erythropoietin treated IH HFRC + IH high fatrefinedcarbohydrate diet + IH LFCC + IH low fatcomplex carbohydrate diet + IHV-IH vehicle + IH ApoEminusminus ApoE-deficient mice PAFRndashndash PAFR-deficient miceIH intermittent hypoxia RA room air CH continued hypoxia LTIH long-term intermittent hypoxia sham LTIHNA not administrated

expression and this resulted in injury of brainstemmotoneu-rons cortex and hippocampus which might contribute toneurobehavioral impairments What is more apolipoproteinE (ApoE) could also attenuate OS induced neuron injury[118] ApoE-deficient mice exhibited increased vulnerabilityto intermittent hypoxia induced spatial learning deficits [107118]

Furthermore certain substance or factors could protectbrain regions from OSA-associated neuronal impairmentMice deficient of cell surface receptor platelet-activatingfactor (PAF) a bioactive mediator of OS and inflammationshowed declined cyclooxygenase-2 and inducible nitric oxidesynthase activities and spatial learning deficits associatedwith IH [108] The study by Dayyat et al [109] demonstratedthat exogenous administration of erythropoietin (EPO)attenuated OS and neurocognitive damage in murine modelof OSA Their research indicated that it might be promis-ing to stop the involution or potentially reverse cognitivemorbidities in OSA by either increasing EPO expressionor the activation of EPO receptors in the CNS RecentlyNair et al [110] found that in mice model treatment withgrowth hormone releasing hormone (GHRH) agonist JI-34 can weaken IH-induced neurocognitive deficits decreaseoxidative stress levels and increase HIF-1120572DNA binding andupregulation of IGF-1 and erythropoietin expression whileGHRH antagonist (MIA-602) did not affect any cognitivedisorders in OSA mice Furthermore Li et al [111] provedthat administration of exogenous growth hormone (GH)

not only upregulated the hippocampal mRNA expressionof IGF-1 EPO and VEGF but also consequently reducedIH-induced hippocampal injury as well as cognitive deficitsStudies confirm that telmisartan an angiotensin II type1 receptor blocker (ARB) can be beneficial for adjustingthe levels of nitric oxide and nitric oxide enzyme whichplay important roles in attenuating oxidative stress anti-inflammatory response and suppressing neural apoptosisThus Yuan et al [112] proved that iNOS was overexpressedin the hippocampus of CIH mice and telmisartan reducedthe iNOS level therefore telmisartan has a protective effecton hippocampal apoptosis induced by CIH In addition astudy found that high fat diet may increase OS damage causedamage in hippocampal CA1 area and then lead to cognitivedysfunction [113] Notably particularly Burckhardt et al [115]found that green tea catechin polyphenols (GTPs) a commonbiologically active compound present in green tea not onlyattenuated IH-induced oxidative stress and inflammatoryload in the cortex and hippocampal CA1 region of model ratbrain but also improved IH-induced spatial learning deficitsResveratrol a natural polyphenolic compound which existsin the skin and seeds of plants such as grapes grains berriespeanuts and red wine has been proved to increase theexpression of antioxidant enzymes and has a neuroprotectiveeffect to many neurodegenerative diseases [116] The latestresearch revealed that resveratrol could also prevent IH-induced spatial memory deficits via reducing activity of thehippocampal oxidative stress pathways and the expression


of p47Phox subunit of NADPH oxidase [116] Those twostudies provided hopeful therapeutic measures in improvingcognitive dysfunction of OSA patients

5 Conclusion

Repetitive episodes of obstruction of the upper airwayinduce chronic intermittent hypoxia then cause dysfunc-tion of mitochondria endoplasmic reticulum and endothe-lium compromised energy metabolism and activation ofNox xanthine oxidase and iNOS consequently contributingto overproduction of ROS and imbalance of oxidation-antioxidation lead to a state of OS which produces proteinlipid and DNA peroxidation damage and result in substan-tial inflammatory response However cerebral neural cellsespecially in the regions of hippocampus and cerebral cortexare susceptible to hypoxemia CIH-induced OS could lead tonecrosis and apoptosis of nerve cell which results in grad-ual neurocognitive dysfunction of OSA patients presentingshort-term declined attention and vigilance and long-termdegeneration of memory as well as executive function Inaddition to CPAP treatment experiments in CIH animalmodels demonstrated that administration of antioxidant suchas EPO GH JI-34 NS-398 or telmisartan might provide amethod to protect IH-vulnerable brain regions from OSA-associated neuronal damage and neurocognitive dysfunctionHowever either CPAP treatment or antioxidant administra-tion methods have shown direct evidence verifying relation-ship between oxidative stress and neurocognitive dysfunctionin OSA patients And the effect of these two methods hasnot yet been confirmed by clinical trials Moreover specificupstreamor downstream signaling pathways and themolecu-lar mechanism underlying OS induced cognitive impairmentare still not clear and need to be investigated further

Competing Interests

Theauthors declare that there is no conflict of interests relatedto this article

Acknowledgments

The authors express their thanks to Professor Guanglei Lifor helping with the language This work was supported byHunan Development and Reform Commission [Grant no(2015)83] and the National Key Clinical Specialty Construc-tion Projects [2012 (no 650)]

References

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[2] J Duran S Esnaola R Rubio and A Iztueta ldquoObstructive sleepapnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yrrdquo American Journal ofRespiratory and Critical Care Medicine vol 163 no 3 pp 685ndash689 2001

[3] R NadeemM SinghM Nida et al ldquoEffect of obstructive sleepapnea hypopnea syndrome on lipid profile a meta-regressionanalysisrdquo Journal of Clinical Sleep Medicine vol 10 no 5 pp475ndash489 2014

[4] AMAdedayoOOlafiranye D Smith et al ldquoObstructive sleepapnea and dyslipidemia evidence and underlying mechanismrdquoSleep amp Breathing vol 18 no 1 pp 13ndash18 2014

[5] S Nannapaneni K Ramar and S Surani ldquoEffect of obstructivesleep apnea on type 2 diabetes mellitus a comprehensiveliterature reviewrdquo World Journal of Diabetes vol 4 no 6 pp238ndash244 2013

[6] J Vale P Manuel E Oliveira et al ldquoObstructive sleep apneaand diabetes mellitusrdquo Revista Portuguesa de Pneumologia vol21 no 2 pp 55ndash60 2015

[7] T D Bradley and J S Floras ldquoObstructive sleep apnoea and itscardiovascular consequencesrdquoTheLancet vol 373 no 9657 pp82ndash93 2009

[8] D E Green and D A Schulman ldquoObstructive sleep apneaand cardiovascular diseaserdquo Current Treatment Options inCardiovascular Medicine vol 12 no 4 pp 342ndash354 2010

[9] L Li Q Yu J-B Zhang and C Ming ldquoRole of oxidativestress and sleep structure on cognitive dysfunction in patientwith obstructive sleep apnea-hypopnea sydromerdquo Journal ofSoutheast University (Medical Science Edition) vol 33 pp 71ndash74 2014

[10] J Duran-Cantolla F Aizpuru C Martınez-Null and F Barbe-Illa ldquoObstructive sleep apneahypopnea and systemic hyperten-sionrdquo Sleep Medicine Reviews vol 13 no 5 pp 323ndash331 2009

[11] K M Hla T Young EW Hagen et al ldquoCoronary heart diseaseincidence in sleep disordered breathing The Wisconsin SleepCohort Studyrdquo Sleep vol 38 no 5 pp 677ndash684 2015

[12] O D Lyons and T D Bradley ldquoHeart failure and sleep apneardquoThe Canadian Journal of Cardiology vol 31 no 7 pp 898ndash9082015

[13] O D Lyons and C M Ryan ldquoSleep apnea and strokerdquo TheCanadian Journal of Cardiology vol 31 no 7 pp 918ndash927 2015

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[16] R S BucksMOlaithe and P Eastwood ldquoNeurocognitive func-tion in obstructive sleep apnoea a meta-reviewrdquo Respirologyvol 18 no 1 pp 61ndash70 2013

[17] L Lavie ldquoOxidative stress in obstructive sleep apnea andintermittent hypoxiamdashrevisitedmdashthe bad ugly and good impli-cations to the heart and brainrdquo Sleep Medicine Reviews vol 20pp 27ndash45 2015

[18] B Jurado-Gamez M C Fernandez-Marin J L Gomez-Chaparro et al ldquoRelationship of oxidative stress and endothelialdysfunction in sleep apnoeardquoTheEuropean Respiratory Journalvol 37 no 4 pp 873ndash879 2011

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human studiesrdquoOxidative Medicine and Cellular Longevity vol2015 Article ID 608438 9 pages 2015

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[22] Y J Suzuki V Jain A-M Park and RMDay ldquoOxidative stressand oxidant signaling in obstructive sleep apnea and associatedcardiovascular diseasesrdquo Free Radical Biology amp Medicine vol40 no 10 pp 1683ndash1692 2006

[23] I Tasci ldquoOxidative stress obstructive sleep apnea and cardio-vascular diseaserdquo Sleep amp Breathing vol 16 no 3 article 5852012

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[33] L Lavie ldquoOxidative stressmdasha unifying paradigm in obstructivesleep apnea and comorbiditiesrdquo Progress in CardiovascularDiseases vol 51 no 4 pp 303ndash312 2009

[34] L Lavie A Vishnevsky and P Lavie ldquoEvidence for lipidperoxidation in obstructive sleep apneardquo Sleep vol 27 no 1 pp123ndash128 2004

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[41] F Yagihara L M Lucchesi V DrsquoAlmeida M T de Mello STufik and L R A Bittencourt ldquoOxidative stress and quality oflife in elderly patients with obstructive sleep apnea syndromeare there differences after six months of Continuous PositiveAirway Pressure treatmentrdquo Clinics vol 67 no 6 pp 565ndash5712012

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[43] J-I Oyama H Yamamoto T Maeda A Ito K Node andN Makino ldquoContinuous positive airway pressure therapyimproves vascular dysfunction and decreases oxidative stressin patients with the metabolic syndrome and obstructive sleepapnea syndromerdquoClinical Cardiology vol 35 no 4 pp 231ndash2362012

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[46] G E Carpagnano S A Kharitonov O Resta M P Foschino-Barbaro E Gramiccioni and P J Barnes ldquo8-isoprostane amarker of oxidative stress is increased in exhaled breathcondensate of patients with obstructive sleep apnea after nightand is reduced by continuous positive airway pressure therapyrdquoChest vol 124 no 4 pp 1386ndash1392 2003

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[48] Y Wang S X L Zhang and D Gozal ldquoReactive oxygenspecies and the brain in sleep apneardquo Respiratory Physiology ampNeurobiology vol 174 no 3 pp 307ndash316 2010

[49] H Y Chung B S Baek S H Song et al ldquoXanthine dehydroge-nasexanthine oxidase and oxidative stressrdquo Age vol 20 no 3pp 127ndash140 1997

[50] H S Hira P Samal A Kaur and S Kapoor ldquoPlasma levelof hypoxanthinexanthine as markers of oxidative stress withdifferent stages of obstructive sleep apnea syndromerdquo Annals ofSaudi Medicine vol 34 no 4 pp 308ndash313 2014

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sleep apnea syndromerdquo European Neurology vol 63 no 4 pp215ndash220 2010

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[73] K Yaouhi F Bertran P Clochon et al ldquoA combined neuropsy-chological and brain imaging study of obstructive sleep apneardquoJournal of Sleep Research vol 18 no 1 pp 36ndash48 2009

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[79] P M Macey R Kumar M A Woo E M Valladares F L Yan-Go and R M Harper ldquoBrain structural changes in obstructivesleep apneardquo Sleep vol 31 no 7 pp 967ndash977 2008

[80] E Y Joo W S Tae M J Lee et al et al ldquoReduced brain graymatter concentration in patients with obstructive sleep apneasyndromerdquo Sleep vol 33 no 2 pp 235ndash241 2010

[81] K C Chan L Shi H K So et al ldquoNeurocognitive dysfunctionand greymatter density deficit in childrenwith obstructive sleepapnoeardquo Sleep Medicine vol 15 no 9 pp 1055ndash1061 2014

[82] O Algin G Gokalp G Ocakoglu A Ursavas O Taskapiliogluand B Hakyemez ldquoNeurochemical-structural changes evalua-tion of brain in patientswith obstructive sleep apnea syndromerdquoEuropean Journal of Radiology vol 81 no 3 pp 491ndash495 2012

[83] N Canessa V Castronovo S F Cappa et al ldquoObstructive sleepapnea brain structural changes and neurocognitive functionbefore and after treatmentrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 183 no 10 pp 1419ndash1426 2011

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dysfunction in patients with obstructive sleep apneardquo Sleep andBreathing vol 16 no 3 pp 821ndash827 2012

[85] S F Quan R Wright C M Baldwin et al ldquoObstructive sleepapnea-hypopnea and neurocognitive functioning in the SleepHeart Health Studyrdquo Sleep Medicine vol 7 no 6 pp 498ndash5072006

[86] M J Sateia ldquoNeuropsychological impairment and quality of lifein obstructive sleep apneardquoClinics in ChestMedicine vol 24 no2 pp 249ndash259 2003

[87] L Kheirandish D Gozal J-M Pequignot J Pequignotand B W Row ldquoIntermittent hypoxia during developmentinduces long-term alterations in spatial working memorymonoamines and dendritic branching in rat frontal cortexrdquoPediatric Research vol 58 no 3 pp 594ndash599 2005

[88] S Naismith V Winter H Gotsopoulos I Hickie and P Cis-tulli ldquoNeurobehavioral functioning in obstructive sleep apneadifferential effects of sleep quality hypoxemia and subjectivesleepinessrdquo Journal of Clinical and Experimental Neuropsychol-ogy vol 26 no 1 pp 43ndash54 2004

[89] LMOrsquoBrien C BMervis C R Holbrook et al ldquoNeurobehav-ioral implications of habitual snoring in childrenrdquo Pediatricsvol 114 no 1 pp 44ndash49 2004

[90] M M Ohayon R G Priest J Zulley and S Smirne ldquoThe placeof confusional arousals in sleep and mental disorders findingsin a general population sample of 13057 subjectsrdquoThe Journal ofNervous and Mental Disease vol 188 no 6 pp 340ndash348 2000

[91] D Gozal O Sans Capdevila V McLaughlin Crabtree L DSerpero L AWitcher and L Kheirandish-Gozal ldquoPlasma IGF-1 levels and cognitive dysfunction in children with obstructivesleep apneardquo Sleep Medicine vol 10 no 2 pp 167ndash173 2009

[92] R OrsquoHara C M Schroder H C Kraemer et al ldquoNocturnalsleep apneahypopnea is associated with lower memory perfor-mance in APOE 1205764 carriersrdquo Neurology vol 65 no 4 pp 642ndash644 2005

[93] K M Edwards R Kamat L M Tomfohr S Ancoli-Israel andJ E Dimsdale ldquoObstructive sleep apnea and neurocognitiveperformance the role of cortisolrdquo Sleep Medicine vol 15 no 1pp 27ndash32 2014

[94] D Gozal J M Daniel and G P Dohanich ldquoBehavioral andanatomical correlates of chronic episodic hypoxia during sleepin the ratrdquoThe Journal of Neuroscience vol 21 no 7 pp 2442ndash2450 2001

[95] M A Daulatzai ldquoPathogenesis of cognitive dysfunction inpatients with obstructive sleep apnea a hypothesis with empha-sis on the nucleus tractus solitariusrdquo Sleep Disorders vol 2012Article ID 251096 18 pages 2012

[96] L V Sales V M S Bruin V DrsquoAlmeida et al ldquoCognitionand biomarkers of oxidative stress in obstructive sleep apneardquoClinics vol 68 no 4 pp 449ndash455 2013

[97] L Li and Y Qin ldquoSerum nitric oxide and cognitive functionin patients with obstructive sleep apnea syndromerdquo ChineseJournal of Practical Internal Medicine vol 27 pp 1457ndash14582007

[98] J C Huang J L Zhou Q C Lin B Y Wang Y X Jin andD Hb ldquoOxidative stress in obstructive sleep apnea hypopneasyndrome patient with cognition dysfunctionrdquo Journal of FujianMedical University vol 48 pp 308ndash312 2014

[99] X H Yang X Liu J Shang H G Liu and Y J Xu ldquoCorrelationbetween the serum level of advanced oxidation protein productsand the cognitive function in patients with obstructive sleepapnea hypopnea syndromerdquoChinese Journal of Tuberculosis andRespiratory Diseases vol 36 pp 274ndash279 2013

[100] Z F Wang B Dai and J Kang ldquoInfluence of chronic intermit-tent hypoxia on apoptosis of neuronal cells and expression ofhypoxia inducible factor-1120572 in the brain of ratsrdquoChinese Journalof Pathophysiology vol 26 pp 593ndash595 2010

[101] W Xu L Chi B W Row et al ldquoIncreased oxidative stress isassociated with chronic intermittent hypoxia-mediated braincortical neuronal cell apoptosis in a mouse model of sleepapneardquo Neuroscience vol 126 no 2 pp 313ndash323 2004

[102] B W Row R Liu W Xu L Kheirandish and D Gozal ldquoInter-mittent hypoxia is associated with oxidative stress and spatiallearning deficits in the ratrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 167 no 11 pp 1548ndash1553 2003

[103] X Shan L Chi Y Ke et al ldquoManganese superoxide dismutaseprotects mouse cortical neurons from chronic intermittenthypoxia-mediated oxidative damagerdquo Neurobiology of Diseasevol 28 no 2 pp 206ndash215 2007

[104] D Nair E A Dayyat S X Zhang Y Wang and D GozalldquoIntermittent hypoxia-induced cognitive deficits are mediatedby NADPH oxidase activity in a murine model of sleep apneardquoPLoS ONE vol 6 no 5 Article ID e19847 2011

[105] G Zhan F Serrano P Fenik et al ldquoNADPH oxidase mediateshypersomnolence and brain oxidative injury in amurinemodelof sleep apneardquo American Journal of Respiratory and CriticalCare Medicine vol 172 no 7 pp 921ndash929 2005

[106] X-H YangH-G Liu X Liu and J-N Chen ldquoThioredoxin andimpaired spatial learning and memory in the rats exposed tointermittent hypoxiardquo Chinese Medical Journal vol 125 no 17pp 3074ndash3080 2012

[107] L Kheirandish B W Row R C Li K R Brittian andD Gozal ldquoApolipoprotein E-deficient mice exhibit increasedvulnerability to intermittent hypoxia-induced spatial learningdeficitsrdquo Sleep vol 28 no 11 pp 1412ndash1417 2005

[108] B W Row L Kheirandish R C Li et al ldquoPlatelet-activatingfactor receptor-deficient mice are protected from experimentalsleep apnea-induced learning deficitsrdquo Journal of Neurochem-istry vol 89 no 1 pp 189ndash196 2004

[109] E A Dayyat S X L Zhang Y Wang Z J Cheng and DGozal ldquoExogenous erythropoietin administration attenuatesintermittent hypoxia-induced cognitive deficits in a murinemodel of sleep apneardquo BMC Neuroscience vol 13 article 772012

[110] DNair V Ramesh RC Li AV Schally andDGozal ldquoGrowthhormone releasing hormone (GHRH) signaling modulatesintermittent hypoxia-induced oxidative stress and cognitivedeficits in mouserdquo Journal of Neurochemistry vol 127 no 4 pp531ndash540 2013

[111] R C Li S Z Guo M Raccurt et al ldquoExogenous growthhormone attenuates cognitive deficits induced by intermittenthypoxia in ratsrdquo Neuroscience vol 196 pp 237ndash250 2011

[112] X Yuan X Guo Y Deng D Zhu J Shang and H LiuldquoChronic intermittent hypoxia-induced neuronal apoptosis inthe hippocampus is attenuated by telmisartan through sup-pression of iNOSNO and inhibition of lipid peroxidation andinflammatory responsesrdquo Brain Research vol 1596 pp 48ndash572015

[113] A D Goldbart B W Row L Kheirandish-Gozal Y Cheng KR Brittian and D Gozal ldquoHigh fatrefined carbohydrate dietenhances the susceptibility to spatial learning deficits in ratsexposed to intermittent hypoxiardquo Brain Research vol 1090 no1 pp 190ndash196 2006

[114] R C Li B W Row E Gozal et al ldquoCyclooxygenase 2and intermittent hypoxia-induced spatial deficits in the ratrdquo


American Journal of Respiratory and Critical Care Medicine vol168 no 4 pp 469ndash475 2003

[115] I C Burckhardt D Gozal E Dayyat et al ldquoGreen tea catechinpolyphenols attenuate behavioral and oxidative responses tointermittent hypoxiardquo American Journal of Respiratory andCritical Care Medicine vol 177 no 10 pp 1135ndash1141 2008

[116] B A Abdel-Wahab and M M Abdel-Wahab ldquoProtective effectof resveratrol against chronic intermittent hypoxia-inducedspatial memory deficits hippocampal oxidative DNA damageand increased p47Phox NADPH oxidase expression in youngratsrdquo Behavioural Brain Research vol 305 pp 65ndash75 2016

[117] B L Chen M L Sheu K S Tsai et al ldquoCCAAT-enhancer-binding protein homologous protein deficiency attenuatesoxidative stress and renal ischemia-reperfusion injuryrdquo Antiox-idants amp Redox Signaling vol 23 no 15 pp 1233ndash1245 2015

[118] T B Shea E Rogers D Ashline D Ortiz and M-S SheuldquoApolipoprotein E deficiency promotes increased oxidativestress and compensatory increases in antioxidants in braintissuerdquo Free Radical Biology amp Medicine vol 33 no 8 pp 1115ndash1120 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


endogenous stimulation or stress It could be induced byoverproduction of reactive oxygen species (ROS) and reactivenitrogen species (RNS) or a decreased capacity of antioxidantThere are two kinds of antioxidantsThe first one is enzymaticprocesses including superoxide dismutase (SOD) catalase(CAT) glutathione peroxidase (GSH-Px) peroxiredoxinglutathione reductase and thioredoxin reductase (TRXR)The other type of antioxidant includes ergothioneine vitaminC vitamin E glutathione melatonin alpha lipoic acidcarotenoid copper zinc and selenium Recent studies havesuggested that the recurrence of the process of hypoxiareox-ygenation in OSAS contributes to the imbalance betweenantioxidant defense system and oxidant system which couldlead to OS and then activate and accelerate peroxidationdamage and inflammation reaction A series of transcriptionfactors such as hypoxia inducible transcription factors-1120572(HIF-1120572) nuclear factor-like 2 (Nrf2) activator protein 1(AP1) and nuclear factor 120581120573 (NF120581120573) are activated in OSAS[17] Consequently damage to tissue and cells endothelialdysfunction [18] and metabolic disturbance occurred andother comorbidities such as type 2 diabetes dyslipidemiacardiovascular complications [19ndash23] and neurocognitiveimpairment followed [17 24]

21 Biomarkers of OS Levels OS is a result of imbalanceof oxidative system and antioxidative system The majorOS damage includes lipid peroxidation protein oxidationRNA and DNA damage protein nitration production ofROS and peroxide and change of total antioxidant capacityBiomarkers related to OS include protein oxidation (proteincarbonyl advanced oxidative protein production AGE glu-tathione [25] GSSG 3-nitrotyrosine) lipid peroxidation (8-hydroxyguanosine thiobarbituric acid reactive substancesox-LDL malondialdehyde (MDA) [26] 4-hydroxynonenaland LOOH) DNA damage (8-hydroxydeoxyguanosine [27]8-hydroxyguanosine and comet assay) antioxidation (SODCAT and GSH-Px) ROS nitrate nitrite NADPH oxidase(Nox) Cp paraoxonase arylesterase sulfhydryl group TASTOS and OSI In addition previous research suggeststhat CCAT-enhancer binding protein (CEBP) homologousbinding protein (CHOP) which is indispensable for pro-cesses like NADPH oxidase subtype 2 (Nox2) ROS andhypoxia inducible factor-1120572 activation (HIF-1120572) might bean upstream target to protect OSAS patients from oxidativedamage [28] Furthermore the concentration of ROS RNSand oxygen ion can be directly and accurately measured byan advanced method electron paramagnetic resonance withhigh sensitivity [29]

A multitude of studies have manifested the occurrenceof oxidative stress in obstructive sleep apnea (OSA) patients[30ndash33] A study by Lavie et al [34] has investigated 114OSA patients and 30 nonapneic controls Among the OSApatients 59 have cardiovascular disease (CVD) 55 have nocardiovascular disease (CVD) It was found that the levelof paraoxonase-1 (PON1) is lower and the concentrations ofthiobarbituric reactive substances (TBARS) and peroxides(PD) are higher in OSA patients group compared withcontrol subjects Besides a negative association betweenPON1 activity and respiratory disturbance index (RDI) was

observed while TBARS and PD were significantly positivelycorrelated with RDI After nCPAP treatment the levels ofTBARS and PD were significantly decreased Increased levelsof other lipid peroxidation biomarkers such as MDA and 8-isoprostane were also observed in OSAS patients in otherresearches and improved after CPAP treatment [18 35 36]

Mancuso et al [37] have assessed levels of advancedoxidation protein products (AOPP) ferric reducing antiox-idant power (FRAP) and total glutathione (GSH) in twogroups (41 OSA patients and 32 healthy control subjects)All the subjects are free of comorbidities and are non-smokers They found a significant increase in serum AOPPconcentration and a decrease in FRAP and GSH levels inOSA patients This study revealed that OSAS patients weresubjected to protein oxidation and antioxidative capacityimpairment CPAP treatment improved the abnormal FRAPlevel which suggests that FRAP is likely to be a potentialbiomarker to access OS level after CPAP treatment A cross-sectional study measuring urinary excretion of 8-hydroxy-21015840-deoxyguanosine (8-OHdG) as an indicator of DNA OSdamage also showed similar results [27]

Hopps et al [38] have measured concentration of TBARSand carbonyl between a group of 27 severe OSAS patients(AHI gt 30) and a group of 21 mild-to-moderate OSASpatients (AHI lt 30) Significantly higher levels of TBARSand carbonyl were found in severe OSAS group Besidesthese biomarkers were positively associated with neck andwaist circumference AHI value and oxygen desaturationindex respectively and negatively associated with the meanoxygen saturation Similarly Franco et al [39] have reportedsignificantly higher superoxide radical and lower levels ofserum nitrates and nitrites in OSAS patients compared tohealthy subjects in a severity-dependent manner They alsofound thatmoderate and severeOSAS patients had semblableOS profile and condition which were remarkably differentfrom mild patients That is a critical condition probablyexists in the triggering of oxidative stress metabolism andsymptoms between mild and moderate OSAS

22 Posttreatment OS Levels A number of studies havesuggested that treatment with CPAP could attenuate OSlevels in OSA patients [35 40ndash45] Carpagnano et al [46]have reported that serum and exhaled breath condensateconcentration of 8-isoprostane were progressively decreasedafter CPAP treatment Relevant conclusions in the populationof elderly OSAS were also reached by Yagihara et al [41] whoreported significantly reducedMDA levels after sixmonths ofCPAP therapy Similarly Oyama et al [43] found markedlyraised plasma levels of nitric oxide and declined TBARS andasymmetrical dimethylarginine levels after three months ofCPAP treatment In recent years the relationship betweenOS and pediatric OSA became a rising concern Similar toadults pediatric OSA is associated with an increased OSThe study conducted by Tauman found that OSA in childrenis associated with increased lipid peroxidation which waspositively correlated with disease severity and the degree ofintermittent hypoxia [31]






















ER stress

Oxidative stress


ERO1L


OSAS


Antioxidant PR

PGE2

EPOVEGFHO-1

PR

NO uarr


Nox uarr

HIF-1120572

CHOP uarr


enzymes uarr



uarrIGF-1







function Relevance







Test



Showingcorrelation





MDAconcentration in

OSAHS

MoCA


OSAS



function


NOconcentration

WMS-RCWAIS-RC






OSAHS

MMSE MoCA








MMSE ESSand CDT

Impairedattention


AOPP MDAand SOD



















mice + CH


RNANA



group

Xu et al 2004[101]


C578L6J mice+ IH


C578L6J mice +RA


apoptosis



NCM


oxo8dGoxo8G







(1) Transgenicmice


C578L6J mice+ IH









C578L6J mice+ IH







mice



C578L6J mice+ IH




NA




CIH + NSgroup

CIH + NACgroup

Sham CIH + NSgroup

sham CIH + NACgroup



region


in CIH-rats



Chou et al 2013[28]



LTIH


sham LTIH


NA







Table 2 Continued




littermates in IH


littermates in RA


region





mice exposed to IH

Row et al 2004[108]


littermates in IH


littermates in RA








(1) V-IHEPO-IH









expression






EPO

Li et al 2011[111]

V-IHGH-IH



expression






V-IHtelmisartan-IH

V-RAtelmisartan-RA


NA






HFRC + IHLFCC + IH

HFRC + RALFCC + RA


hippocampus




in CA1 of IH mice





brain





deficits




Table 2 Continued



GTP-RA




rat model







V-IHresveratrol-IH

V-RAresveratrol-RA



the hippocampus












5 Conclusion


Competing Interests


Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































ER stress

Oxidative stress


ERO1L


OSAS


Antioxidant PR

PGE2

EPOVEGFHO-1

PR

NO uarr


Nox uarr

HIF-1120572

CHOP uarr


enzymes uarr



uarrIGF-1







function Relevance







Test



Showingcorrelation





MDAconcentration in

OSAHS

MoCA


OSAS



function


NOconcentration

WMS-RCWAIS-RC






OSAHS

MMSE MoCA








MMSE ESSand CDT

Impairedattention


AOPP MDAand SOD



















mice + CH


RNANA



group

Xu et al 2004[101]


C578L6J mice+ IH


C578L6J mice +RA


apoptosis



NCM


oxo8dGoxo8G







(1) Transgenicmice


C578L6J mice+ IH









C578L6J mice+ IH







mice



C578L6J mice+ IH




NA




CIH + NSgroup

CIH + NACgroup

Sham CIH + NSgroup

sham CIH + NACgroup



region


in CIH-rats



Chou et al 2013[28]



LTIH


sham LTIH


NA







Table 2 Continued




littermates in IH


littermates in RA


region





mice exposed to IH

Row et al 2004[108]


littermates in IH


littermates in RA








(1) V-IHEPO-IH









expression






EPO

Li et al 2011[111]

V-IHGH-IH



expression






V-IHtelmisartan-IH

V-RAtelmisartan-RA


NA






HFRC + IHLFCC + IH

HFRC + RALFCC + RA


hippocampus




in CA1 of IH mice





brain





deficits




Table 2 Continued



GTP-RA




rat model







V-IHresveratrol-IH

V-RAresveratrol-RA



the hippocampus












5 Conclusion


Competing Interests


Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















function Relevance







Test



Showingcorrelation





MDAconcentration in

OSAHS

MoCA


OSAS



function


NOconcentration

WMS-RCWAIS-RC






OSAHS

MMSE MoCA








MMSE ESSand CDT

Impairedattention


AOPP MDAand SOD



















mice + CH


RNANA



group

Xu et al 2004[101]


C578L6J mice+ IH


C578L6J mice +RA


apoptosis



NCM


oxo8dGoxo8G







(1) Transgenicmice


C578L6J mice+ IH









C578L6J mice+ IH







mice



C578L6J mice+ IH




NA




CIH + NSgroup

CIH + NACgroup

Sham CIH + NSgroup

sham CIH + NACgroup



region


in CIH-rats



Chou et al 2013[28]



LTIH


sham LTIH


NA







Table 2 Continued




littermates in IH


littermates in RA


region





mice exposed to IH

Row et al 2004[108]


littermates in IH


littermates in RA








(1) V-IHEPO-IH









expression






EPO

Li et al 2011[111]

V-IHGH-IH



expression






V-IHtelmisartan-IH

V-RAtelmisartan-RA


NA






HFRC + IHLFCC + IH

HFRC + RALFCC + RA


hippocampus




in CA1 of IH mice





brain





deficits




Table 2 Continued



GTP-RA




rat model







V-IHresveratrol-IH

V-RAresveratrol-RA



the hippocampus












5 Conclusion


Competing Interests


Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























mice + CH


RNANA



group

Xu et al 2004[101]


C578L6J mice+ IH


C578L6J mice +RA


apoptosis



NCM


oxo8dGoxo8G







(1) Transgenicmice


C578L6J mice+ IH









C578L6J mice+ IH







mice



C578L6J mice+ IH




NA




CIH + NSgroup

CIH + NACgroup

Sham CIH + NSgroup

sham CIH + NACgroup



region


in CIH-rats



Chou et al 2013[28]



LTIH


sham LTIH


NA







Table 2 Continued




littermates in IH


littermates in RA


region





mice exposed to IH

Row et al 2004[108]


littermates in IH


littermates in RA








(1) V-IHEPO-IH









expression






EPO

Li et al 2011[111]

V-IHGH-IH



expression






V-IHtelmisartan-IH

V-RAtelmisartan-RA


NA






HFRC + IHLFCC + IH

HFRC + RALFCC + RA


hippocampus




in CA1 of IH mice





brain





deficits




Table 2 Continued



GTP-RA




rat model







V-IHresveratrol-IH

V-RAresveratrol-RA



the hippocampus












5 Conclusion


Competing Interests


Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 2 Continued




littermates in IH


littermates in RA


region





mice exposed to IH

Row et al 2004[108]


littermates in IH


littermates in RA








(1) V-IHEPO-IH









expression






EPO

Li et al 2011[111]

V-IHGH-IH



expression






V-IHtelmisartan-IH

V-RAtelmisartan-RA


NA






HFRC + IHLFCC + IH

HFRC + RALFCC + RA


hippocampus




in CA1 of IH mice





brain





deficits




Table 2 Continued



GTP-RA




rat model







V-IHresveratrol-IH

V-RAresveratrol-RA



the hippocampus












5 Conclusion


Competing Interests


Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 2 Continued



GTP-RA




rat model







V-IHresveratrol-IH

V-RAresveratrol-RA



the hippocampus












5 Conclusion


Competing Interests


Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















5 Conclusion


Competing Interests


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 role of oxidative stress in the

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