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Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 484613 18 pageshttpdxdoiorg1011552013484613

Review ArticleRole of Redox Signaling in Neuroinflammation andNeurodegenerative Diseases

Hsi-Lung Hsieh1 and Chuen-Mao Yang2

1 Department of Nursing Division of Basic Medical Sciences Chang Gung University of Science and Technology Taoyuan Taiwan2Department of Physiology and Pharmacology and Health Aging Research Center College of Medicine Chang Gung University259 Wen-Hwa 1st Road Kwei-San Taoyuan Taiwan

Correspondence should be addressed to Chuen-Mao Yang chuenmaomailcguedutw

Received 11 September 2013 Revised 30 October 2013 Accepted 21 November 2013

Academic Editor Sulagna Das

Copyright copy 2013 H-L Hsieh and C-M YangThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Reactive oxygen species (ROS) a redox signal are produced by various enzymatic reactions and chemical processes whichare essential for many physiological functions and act as second messengers However accumulating evidence has implicatedthe pathogenesis of several human diseases including neurodegenerative disorders related to increased oxidative stress Underpathological conditions increasing ROS production can regulate the expression of diverse inflammatory mediators during braininjury Elevated levels of several proinflammatory factors including cytokines peptides pathogenic structures and peroxidants inthe central nervous system (CNS) have been detected in patients with neurodegenerative diseases such as Alzheimerrsquos disease (AD)These proinflammatory factors act as potent stimuli in brain inflammation through upregulation of diverse inflammatory genesincluding matrix metalloproteinases (MMPs) cytosolic phospholipase A

2(cPLA

2) cyclooxygenase-2 (COX-2) and adhesion

molecules To date the intracellular signaling mechanisms underlying the expression of target proteins regulated by these factorsare elusive In this review we discuss the mechanisms underlying the intracellular signaling pathways especially ROS involved inthe expression of several inflammatory proteins induced by proinflammatory factors in brain resident cells Understanding redoxsignaling transductionmechanisms involved in the expression of target proteins and genesmay provide useful therapeutic strategiesfor brain injury inflammation and neurodegenerative diseases

1 Introduction

In general inflammation is a protective response to variouscell and tissue injuries The purpose of this process is todestroy and remove the detrimental agents and injuredtissues thereby benefiting tissue repair When this helpfulresponse is uncontrolled the effect initiates excessive celland tissue damages that result in destruction of normaltissue and chronic inflammation [1ndash3] Moreover the braininflammatory diseases including Alzheimerrsquos disease (AD)and Parkinsonrsquos disease (PD) are characterized by ldquoredoxstaterdquo imbalance and chronic inflammation a major causeof cell damage and death Reactive oxygen species (ROS)are widely recognized as key mediators of cell survivalproliferation differentiation and apoptosis [4 5] Excessive

production of ROS (termed ldquooxidative stressrdquo) by mitochon-dria and NADPH oxidase (Nox) is usually thought to beresponsible for tissue injury associated with a range of braininjury inflammation and degenerative diseases such as AD[5ndash8] Moreover many of the well-known inflammatorytarget proteins includingmatrixmetalloproteinase-9 (MMP-9) cytosolic phospholipase A

2(cPLA

2) cyclooxygenase-

2 (COX-2) inducible nitric oxide synthase (iNOS) andadhesionmolecules are associatedwith oxidative stress (ROSgeneration) induced by proinflammatory factors such ascytokines peptides infections and peroxidants [3 5 9]Brain cells especially neuroglial cells are susceptible to theinjurious effects of oxidative stress Several studies haveshown that brain cells like microglia and astrocytes induceand release diverse inflammatory mediators in response to

2 BioMed Research International

oxidative stress [9ndash11] In addition ROS act as a critical sig-naling molecule to trigger inflammatory responses in centralnervous systems (CNS) through the activation of the redox-sensitive transcription factors including nuclear factor-120581B(NF-120581B) and activator protein-1 (AP-1) [5 9] Thus thisreview will focus on many general aspects of oxidative stressregulation and summarize the current progresses regardingthe occurrence and effects of redox signals on CNS andtheir involvement in the expression of inflammatory targetproteins in response to proinflammatory factors during braininflammation Moreover the pharmacological interventionswhich protect against oxidative stress-induced neuroinflam-mation and neurodegenerative diseases will be discussed

2 Role of Neuroglial Cells in CNSPhysiological and Pathological Events

CNS consists of neurons and glial cells Among glial cellsastrocytes constitute nearly 40 of the total CNS cell popula-tion in the adult human brain and theymaintain homeostasisin normal CNS Astrocytes have also been proposed to exerta wide range of functions including guidance of the develop-ment and migration of neurons during brain developmentproduction of growth factors maintenance of the integrityof the blood-brain barrier (BBB) and participating in theimmune and repairing responses to disease and brain injury[12 13]Microglial cells represent resident brainmacrophagesand can be transformed into activated immunocompetentantigen-presenting cells during the pathological process Anincreased number of activated microglial cells have consis-tently been reported in PD which may have a deleteriouseffect on dopaminergic neurons [14] Astrocytes as well asmicroglia display an array of receptors involved in innateimmunity including Toll-like receptors (TLRs) nucleotide-binding oligomerization domains double-stranded RNAdependent protein kinase mannose receptor and compo-nents of the complement system [10] One common featureof a variety of neurodegenerative disorders is the presenceof a large number of activated glial cells including astrocytesand microglia that involve the changes of morphology andexpression of many inflammation-related proteins Gliosisespecially astrogliosis is characterized by astrocytic prolifer-ation extensive hypertrophy of the cell body and functionalchanges when stimulated with various factors includinglipopolysaccharide (LPS) interleukin-1120573 (IL-1120573) and tumornecrosis factor-(TNF-120572) [15 16]

Moreover the cell-cell interactions between glial cellsand neurons may be important in the regulation of braininflammation and neurodegeneration Many recent reportsimplicate that inflammation contributes to a wide variety ofbrain pathologies apparently killing neurons via glia [10 1117] Thus the activated glial cells especially microglia andastrocytes are thought to play a critical role in the patho-genesis and progression of neurodegeneration (Figure 1) Pre-viously many reports have shown that microglial cells maybe a major inflammatory cell of the brain [14] The activatedmicroglia produce several inflammatorymediators includingCOX-2prostaglandins (PGs) iNOSnitric oxide (NO) or

Neuroinflammationneuronal death

Inflammatory mediators

Proinflammatory factors

Neuroglial cells (microglia and astrocytes)

Figure 1 Schematic presentation of the interaction of the braincells including neurons and glial cells In the central nervous system(CNS) proinflammatory factors induce the expression of variousinflammatory mediators in neuroglial cells particularly microgliaand astrocytes These induced inflammatory mediators from glialcells may cause the neuroinflammation or neuronal death and thenleading to neurodegenerative disorders

cytokines as well as neurotoxic substances which are thoughtto be responsible for brain injuries and diseases includingtrauma AD and neural death due to the exposure of LPSinterferon-120574 or 120573-amyloid [18 19] Although most studieshave demonstrated that microglial cells play an importantrole in neuroinflammation and neurodegeneration accu-mulating evidence has also demonstrated the characteristicchanges of astrocytes in neurodegenerative diseases such asdementia [10 11 20] Recently we have demonstrated theupregulation of several inflammatory mediators includingMMP-9 cPLA

2 COX-2 iNOS and oxidative stress by var-

ious proinflammatory factors such as cytokines (eg IL-1120573) peptides (eg bradykinin (BK) or endothelin-1 (ET-1)) infections (eg bacteria or virus) and peroxidants(eg oxidized low-density lipoprotein (oxLDL)) in rat brainastrocytes [21ndash29] More recent data indicated that multi-ple factors including ROS MMP-9 and heme oxygenase-1(HO-1)carbon monoxide (CO) from BK-challenged brainastrocytes may contribute to the neuronal cell apoptosis[30] Together these results implicate that activated neuroglialcells especially astrocytes play a key role in the pathogenesisof the CNS inflammation leading to neurodegenerative dis-eases (Figure 1)

BioMed Research International 3

Oxidative stress Antioxidants

Nox Xox

P450 COX

NOS

SOD Catalase

GPx Thioredoxin

HO-1

Inflammation Anti-inflammation

Figure 2 Oxidative stress and antioxidants imbalance in inflamma-tion In inflammation the balance appears to be tipped in favor ofincreased oxidative stress by various specialized enzymes includingNox Xox P450 COX or NOS either because of excessive ROSrelease or inflammatory mediators leading to the amplificationof the proinflammatory effects In contrast induction of severalantioxidants such as SOD catalase GPx thioredoxin or HO-1 mayreduce ROS generation and attenuate the inflammatory response(anti-inflammation) Nox NADPH oxidase Xox Xanthine oxidaseP450 P450 enzyme COX cyclooxygenase NOS nitric oxidesynthase SOD superoxide dismutase GPx glutathione peroxidaseHO-1 heme oxygenase-1

3 Role of Oxidative Stress (Redox Signaling)in the Brain Inflammation andNeurodegenerative Diseases

In CNS inflammation various proinflammatory factors maycause the development of an oxidative stress and antioxidantsimbalance which induces redox signal-dependent expressionof genes for inflammatory mediators or protective antioxi-dants (Figure 2) The oxidative stress (ie ROS and reactivenitrogen species (RNS)) is produced by various enzymaticreactions and chemical processes or directly inhaled ROSthat are particularly responsible in oxidative stress includesuperoxide anion (O

2

∙minus) hydrogen peroxide (H2O2) and

hydroxyl radical (∙OH) Furthermore the RNS include nitricoxide (NO) and peroxynitrite (ONOOminus) These oxidativestresses (ie ROSRNS) are essential for many physiologicalfunctions at low concentrations [2ndash6] and killing invadingmicroorganisms [31] However several lines of evidencehave suggested that the pathogenesis of human diseases isattributed to increased oxidative stress [2 31] Moreoveroxidative stress has been shown to mediate the pathogenesisof neurodegenerative diseases including PD [6] AD [32]and cerebrovascular disorders such as stroke [31] Thereare several major sources of ROSRNS generation in thecells including Nox Xanthine oxidase (Xox) P450 enzymesCOX and NOS (Figure 2) which contribute to severalphysiological and pathological functions including braininflammation and neurodegeneration [8] The physiologicalrole of ROSRNS (along with O

2

∙minus and NO) also extendsto the control of vascular tone in the brain which is tightlymodulated by the metabolic activity within neurons [6 33]Particularly in the brain even small redox imbalances can

be deleterious Recently accumulating evidence attributesthe cellular damage in the CNS degenerative disorders tooxidative stress [5ndash9] suggesting that oxidative stress is anearly event in AD [32] Oxidative stress may be responsiblefor brain inflammatory disorders which cause deleteriouseffects during CNS pathogenesis [34] Furthermore severalreports have shown that ROS levels are increased with agein several major organs including brain [32] Abnormallyelevated ROS is implicated in age-related long-term potenti-ation (LTP) impairment [35] ROS further induce expressionand activation of proinflammatory factors or inflammatorymediators during brain injury and inflammation Undervarious pathological conditions excessive amounts of ROScan damage DNA lipids proteins and carbohydrates leadingto impairing cellular functions and enhancing inflammatoryreactions [34 36] In brains of AD patients cellular andanimal models of AD the elevated levels of these oxidativestress-modified molecules are also detected [32] Recentlyincreasing evidence attributes the cellular damage in neu-rodegenerative disorders such as AD and PD to oxidativestress that leads to generation of ROS associated with braininflammatory disorders [2 6] Thus these results indicatethat oxidative stress (ie ROS production) plays an importantrole in CNS inflammation and neurodegenerative disorders(Figure 4)

Oxidative stress activates several intracellular signalingcascades that may have a deleterious effect on the cellularhomeostasis The molecular mechanisms associated withROS production (eg mitochondrial dysfunction and Noxactivation) and its influences have been investigated in var-ious models of chronic inflammation and neurodegenerativedisorders [9] Recently there are extensive pieces of literaturesupporting a role of mitochondrial dysfunction and oxidativedamage in the pathogenesis of AD [5 37] and ROS areassociated with neuroinflammatory and neurodegenerativeprocesses [9 17 32] Several proinflammatory factors (egLPS and BK) have been shown to induce the expressionand activation of various inflammatory mediators via a ROS-dependent manner in brain cells [25 36] In microglialcells ROS as a major signaling molecule mediate microglialactivation induced by proinflammatory mediators such asA120573 or LPS [38 39] However the roles of oxidative stressthat contribute to these events are not well characterizedin brain cells including astrocytes Our recent reports havedemonstrated that ROS signals contribute to the expres-sion of many inflammatory genes (eg MMP-9) by sev-eral proinflammatory factors including BK [25] LTA [27]and TGF-1205731 [40] in brain astrocytes More recent resultindicates that ROS generation from BK-challenged astro-cytes contributes to neuronal apoptosis through a caspase-3-dependent manner [30] Although oxidative stress is impli-cated as a causative factor in neurodegenerative disorders thesignaling pathways linking ROS production with neuronalcell death are not well characterized [6] Hence there areseveral targets and signals that need to be identified andexplored for the development of therapeutic strategies in thefuture


NoxXoxP450COXNOS SOD Catalase

MPO

HOCl

L-ArgNOS


GPxH2OH2O2O2

ONOOminus ∙OHminusNO∙

O2∙minus

Figure 3 Major pathways of reactive oxygen (nitrogen) speciesgeneration and metabolism Several proinflammatory factors canstimulate O

2

∙minus generation through activation of several specializedenzymes such as the Nox Xox P450 COX or NOS SOD thenconverts the O

2

∙minus to H2O2 which is then converted into the

highly reactive ∙OH or has to be rapidly removed from the systemthat is generally achieved by catalase or peroxidases such as theGPx Further O

2

∙minus can be either converted into ROO∙ or canreact with NO to yield ONOOminus NO is mostly generated by L-Arg via NOS H

2O2can be converted to HOCl by the action of

MPO myeloperoxidase O2 molecular oxygen H

2O water O

2

∙minussuperoxide radical anion ∙OH hydroxyl radical ROO∙ peroxylradical H

2O2 hydrogen peroxide ONOOminus peroxynitrite NO

nitric oxide L-Arg L-arginine HOCl hypochlorous acid

4 Redox Signaling and ProinflammatoryFactors in Brain Inflammation andNeurodegenerative Diseases

The senile and neuritic plaque of AD are accompanied byinflammatory responses in activated glial cells (ie astrocytesand microglia) In CNS several cytokines and inflammatorymediators produced by activated glia have the potential toinitiate or exacerbate the progression of neuropathology [41]Moreover traumatic injury to CNS results in the produc-tion of inflammatory cytokines via intrinsic (brain cells)and extrinsic means (by infiltrating macrophages and otherleukocytes)The expression ofmany inflammatorymediatorsincluding cytokines MMPs cPLA

2 COX-2 and iNOS has

been shown to be regulated by various extracellular stimulisuch as proinflammatory cytokines (eg IL-1120573 and TNF-120572)peptides (eg BK ET-1 and A120573) infections (eg bacteriaand virus) peroxidants (eg oxLDL and H

2O2) and other

stresses (eg TGF-120573) in neuronal and neuroglial cells [4ndash9 42] (Figure 4)

41 Cytokines IL-1120573 and TNF-120572 are two of the inflamma-tory cytokines significantly elevated in neurodegenerativediseases such as AD and they play a central role in initiatingand regulating the cytokine cascades during inflammatoryresponses [43] IL-1120573 is a pleiotropic cytokine and classifiedas a dominant injury biomarker Furthermore several studieshave shown that the level of IL-1120573 is elevated in the cere-brospinal fluid (CSF) of patients with AD traumatic braininjury [44] and stroke [45] Thus IL-1120573 plays an importantrole in both acute and chronic neurodegenerative diseases

Neuroglial cell activation

Redox signals(ROS)


NeuroinflammationNeuronal death

Proinflammatory factorscytokines (eg IL-1120573 TNF-120572)

metalloproteinases (eg MMP-9)

phospholipases (eg cPLA2)

cyclooxygenases (eg COX-2)

NO synthases (eg iNOS)

adhesion molecules (eg ICAM)

peptides (eg BK ET-1 and A120573)

infections (eg bacteria virus)

peroxidants (eg oxLDL

others (eg TGF-120573)

H2O2)

Figure 4 Schematic representation of the redox signals (ROSproduction) and their role in the development of neuroinflamma-tion and neuronal death Many of the well-known inflammatorytarget proteins such as MMP-9 ICAM-1 VCAM-1 COX-2 andcPLA

2 can be upregulated by various proinflammatory factors

including cytokines peptides bacterial or viral infection peroxi-dants via a ROS signal-dependent manner in neuroglial cellsTheseinflammatory mediators can cause neuroinflammation and neu-ronal death IL-1120573 interleukin-1120573 TNF-120572 tumor necrosis factor-120572 BK bradykinin ET-1 endothelin-1 A120573 120573-amyloid oxLDLoxidized low-density lipoprotein H

2O2 hydrogen peroxide TGF-120573

transforming growth factor-120573 MMP-9 matrix metalloproteinase-9 cPLA

2 cytosolic phospholipase A

2 COX-2 cyclooxygenase-2

iNOS inducible nitric oxide synthase ICAM intercellular adhesion

The effects of IL-1120573 on ROS generation have been reportedto be associated with brain inflammatory disorders cancersand myocardial remodeling [46 47] ROS generation by IL-1120573 leads to the expression of several inflammatory geneslike MMP-9 which may increase BBB permeability recruitimmune cells infiltrating through BBB into the tissues andsubsequently result in brain inflammation and edema duringbrain injury [6 34] ROS may also act as an inflammatorysignaling factor mediated microglial activation induced byIL-1120573 [39] Moreover in culture of glianeuron IL-1120573 induces


neurotoxicity through the release of free radicals [48] Inaddition TNF-120572 is also produced in response to oxidativestress and A120573 In brain TNF-120572 is produced by microgliaand its overproduction has been linked with neuronal celldeath [49] These studies indicate that cytokines especiallyIL-1120573 and TNF-120572 contribute to the CNS inflammation andneurodegenerative diseases through redox signalings

42 Peptides AD is defined by progressive impairments inmemory and cognition and by the presence of extracellularneuritic plaques (A120573) and intracellular neurofibrillary tangles(tau protein) [5 32] Among these molecules A120573 is aninsoluble fibrous protein and aggregates sharing specificstructural traits It arises from at least 18 inappropriatelyfolded versions of proteins and polypeptides present naturallyin the body The misfolded structures alter their properconfiguration such that they erroneously interact with othercell components forming insoluble fibrils A120573 has been asso-ciated with the pathology of more than 20 human diseasesincluding AD Abnormal accumulation of amyloid fibrilsin brain may play a role in neurodegenerative disordersAlthough A120573 peptide is neurotoxic species implicated in thepathogenesis of ADmechanisms throughwhich intracellularA120573 impairs cellular properties and produces neuronal dys-function remain unclear Accumulating evidence has indi-cated that A120573 can stimulate the production of free radicals[50] Interestingly intracellular A120573 is present in mitochon-dria from brains of transgenic mice with targeted neuronaloverexpression of mutant human amyloid precursor proteinand AD patients Importantly mitochondria-associated A120573principally A120573

1ndash42 was detected as early as 4 months beforeextensive extracellular A120573 deposits [51] Moreover activationof Nox by A120573

1ndash42 results in ROS production in rat primaryculture of microglial cells [52] In mouse models of plaqueformation oxidative stress occurs prior to A120573 depositionin a Tg2576 APP transgenic mice [53] Moreover increasedlevels of oxidative damage occur in individuals with mildcognitive impairment (MCI) which is often believed to beone of the earliest stages of AD [54] Additionally glial HO-1 expression in the MCI temporal cortex and hippocampusis also significantly greater than that of the nondementedgroup [55]These results support A120573-induced redox signalingserving as an early event that leads to the development of theCNS pathological features such as AD Moreover glial cellsmay play a key role in the events

In addition to A120573 peptide BK and related peptides areproduced and released during trauma stroke andneurogenicinflammation [56] All these pathological processes maybe involved in tissue remodeling which were regulated byMMPs Moreover astrocytes possess receptors for numeroustransmitters such as glutamate and BK [57] These peptidesmediate several inflammatory responses including increasingvasodilatation and vascular permeability promotion of fluidsecretion and ion transport and eliciting itching and painat the sites exposed to noxious stimuli Thus the elevatedlevel of BK plays a key role in the initiation of inflamma-tory responses in target tissues including CNS It is wellestablished that BK interacts with two BK receptor subtypesincluding BKB1 and B2 [58] Astrocytes are known to express

B2-type BK receptors and this type of receptors is foundonly on astrocytes type 1 [57] The B2 BK receptor is aheterotrimeric G-protein-coupled receptor (GPCR) that canbe coupled to intracellular signalingmolecules via interactionwith Gq protein [59] Activation of BK receptors stimulatesintracellular signaling molecules including Ca2+ PKCs andMAPKs in several cell types including astrocytes [57ndash59]Activation of these signaling pathways may lead to cellsurvival proliferation differentiation and the expression ofseveral inflammatory genes such as iNOS and MMP-9 [3660] During brain injury BK has been shown to induce theexpression of several inflammatory genes by increasing ROSproduction [6 34] Moreover Nox is expressed in astrocytesand contributes to ROS generation [61 62] In brain astro-cytes BK induces the expression of several inflammatorygenes like MMP-9 by ROS-dependent signaling pathways[25] Moreover ROS released from BK-challenged brainastrocytes cause neuronal cell apoptosis [30] These pieces ofliterature suggest that BK plays an important role in braininflammation and neurodegenerative disorders

Endothelial cells are known to produce vasotone media-tors such as endothelins (ETs) and NO to maintain hemody-namic responsesThe ETs are 21-amino acid vasoconstrictingpeptides produced primarily in the endothelium which playa key role in vascular homeostasis and have been implicatedin brain inflammatory diseases Among the ET family thebioactivity of ET-1 is mediated through potent vasocon-strictor and proinflammatory action in vascular diseasesincluding the heart circulation system and brain [63ndash66]Two types of ET receptors ET type A (ETA) and type B(ETB) are responsible for ET-1-triggered biological effectswhich are mediated via G-protein-dependent processes [63ndash65] In CNS ET-1 also plays a substantial role in thenormal development and CNS diseases Both endothelialcells and astrocytes are potential sources of ET-1 release inresponse to hypoxicischemic injury of the brain [66] Onastrocytes the ETB receptors are predominantly expressedand modulate postinjury responses of astrocytes in CNS[67] Circumstantial evidence has further demonstrated thatoverexpression of ET-1 has deleterious effects on astrocytesin ischemic brain [68] Similarly ET-1 causes hypertrophyof ETBGFAP-immunoreactive astrocytes a typical charac-teristic of astrogliosis in the normal optic nerve leading toglial scar formation following CNS injury [68] EndothelialET-1 induces cytokine production such as IL-1120573 releasedby astrocytes which directly contributes to BBB breakdownduring CNS inflammation [69] These findings further implythe involvement of ET-1 in the CNS inflammation anddiseases

43 Infections Bacterial infections have been shown to beinvolved in brain inflammation [70] A well-known endo-toxin fromGram-negative bacteria LPS regulates the expres-sion of inflammatory proteins associated with inflammatorydiseases Many studies have also shown that ROS are themajor signaling molecule which mediates microglial activa-tion induced by inflammatory mediators including LPS [71]However the signaling mechanisms of which activated brain


cells in response to Gram-positive bacterial infection remainundefined Gram-positive bacterial infections of CNS occurin bacterial meningitis and brain abscess being localized tothe membranes surrounding the brain and in its parenchyma[72] Lipoteichoic acid (LTA) an amphiphilic polymer isembedded in-cell wall of Gram-positive bacteria [73] TheGram-positive bacterium Streptococcus pneumoniae is themost common cause of acute bacterial meningitis worldwide[74] revealing a close relationship between LTA challengesand CNS diseases For the initiation of LTA signaling TLRsare believed to be responsible for LTA recognition challengedby Gram-positive bacteria such as Staphylococcus aureusand Streptococcus pneumoniae [75] Upon binding to TLRheterodimers (ie TLR2TLR1 or TLR2TLR6 complex) LTAexerts a sequential activation of members of IL-1 receptor-associated kinase (IRAK) family and tumor necrosis factorreceptor-associated factor 6 (TRAF6) mediated by a TLRadaptor protein MyD88 Ultimately TLR signalings activateMAPK family and NF-120581B leading to modulation of geneexpression of cytokines and other inflammatory proteins[76] Among the diverse cell types in CNS glial cells suchas astrocytes and microglia are regarded as targets in Gram-positive bacterial infection [77ndash79] Several lines of evidencesuggest a causal relationship between LTA challenges andthe CNS diseases which involves glial activation and TLR2signalings [77ndash79] TLR signalings in astrocytes have beenshown to be involved in inflammatory responses in CNS [80]accompanied with upregulation of genes with inflammatoryand proapoptotic effects [81] The pathogenic progressioninvolves glial activation and TLR2 signalings stimulated byLTA which are linked to inflammatory neurodegeneration[82] Additionally LTA exhibits detrimental effects on braincellular functions including induction of apoptosis produc-tion of oxidative stresses and disruption of BBB followinggroup B Streptococcus or Staphylococcus aureus challenge inCNS [82] Although the effects of LTA on ROS generationhave been reported in several cell types such as renal diseases[83] LTA-induced brain cell responses through the ROSsignals are not well characterized Recent report indicatesthat LTA-induced MMP-9 expression is mediated throughNox2-derived ROS generation in brain astrocytes [27]Thesedata suggest that targeting LTA and its specific signalingcomponents could yield useful therapeutic targets for CNSinflammatory diseases upon infection with Gram-positivebacteria

Moreover increasing evidence has shown that viralinfections such as Japanese encephalitis virus (JEV) andEnterovirus 71 (EV71) may contribute to several inflam-matory responses in CNS [28] Neurotropic viruses cancausemassive neuronal dysfunction and destruction that leadto neurological diseases EV71 a single-positive-strandedRNA virus belongs to the Enterovirus B genus of thePicornaviridae family [84] EV71 and Coxsackievirus A16(CVA16) are the major causative agents of hand-foot-and-mouth disease (HFMD) that is usually mild exanthematousinfection and self-limiting in the young children HoweverEV71 but not CVA16 can progress to severe neurologicaldiseases including fatal encephalitis aseptic meningitis andfatal neurogenic pulmonary edema [85] Children under 5

years old of age group are susceptible to these infectionsand may develop permanent neurological sequelae or evensuccumb to such disorders [86] In 1998 an EV71 outbreakinfected more than 130000 children resulted in 78 fatali-ties Since then EV71 infection has recurred every year inTaiwan and EV71 outbreaks have been periodically reportedthroughout the world representing a major public healthconcern particularly in the Asia-Pacific regions includingTaiwan Malaysia Singapore Japan and China [85 87] Theemerging evidence suggests that ROS affect the interactionbetween host and viral pathogens Recently EV71 has beenshown to induce oxidative stress-dependent viral replicationin human neuroblastoma SK-N-SH cell line [88] SimilarlyJEV is a single-stranded positive-sense RNA virus belongingto the family Flaviviridae JEV is transmitted between animalsand humans by culex mosquitoes [89] After the bite ofan infected mosquito JEV amplifies peripherally producingtransient viremia before entering intoCNS [89]Theprincipaltarget cells for JEV are localized in CNS including neuronsand astrocytes [90] Several lines of evidence suggest thatJEV frequently causes severe encephalitis in the worldespecially in Eastern and Southeastern Asia The infectionwith JEV is characterized by clinical manifesting with feverheadache vomiting signs ofmeningeal irritation and alteredconsciousness leading to high mortality [89 90] The gen-eration of ROS plays an important role in diverse cellularfunctions including signal transduction oxygen sensing andhost defense during infection by viruses such as JEV [91]In CNS JEV infection has been shown to upregulate MMP-9 gene expression through ROS-dependent pathways inbrain astrocytes [28]These findings concerning JEV-inducedexpression of inflammatory genes in brain astrocytes implythat JEV might play a critical role in the brain inflammationand neurodegenerative diseases

44 Peroxidants Oxidative stress may cause production ofseveral peroxidants such as oxidized lipoprotein Clinicalreports reveal that the patients with AD exhibit an increasedoxidation of lipoproteins potentially toxic to neurons inCNS [92] Among these the oxidized low-density lipopro-tein (oxLDL) is a well-known predominantly risk factorof atherosclerosis which has been reported to participatein the progression of the CNS diseases In CNS oxLDLexhibits detrimental effects on brain cell functions includinginduction of apoptosis disruption of capillary homeostasisand alteration of inflammatory protein activity in variousbrain cells [93] Furthermore in patients with cerebral infarc-tion oxLDL is present in brain parenchyma and stimulatesastrocytes to secrete interleukin-6 [94] and may serve as anindicator to reflect the level of oxidative stress [95] In brainastrocytes oxLDL can induce MMP-9 expression and cellmigration which plays a critical role in the progression ofinflammatory diseases and remodeling processes in targettissues including CNS [29 96] These findings suggestthat peroxidants like oxLDL might play a key role in theprogression of the CNS diseases and also that targeting theseperoxidants-stimulated signaling components may provideuseful therapeutic strategies for brain inflammation andneurodegenerative diseases


45 Others In addition to these well-known factors thereare many factors that may also contribute to neuroinflam-matory responses Among these TGF-120573 has been implicatedto participate in the responses TGF-120573 binds to two ser-inethreonine kinase receptors which consist of TGF-120573RI andTGF-120573RII During ligand binding TGF-120573RII phosphorylatesTGF-120573RI and activates Smad-dependent intracellular signal-ing pathways and thus leads to expression of several genes [9798] In addition to activation of Smad-dependent pathwaysTGF-120573 can affect several signal transduction pathways ina Smad-independent manner such as MAPKs [97 98]In human gingival and skin fibroblasts both p38 MAPKand Smad3 cooperate in regulating TGF-120573-induced MMP-13 expression whereas ERK12 cooperates with Smad3 inregulating connective tissue growth factor expression [99]Recently increasing evidence has attributed the cellulardamage in neurodegenerative disorders to oxidative stressleading to generation of ROS that are responsible for braininflammation and neurodegenerative disorders [6 34] TGF-120573 can stimulate ROS production which participates in theexpression of diverse inflammatory genes such as MMPs inthe processes of several human inflammatory diseases [100]In brain astrocytes TGF-1205731 has been shown to induce inflam-matory protein expression via a ROS-dependent manner[40] These results suggest that TGF-1205731 may play a key rolein the process of brain inflammation and neurodegenerativediseases

5 Role of Redox Signaling in the Regulation ofInflammatory Mediators

Neuroinflammation is an active defensive process againstdiverse insults metabolic and traumatic injuries infectionand neurodegenerative diseases Although neuroinflamma-tion serves as a neuroprotective mechanism associated withrepair and recovery it can also cause brain damage [101]However if inflammation in the brain is chronic or inappro-priately controlled it may become detrimental to neuronsthus representing one of the various pathological insultsinduced by various proinflammatory factors and by inflam-matory mediators in CNS [101] Experimental and clinicalstudies have shown that various inflammatory mediatorsare present in brain CSF and blood in brain injury Inparticular the histological analysis of human brain fromindividuals with brain disorder such as AD or epilepsy ofvarious etiologies strongly suggests the existence of a chronicinflammatory state in the brain almost invariably associatedwith neuronal loss or reactive gliosis [102] In experimentalmodels of rodent brain seizures a variety of inflammatorymediator mRNAs and protein levels are rapidly increasedafter the induction of seizures including MMPs (eg MMP-9 especially) multiple forms of PLA

2(eg cPLA

2) COX-2

NOS (eg iNOS) and adhesion molecules (eg ICAM-1 andVCAM-1) [102 103] After expression of these inflammatorymediators several CNS damaging factors will be producedsuch as cytokines shedding by MMPs arachidonic acid(AA)PGE

2releasing by cPLA

2COX-2 system and NO

generation by NOS [102 103] Herein we reviewed the role

andmechanism of these inflammatorymediators in the braininflammation and neurodegeneration and whether oxidativestress plays a crucial role in these events

51 Matrix Metalloproteinases MMPs are a large family ofzinc-dependent endopeptidases which play an importantrole in the turnover of extracellular matrix (ECM) andpathophysiological processes [104] To date 24 MMPs havebeen identified in mammals Among these MMPs someare membrane-type MMPs which are anchored to the cellsurface and others are secreted into the extracellular space Ingeneral MMPs are released as inactive proform MMPs andactivated by proteolytic cleavage of the N-terminal domainIn gelatinase subfamily of MMPs (ie MMP-2 and MMP-9) the catalytic domain that contains the Zn2+ binding siteand repeats of fibronectin motifs allowing the ability to bindtheir major substrate gelatin MMP-9 (gelatinase B 92 kDa)is usually low and its expression can be induced by variousproinflammatory factors such as cytokines The other classof gelatinase MMP-2 (gelatinase A 72 kDa) is constitutivelyexpressed in several cell types and usually not inducible InCNS MMPs especially MMP-9 are implicated in severalimportant physiological events including morphogenesiswounding healing and neurite outgrowth [105] Moreoverupregulation of MMP-9 may contribute to the pathogenesisof several CNS diseases such as stroke ADmultiple sclerosisandmalignant glioma [105] Several proinflammatory factorsincluding cytokines endotoxins and oxidative stress havebeen shown to upregulate MMP-9 in astrocytes in vitro[106 107] implying that MMP-9 activity may be regulated bydiverse factors in CNS during neuroinflammationMoreovermany proinflammatory mediators like cytokines and BKinduce the expression of MMP-9 during brain injury byincreasing ROS production [25 62] Recently upregulatedMMP-9 and ROS generation from brain astrocytes have beenreported to contribute to neuronal cell death in vitro [30]These studies suggest that upregulation and activation ofMMP-9 by proinflammatory factors are mediated throughoxidative stress (ROS production) during brain injury andinflammation (Figure 4) Therefore the inhibition of MMP-9-mediated inflammatory pathways may provide therapeuticstrategies to brain inflammation and neurodegenerative dis-eases

52 Cytosolic Phospholipase A2 There are three forms of

phospholipaseA2(PLA2) superfamily including the secretory

PLA2 type IV PLA

2 also known as cPLA

2 and calcium-

independent PLA2in mammalian cells [108ndash110] The sec-

retary PLA2(sPLA

2) is expressed in a variety of cell types

and it has no preference for AA at sn-2 position requiresmillimolar amounts of Ca2+ for activity and is sensitive tosulfhydryl reducing agents such as dithiothreitol (DTT) andis resistant to heat or acid conditions [109] The calcium-independent PLA

2(iPLA

2) does not requireCa2+ for catalytic

activity The iPLA2prefers plasmalogen substrates and does

not appear to have a preference for the type of fatty acid at thesn-2 position The third class is the novel and high molecularweight (85 kDa) cPLA

2The cPLA

2catalyzes the hydrolysis of

the sn-2 position ofmembrane glycerophospholipids leading


to production of free fatty acids and lysophospholipids Thisreaction is of particular importance if the esterified fatty acidis AA which is converted by downstreammetabolic enzymesto various bioactive lipophilic compounds called eicosanoidsincluding PGs and leukotrienes (LTs) [110] PLA

2could be

the initial and rate-limiting enzyme in this conversion Theincrease in cPLA

2activation and expression following exter-

nal stimuli including proinflammatory cytokines growthfactors and microbial toxin is often observed in severalsystems [111] Among these enzymes cPLA

2is the only

one that plays a key role in mediating agonist-induced AArelease for eicosanoid production in various cell types [112]Several studies have indicated that cPLA

2is constitutively

expressed in the cytosol of most resting brain cells andtissues In brain cPLA

2has been shown to co-localize with

glial fibrillary acidic protein (GFAP) a principal marker forbrain astrocytes [113] Moreover under brain inflammatoryand neurodegenerative conditions such as AD there is anincrease in immunoreactivity to cPLA

2in astrocytes from

the cortex of patients [114 115] A variety of proinflamma-tory factors including IL-1120573 TNF-120572 or BK may exert asmodulators of cPLA

2activity andor expression in various

cell types including astrocytes [23 111] Upregulation andactivation of cPLA

2leading to PGE

2production have been

implicated in a number of neurodegenerative diseases [111114 115] Recently PGE

2production and cPLA

2activation

have also been shown to regulate the CREB-dependent iNOSexpression in microglia [116] or cPLA

2expression in amnion

fibroblasts [117] However a series of highly reactive PGs freefatty acids lysophospolipids eicosanoids platelet-activatingfactor and ROS all generated by enhanced PLA

2activity

and AA release participate in cellular injury particularly inneurodegeneration [118] Thus cPLA

2seems to function as a

crucial upstream regulator of the production of eicosanoidsduring brain inflammation and is correlated to the processof neurodegenerative diseases (Figure 4) The inhibition ofcPLA2-mediated pathways may provide a therapeutic strat-

egy to brain inflammation and neurodegenerative diseases

53 Cyclooxygenase-2 COX known as a prostaglandin-endoperoxide synthase is a rate-limiting key enzyme inthe synthesis of PGs In this process PLA

2catalyzes the

release of AA from membrane phospholipids while COXcatalyzes the conversion of AA into PGs [119] Significantadvances have been made in understanding the role ofCOX in certain biologic processes including inflammationangiogenesis development and several homeostasis [119]COX exists in two isoforms COX-1 which is expressed con-stitutively under normal conditions in most tissues mediatesregulating normal physiological responses and controls renalhomeostasis and the inducible COX-2 is not detectablein most normal tissues or resting cells but its expressioncan be induced rapidly by a variety of stimuli includingcytokines bacterial or viral infections and othermediators toproduce PGs during inflammation [120] In addition COX-2gene promoter which contains multiple regulatory elementshas been shown to be regulated by different transcriptionfactors including NF-120581B AP-1 and cyclic AMP-responseelement binding protein (CREB) in various cell types [121]

Previous studies showed that COX-2 immunoreactivity is acharacteristic finding in the synovial macrophage of patientswith arthritis as well as in other forms of inflammationMoreover several lines of evidence have confirmed COX-2 asa major therapeutic target for the treatment of inflammatorydisorders such as arthritis [119 122] Recently the mice withhomozygous deletion of theCOX-2 gene suppress endotoxin-induced inflammation [123] In brain expression of COX-2 leads to increased production of prostanoids which arepotent inflammatory mediators and upregulated COX-2expression has been reported in neurodegenerative disorders[124] Moreover upregulation of COX-2 and PGE

2release

by viral infection such as EV71 have been reported inbrain astrocytes and human neuroblastoma cells via diversesignaling pathways [125 126] Upregulation of COX-2PGE

2

by ET-1 via MAPK-dependent NF-120581B pathway in brainmicrovascular endothelial cells [127] A recent report alsoindicates that the ROS-induced COX-2 expression can befound in ALS [128] However the expression of COX-2appears to be strongly induced and activated during ADindicating the importance of inflammatory gene pathways asa response to brain injury [118] Thus COX-2 may play animportant role in the development of brain inflammation andneurodegenerative diseases

54 Nitric Oxide Synthase NO is a free radical that displaysdiverse bioactivity in various organ systems including CNSDepending on the concentration excess NO levels are impli-cated in the pathogenesis of CNS diseases including ischemiatrauma neuroinflammatory and neurodegenerative diseases[129ndash131] Production of NO from L-arginine is catalyzed byNOS The level of iNOS in healthy brain is undetectableAccumulating evidence supports the role of iNOS in thepathogenesis ofCNSdisorders InCNS upregulation of iNOSin various cell types including astrocytes and microglia isproposed to be the leading source of NO production duringneuroinflammation [132] Furthermore knockout strategiesof iNOS gene protect against focal cerebral ischemia andLPS challenges [133 134] iNOS is induced by a variety ofstimuli such as viral and bacterial infections cytokines cell-cell contact and neurotoxins [131] The consequent productNO reacts with superoxide to form peroxynitrite (ONOOminus)themost toxic derivative of NO (Figure 3) As for the involve-ment of NO derivatives in neuropathology many studieshave revealed that the reference of iNOSNOONOOminus playsan important role in neurodegenerative disorders [131]However following inflammatory insults reactive astrocytesexpress iNOS which causes the neuronal damage associatedwith cerebral ischemia andor demyelinating diseases [132]In CNS appearance of iNOS in astrocytes is related toseveral neurodegenerative diseases such as ALS [130] andmultiple sclerosis (MS) [129] These findings imply thatastrocytes are the leading regulators in neurodegenerativediseasesMoreover activation of astrocytes has been reportedto involve in the expression of inflammatory genes It hasbeen well established that the regulation of iNOS expressionis mediated via tyrosine kinases such as JAK MAPKs ROSand various transcription factors including STAT-1 NF-120581Band AP-1 in astrocytes [131] Increasing evidence suggests


that activation of signal transduction pathways like c-SrcPI3KAkt and MAPK cascades contributes to activation ofastrocytes and microglia leading to expression of inflam-matory proteins and advanced damage in neurodegenerativediseases [25 26 135]

55 Adhesion Molecules Cell adhesion molecules play animportant role in inflammatory responses Leukocytes con-tinuously circulate throughout the body in order to come incontact with antigens sequestered within tissues To enter tis-sues circulating leukocytes migrate from the blood betweenvascular endothelial cells and into the tissue [136]During thismigration leukocytes initially bind to endothelial cells vialow-affinity adhesion molecules The low-affinity adhesionin combination with the force of the blood flow results inrolling leukocytes on endothelial cells Subsequently adhe-sion molecule affinity is upregulated and leukocytes firmlyadhere to the endothelium [136] Finally bound leukocytesmigrate between the endothelial cells and into the tissueThe vascular cell adhesion molecule 1 (VCAM-1) is oneof the inducible cell transmembrane glycoproteins of theimmunoglobulin supergene family expressed on several celltypes and plays an important role in a number of inflam-matory and immune responses [137] It was first identifiedas an adhesion molecule induced on endothelial cells byproinflammatory cytokines or LPS [138] VCAM-1 expres-sion is induced on endothelial cells during inflammatorybowel disease atherosclerosis and infections [139] Upregu-lation of VCAM-1 expression on cytokine-triggered vascularendothelial cells enhances the targeted transmigration ofPMNs into extravascular space of inflammation [137] Inbrain proinflammatory cytokine-mediated expression of cellsurface adhesion molecules plays a key role in endothelialcell injury leading to vascular inflammation and the devel-opment of many cerebrovascular diseases [140] Moreoverastrocytes can be induced by viral infections to express theadhesion molecules Upregulation of adhesion moleculessuch as ICAM-1 (intercellular adhesion molecule 1) andVCAM-1 in astrocytes is required for monocyte-astrocyteinteraction which increases infiltration of monocytes into theCNS observed in the patients with HIV-1 dementia [141]HIV-1 Tat enhances monocyte adhesion by upregulationof ICAM-1 and VCAM-1 genes via a ROS-dependent NF-120581B activation in astrocytes [141] Understanding the role ofROS in proinflammatory factor-mediated adhesionmoleculeexpression and subsequently increased adhesion ofmonocyteto brain cells provides an occasion for the developmentof anti-inflammatory compounds that may be useful astherapeutic strategies for the CNS inflammation and ROS-associated neurotoxicity

56 Stress Protective Proteins In contrast with inflammatoryproteins recent reports indicate that the ROS can alsoinduce several stress protective proteins such as HO-1 andheat-shock proteins (HSP70 in particular) which may exertprotective effects from the deleterious effects of inflamma-tion [142] Abnormal protein folding has been shown as acause of various diseases like neurodegenerative diseases in

association with inflammatory mechanisms In the eventsthe HSPs play a crucial role in preventing protein misfoldingand inhibiting apoptotic activity and represent a class of pro-teins potentially involved in PD pathogenesis [143] Recentstudies have shown that HSPs are colocalized in proteinaggregates in AD PD and other neurodegenerative disorders[144 145] Many experimental findings have demonstratedthat selective overexpression of HSP70 prevents the diseaseprogression in various animal models and cellular models[145] Furthermore HSP70 dysfunction activates intracel-lular signaling like NF-120581B that can also promote neurode-generation [146] Thus the expression of HSP70 may provediagnostic and prognostic values in inflammatory conditionsand therapeutical applications are being considered on thebasis of these reports

6 Redox Signal-MediatedSignaling Transduction

Recently increasing evidence has demonstrated that oxida-tive stress (ROS generation) also plays a key signalingmolecule in regulation of various inflammatory mediatorsin several cell types Although many cells from brain tissuecan produce various inflammatory mediators [42 105] theintracellular signaling mechanisms responsible for the regu-lation of diverse inflammation-relating mediators expressioninduced by proinflammatory factors in brain cells like astro-cytes are not completely characterized Next we review somesignaling molecules in several inflammatory target proteinexpressions induced by proinflammatory factors in braincells

61 Mitogen-Activated Protein Kinases Many proinflamma-tory cytokines and chemokines transducer signals are medi-ated via activation of MAPKs pathways There is growingevidence that members of the MAPK family may play a cen-tral role in neurodegeneration [147] MAPKs are importantcomponents of signaling modules activated by neurotrans-mitters cytokines and growth factors as well as chemical andmechanical stressors In mammals three groups of MAPKshave been identified the extracellular signal-regulated pro-tein kinases (ERKs) the c-Jun NH

2-terminal kinases (JNKs)

and the p38 MAPK ERK is activated by diverse stimuliincluding growth factors and cytokines [147]The p38MAPKis activated by cellular stresses including cytokines LPSgrowth factors and UV radiation The JNK is activatedby many of the same stimuli that activate p38 MAPKsuch as cellular stresses and various cytokines Moreoverabnormal MAPK regulation might be implicated in CNSinjury and inflammation [148] Several mediators such as BKhave been reported to act as an important proinflammatoryfactors through activation of MAPK cascades in differentcell types [21ndash26] In brain cells the activation of ERK12is mainly associated with proliferation differentiation anddevelopment in response to nerve growth factors In contrastthe JNK and p38 MAPK signaling pathways are activatedby various environmental stress and inflammatory factorsthat have been shown to promote neuronal cell death [149]


Moreover the JNK and p38 MAPK signaling cascades canalso be strongly activated by stress-induced ROS productionor a mild oxidative shift of the redox state [28] BothJNK and p38 MAPK are recognized as contributors toneurodegeneration by their ability to mediate intracellularstress events in transgenic mouse models of AD [19] Thep38 MAPK activation and COX-2 and PGE

2induction are

served as contributors to neuronal damage in AD in responseto oxidative stress [150]

In nonneural cells like astrocytes many studies havefound that A120573 peptide can activate astrocytes includingmorphological alterations cytokine induction NO release[151] and chemokine and matrix-degrading proteinases pro-duction [152] These findings further indicate that inductionof several inflammatory mediators by the A120573-stimulatedactivation of MAPKs in glial cells may be involved in ADprogression Moreover our recent reports in astrocytes havedemonstrated that the proinflammatory factors includingTGF-120573 and BK can induce many inflammatory mediatorssuch as MMP-9 expression through the ROS-dependentMAPK cascades [40]These results suggest that upregulationof inflammatory mediators via ROS-mediated activation ofMAPKs in astrocytes might play a key role during theCNS inflammation and neurodegeneration Moreover theseresults also implicate that the distinct groups of MAPKsare activated by a ROS-dependent manner which contributeto the expression of various inflammatory genes and aredependent on the external stimuli during brain inflamma-tion Thus ROS may mediate MAPKs activation and expres-sion of inflammatory genes in response to proinflammatorymediators in the CNS inflammatory disorders (Figure 5)

62 Transactivation of Receptor Tyrosine Kinases Cross-communication between different signaling systems allowsthe integration of the great diversity of stimuli that a cellreceives under varying physiological situations The mostdirect mechanism is receptor heterodimerization that iswell described for members of the epidermal growth factorreceptor (EGFR) family [153] In addition to growth factorreceptor tyrosine kinases (RTKs) cross-talk also completelyunrelated cell surface receptors are able to communicate andinfluence each other which play a key role in the transmissionof information from outside the cell into the cytoplasmand nucleus A variety of cytokines and growth factors thatact as respective receptors have been reported to induceproduction of ROS in nonimmune cells The prototype forsuch a pathway is theGPCR-induced transactivation of EGFRsignal [154] Treatment of cells with GPCR agonists inducesphosphorylation of the EGFR by metalloprotease-dependentrelease of EGF-like ligands such as HB-EGF thereby cou-pling GPCRs to EGFR characteristic downstream signalingpathways such as MAPKs or PI3KAkt pathway [155] Inaddition to the EGFR other RTKs have been shown to beactivated in response to GPCR stimulation comprising theTrk receptor [156] and platelet-derived growth factor receptor(PDGFR) [157] Previous studies have shown that in devel-oping carcinoma cells the early effects of COX-2-derivedPGE2and lysophosphatidic acid are in part mediated by the

EGFR or PDGER and this transactivation is responsible for

Signaling moleculesROS

EGFRPDGFRPI3KAktMAPKs

Proinflammatory factorscytokines peptides

infections peroxidants andoxidative stress

Inflammatory target proteins

Transcription factors(eg NF-120581B AP-1)

Neurodegenerative diseasesAlzheimerrsquos diseaseParkinsonrsquos disease

Amyotrophic lateral sclerosisMultiple sclerosis

Figure 5 Proposed mechanisms of proinflammatory factors-stimulated activation of various signaling molecules and tran-scription factors leading to the expression of inflammatory targetgenes in brain resident cells The intracellular signaling moleculesinclude ROS EGFRPDFER PI3KAkt and MAPKs Oxidativestress may regulate these signaling pathways leading to activationof transcription factors such as NF-120581B and AP-1 and recruit-ment of coactivator p300 in the transcription initiation complexUltimately upregulation of diverse inflammatory target proteinscan cause the pathogenesis of several neurodegenerative diseasesEGFR epidermal growth factor receptor PDGFR platelet-derivedgrowth factor receptor PI3K phosphoinositide-31015840-kinase MAPKsmitogen-activated protein kinases NF-120581B Nuclear factor-120581B AP-1activator protein-1

subsequent downstream effects including the stimulation ofcell migration and invasion [158] However receptor cross-talk can also occur in a ligand-independentmanner involvingfor instance non-RTKs such as c-Src [159] Production ofROS results from the activation of signaling through theEGF and PDGF receptors [160] In addition ROS havebeen shown to stimulate c-Src-dependent transactivationof PDGFR120572 [161] Accumulating evidence has shown thatPKC-dependent activation of Nox is essential for PDGF-stimulated ROS generation which is important for PDGF-inducedMAPKs activation [162] In the adult CNS the EGFRpathway is highly upregulated and activated in astrocytesfollowing neuronal injury [163] Activation of the EGFRpathway triggers quiescent astrocytes to become reactiveastrocytes that appear to be destructive to neurons in theadult CNS [163] Regulation of RTKs such as EGFR in


astrocytesmay be a new therapeutic strategy for the treatmentof neural disorders These studies suggest that growth factorRTKs may play a pivotal role in mediating inflammatorygenes regulation through ROS signal in several diseasesincluding the CNS disorders (Figure 5)

63 Phosphoinositide-31015840-Kinase (PI3K)Akt Cascade Thephosphoinositide-31015840-kinase (PI3K)Akt cascade the com-mon downstream signal of EGF and PDGF receptors is acell survival pathway and regulated by various growth factorreceptor-dependent mechanisms Recent studies suggestedthat numerous components of the PI3KAkt pathway play acrucial role in the expression and activation of inflammatorymediators inflammatory cell recruitment immune cellfunction and tissue remodeling in chronic inflammatorydiseases In astrocytes we demonstrated that ET-1 inducediNOS expression and NO production through PI3KAktcascade [26] Moreover PI3KAkt cascade contributes tothe expression of various inflammatory mediators inducedby several proinflammatory factors in brain cells includingastrocytes [125 127] Selective PI3K inhibitors such aswortmannin and LY294002 have been developed thatreduce inflammation and some characteristics of disease inexperimental animal models In addition ROS induction isoften accompanied by the activation of PI3KAkt cascade Forexample LY294002 has been shown to reduce chemokine-induced ROS generation in phagocytes [164] which wasfurther confirmed by studies using PI3K knockout miceMany studies have indicated the ROS generation inducedby cytokines PDGF or VEGF in several cell types which isreduced by inhibition of PI3K activity suggesting that PI3Kis involved in the ROS production induced by cytokinesand growth factors In addition to the role of PI3KAktcascade in ROS production several reports support that theopposite hierarchical relationship exists between ROS andPI3KAkt cascade PI3KAkt was activated in response tothe exogenous treatment of H

2O2in several cell types [165]

Moreover ROS have been shown to regulate phosphorylationof Akt [166] and then induce the expression of inflammatorygenes associated with inflammation in various cell typesTaken together these results implicate that ROS-dependentPI3KAkt cascade or PI3KAkt-mediated ROS signal maybe critical for regulating the expression of inflammatoryproteins in the brain inflammation and neurodegenerativedisorders (Figure 5)

64 Transcription Factors The progressive increase of oxida-tive stress during injuries not only causes oxidative damageto cellular macromolecules but also modulates the pattern ofgene expression through functional alterations of transcrip-tion factors Here we focus on the roles of many transcriptionfactors (eg NF-120581B and AP-1) which are well known to bemodulated during oxidative stress associated with physiolog-ical and pathological events [32] The transcription factorssuch as NF-120581B and AP-1 play a key role in the regula-tion of several gene expressions including proinflammatorycytokines adhesion molecules chemokines growth factorsand inducible enzymes (eg MMPs cPLA

2 COX-2 and

iNOS) during inflammation immunity cell proliferation

stress response and apoptosis [167ndash169] One important andwidely investigated transcription factor which is NF-120581B is amajor participant in signaling pathways governing cellularresponses to environmental (oxidative) stresses [168] Thenuclear translocation and activation of NF-120581B in responseto various stimuli such as proinflammatory cytokines LPSand oxidative challenge (ROS production) are sequentiallyorganized at the molecular level [168] Moreover NF-120581B actas a positive regulator in the expression of many inflamma-tory genes such as COX-2 involved in chronic inflammatorydiseases [169] Cytokines such as IL-1120573 and TNF-120572 have beenshown to activate NF-120581B leading to upregulation of variousNF-120581B-dependent genes in several cell types [168] It is ofinterest that many of the genes regulated by these MAPKpathways are dependent on NF-120581B for transcription and leadto expression of inflammatory genes such as MMP-9 at thetranscriptional level [169 170] In astrocytes various stimulican induce the expression of several inflammatorymediatorsincluding MMP-9 cPLA

2 COX-2 and iNOS through ROS-

mediated activation of NF-120581B manner [40 62]In addition activator protein-1 (AP-1) is a sequence-

specific transcriptional activator mainly composed of mem-bers of the Fos Jun and ATF-2 families These proteinsassociate to form a variety of homodimers or heterodimersthat bind to an AP-1 binding element within the promoterregion of inflammatory genes such as COX-2 and MMP-9 It is a well-known redox-regulated transcription factorfor the expression of several AP-1-dependent genes inducedby diverse stress signals such as ROS generation associatedwith physiological and pathological events [25 62 170]Several reports indicate that AP-1 is also involved in thepathogenesis of brain inflammation (Figure 5) Many studieshave demonstrated that ROS signals (eg O

2

∙minus and H2O2)

contribute to the expression or activation of AP-1 proteins(eg c-Fos) [62] Recently Kim et al demonstrated that apoc-ynin (a Nox inhibitor) shows potential antioxidant activitiesand inhibitory effects on the activation of redox-sensitivetranscription factors such as AP-1 induced by proinflam-matory stimuli such as TNF-120572 [171] The reports indicatethat CSE induces cPLA

2expression through the production

of ROS and subsequent activation of the MAPK pathwayand AP-1 in human tracheal smooth muscle cells [172] Inastrocytes we have demonstrated that AP-1 participates inthe expression of several genes including MMP-9 and HO-1 by BK through ROS-dependent manner [25 62] Theseresults implicate that ROS play a central role in regulatingAP-1 activation or expression and lead to inflammatory genesexpression in brain inflammation and neurodegenerativedisorders (Figure 5)

65 TranscriptionCoactivators The transcription coactivatorp300CREB binding protein (CBP) is vital for the coacti-vation of several transcription factors such as NF-120581B andAP-1 in the transcription machinery which has a significantrole in the activation of transcription factor-mediated geneexpression for proinflammatory factors [173ndash175] The p300protein is a key regulator of RNA polymerase II-mediatedtranscription Several studies indicate that p300 participatesin the expression of inflammatory genes induced by cytokines


and growth factors Furthermore the transcriptional cofactorp300CBP is an important component of the transcriptionalmachinery that participates in regulation at the levels ofboth chromatin modification and transcription initiation[173ndash175] Previous studies have indicated that the promoterof several gene transcriptions chromatin remodeling andhistone modification is regulated by p300CBP [175] How-ever in astrocytes the p300 is vital for the coactivation ofseveral transcription factors such as AP-1 in the transcriptionmachinery which has a significant role in the activation ofAP-1-mediated gene expression for proinflammatory medi-ators [173] Previous results have indicated that p300 playsan important role in BK- IL-1120573- and oxLDL-inducedMMP-9 expression in astrocytes [21 22 96] Recently a studyhas shown that ROS-dependent p300 activation leads tocPLA2expression by cigarette smoke extract in human

tracheal smooth muscle cells [172] Consistently we havedemonstrated that LTA induces p300AP-1-dependentMMP-9 expression via ROS-mediated pathway in astrocytes [27]Moreover oxidative stress activates NF-120581B resulting in theexpression of proinflammatory mediators through the acti-vation of intrinsic HAT activity on coactivator moleculesOxidative stress also inhibits HDAC activity and in doingso enhances the expression of inflammatory genes whichleads to a chronic inflammatory response Oxidative stresscan also increase complex formation between the coactivatorp300 and the p65 subunit of NF-120581B suggesting a further roleof oxidative stress in chromatin remodeling [1] Togetherthese studies indicate that the oxidative stress-stimulatedcoactivator p300 may play a critical role in the expression ofinflammatory genes during brain inflammation andneurode-generative disorders

7 Conclusions

Glial cells maintain brain plasticity and protect the brainfor functional recovery from injuries Reactivation of glialcells may promote neuroinflammation and neurodegenera-tion (Figure 1) and ultimately the retraction of neuronalsynapses which leads to cognitive deficits [10] Moreoverredox signaling is a critical event in several inflammatorydiseases such as AD that precedes the formation of thesedisease pathologies To date although numerous effectshave been made to develop therapies based on antioxidantsin the past years the actual benefits to the patients havebeen very limited It is likely due to lack of potency lateadministration and poor penetration into the brain cells [732] Alternative strategies including searching for factors thatinitiate endogenous antioxidants are necessary to improvethe efficacy of treatment (Figure 2) Moreover increasedoxidative stresses (ROS) by various proinflammatory factorssuch as cytokines peptides bacterial or viral infectionsperoxidants and other stress serve as intracellular signalsin gene regulation and signaling transduction in additionto their deleterious effects on cellular components Thusunderstanding how oxidative stress produces and modulatesexpression of several genes that might help to develop effec-tively therapeutic strategies for CNS diseases First the focus

of this review is on glial cells and their effects on the CNSdisorders Moreover this review summarized the interplaybetween oxidative stress and neuroinflammation via ROSproduction which contributes to neurodegeneration therebyenhancing disease progression based on data collected frombrain cells particularly astrocytes in in vitro and in vivostudies (Figure 1) Perhaps modifying the activity of glialcells to reduce their neurotoxic properties and enhance theirneuroprotective effects may offer potential targets for thera-peutic interventions in neurodegenerative diseasesOxidativestress-induced signaling transduction pathways includingROS transactivation of EGFRor PDGFR PI3KAktMAPKsNF-120581B and AP-1 that are associated with the CNS disorderswere discussed (Figure 4) Moreover the review highlightedcurrent progress on the association of oxidative stresswith theexpression of various inflammatory genes including MMP-9 cPLA

2 COX-2 iNOS and adhesion molecules and redox

signal-sensitive transcription factors that may contribute tothe development of the CNS inflammation and neurode-generative diseases (Figure 5) Possible therapeutic strategiesto target redox-sensitive signaling molecules transcriptionfactors or cofactors are implicated based on the updated viewof ROS-mediated regulation of inflammatory target genes inbrain inflammation and neurodegenerative disorders

Abbreviations

ROS Reactive oxygen speciesCNS Central nervous systemAD Alzheimerrsquos diseasePD Parkinsonrsquos diseaseMMPs Matrix metalloproteinasescPLA2 Cytosolic phospholipase A

2

COX-2 Cyclooxygenase-2Nox2 NADPH oxidase 2iNOS Inducible nitric oxide synthaseLPS LipopolysaccharideIL-1120573 Interleukin-1TNF-120572 Tumor necrosis factor-120572BBB Blood-brain barrierTLRs Toll-like receptorsPGs ProstaglandinsNO Nitric oxideA120573 120573-AmyloidBK BradykininET-1 Endothelin-1oxLDL Oxidized low-density lipoproteinHO-1 Heme oxygenase-1CO Carbon monoxideRNS Reactive nitrogen speciesXox Xanthine oxidaseGPCR G-Protein-coupled receptorLTA Lipoteichoic acidJEV Japanese encephalitis virusEV71 Enterovirus 71AA Arachidonic acidVCAM-1 Vascular cell adhesion molecule 1MAPKs Mitogen-activated protein kinasesERKs Extracellular signal-regulated protein kinases


JNKs c-Jun NH2-terminal kinases

EGFR Epidermal growth factor receptorRTKs Receptor tyrosine kinasesPDGFR Platelet-derived growth factor receptorPI3K Phosphoinositide-31015840-kinaseNF-120581B Nuclear factor-120581BAP-1 Activator protein 1CREB Cyclic AMP-response element binding

proteinCBP CREB binding protein

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgments

This work was supported by National Science CouncilTaiwan Grant nos NSC102-2321-B-182-011 NSC101-2320-B-182-039-MY3 and NSC102-2320-B-255-005-MY3 Chang Gung Medical Research Foundation Grantnos CMRPD1C0101 CMRPD1B0382 CMRPD1C0561CMRPF1C0191 and CMRPF1A0063 and the Ministryof Education Taiwan Grant nos EMRPD1C0261 andEMRPD1C0271

References

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

[3] I T Lee and C M Yang ldquoRole of NADPH oxidaseROS inpro-inflammatory mediators-induced airway and pulmonarydiseasesrdquo Biochemical Pharmacology vol 84 no 5 pp 581ndash5902012

[4] W Droge ldquoFree radicals in the physiological control of cellfunctionrdquo Physiological Reviews vol 82 no 1 pp 47ndash95 2002

[5] R von Bernhardi and J Eugenın ldquoAlzheimerrsquos disease redoxdysregulation as a commondenominator for diverse pathogenicmechanismsrdquo Antioxidants and Redox Signaling vol 16 no 9pp 974ndash1031 2012

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

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

[8] A Melo L Monteiro R M F Lima D M de OliveiraM D de Cerqueira and R S El-Bacha ldquoOxidative stressin neurodegenerative diseases mechanisms and therapeuticperspectivesrdquo Oxidative Medicine and Cellular Longevity vol2011 Article ID 467180 14 pages 2011

[9] V Chiurchiu and M MacCarrone ldquoChronic inflammatorydisorders and their redox control from molecular mechanisms

to therapeutic opportunitiesrdquoAntioxidants andRedox Signalingvol 15 no 9 pp 2605ndash2641 2011

[10] D Farfara V Lifshitz and D Frenkel ldquoNeuroprotective andneurotoxic properties of glial cells in the pathogenesis ofAlzheimerrsquos disease Alzheimerrsquos review seriesrdquo Journal of Cel-lular and Molecular Medicine vol 12 no 3 pp 762ndash780 2008

[11] S Fuller M Steele and G Munch ldquoActivated astroglia duringchronic inflammation in Alzheimerrsquos disease-Do they neglecttheir neurosupportive rolesrdquo Mutation Research vol 690 no1-2 pp 40ndash49 2010

[12] H K Kimelberg ldquoReceptors on astrocytesmdashwhat possiblefunctionsrdquo Neurochemistry International vol 26 no 1 pp 27ndash40 1995

[13] L F Eng and R S Ghirnikar ldquoGFAP and astrogliosisrdquo BrainPathology vol 4 no 3 pp 229ndash237 1994

[14] Y S Kim and T H Joh ldquoMicroglia major player in the braininflammation their roles in the pathogenesis of Parkinsonrsquosdiseaserdquo Experimental and Molecular Medicine vol 38 no 4pp 333ndash347 2006

[15] M Eddelston and L Mucke ldquoMolecular profile of reactiveastrocytesmdashimplications for their role in neurologic diseaserdquoNeuroscience vol 54 no 1 pp 15ndash36 1993

[16] J L Ridet S K Malhotra A Privat and F H Gage ldquoReactiveastrocytes cellular and molecular cues to biological functionrdquoTrends in Neurosciences vol 20 no 12 pp 570ndash577 1997

[17] G C Brown ldquoMechanisms of inflammatory neurodegenera-tion INOS and NADPH oxidaserdquo Biochemical Society Transac-tions vol 35 no 5 pp 1119ndash1121 2007

[18] M Koistinaho M I Kettunen G Goldsteins et al ldquo120573-amyloidprecursor protein transgenic mice that harbor diffuse A120573deposits but do not form plaques show increased ischemicvulnerability role of inflammationrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no3 pp 1610ndash1615 2002

[19] M J Savage Y-G Lin J R Ciallella D G Flood and RW Scott ldquoActivation of c-Jun N-Terminal Kinase and p38 inan Alzheimerrsquos Disease Model Is Associated with AmyloidDepositionrdquoThe Journal of Neuroscience vol 22 no 9 pp 3376ndash3385 2002

[20] R E Mrak J G Sheng and W S T Griffin ldquoGlial cytokinesin Alzheimerrsquos disease review and pathogenic implicationsrdquoHuman Pathology vol 26 no 8 pp 816ndash823 1995

[21] C-Y Wu H-L Hsieh C-C Sun C-P Tseng and C-M YangldquoIL-1120573 induces proMMP-9 expression via c-Src-dependentPDGFRPI3KAktp300 cascade in rat brain astrocytesrdquo Jour-nal of Neurochemistry vol 105 no 4 pp 1499ndash1512 2008

[22] H-L Hsieh C-Y Wu and C-M Yang ldquoBradykinin inducesmatrix metalloproteinase-9 expression and cell migrationthrough a PKC-120575-dependent ERKElk-1 pathway in astrocytesrdquoGlia vol 56 no 6 pp 619ndash632 2008

[23] H-L Hsieh C-Y Wu T-L Hwang M-H Yen P Parkerand C-M Yang ldquoBK-induced cytosolic phospholipase A2expression via sequential PKC-120575 p42p44 MARK and NF-120581Bactivation in rat brain astrocytesrdquo Journal of Cellular Physiologyvol 206 no 1 pp 246ndash254 2006

[24] H-L Hsieh H-H Wang C-Y Wu et al ldquoBK-induced COX-2expression via PKC-120575-dependent activation of p42p44 MAPKand NF-120581B in astrocytesrdquo Cellular Signalling vol 19 no 2 pp330ndash340 2007

[25] C C Lin H L Hsieh R H Shih et al ldquoNADPH oxi-dase 2-derived reactive oxygen species signal contributes


to bradykinin-induced matrix metalloproteinase-9 expressionand cell migration in brain astrocytesrdquoCell Communication andSignaling vol 10 no 1 p 35 2012

[26] H-H Wang H-L Hsieh and C-M Yang ldquoNitric oxideproduction by endothelin-1 enhances astrocytic migration viathe tyrosine nitration of matrix metalloproteinase-9rdquo Journal ofCellular Physiology vol 226 no 9 pp 2244ndash2256 2011

[27] H L Hsieh C C Lin R H Shih L D Hsiao and CM Yang ldquoNADPH oxidase-mediated redox signal contributesto lipoteichoic acid-induced MMP-9 upregulation in brainastrocytesrdquo Journal of Neuroinflammation vol 9 p 110 2012

[28] W-H Tung H-W Tsai I-T Lee et al ldquoJapanese encephalitisvirus inducesmatrixmetalloproteinase-9 in rat brain astrocytesvia NF-ΚB signalling dependent on MAPKs and reactiveoxygen speciesrdquo British Journal of Pharmacology vol 161 no7 pp 1566ndash1583 2010

[29] H-H Wang H-L Hsieh C-Y Wu C-C Sun and C-MYang ldquoOxidized low-density lipoprotein induces matrixmetalloproteinase-9 expression via a p42p44 and JNK-dependent AP-1 pathway in brain astrocytesrdquo Glia vol 57 no1 pp 24ndash38 2009

[30] C M Yang H L Hsieh C C Lin et al ldquoMultiple factors frombradykinin-challenged astrocytes contribute to the neuronalapoptosis involvement of astroglial ROS MMP-9 and HO-1CO systemrdquo Molecular Neurobiology vol 47 no 3 pp 1020ndash1033 2013

[31] S Chrissobolis and F M Faraci ldquoThe role of oxidative stressand NADPH oxidase in cerebrovascular diseaserdquo Trends inMolecular Medicine vol 14 no 11 pp 495ndash502 2008

[32] Q Shi and G E Gibson ldquoOxidative stress and transcriptionalregulation in Alzheimer diseaserdquo Alzheimer Disease and Asso-ciated Disorders vol 21 no 4 pp 276ndash291 2007

[33] I T Demchenko T D Oury J D Crapo and C A PiantadosildquoRegulation of the brainrsquos vascular responses to oxygenrdquo Circu-lation Research vol 91 no 11 pp 1031ndash1037 2002

[34] P H Chan ldquoReactive oxygen radicals in signaling and damagein the ischemic brainrdquo Journal of Cerebral Blood Flow andMetabolism vol 21 no 1 pp 2ndash14 2001

[35] F Serrano and E Klann ldquoReactive oxygen species and synapticplasticity in the aging hippocampusrdquo Ageing Research Reviewsvol 3 no 4 pp 431ndash443 2004

[36] H Kamata and H Hirata ldquoRedox regulation of cellular sig-nallingrdquo Cellular Signalling vol 11 no 1 pp 1ndash14 1999

[37] A Federico E Cardaioli P da Pozzo P Formichi G N Gallusand E Radi ldquoMitochondria oxidative stress and neurodegener-ationrdquo Journal of the Neurological Sciences vol 322 no 1-2 pp254ndash262 2012

[38] J Kang E J Park I Jou J-H Kim and E-H Joe ldquoReactiveoxygen species mediate A120573(25-35)-induced activation of BV-2microgliardquo NeuroReport vol 12 no 7 pp 1449ndash1452 2001

[39] L Qin Y Liu T Wang et al ldquoNADPH oxidase mediateslipopolysaccharide-induced neurotoxicity and proinflamma-tory gene expression in activated microgliardquo The Journal ofBiological Chemistry vol 279 no 2 pp 1415ndash1421 2004

[40] H-L Hsieh H-H Wang W-B Wu P-J Chu and C-MYang ldquoTransforming growth factor-1205731 induces matrixmetalloproteinase-9 and cell migration in astrocytes roles ofROS-dependent ERK- and JNK-NF-120581B pathwaysrdquo Journal ofNeuroinflammation vol 7 article 88 2010

[41] P L McGeer and E G McGeer ldquoThe inflammatory responsesystemof brain implications for therapy ofAlzheimer and other

neurodegenerative diseasesrdquoBrain Research Reviews vol 21 no2 pp 195ndash218 1995

[42] G A Rosenberg ldquoMatrix metalloproteinases in neuroinflam-mationrdquo Glia vol 39 no 3 pp 279ndash291 2002

[43] H Fillit W Ding L Buee et al ldquoElevated circulating tumornecrosis factor levels in Alzheimerrsquos diseaserdquo NeuroscienceLetters vol 129 no 2 pp 318ndash320 1991

[44] S M Allan P J Tyrrell and N J Rothwell ldquoInterleukin-1 andneuronal injuryrdquo Nature Reviews Immunology vol 5 no 8 pp629ndash640 2005

[45] K Fassbender S Rossol T Kammer et al ldquoProinflammatorycytokines in serum of patients with acute cerebral ischemiakinetics of secretion and relation to the extent of brain damageand outcome of diseaserdquo Journal of the Neurological Sciencesvol 122 no 2 pp 135ndash139 1994

[46] J A Smith A Das S K Ray and N L Banik ldquoRole of pro-inflammatory cytokines released from microglia in neurode-generative diseasesrdquo Brain Research Bulletin vol 87 no 1 pp10ndash20 2012

[47] D A Siwik and W S Colucci ldquoRegulation of matrix metallo-proteinases by cytokines and reactive oxygennitrogen speciesin the myocardiumrdquoHeart Failure Reviews vol 9 no 1 pp 43ndash51 2004

[48] P Thornton E Pinteaux R M Gibson S M Allan and N JRothwell ldquoInterleukin-1-induced neurotoxicity is mediated byglia and requires caspase activation and free radical releaserdquoJournal of Neurochemistry vol 98 no 1 pp 258ndash266 2006

[49] N H Greig M P Mattson T Perry et al ldquoNew therapeuticstrategies and drug candidates for neurodegenerative diseasesp53 and TNF-120572 inhibitors andGLP-1 receptor agonistsrdquoAnnalsof the New York Academy of Sciences vol 1035 pp 290ndash3152004

[50] D A Butterfield J Drake C Pocernich and A Castegna ldquoEvi-dence of oxidative damage in Alzheimerrsquos disease brain centralrole for amyloid 120573-peptiderdquo Trends in Molecular Medicine vol7 no 12 pp 548ndash554 2001

[51] C Caspersen N Wang J Yao et al ldquoMitochondrial A120573 apotential focal point for neuronal metabolic dysfunction inAlzheimerrsquos diseaserdquo The FASEB Journal vol 19 no 14 pp2040ndash2041 2005

[52] VDella Bianca SDusi E Bianchini I Dal Pra and F Rossi ldquo120573-amyloid activates theOminus

2formingNADPHoxidase inmicroglia

monocytes and neutrophils A possible inflammatory mecha-nism of neuronal damage in Alzheimerrsquos diseaserdquoThe Journal ofBiological Chemistry vol 274 no 22 pp 15493ndash15499 1999

[53] G P Lim T Chu F Yang W Beech S A Frautschy and GM Cole ldquoThe curry spice curcumin reduces oxidative damageand amyloid pathology in an Alzheimer transgenic mouserdquoTheJournal of Neuroscience vol 21 no 21 pp 8370ndash8377 2001

[54] Q Ding E Dimayuga and J N Keller ldquoOxidative damage pro-tein synthesis and protein degradation in Alzheimerrsquos diseaserdquoCurrent Alzheimer Research vol 4 no 1 pp 73ndash79 2007

[55] H M Schipper D A Bennett A Liberman et al ldquoGlial hemeoxygenase-1 expression inAlzheimer disease andmild cognitiveimpairmentrdquo Neurobiology of Aging vol 27 no 2 pp 252ndash2612006

[56] T Kamiya Y Katayama F Kashiwagi and A Terashi ldquoTherole of bradykinin in mediating ischemic brain edema in ratsrdquoStroke vol 24 no 4 pp 571ndash576 1993

[57] A Verkhratsky R K Orkand and H Kettenmann ldquoGlialcalcium homeostasis and signaling functionrdquo PhysiologicalReviews vol 78 no 1 pp 99ndash141 1998


[58] D Regoli N-E Rhaleb SDion andGDrapeau ldquoNew selectivebradykinin receptor antagonists and bradykinin B2 receptorcharacterizationrdquoTrends in Pharmacological Sciences vol 11 no4 pp 156ndash161 1990

[59] K D Bhoola C D Figueroa and K Worthy ldquoBioregulation ofkinins kallikreins kininogens and kininasesrdquo PharmacologicalReviews vol 44 no 1 pp 1ndash80 1992

[60] C-W Lin S-C Shen C-C Chien L-Y Yang L-T Shia andY-C Chen ldquo12-O-tetradecanoylphorbol-13-acetate-inducedinvasionmigration of glioblastoma cells through activatingPKC120572ERKNF-120581B-dependent MMP-9 expressionrdquo Journal ofCellular Physiology vol 225 no 2 pp 472ndash481 2010

[61] A Y Abramov J Jacobson F Wientjes J Hothersall LCanevari and M R Duchen ldquoExpression and modulation ofan NADPH oxidase in mammalian astrocytesrdquo The Journal ofNeuroscience vol 25 no 40 pp 9176ndash9184 2005

[62] H-L Hsieh H-H Wang C-Y Wu and C-M Yang ldquoReactiveoxygen species-dependent c-fosactivator protein 1 inductionupregulates heme oxygenase-1 expression by bradykinin inbrain astrocytesrdquo Antioxidants and Redox Signaling vol 13 no12 pp 1829ndash1844 2010

[63] E R Levin ldquoEndothelinsrdquo The New England Journal ofMedicine vol 333 no 6 pp 356ndash363 1995

[64] S Schinelli ldquoPharmacology and physiopathology of the brainendothelin system an overviewrdquo Current Medicinal Chemistryvol 13 no 6 pp 627ndash638 2006

[65] F Bohm and J Pernow ldquoThe importance of endothelin-1 forvascular dysfunction in cardiovascular diseaserdquo CardiovascularResearch vol 76 no 1 pp 8ndash18 2007

[66] M Hasselblatt P Lewczuk B-M Loffler et al ldquoRole ofthe astrocytic ETB receptor in the regulation of extracellularendothelin-1 during hypoxiardquo Glia vol 34 no 1 pp 18ndash262001

[67] S D Rogers C M Peters J D Pomonis H Hagiwara JR Ghilardi and P W Mantyh ldquoEndothelin B receptors areexpressed by astrocytes and regulate astrocyte hypertrophy inthe normal and injured CNSrdquo Glia vol 41 no 2 pp 180ndash1902003

[68] A C Y Lo A Y S Chen V K L Hung et al ldquoEndothelin-1overexpression leads to further water accumulation and brainedema after middle cerebral artery occlusion via aquaporin4 expression in astrocytic end-feetrdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 8 pp 998ndash1011 2005

[69] N Didier I A Romero C Creminon A Wijkhuisen J Grassiand A Mabondzo ldquoSecretion of interleukin-1120573 by astrocytesmediates endothelin-1 and tumour necrosis factor-120572 effectson human brain microvascular endothelial cell permeabilityrdquoJournal of Neurochemistry vol 86 no 1 pp 246ndash254 2003

[70] S J Lee and S Lee ldquoToll-like receptors and inflammation in theCNSrdquo Current Drug Targets Inflammation amp Allergy vol 1 no2 pp 181ndash191 2002

[71] S-Y Kim J-G Lee W-S Cho et al ldquoRole of NADPHoxidase-2 in lipopolysaccharide-induced matrix metallopro-teinase expression and cell migrationrdquo Immunology and CellBiology vol 88 no 2 pp 197ndash204 2010

[72] G W Konat T Kielian and I Marriott ldquoThe role of Toll-likereceptors in CNS response to microbial challengerdquo Journal ofNeurochemistry vol 99 no 1 pp 1ndash12 2006

[73] I C Sutcliffe and N Shaw ldquoAtypical lipoteichoic acids of gram-positive bacteriardquo Journal of Bacteriology vol 173 no 22 pp7065ndash7069 1991

[74] X Saez-Llorens and G H McCracken Jr ldquoBacterial meningitisin childrenrdquoThe Lancet vol 361 no 9375 pp 2139ndash2148 2003

[75] S C Mullaly and P Kubes ldquoThe role of TLR2 in vivo followingchallenge with Staphylococcus aureus and prototypic ligandsrdquoThe Journal of Immunology vol 177 no 11 pp 8154ndash8163 2006

[76] J A Mitchell M J Paul-Clark G W Clarke S K McMasterand N Cartwright ldquoCritical role of toll-like receptors andnucleotide oligomerisation domain in the regulation of healthand diseaserdquo Journal of Endocrinology vol 193 no 3 pp 323ndash330 2007

[77] A Kinsner V Pilotto S Deininger et al ldquoInflammatoryneurodegeneration induced by lipoteichoic acid from Staphy-lococcus aureus is mediated by glia activation nitrosative andoxidative stress and caspase activationrdquo Journal of Neurochem-istry vol 95 no 4 pp 1132ndash1143 2005

[78] S Lehnardt P Henneke E Lien et al ldquoA mechanism forneurodegeneration induced by group B Streptococci throughactivation of the TLR2MyD88 pathway in microgliardquo TheJournal of Immunology vol 177 no 1 pp 583ndash592 2006

[79] P A Carpentier D S Duncan and S D Miller ldquoGlial toll-like receptor signaling in central nervous system infection andautoimmunityrdquo Brain Behavior and Immunity vol 22 no 2pp 140ndash147 2008

[80] M Bsibsi J J Bajramovic E van Duijvenvoorden et al ldquoIden-tification of soluble CD14 as an endogenous agonist for toll-like receptor 2 on human astrocytes by genome-scale functionalscreening of glial cell derived proteinsrdquo Glia vol 55 no 5 pp473ndash482 2007

[81] C S Jack N Arbour J Manusow et al ldquoTLR signaling tailorsinnate immune responses in human microglia and astrocytesrdquoThe Journal of Immunology vol 175 no 7 pp 4320ndash4330 2005

[82] J J Neher and G C Brown ldquoNeurodegeneration in modelsof Gram-positive bacterial infections of the central nervoussystemrdquo Biochemical Society Transactions vol 35 no 5 pp1166ndash1167 2007

[83] P K Chatterjee K Zacharowski S Cuzzocrea et alldquoLipoteichoic acid from Staphylococcus aureus reducesrenal ischemiareperfusion injuryrdquo Kidney International vol62 no 4 pp 1249ndash1263 2002

[84] G Palacios and M S Oberste ldquoEnteroviruses as agents ofemerging infectious diseasesrdquo Journal of NeuroVirology vol 11no 5 pp 424ndash433 2005

[85] P C McMinn ldquoAn overview of the evolution of enterovirus 71and its clinical and public health significancerdquo FEMS Microbi-ology Reviews vol 26 no 1 pp 91ndash107 2002

[86] C-C Huang C-C Liu Y-C Chang C-Y Chen S-T Wangand T-F Yeh ldquoNeurologic complications in children withenterovirus 71 infectionrdquoThe New England Journal of Medicinevol 341 no 13 pp 936ndash942 1999

[87] MHo E-R Chen K-HHsu et al ldquoAn epidemic of enterovirus71 infection in Taiwanrdquo The New England Journal of Medicinevol 341 no 13 pp 929ndash935 1999

[88] W-H Tung H-L Hsieh I-T Lee and C-M YangldquoEnterovirus 71 induces integrin 1205731EGFR-Rac1-dependentoxidative stress in SK-N-SH cells role of HO-1CO in viralreplicationrdquo Journal of Cellular Physiology vol 226 no 12 pp3316ndash3329 2011

[89] U K Misra and J Kalita ldquoOverview Japanese encephalitisrdquoProgress in Neurobiology vol 91 no 2 pp 108ndash120 2010


[90] S-L Raung S-Y Chen S-L Liao J-H Chen and C-JChen ldquoTyrosine kinase inhibitors attenuate Japanese encephali-tis virus-induced neurotoxicityrdquo Biochemical and BiophysicalResearch Communications vol 327 no 2 pp 399ndash406 2005

[91] M K Mishra P Koli S Bhowmick and A Basu ldquoNeuropro-tection conferred by astrocytes is insufficient to protect animalsfrom succumbing to Japanese encephalitisrdquo NeurochemistryInternational vol 50 no 5 pp 764ndash773 2007

[92] T J Montine K S Montine and L L Swift ldquoCentral nervoussystem lipoproteins inAlzheimerrsquos diseaserdquoAmerican Journal ofPathology vol 151 no 6 pp 1571ndash1575 1997

[93] J N Keller K B Hanni and W R Markesbery ldquoOxidizedlow-density lipoprotein induces neuronal death implicationsfor calcium reactive oxygen species and caspasesrdquo Journal ofNeurochemistry vol 72 no 6 pp 2601ndash2609 1999

[94] F-S Shie M D Neely I Maezawa et al ldquoOxidized low-density lipoprotein is present in astrocytes surrounding cerebralinfarcts and stimulates astrocyte interleukin-6 secretionrdquoAmer-ican Journal of Pathology vol 164 no 4 pp 1173ndash1181 2004

[95] M Uno M Harada O Takimoto et al ldquoElevation of plasmaoxidized LDL in acute stroke patients is associated withischemic lesions depicted by DWI and predictive of infarctenlargementrdquo Neurological Research vol 27 no 1 pp 94ndash1022005

[96] H-HWang H-L Hsieh C-YWu and C-M Yang ldquoOxidizedlow-density lipoprotein-induced matrix metalloproteinase-9expression via PKC-120575p42p44 MAPKElk-1 cascade in brainastrocytesrdquoNeurotoxicity Research vol 17 no 1 pp 50ndash65 2010

[97] P Ten Dijke and C S Hill ldquoNew insights into TGF-120573-Smadsignallingrdquo Trends in Biochemical Sciences vol 29 no 5 pp265ndash273 2004

[98] J Massague ldquoHow cells read TGF-120573 signalsrdquo Nature ReviewsMolecular Cell Biology vol 1 no 3 pp 169ndash178 2000

[99] S-K Leivonen A Chantry L Hakkinen J Han and V-M Kahari ldquoSmad3 mediates transforming growth factor-120573-induced collagenase-3 (matrix metalloproteinase-13) expres-sion in human gingival fibroblasts evidence for cross-talkbetween Smad3 and p38 signaling pathwaysrdquo The Journal ofBiological Chemistry vol 277 no 48 pp 46338ndash46346 2002

[100] K Koli M Myllarniemi J Keski-Oja and V L KinnulaldquoTransforming growth factor-120573 activation in the lung focus onfibrosis and reactive oxygen speciesrdquo Antioxidants and RedoxSignaling vol 10 no 2 pp 333ndash342 2008

[101] F Zipp and O Aktas ldquoThe brain as a target of inflammationcommon pathways link inflammatory and neurodegenerativediseasesrdquo Trends in Neurosciences vol 29 no 9 pp 518ndash5272006

[102] A Vezzani and T Granata ldquoBrain inflammation in epilepsyexperimental and clinical evidencerdquo Epilepsia vol 46 no 11 pp1724ndash1743 2005

[103] A Simi N Tsakiri P Wang and N J Rothwell ldquoInterleukin-1 and inflammatory neurodegenerationrdquo Biochemical SocietyTransactions vol 35 no 5 pp 1122ndash1126 2007

[104] V W Yong C A Krekoski P A Forsyth R Bell and D REdwards ldquoMatrix metalloproteinases and diseases of the CNSrdquoTrends in Neurosciences vol 21 no 2 pp 75ndash80 1998

[105] V W Yong C Power P Forsyth and D R Edwards ldquoMetal-loproteinases in biology and pathology of the nervous systemrdquoNature Reviews Neuroscience vol 2 no 7 pp 502ndash511 2001

[106] P E Gottschall and X Yu ldquoCytokines regulate gelatinase A andB (matrix metalloproteinase 2 and 9) activity in cultured rat

astrocytesrdquo Journal of Neurochemistry vol 64 no 4 pp 1513ndash1520 1995

[107] W J Lee C Y Shin B K Yoo et al ldquoInduction ofmatrix metalloproteinase-9 (MMP-9) in lipopolysaccharide-stimulated primary astrocytes is mediated by extracellularsignal-regulated protein kinase 12 (Erk12)rdquo Glia vol 41 no1 pp 15ndash24 2003

[108] M Hernandez M L Nieto andM Sanchez Crespo ldquoCytosolicphospholipase A2 and the distinct transcriptional programs ofastrocytoma cellsrdquo Trends in Neurosciences vol 23 no 6 pp259ndash264 2000

[109] I Kudo and M Murakami ldquoPhospholipase A2enzymesrdquo

Prostaglandins and Other Lipid Mediators vol 68-69 pp 3ndash582002

[110] J Y Park M H Pillinger and S B Abramson ldquoProstaglandinE2 synthesis and secretion the role of PGE2 synthasesrdquo ClinicalImmunology vol 119 no 3 pp 229ndash240 2006

[111] J Xu M Chalimoniuk Y Shu et al ldquoProstaglandin E2 produc-tion in astrocytes regulation by cytokines extracellular ATPand oxidative agentsrdquo Prostaglandins Leukotrienes and EssentialFatty Acids vol 69 no 6 pp 437ndash448 2003

[112] C C Leslie ldquoProperties and regulation of cytosolic phospho-lipase A2rdquo The Journal of Biological Chemistry vol 272 no 27pp 16709ndash16712 1997

[113] G Y Sun J Xu M D Jensen et al ldquoPhospholipase A2 inastrocytes responses to oxidative stress inflammation andG protein-coupled receptor agonistsrdquo Molecular Neurobiologyvol 31 no 1ndash3 pp 27ndash41 2005

[114] D Stephenson K Rash B Smalstig et al ldquoCytosolic phospho-lipase A2 is induced in reactive glia following different forms ofneurodegenerationrdquo Glia vol 27 no 2 pp 110ndash128 1999

[115] M T Gentile M G Reccia P P Sorrentino et al ldquoRole ofcytosolic calcium-dependent phospholipase A2 in Alzheimerrsquosdisease pathogenesisrdquoMolecular Neurobiology vol 45 no 3 pp596ndash604 2012

[116] I Szaingurten-Solodkin N Hadad and R Levy ldquoRegulatoryrole of cytosolic phospholipase A2120572 in NADPH oxidase activityand in inducible nitric oxide synthase induction by aggregatedA1205731-42 in microgliardquo Glia vol 57 no 16 pp 1727ndash1740 2009

[117] C Guo J Li L Myatt X Zhu and K Sun ldquoInduction ofG120572s contributes to the paradoxical stimulation of cytosolicphospholipase A2120572 expression by cortisol in human amnionfibroblastsrdquo Molecular Endocrinology vol 24 no 5 pp 1052ndash1061 2010

[118] N G Bazan V Colangelo andW J Lukiw ldquoProstaglandins andother lipid mediators in Alzheimerrsquos diseaserdquo Prostaglandinsand Other Lipid Mediators vol 68-69 pp 197ndash210 2002

[119] C S Williams M Mann and R N DuBois ldquoThe role ofcyclooxygenases in inflammation cancer and developmentrdquoOncogene vol 18 no 55 pp 7908ndash7916 1999

[120] T A Samad K A Moore A Sapirstein et al ldquoInterleukin-1 120573-mediated induction of Cox-2 in the CNS contributes toinflammatory pain hypersensitivityrdquo Nature vol 410 no 6827pp 471ndash475 2001

[121] T Tanabe and N Tohnai ldquoCyclooxygenase isozymes and theirgene structures and expressionrdquo Prostaglandins and Other LipidMediators vol 68-69 pp 95ndash114 2002

[122] M Korotkova M Westman K R Gheorghe et al ldquoEffects ofantirheumatic treatments on the prostaglandin E2 biosyntheticpathwayrdquo Arthritis and Rheumatism vol 52 no 11 pp 3439ndash3447 2005


[123] K Ejima M D Layne I M Carvajal et al ldquoCyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammationand deathrdquo The FASEB Journal vol 17 no 10 pp 1325ndash13272003

[124] G Tocco J Freire-Moar S S Schreiber S H Sakhi P S Aisenand G M Pasinetti ldquoMaturational regulation and regionalinduction of cyclooxygenase-2 in rat brain implications forAlzheimerrsquos diseaserdquoExperimental Neurology vol 144 no 2 pp339ndash349 1997

[125] W-H Tung I-T Lee H-L Hsieh and C-M Yang ldquoEV71induces COX-2 expression via c-SrcPDGFRPI3KAktp42p44 MAPKAP-1 and NF-120581B in rat brain astrocytesrdquoJournal of Cellular Physiology vol 224 no 2 pp 376ndash386 2010

[126] W-H Tung H-L Hsieh I-T Lee and C-M Yang ldquoEnter-ovirus 71 modulates a COX-2PGE2cAMP-dependent viralreplication in human neuroblastoma cells role of the c-SrcEGFRp42p44 MAPKCREB signaling pathwayrdquo Journal ofCellular Biochemistry vol 112 no 2 pp 559ndash570 2011

[127] H L Hsieh C C Lin H J Chan C M Yang and C M Yangldquoc-Src-dependent EGF receptor transactivation contributesto ET-1-induced COX-2 expression in brain microvascularendothelial cellsrdquo Journal of Neuroinflammation vol 9 p 1522012

[128] D S Kim J Y Kim andYHan ldquoCurcuminoids in neurodegen-erative diseasesrdquo Recent Patents on CNS Drug Discovery vol 7no 3 pp 184ndash204 2012

[129] K J Smith and H Lassmann ldquoThe role of nitric oxide inmultiple sclerosisrdquoThe Lancet Neurology vol 1 no 4 pp 232ndash241 2002

[130] L H Barbeito M Pehar P Cassina et al ldquoA role for astrocytesin motor neuron loss in amyotrophic lateral sclerosisrdquo BrainResearch Reviews vol 47 no 1ndash3 pp 263ndash274 2004

[131] R N Saha and K Pahan ldquoRegulation of inducible nitric oxidesynthase gene in glial cellsrdquo Antioxidants and Redox Signalingvol 8 no 5-6 pp 929ndash947 2006

[132] E Galea D L Feinstein and D J Reis ldquoInduction of calcium-independent nitric oxide synthase activity in primary rat glialculturesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 89 no 22 pp 10945ndash10949 1992

[133] S Parmentier-Batteur G A Bohme D Lerouet et al ldquoAnti-sense oligodeoxynucleotide to inducible nitric oxide synthaseprotects against transient focal cerebral ischemia-induced braininjuryrdquo Journal of Cerebral Blood Flow and Metabolism vol 21no 1 pp 15ndash21 2001

[134] J Li O Baud T Vartanian J J Volpe and P A RosenbergldquoPeroxynitrite generated by inducible nitric oxide synthase andNADPH oxidase mediates microglial toxicity to oligodendro-cytesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 102 no 28 pp 9936ndash9941 2005

[135] S-H Choi E H Joe S U Kim and B K Jin ldquoThrombin-induced microglial activation produces degeneration of nigraldopaminergic neurons in vivordquoThe Journal of Neuroscience vol23 no 13 pp 5877ndash5886 2003

[136] T A Springer ldquoTraffic signals for lymphocyte recirculation andleukocyte emigration the multistep paradigmrdquo Cell vol 76 no2 pp 301ndash314 1994

[137] J M Cook-Mills ldquoVCAM-1 signals during lymphocyte migra-tion role of reactive oxygen speciesrdquo Molecular Immunologyvol 39 no 9 pp 499ndash508 2002

[138] L Osborn C Hession R Tizard et al ldquoDirect expressioncloning of vascular cell adhesionmolecule 1 a cytokine-induced

endothelial protein that binds to lymphocytesrdquo Cell vol 59 no6 pp 1203ndash1211 1989

[139] MMichalska LMachtoub HDManthey et al ldquoVisualizationof vascular inflammation in the atherosclerotic mouse byultrasmall superparamagnetic iron oxide vascular cell adhesionmolecule-1-specific nanoparticlesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 32 no 10 pp 2350ndash2357 2012

[140] C TangH-L Xue C-L Bai andR Fu ldquoRegulation of adhesionmolecules expression inTNF-120572-stimulated brainmicrovascularendothelial cells by tanshinone IIA involvement of NF-120581B andROS generationrdquo Phytotherapy Research vol 25 no 3 pp 376ndash380 2011

[141] H Y Song J Ryu S M Ju et al ldquoExtracellular HIV-1 Tatenhances monocyte adhesion by up-regulation of ICAM-1 andVCAM-1 gene expression via ROS-dependent NF-120581B activationin astrocytesrdquo Experimental andMolecularMedicine vol 39 no1 pp 27ndash37 2007

[142] M R Jacquier-Sarlin K Fuller A T Dinh-XuanM-J Richardand B S Polla ldquoProtective effects of hsp70 in inflammationrdquoExperientia vol 50 no 11-12 pp 1031ndash1038 1994

[143] P Aridon F Geraci G TurturiciMDrsquoamelio G Savettieri andG Sconzo ldquoProtective role of heat shock proteins in Parkinsonrsquosdiseaserdquo Neurodegenerative Diseases vol 8 no 4 pp 155ndash1682011

[144] W Luo W Sun T Taldone A Rodina and G Chiosis ldquoHeatshock protein 90 in neurodegenerative diseasesrdquo MolecularNeurodegeneration vol 5 no 1 article 24 2010

[145] S Patury Y Miyata and J E Gestwicki ldquoPharmacologicaltargeting of the Hsp70 chaperonerdquo Current Topics in MedicinalChemistry vol 9 no 15 pp 1337ndash1351 2009

[146] T Yamashima ldquoHsp701 and related lysosomal factors fornecrotic neuronal deathrdquo Journal of Neurochemistry vol 120no 4 pp 477ndash494 2012

[147] J M Kyriakis and J Avruch ldquoMammalian mitogen-activatedprotein kinase signal transduction pathways activated by stressand inflammationrdquo Physiological Reviews vol 81 no 2 pp 807ndash869 2001

[148] E A Irving and M Bamford ldquoRole of mitogen- and stress-activated kinases in ischemic injuryrdquo Journal of Cerebral BloodFlow and Metabolism vol 22 no 6 pp 631ndash647 2002

[149] S J Harper and P Lograsso ldquoSignalling for survival and deathin neurones the role of stress-activated kinases JNK and p38rdquoCellular Signalling vol 13 no 5 pp 299ndash310 2001

[150] K Hensley R A Floyd N-Y Zheng et al ldquop38 Kinase isactivated in the Alzheimerrsquos disease brainrdquo Journal of Neuro-chemistry vol 72 no 5 pp 2053ndash2058 1999

[151] J Hu K T Akama G A Krafft B A Chromy and L Jvan Eldik ldquoAmyloid-120573 peptide activates cultured astrocytesmorphological alterations cytokine induction and nitric oxidereleaserdquo Brain Research vol 785 no 2 pp 195ndash206 1998

[152] S Deb JW Zhang and P E Gottschall ldquo120573-amyloid induces theproduction of activematrix-degrading proteases in cultured ratastrocytesrdquo Brain Research vol 970 no 1-2 pp 205ndash213 2003

[153] Y Yarden and M X Sliwkowski ldquoUntangling the ErbB sig-nalling networkrdquo Nature Reviews Molecular Cell Biology vol 2no 2 pp 127ndash137 2001

[154] H Daub F U Weiss C Wallasch and A Ullrich ldquoRole oftransactivation of the EGF receptor in signalling by G-protein-coupled receptorsrdquoNature vol 379 no 6565 pp 557ndash560 1996

[155] N Prenzel E Zwick H Daub et al ldquoEGF receptor transactiva-tion byG-protein-coupled receptors requiresmetalloproteinase


cleavage of proHB-EGFrdquo Nature vol 402 no 6764 pp 884ndash888 1999

[156] F S Lee and M V Chao ldquoActivation of Trk neurotrophinreceptors in the absence of neurotrophinsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 98 no 6 pp 3555ndash3560 2001

[157] A Herrlich H Daub A Knebel et al ldquoLigand-independentactivation of platelet-derived growth factor receptor is a nec-essary intermediate in lysophosphatidic acid-stimulated mito-genic activity in L cellsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 95 no 15 pp 8985ndash8990 1998

[158] F G Buchanan D Wang F Bargiacchi and R N DuBoisldquoProstaglandin E2 regulates cell migration via the intracellularactivation of the epidermal growth factor receptorrdquoThe Journalof Biological Chemistry vol 278 no 37 pp 35451ndash35457 2003

[159] T Tanimoto Z-G Jin and B C Berk ldquoTransactivation ofvascular endothelial growth factor (VEGF) receptor Flk-1KDRis involved in sphingosine 1-phosphate-stimulated phosphory-lation of Akt and endothelial nitric-oxide synthase (eNOS)rdquoThe Journal of Biological Chemistry vol 277 no 45 pp 42997ndash43001 2002

[160] G Neufeld T Cohen S Gengrinovitch and Z PoltorakldquoVascular endothelial growth factor (VEGF) and its receptorsrdquoThe FASEB Journal vol 13 no 1 pp 9ndash22 1999

[161] H Lei and A Kazlauskas ldquoGrowth factors outside of theplatelet-derived growth factor (PDGF) family employ reactiveoxygen speciesSrc family kinases to activate PDGF receptor120572 and thereby promote proliferation and survival of cellsrdquo TheJournal of Biological Chemistry vol 284 no 10 pp 6329ndash63362009

[162] K C-W Chen Y Zhou K Xing K Krysan and M FLou ldquoPlatelet derived growth factor (PDGF)-induced reactiveoxygen species in the lens epithelial cells the redox signalingrdquoExperimental Eye Research vol 78 no 6 pp 1057ndash1067 2004

[163] B Liu andAHNeufeld ldquoActivation of epidermal growth factorreceptors in astrocytes from development to neural injuryrdquoJournal of Neuroscience Research vol 85 no 16 pp 3523ndash35292007

[164] A Ptasznik E R Prossnitz D Yoshikawa A Smrcka A ETraynor-Kaplan and G M Bokoch ldquoA tyrosine kinase signal-ing pathway accounts for the majority of phosphatidylinositol345-trisphosphate formation in chemoattractant-stimulatedhuman neutrophilsrdquo The Journal of Biological Chemistry vol271 no 41 pp 25204ndash25207 1996

[165] C Angeloni E Motori D Fabbri et al ldquoH2O2preconditioning

modulates phase II enzymes through p38MAPK and PI3KAktactivationrdquo American Journal of PhysiologymdashHeart and Circu-latory Physiology vol 300 no 6 pp H2196ndashH2205 2011

[166] J Pan Q Chang X Wang et al ldquoReactive oxygen species-activated AktASK1p38 signaling pathway in nickel com-pound-induced apoptosis in BEAS 2B cellsrdquo Chemical Researchin Toxicology vol 23 no 3 pp 568ndash577 2010

[167] A S Jr Baldwin ldquoThe NF-kB and IkB proteins new discoveriesand insightsrdquo Annual Review of Immunology vol 14 pp 649ndash683 1996

[168] J J Haddad ldquoOxygen-sensitive pro-inflammatory cytokinesapoptosis signaling and redox-responsive transcription factorsin development and pathophysiologyrdquo Cytokines Cellular andMolecular Therapy vol 7 no 1 pp 1ndash14 2002

[169] P J Barnes and M Karin ldquoNuclear factor-120581Bmdasha pivotaltranscription factor in chronic inflammatory diseasesrdquoTheNewEngland Journal ofMedicine vol 336 no 15 pp 1066ndash1071 1997

[170] W Eberhardt A Huwiler K-F Beck S Walpen and JPfeilschifter ldquoAmplification of IL-1120573-induced matrix metallo-proteinase-9 expression by superoxide in rat glomerularmesan-gial cells is mediated by increased activities of NF-120581B andactivating protein-1 and involves activation of the mitogen-activated protein kinase pathwaysrdquoThe Journal of Immunologyvol 165 no 10 pp 5788ndash5797 2000

[171] S Y Kim K-A Moon H-Y Jo et al ldquoAnti-inflammatoryeffects of apocynin an inhibitor of NADPH oxidase in airwayinflammationrdquo Immunology and Cell Biology vol 90 no 4 pp441ndash448 2012

[172] S-E Cheng C-C Lin I-T Lee C-K Hsu Y R Kouand C-M Yang ldquoCigarette smoke extract regulates cytosolicphospholipase A2 expression viaNADPHoxidaseMAPKsAP-1 and p300 in human tracheal smooth muscle cellsrdquo Journal ofCellular Biochemistry vol 112 no 2 pp 589ndash599 2011

[173] H M Chan and N B La Thangue ldquop300CBP proteins HATsfor transcriptional bridges and scaffoldsrdquo Journal of Cell Sciencevol 114 no 13 pp 2363ndash2373 2001

[174] H Asahara S Tartare-Deckert T Nakagawa et al ldquoDual rolesof p300 in chromatin assembly and transcriptional activationin cooperation with nucleosome assembly protein 1 in vitrordquoMolecular and Cellular Biology vol 22 no 9 pp 2974ndash29832002

[175] H Ma C Nguyen K-S Lee and M Kahn ldquoDifferential rolesfor the coactivators CBP and p300 on TCF120573-catenin-mediatedsurvivin gene expressionrdquo Oncogene vol 24 no 22 pp 3619ndash3631 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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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

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OphthalmologyJournal of


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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


oxidative stress [9ndash11] In addition ROS act as a critical sig-naling molecule to trigger inflammatory responses in centralnervous systems (CNS) through the activation of the redox-sensitive transcription factors including nuclear factor-120581B(NF-120581B) and activator protein-1 (AP-1) [5 9] Thus thisreview will focus on many general aspects of oxidative stressregulation and summarize the current progresses regardingthe occurrence and effects of redox signals on CNS andtheir involvement in the expression of inflammatory targetproteins in response to proinflammatory factors during braininflammation Moreover the pharmacological interventionswhich protect against oxidative stress-induced neuroinflam-mation and neurodegenerative diseases will be discussed

2 Role of Neuroglial Cells in CNSPhysiological and Pathological Events

CNS consists of neurons and glial cells Among glial cellsastrocytes constitute nearly 40 of the total CNS cell popula-tion in the adult human brain and theymaintain homeostasisin normal CNS Astrocytes have also been proposed to exerta wide range of functions including guidance of the develop-ment and migration of neurons during brain developmentproduction of growth factors maintenance of the integrityof the blood-brain barrier (BBB) and participating in theimmune and repairing responses to disease and brain injury[12 13]Microglial cells represent resident brainmacrophagesand can be transformed into activated immunocompetentantigen-presenting cells during the pathological process Anincreased number of activated microglial cells have consis-tently been reported in PD which may have a deleteriouseffect on dopaminergic neurons [14] Astrocytes as well asmicroglia display an array of receptors involved in innateimmunity including Toll-like receptors (TLRs) nucleotide-binding oligomerization domains double-stranded RNAdependent protein kinase mannose receptor and compo-nents of the complement system [10] One common featureof a variety of neurodegenerative disorders is the presenceof a large number of activated glial cells including astrocytesand microglia that involve the changes of morphology andexpression of many inflammation-related proteins Gliosisespecially astrogliosis is characterized by astrocytic prolifer-ation extensive hypertrophy of the cell body and functionalchanges when stimulated with various factors includinglipopolysaccharide (LPS) interleukin-1120573 (IL-1120573) and tumornecrosis factor-(TNF-120572) [15 16]

Moreover the cell-cell interactions between glial cellsand neurons may be important in the regulation of braininflammation and neurodegeneration Many recent reportsimplicate that inflammation contributes to a wide variety ofbrain pathologies apparently killing neurons via glia [10 1117] Thus the activated glial cells especially microglia andastrocytes are thought to play a critical role in the patho-genesis and progression of neurodegeneration (Figure 1) Pre-viously many reports have shown that microglial cells maybe a major inflammatory cell of the brain [14] The activatedmicroglia produce several inflammatorymediators includingCOX-2prostaglandins (PGs) iNOSnitric oxide (NO) or

Neuroinflammationneuronal death



Neuroglial cells (microglia and astrocytes)

Figure 1 Schematic presentation of the interaction of the braincells including neurons and glial cells In the central nervous system(CNS) proinflammatory factors induce the expression of variousinflammatory mediators in neuroglial cells particularly microgliaand astrocytes These induced inflammatory mediators from glialcells may cause the neuroinflammation or neuronal death and thenleading to neurodegenerative disorders

cytokines as well as neurotoxic substances which are thoughtto be responsible for brain injuries and diseases includingtrauma AD and neural death due to the exposure of LPSinterferon-120574 or 120573-amyloid [18 19] Although most studieshave demonstrated that microglial cells play an importantrole in neuroinflammation and neurodegeneration accu-mulating evidence has also demonstrated the characteristicchanges of astrocytes in neurodegenerative diseases such asdementia [10 11 20] Recently we have demonstrated theupregulation of several inflammatory mediators includingMMP-9 cPLA

2 COX-2 iNOS and oxidative stress by var-

ious proinflammatory factors such as cytokines (eg IL-1120573) peptides (eg bradykinin (BK) or endothelin-1 (ET-1)) infections (eg bacteria or virus) and peroxidants(eg oxidized low-density lipoprotein (oxLDL)) in rat brainastrocytes [21ndash29] More recent data indicated that multi-ple factors including ROS MMP-9 and heme oxygenase-1(HO-1)carbon monoxide (CO) from BK-challenged brainastrocytes may contribute to the neuronal cell apoptosis[30] Together these results implicate that activated neuroglialcells especially astrocytes play a key role in the pathogenesisof the CNS inflammation leading to neurodegenerative dis-eases (Figure 1)



Nox Xox

P450 COX

NOS

SOD Catalase

GPx Thioredoxin

HO-1





2



2






MPO

HOCl

L-ArgNOS


GPxH2OH2O2O2


O2∙minus


2


2



2




2O water O

2








2O2) and other




Redox signals(ROS)













H2O2)




























2(eg cPLA

2) COX-2


2releasing by cPLA







PLA2 type IV PLA


2 and calcium-


retary PLA2(sPLA



2(iPLA




2The cPLA





2could be




2is the only


2is constitutively




2in astrocytes from




2leading to PGE




2activation




2activity






2catalyzes the



2release


2















2induction are





















2 COX-2 and






2

∙minus and H2O2)








7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Nox Xox

P450 COX

NOS

SOD Catalase

GPx Thioredoxin

HO-1





2



2






MPO

HOCl

L-ArgNOS


GPxH2OH2O2O2


O2∙minus


2


2



2




2O water O

2








2O2) and other




Redox signals(ROS)













H2O2)




























2(eg cPLA

2) COX-2


2releasing by cPLA







PLA2 type IV PLA


2 and calcium-


retary PLA2(sPLA



2(iPLA




2The cPLA





2could be




2is the only


2is constitutively




2in astrocytes from




2leading to PGE




2activation




2activity






2catalyzes the



2release


2















2induction are





















2 COX-2 and






2

∙minus and H2O2)








7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















MPO

HOCl

L-ArgNOS


GPxH2OH2O2O2


O2∙minus


2


2



2




2O water O

2








2O2) and other




Redox signals(ROS)













H2O2)




























2(eg cPLA

2) COX-2


2releasing by cPLA







PLA2 type IV PLA


2 and calcium-


retary PLA2(sPLA



2(iPLA




2The cPLA





2could be




2is the only


2is constitutively




2in astrocytes from




2leading to PGE




2activation




2activity






2catalyzes the



2release


2















2induction are





















2 COX-2 and






2

∙minus and H2O2)








7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































2(eg cPLA

2) COX-2


2releasing by cPLA







PLA2 type IV PLA


2 and calcium-


retary PLA2(sPLA



2(iPLA




2The cPLA





2could be




2is the only


2is constitutively




2in astrocytes from




2leading to PGE




2activation




2activity






2catalyzes the



2release


2















2induction are





















2 COX-2 and






2

∙minus and H2O2)








7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















2could be




2is the only


2is constitutively




2in astrocytes from




2leading to PGE




2activation




2activity






2catalyzes the



2release


2















2induction are





















2 COX-2 and






2

∙minus and H2O2)








7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























2induction are





















2 COX-2 and






2

∙minus and H2O2)








7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















2 COX-2 and






2

∙minus and H2O2)








7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















7 Conclusions





Abbreviations


2








Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















Acknowledgments


References




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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Transcript of Review Article Role of Redox Signaling in ...downloads.hindawi.com/journals/bmri/2013/484613.pdf ·...