Table Of ContentOxidative Stress in Applied Basic Research
and Clinical Practice
Editor-in-Chief
Donald Armstrong
For other titlespublished inthis series, goto
http://www.springer.com/series/8145
Note from the Editor-in-Chief
All books in this series illustrate point-of-care testing and critically evaluate the
potential of antioxidant supplementation in various medical disorders associated
with oxidative stress. Future volumes will be updated as warranted by emerging
newtechnology,or fromstudiesreportingclinicaltrials.
Donald Armstrong
Editor-in-Chief
Natan Gadoth Hans Hilmar Go¨bel
l
Editors
Oxidative Stress and
Free Radical Damage
in Neurology
Editors
NatanGadoth HansHilmarGo¨bel
SacklerFacultyofMedicine JohannesGutenbergUniversity
TelAvivUniversity MedicalCenter
TelAviv69978,Israel Mainz,Germany
and [email protected]
DepartmentofNeurology
MayaneiHayeshuaMedicalCenter
Bnei-Brak51544
[email protected]
ISBN978-1-60327-513-2 e-ISBN978-1-60327-514-9
DOI10.1007/978-1-60327-514-9
SpringerNewYorkDordrechtHeidelbergLondon
LibraryofCongressControlNumber:2010937792
#SpringerScience+BusinessMedia,LLC2011
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Preface
Thepossibleroleoffreeradicalsandoxidativestressinneurologicaldisorderswasnot
recognized until recently and thus is relatively unknown to practicing as well as
academically minded clinicalneurologists. This fact can be appreciated as one goes
throughthemajortextbooksrecommendedandusedbyresidentsinneurologylooking,
invain,forinformationonthistopic.Onemayfindonlyshortremindersofthepossible
associationofsuperoxidasedismutasewithfamilialamyotrophiclateralsclerosisand
nitrousoxidewithmigraine.Wemayalsofindbitsofinformationregardingthepossible
roleoffreeradicalsinthepathogenesisoftraumaticbraininjury.
Thislimitationisnotatallsurprising,becausethebiologicalroleoffreeradicals
was discovered and scientifically accepted only recently. Denham Harman pro-
posedthefreeradicaltheoryofagingmorethan50yearsago,butacceptanceofthis
theory was slow until only a few years ago. During the late 1940s toearly 1950s,
retrolental fibroplasia in premature newborns was recognized as being caused by
oxygen toxicity. The presence of free radicals in biological systems was not
generally considered likely until the discovery of superoxide dismutase in 1969
by Irwin Fridovich, although in the 1950s, the basis of oxygen toxicity and
X-irradiationwasproposedtobeacommonfreeradicalmechanism.
Thus,thegoalofintroducingthistopictoneurologyforteachingandpracticeledus
tocompilethisvolumewiththehelpofanumberofcolleagues,whoagreedtocover
severalaspectsofclinicalandresearchissuesregardingfreeradicalsandthenervous
system.Familiaritywiththevariousantioxidantsandtheirpossibletherapeuticrolein
some neurological disorders, which is described in the relevant chapters throughout
thisvolume,isanadditionalimportantanduniquecontributionofthisvolume.
Wehopethatcliniciansaswellasbasicresearchersinneurosciencewillfindthis
volume of help in expanding their understanding, not only of the widespread
involvement of free radicals in the central nervous system, but also of some
ambiguous issues related to answering the question of the primary or secondary
roleoffreeradicaldamageinneurology.
Tel-Aviv,Israel NatanGadoth
Mainz,Germany HansH.Go¨bel
v
Contents
1 TheRoleofFreeRadicalsintheNervousSystem..................... 1
JosephFriedman
2 WhyIstheNervousSystemVulnerable
toOxidativeStress?...................................................... 19
JosephFriedman
3 PerinatalHypoxic-IschemicNeuralInjury
andFreeRadicalInjury:AFineBalance.............................. 29
M.PerlmanandPo-YinCheung
4 OxidativeStressinNeonatalHypoxic-Ischemic
Encephalopathy........................................................... 47
K.G.Todd,L.L.Jantzie,andPo-YinCheung
5 OxidativeStressinMultipleSclerosisPathology
andTherapeuticPotentialofNrf2Activation.......................... 65
HelgaE.deVries,GertySchreibelt,andJackvanHorssen
6 FreeRadicalsinCentralNervousSystemInflammation.............. 79
D.CraigHooper,MarzenaJ.Fabis,andAnirbanRoy
7 TheRoleofReactiveOxygenSpeciesinthePathogenesis
ofTraumaticBrainInjury............................................... 99
EstherShohamiandRonKohen
8 DistinctRolesofCyclooxygenase-1andCyclooxygenase-2
inInflammatoryandExcitotoxicBrainInjury ........................ 119
SabaA¨ıd,Sang-HoChoi,ChristopherD.Toscano,
andFrancescaBosetti
vii
viii Contents
9 StrokeandOxidativeStress............................................. 137
AriannaVignini
10 FreeRadicalsinEpilepsy................................................ 153
TaliSiman-TovandNatanGadoth
11 NeurologicalDisordersAssociatedwithIron
Misdistribution:TheTherapeuticPotential
ofSiderophores........................................................... 169
OrKakhlon,BillBreuer,ArnoldMunnich,
andZ.IoavCabantchik
12 OxidativeStressinParkinson’sDisease................................ 191
JacobVaya,YuvalAluf,andJohnP.M.Finberg
13 TetrahydrobiopterinDeficiency......................................... 225
MaryKayKoenigandIanJ.Butler
14 RadicalsAttacktheEarTheToll:ALossofHearing................. 235
HaimSohmerandCahtiaAdelman
15 ReactiveOxygenSpeciesinMitochondrial
Encephalomyopathy:MechanismsandEffects........................ 253
SunYoungParkandRonaldG.Haller
16 PotentialRoleofOxidativeDamageinNeurological
ManifestationsofAcuteIntermittentPorphyria....................... 293
ElenaPischikandRailiKauppinen
Index............................................................................ 313
Chapter 1
The Role of Free Radicals in the Nervous System
JosephFriedman
Abstract Thischapterisanintroductiontothebiologyofreactiveoxygenspecies
(ROS)inthebrain.Inhealthyaerobes,thereisabalancebetweentheproductionof
variousROSandantioxidantdefenses.Livingorganismshavenotonlyadaptedto
coexistence with free radicals but have developed various mechanisms for the
advantageous use of free radicals in various physiological functions. Infectious
diseases were a powerful driver of natural selection in early human civilizations.
Indeed,ROSparticipatedirectlyindefenseagainstinfection.Inanormalsituation,
microglia, which are resident macrophages of the brain, fight against infection by
ROS.ROSarewellrecognizedforplayingadualrole,havingbothdeleteriousand
beneficial effects, which in most cases depend on concentration. At high ROS
concentrations there are harmful effects, and in a low–moderate concentration
ROSareinvolvedinphysiologicalrolesincellularresponsetonoxiousstimuli.It
was suggested that the main effects of ROS on cells are through their actions on
signaling pathways rather than causing nonspecific damage. With aging, when
these pathways deteriorate, accumulation of higher concentrations of ROS occurs
inamountsbeyondthecapacityofantioxidantstocope.Thisdeteriorationresultsin
theage-associatedneurodegenerativedisorderssuchasstrokeandcentralnervous
system(CNS)traumaaswellasParkinson’sandAlzheimer’sdisease.Someofthe
CNS-evolvedspecificsignalingpathwaysaredescribed.
Keywords Neuron(cid:1)Microglia(cid:1)Mitochondria(cid:1)ComplexI(cid:1)ROS(cid:1)OS(cid:1)NADPH
oxidase (cid:1) Excitoxicity (cid:1) Antioxidants (cid:1) BBB (cid:1) Signaling pathways (cid:1) Brain stroke (cid:1)
Braintrauma(cid:1)Parkinson’sdisease(cid:1)Alzheimer’sdisease
J.Friedman(*)
LifeScienceLaboratory,WeizmannSciencePark,Ness-Ziona,Israel
e-mail:[email protected]
N.GadothandH.H.Go¨bel(eds.),OxidativeStressandFreeRadicalDamage 1
inNeurology,OxidativeStressinAppliedBasicResearchandClinicalPractice,
DOI10.1007/978-1-60327-514-9_1,#SpringerScience+BusinessMedia,LLC2011
2 J.Friedman
1 Introduction to ROS
In the structure of atoms and molecules, electrons usually associate in pairs, each
movingwithinadefinedregionofspacearoundthenucleus.Thisspaceisreferred
toastheatomicormolecularorbital.Oneelectronineachpairhasaspinquantum
number of þ½, and the other, –½. The process of removing electrons is called
oxidation, and the substance receiving electrons becomes reduced. The reactions
involved in electron transfer are called redox (reduction–oxidation) reactions. A
free radical is any species capable of independent existence (hence the term free)
that contains one or more unpaired electrons [1, 2]. Free radicals are sometimes
reactive,althoughthechemicalreactivityofradicalsvariesoverawidespectrum.
Consideration of our broad definition shows that there are many free radicals in
chemistryandbiology.Thesimplestistheatomichydrogenwithoneprotonanda
single electron, which must therefore be unpaired. Hence, removal of a hydrogen
atomfromabiologicalmoleculeleavesbehindanunpairedelectronontheatomto
which hydrogen was originally attached. The diatomic oxygen molecule O qua-
2
lifiesasaradicalinasmuchasitpossessestwounpairedelectrons,eachlocatedina
differentorbitalbutbothhavingthesamespinquantumnumber:thatisthereason
whyO itselfhasarelativelylowreactivityincontrasttootherradicals,whichcan
2
be highly reactive. Radicals can be formed by the loss of a single electron from
a nonradical: x ! e¯ þ xþ, or by the gain of a single electron by a nonradical:
yþe¯!y(cid:3).Radicalscanreactwithothermoleculesinanumberofways.Thus,if
two radicals meet, they can combine their unpaired electrons and join to form a
covalentbond:xlþyl!x(cid:3)y.
Aradicalmightdonateitsunpairedelectrontoanothermolecule:xlþy!xþþy(cid:3).
Or,itmightcatchanelectronfromanothermoleculetopair:xlþy!x–þy(cid:3).
TherearereactiveoxygenmoleculessuchasH O thatdonotfitthedefinitionof
2 2
freeradicals,soallthereactivespecies,radicalsornot,arecalledreactiveoxygen
species(ROS).
The first organic free radical, identified by Moses Gomberg in 1900, was the
triphenylmethylradical.Until40–50yearsago,ROSwerenotthoughttooccurin
biologicalsystemsbecauseoftheirhighreactivityandlackofselectivity.Thispoint
of view was changed in 1956 by Denham Harman, who proposed the concept of
free radicals playing a role in aging. A second epoch of research regarding free
radicals in biological systems was reached in 1969 when McCord and Fridovich
discoveredtheenzymesuperoxidedismutase(SOD)andthusprovidedconvincing
evidenceabouttheimportanceoffreeradicalsinlivingsystems.
Morethan90%oftheoxygenthatentershumancellsisusedfortheproduction
of energy. Mitochondria produce more than 80% of the adenosine triphosphate
(ATP) needed by the mammalian cells. During this process, four electrons are
added to each O molecule, resulting in the formation of two molecules of water.
2
Anestimated1–5%oftheO takenintocells,however,formspartiallyreducedO
2 2
species, the ROS. Some of them contain an unpaired electron and are therefore
referredtoasfreeradicals:
