Table Of ContentRichard M. Kostrzewa
Editor
Handbook of
Neurotoxicity
Second Edition
Handbook of Neurotoxicity
Richard M. Kostrzewa
Editor
Handbook of
Neurotoxicity
Second Edition
With296Figuresand68Tables
Editor
RichardM.Kostrzewa
DepartmentofBiomedicalSciences
QuillenCollegeofMedicine
EastTennesseeStateUniversity
JohnsonCity,TN,USA
ISBN978-3-031-15079-1 ISBN978-3-031-15080-7(eBook)
https://doi.org/10.1007/978-3-031-15080-7
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Preface
Inthe1930s,thenotedPhysiologistWalterB.Canonpromotedthepreceptthatthe
functions of a neural system could be discerned by determining the realm of lost
functions when that neural component was destroyed. In the 1950s, the Nobel
Laureate, Professor Dr. Rita Levi-Montalcini, discovered that a protein termed
Nerve Growth Factor (NGF) would promote the proliferation of axonal branches
inisolatedneuralcells.IncollaborationwithProf.Dr.StanleyCohen,antibodiesto
thatprotein,termedanti-NGF,wereshowntoabatethedevelopmentofnoradrener-
gicnervesinperinatalrodents,toresultinalife-longneartotallossofonebranchof
the autonomic nervous system, namely, noradrenergic sympathetic nerves. This
discovery opened the door for the ultimate discovery and development of highly
selectiveneurotoxins.
In the 1960s, Prof. Drs. Hans Thoenen and J.P. Tranzer demonstrated that the
dopamineanalog,6-hydroxydopamine(6-OHDA),producedultimatedestructionof
noradrenergic nerves. When administered directly into brain, 6-OHDA destroyed
bothnoradrenergicanddopaminergicnerves,andthiseffectwaslife-long.Theeraof
discovery of highly selective neurotoxins had begun, and over the next decades,
multiple other selective neurotoxins came into being and proved to be useful in
determining lost functions when specific nerves were destroyed – enriching the
forward-lookingviewofW.B.Canon.
This Handbook of Neurotoxicity highlights the vast realm of individual highly
selectiveneurotoxins.Eachneurotoxiniscategorized,providingtheknownoverall
effect of that neurotoxin, giving insight to the mechanisms of action at a cellular
level,aswellasadescriptionoftheultimateneurologictemplateensuingfromloss
of the associated neuronal phenotype, and the produced behavioral and other
functionallossresultantfromtheabsenceofthatneuralphenotype.
The first section of the book, on Principles of Neurotoxicity, provides an
overview of elements most relevant to the mechanisms and actions of Selective
Neurotoxins.
Thenextsection,onSelectiveNeurotoxins:Overview,listsindividualselective
neurotoxins,demonstrating theexpansiveness ofthis broadfieldofresearch.Here,
the major actions of common selective neurotoxins are described, as well as the
utility of each neurotoxin in producing a dysfunctional outcome. As “each action
v
vi Preface
causes a reaction,” the adjustments made by alternate neural phenotypes to any
particularneurotoxicityaredelineated.
The following sections of this book provide details of individual neurotoxins,
listing details of each neurotoxin on the relevant nerve-type that is destroyed:
actions,mechanisms,deriveddenervationtemplate,adjustmentsbyalternateneural
phenotypes,functionalloss,andbehavioraloutcome.Whereapplicable,strategiesto
preventneurotoxicityareindicated.
The next section is focused on Neurotoxins: Dopaminergic, Noradrenergic,
and Serotoninergic Neurons, with a focus on Monoaminergic Neurotoxicity –
Overview,withcategorizationofSelectiveMonoaminergicNeurotoxins,Dopamine
ReceptorSupersensitivityasaNeurotoxicityOutcomeandDopaminergicNeurotox-
icityandSynapticPlasticity.
The section on Excitotoxicity, Excitotoxins, Excitoprotectants highlights the
fact that over-excitatory actions of amino acids and other elements can result in
energy depletion and production of oxidative species in target nerves with the
relevantreceptorstotheseexcitotoxins,leadingtoneuralcelldeath.
Anothersection,onCholinergicNeurotoxins,isfocusedontherealmofeffects
of clostridial neurotoxins, providing relevant details of their respective actions and
mechanisms while giving insight to the clinical applicability of botulinum
neurotoxin.
ThereisaSpectrumofAlternateNeurotoxinsdetailedinthissection,providing
relevantdetailsoftheactionsofavarietyofsomewhatselectiveneurotoxinsthatfind
applicabilityinresearchapproaches.Theclinicalrangesofeffectsofsuchagentsare
similarlydescribed.
ThesectiononNeurotoxinModelsofHumanNeurodegenerativeDisordersis
intended to show how individual selective neurotoxins are able to animal-model
humanneuraldisordersthathaveanunderlyingfeatureofneuronaldegenerationofa
body of neurons, sometimes with this being an age-related human neural degener-
ative disease. The subsection on Neurotoxicity and Parkinson’s Disease indicates
howassortedneurotoxinsareabletoanimal-modelParkinson’sdisease,highlighting
therolesofalpha-synuclein,iron,neuromelanin,andotherprinciplesthatareafocus
inthedisorder.ThesubsectiononNeurotoxicityandAlzheimer’sDiseaseisfocused
on experimental templates and targets that are relevant to this human neurodegen-
erative disorder. The subsections on Neurotoxicity and Huntington’s Disease and
Neurotoxicity and Human Neurodegenerative Disorders similarly give insight
betweenlaboratoryfindingsinanimalstowardsthehumancondition.
TheNeurotoxicityandPsychiatricDisorderssectiondemonstrateshowexper-
imentaloutcomesofneurotoxinsinanimalsareapplicabletofeaturesinarangeof
humanpsychiatricdisorders.
The final section on Metals and Neurotoxicity is devoted to the actions and
adverse spectrum of effects of heavy metals that are known to be associated with
neurotoxic events in humans. Proposed mechanisms of action and adversity at the
cellular and behavioral level in animal subjects are described and related to the
neurotoxicityofthesemetalsinhumans.
Preface vii
IndividualchaptersinthisHandbookarewrittenbyleadingauthorities–neuro-
scientists that have led and expanded the breadth of knowledge by their research
studies on a respective neurotoxin. The Handbook is particularly relevant to
researchersinvestedinstudies onanyofthechaptertopics,aswellastoclinicians
treating patients with medical conditions that relate to the topics within the Hand-
book.TheHandbookisasuitablecompendiumtoacademicdepartments,aswellas
tostudentswithafocusintheneurosciences.
ThissecondeditionoftheHandbookofNeurotoxicityisanexpansionofthefirst
edition, with updated information and with greater insights on topics that have
evolvedoverthepastseveralyears.
JohnsonCity,TN,USA RichardM.Kostrzewa
January2023
Contents
Volume 1
PartI PrinciplesofNeurotoxicity ............................ 1
Neurotoxicity:AComplexMultistageProcessInvolvingDifferent
Mechanisms .............................................. 3
EwaNiedzielska-Andres,BartłomiejRospond,
LucynaPomierny-Chamioło,AnnaSadakierska-Chudy,and
MałgorzataFilip
TargetingNecroptosisasTherapeuticPotentialinCentralNervous
SystemDiseases ........................................... 21
HaoLi,MeilingXia,JingChen,RichardM.Kostrzewa,andXingshunXu
Microglia:ACriticalCellforNeurodevelopment ................. 37
ChristopherA.McPhersonandG.JeanHarry
MicroglialCellDysregulationintheAgedBrainand
Neurodegeneration ......................................... 57
MaríaTriolo-Mieses,RicardoFadic,andRommyvonBernhardi
MechanismsUnderlyingLong-LatencyNeurodegenerativeDiseasesof
EnvironmentalOrigin ....................................... 71
PeterS.Spencer,MohamedSalama,andGlenE.Kisby
BDNF-TrkBSignalinginLifelongCentralNervousSystem
MyelinationandMyelinRepair ............................... 95
MadelineNicholson,SangWonYoo,GeorginaA.Craig,SimonS.Murray,
andJessicaL.Fletcher
Necrostatin-1asaNeuroprotectant ............................ 123
DanutaJantasandWładysławLasoń
ix
x Contents
PartII SelectiveNeurotoxins:Overview ..................... 157
SurveyofSelectiveMonoaminergicNeurotoxinsTargeting
Dopaminergic,Noradrenergic,andSerotoninergicNeurons ......... 159
RichardM.Kostrzewa
SurveyoftheSpectrumofClassicSelectiveNeurotoxins ........... 199
RichardM.Kostrzewa
PartIII Neurotoxins:Dopaminergic,Noradrenergic,and
SerotoninergicNeurons ................................... 221
BiomarkersofNeurotoxicityInformMechanismsofVulnerabilityand
ResilienceinDopaminergicNeurons ........................... 223
DavidGerhold,HyunHeeKim,andZhi-BinTong
RCSNCellSystemforIdentifyingDopaminergic
Neurotoxicity ............................................. 239
PabloCaviedes,RaúlCaviedes,andJuanSegura-Aguilar
DopamineandL-DopaasSelectiveEndogenousNeurotoxins ........ 255
JuanSegura-Aguilar,UlisesAhumada-Castro,andIrmgardParis
DopamineHomeostasisandRoleofVMAT2in
Neurodegeneration ......................................... 291
EugeneV.Mosharov
NeuroprotectionandNeurorestorationofNigraStriatalDopamine
NeuronsbyNovelMultitargetDrugs,M30 ...................... 313
ShunitBenAriandMoussaB.H.Youdim
6-Hydroxydopa:APrecursor-NeurotoxinwithRelativeSelectivityfor
NoradrenergicNeurons ..................................... 365
RichardM.Kostrzewa
6-HydroxydopamineLesioningofDopamineNeuronsinNeonatal
andAdultRatsInducesAge-DependentConsequences ............. 377
SophiaT.PapadeasandGeorgeR.Breese
MPTPNeurotoxicity:Actions,Mechanisms,andAnimalModelingof
Parkinson’sDisease ........................................ 443
MichelaFerrucciandFrancescoFornai
MPTP:AdvancesfromanEvergreenNeurotoxin ................. 485
AnnaR.Carta,AugustaPisanu,MariaFrancescaPalmas,CarlosBarcia,
LorenaCuenca-Bermejo,andMaría-TrinidadHerrero
Neurotoxicity:Calpainand1-Methyl-4-phenylpyridinium
(MPP+) .................................................. 517
DonaldC.Shields,AzizulHaque,andNarenL.Banik
Contents xi
NeurotoxicityofMethamphetamine ............................ 533
RosarioMoratalla,SaraAres-Santos,andNoeliaGranado
MethamphetamineandMDMANeurotoxicity:Biochemicaland
MolecularMechanisms ...................................... 563
VerónicaBisagnoandJeanLudCadet
OntheDisbalanceandImpairmentofSerotoninHeteroreceptor
ComplexesintheRatBrainAfterMDMAandHallucinogens
Administration ............................................ 587
KjellFuxeandDasielO.Borroto-Escuela
ModelsofMethamphetamine-InducedNeurotoxicity .............. 605
AnneS.GibsonandKristenA.Keefe
CocaineasaNeurotoxin ..................................... 619
TeresaCunha-Oliveira,A.CristinaRego,andCatarinaR.Oliveira
EntericNeurotoxicityandSalsolinol ........................... 641
MagdalenaKurnik-ŁuckaandKrzysztofGil
NatureofDSP-4-InducedNeurotoxicity ......................... 669
AleksandraBortel
5,6-and5,7-DihydroxytryptaminesasSerotoninergic
Neurotoxins ............................................... 691
JustynaPaterakandRomanStefański
Long-LivedDopamineD -ReceptorSupersensitivity:Neurotoxicity
2
inthePresenceandAbsenceofNeuronalDamage ................ 719
RichardM.KostrzewaandRussellW.Brown
ConsequencesofNeurotoxin-InducedDopamineLossonStriatal
SynapticPlasticity .......................................... 731
AnneS.GibsonandKristenA.Keefe
Volume 2
PartIV Excitotoxicity,Excitotoxins,andExcitoprotectants ...... 745
IonotropicReceptorsintheCentralNervousSystemand
NeurodegenerativeDisease ................................... 747
NadyBraidy,AnnePoljak,TharushaJayasena,GillesJ.Guillemin,and
PerminderSachdev
GlutamateasaNeurotoxin ................................... 769
GabrielleN.TurskiandChrysanthyIkonomidou
GlutamateNeurotoxicityRelatedtoEnergyFailure ............... 803
ArneSchousboe
