Table Of ContentRajanikant G. K. · Pierre Gressens
Sreekala S. Nampoothiri
Gokul Surendran · Cindy Bokobza
IschemiRs:
MicroRNAs
in Ischemic
Stroke
From Basics to Clinics
IschemiRs: MicroRNAs in Ischemic Stroke
Rajanikant G. K. (cid:129) Pierre Gressens (cid:129)
Sreekala S. Nampoothiri (cid:129)
Gokul Surendran (cid:129) Cindy Bokobza
IschemiRs: MicroRNAs
in Ischemic Stroke
From Basics to Clinics
RajanikantG.K. PierreGressens
SchoolofBiotechnology NeuroDiderot,Inserm
NationalInstituteofTechnologyCalicut UniversitédeParis
Calicut,India Paris,France
SreekalaS.Nampoothiri GokulSurendran
DevelopmentandPlasticity SchoolofBiotechnology
oftheNeuroendocrineBrain NationalInstituteofTechnologyCalicut
LilleNeuroscience&Cognition Calicut,India
INSERM1172
Lille,France
CindyBokobza
NeuroDiderot,Inserm
UniversitédeParis
Paris,France
ISBN978-981-15-4797-3 ISBN978-981-15-4798-0 (eBook)
https://doi.org/10.1007/978-981-15-4798-0
#SpringerNatureSingaporePteLtd.2020
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Preface
MicroRNAs are small endogenous noncoding RNA molecules that function as a
regulatorofgeneexpressionattheposttranscriptionallevel.Inrecentyears,thescientific
communityhaswitnessedamassiveincreaseinthewealthofknowledgethatbridgesthe
microRNA and its strategic role as a biomarker and therapeutic in a wide range of
diseases, including ischemic stroke. However, there is still a lack of comprehensive
detailslinkingthissmallRNAmoleculetoanischemicstroke,themorepreponderant
among the two main types of stroke. This monograph is intended as a medium to
examine the emerging role of microRNAs in cerebral ischemia. The book addresses
topics related to the activity of microRNAsin multiple pathological manifestations of
strokessuchasoxidativestress,excitotoxicity,celldeathtrends,theiruseasabiomarker,
diagnosticagents,andcurrentlypracticedtherapeuticinterventions.Italsohighlightsthe
latestresearchonhowmicroRNAshelpinneuroregenerationduringpoststrokeevents,
themyriadofcomputationaltoolsanddatabasesusedinmicroRNAresearch,andhow
theymodulateothercerebrovasculardiseases.Thebookconcludeswithaspecialinsight
intothepotentialsofdevelopingmicroRNA-basedtherapiesforischemicstroke.
Thisbookisthefirstofitskindtobringtogetherpiecesofpuzzleconcerningthe
effectofthemicroRNAsontheischemicstroke.Giventhevastliteratureavailablein
publiclibraries,ourbookseekstoprovidereaderswithcutting-edgeknowledgeon
microRNAcoveringvariousaspectsofstroke.Thisalonemakesourbook,onethat
researchersinthisareawouldbepleasedtohaveintheirbookshelves.Thisbookcan
serve as a comprehensive tool for researchers, doctoral and graduate students, and
cliniciansinthefieldofmiRNAandischemicstrokeandaidinthedevelopmentof
reliablebiomarkersandneurotherapeuticsbyidentifyingsuitablemicroRNAs.
We would like to thank the Springer team, especially Madhurima Kahali and
SelvakumarRajendran,fortheirpatient,professional,andconstantsupportthrough-
outtheproductionofthisbook.
Calicut,India RajanikantG.K.
Paris,France PierreGressens
Lille,France SreekalaS.Nampoothiri
Calicut,India GokulSurendran
Paris,France CindyBokobza
v
Contents
PartI microRNAsandIschemicStroke:BacktoBasics
1 microRNAsinNormalBrainPhysiology. . . . . . . . . . . . . . . . . . . . . 3
1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2 microRNABiogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 miRNAintheBrain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.3.1 miRNAinNeurons. . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.3.2 miRNAinOligodendrocytes. . . . . . . . . . . . . . . . . . . . 7
1.3.3 miRNAinAstrocytes. . . . . . . . . . . . . . . . . . . . . . . . . 8
1.3.4 miRNAinMicroglia. . . . . . . . . . . . . . . . . . . . . . . . . 8
1.4 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2 IschemicStroke:AnImperativeNeedforEffectiveTherapy. . . . . . 15
2.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2 CurrentTreatmentChoicesforIschemicStrokeVictims. . . . . . 16
2.2.1 IVPharmacologicalThrombolysis. . . . . . . . . . . . . . . . 16
2.2.2 EndovascularRecanalizationStrategies. . . . . . . . . . . . 18
2.3 OtherReperfusionStrategies. . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.4 Post-IschemicNeuroprotectiveAgents. . . . . . . . . . . . . . . . . . . 24
2.5 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
PartII microRNAsinIschemicStrokePathophysiology:ABird’s
EyeView
3 MicroRNAsinIschemicStrokePathophysiology:Special
EmphasisonEarlyMolecularEvents. . . . . . . . . . . . . . . . . . . . . . . 33
3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.2 Post-IschemicGlutamateExcitotoxicityandIonicImbalance. . . 34
3.2.1 miRNAsTargetingGlutamateReceptors. . . . . . . . . . . 36
3.2.2 miRNAsandGlutamateTransporters. . . . . . . . . . . . . . 37
3.2.3 miRNARegulationofPost-IschemicCalciumOverload. 37
3.3 miRNAsinPost-IschemicOxidativeStressRegulation. . . . . . . 39
vii
viii Contents
3.3.1 EndogenousAntioxidantDefenseMechanisms. . . . . . . 39
3.3.2 OxidativeStress-InducedMitochondrialDysfunction. . 41
3.3.3 miRNAsandtheMasterRegulatorNrf2. . . . . . . . . . . 41
3.3.4 EndothelialIntegrityandBlood–BrainBarrier. . . . . . . 42
3.4 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4 microRNARegulationofIschemicStrokeInflammatory
andImmuneResponse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.2 StrokeImmunology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.3 microRNAsAssociatedwithIschemicNeuro-Inflammation. . . . 51
4.4 microRNAsandInnateImmuneCellsinIschemicStroke. . . . . 53
4.5 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
5 RegulatoryRoleofmicroRNAsinIschemicCellDeath. . . . . . . . . . 59
5.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
5.2 Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
5.2.1 IntrinsicPathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
5.2.2 ExtrinsicPathway. . . . . . . . . . . . . . . . . . . . . . . . . . . 61
5.3 Autophagy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
5.4 MicroRNAsandAutophagy. . . . . . . . . . . . . . . . . . . . . . . . . . 62
5.5 MicroRNAsandApoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . 63
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
6 TheEmergingRoleofmicroRNAsinPost-ischemicAngiogenesis
andNeurogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
6.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
6.2 Post-StrokeInducedNeurogenesis. . . . . . . . . . . . . . . . . . . . . . 68
6.2.1 miRNARegulationofEarlyStagesofNeurogenesis. . . 68
6.2.2 NeuronalMaturationandIntegration. . . . . . . . . . . . . . 71
6.2.3 miRNAsRegulatingNeurotrophicFactors. . . . . . . . . . 73
6.2.4 miRNAsandNeurogenesisSignalingPathways. . . . . . 74
6.3 miRNARegulationofPost-IschemicAngiogenesis. . . . . . . . . . 75
6.3.1 EC-SpecificmiRNAsinAngiogenesis. . . . . . . . . . . . . 76
6.3.2 Post-IschemicmiRNARegulationofAngiogenic
Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.4 CouplingAngiogenesisandNeurogenesisPost-Ischemia. . . . . . 79
6.5 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
7 MicroRNAsasPotentialDiagnostic,Prognostic,andTherapeutic
BiomarkersinIschemicStroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.2 ImportantCirculatingmicroRNAsinIschemicStroke. . . . . . . . 89
7.2.1 Let7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Contents ix
7.2.2 MiRNA-125a-5p/miR-125b-5p/miR-125b-2(cid:1). . . . . . . . 90
7.3 EmbolicStrokeVersusThromboticStroke. . . . . . . . . . . . . . . . 90
7.4 CellDeath. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
7.5 Inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
7.6 NeurogenesisandAngiogenesis. . . . . . . . . . . . . . . . . . . . . . . . 91
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
8 InterplayBetweenmicroRNAsandOtherCerebrovascular
Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
8.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
8.2 HemorrhagicStroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
8.3 IntracerebralHemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
8.3.1 microRNAsasICHBiomarkers. . . . . . . . . . . . . . . . . 96
8.3.2 RegulatoryRoleofmicroRNAsinICH. . . . . . . . . . . . 97
8.4 SubarachnoidHemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
8.4.1 microRNAsasSAHBiomarkers. . . . . . . . . . . . . . . . . 99
8.4.2 DiseaseModifyingRoleofmicroRNAsinSAH. . . . . . 101
8.5 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
9 NewInsightsintotheRegulatoryRoleoflncRNA,circRNA,
piRNAs,andceRNAsinIschemicStroke. . . . . . . . . . . . . . . . . . . . 107
9.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
9.1.1 Non-codingRNAsataGlance. . . . . . . . . . . . . . . . . . 107
9.2 NewPlayersintheGame. . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
9.2.1 LongNon-codingRNA. . . . . . . . . . . . . . . . . . . . . . . 109
9.2.2 CircularRNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
9.2.3 PIWIRNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
9.3 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
9.4 FuturePerspective.. . . . . . . . . .. . . . . . . . . . .. . . . . . . . . .. . 112
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
PartIII IschemiRs:TheBenchandBeyond
10 ComputationalResourcesformicroRNAResearch. . . . . . . . . . . . . 117
10.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
10.2 MiRNAIdentification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
10.3 MicroRNAPrediction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
10.4 MicroRNADiseaseInteraction. . . . . . . . . . . . . . . . . . . . . . . . 120
10.5 MicroRNA-TargetInteraction. . . . . . . . . . . . . . . . . . . . . . . . . 120
10.6 MicroRNAInteractionwithTranscriptionFactors. . . . . . . . . . . 121
10.7 FutureProspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
x Contents
11 MicroRNA-TargetedTherapeuticsforIschemicStroke:Status,
GapsandtheWayForward. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
11.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
11.2 RestorationofmiRNAFunctionasaPotentialIschemic
StrokeTherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
11.3 DevelopmentofAnti-miRNA-BasedIschemicStroke
Therapeutics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
11.3.1 AntisenseOligonucleotides. . . . . . . . . . . . . . . . . . . . . 127
11.3.2 ChemicallyModifiedAntisenseOligonucleotides/
Antagomirs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
11.3.3 LockedNucleicAcid(LNA). . . . . . . . . . . . . . . . . . . . 128
11.3.4 miRNASponge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
11.4 DeliveryofmiRNAModulatorsforIschemicStrokeTherapy. . 130
11.4.1 Viral-BasedmiRNADeliverySystem. . . . . . . . . . . . . 130
11.4.2 Non-ViralmiRNADeliverySystems. . . . . . . . . . . . . . 131
11.4.3 ExosomalMediatedDeliveryofmiRNAs. . . . . . . . . . 133
11.5 PharmacologicalAgentsandSmall-MoleculesasTherapeutic
ModulatorsofmiRNAs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
11.6 Challenges,Perspectives,andWay-Forward. . . . . . . . . . . . . . . 134
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
About the Authors
RajanikantG.K. iscurrentlyworkingasaProfessorattheSchoolofBiotechnol-
ogyandservedastheCoordinatorofDBT—BioinformaticsInfrastructureFacilityat
National Institute of Technology Calicut, Calicut, India. Having done his Ph.D. in
RadiationBiologyandToxicologyfromDivisionofRadiobiologyandToxicology,
ManipalUniversity,Manipal,India,hewasalsoawardedaSeniorResearchFellow-
shipfromIndianCouncilofMedicalResearch,GovernmentofIndia,NewDelhi,for
theyear2001–2004.Tilldate,hehasworkedasaPrincipalInvestigatorinvarious
government-fundedresearchprojectsandhasfurtherguidedandsupervisedseveral
Doctorate and Post-Doctorate students and researchers. He has also successfully
appliedforanIndianPatentintheyear2017forusingapharmaceuticalcomposition
consisting of 1,4-DI(1H-benzimidazol-2-YL)-1,2,3,4-butanetetrol (BTT) as an
ischemic neuroprotectant. He has also been invited as a speaker to various presti-
gious conferences and has conducted many conferences, workshops, and seminars
successfully.Hehasseveralarticlesinrenownednationalandinternationaljournals,
aswellasbookchaptersandeditedvolumes,tohiscredit.
Pierre Gressens is presently holding several prominent positions, including a
Research Officer (DR1 Inserm) and Director, UMR 1141 Inserm-Paris University,
Robert Debré Hospital, Paris, France; Professor of Fetal and Neonatal Neurology,
KCL, London, UK; Consultant, Service of Pediatric Neurology, Robert Debré
Hospital, Paris, France; Director, PremUP Foundation, Paris; Coordinator of the
University-Hospital Department PROTECT, Robert Debré Hospital, Paris; and
Vice-Deanfor Research,Paris-Diderot MedicalSchool, Paris,France.Heobtained
hisM.D.andPh.D.degreesfromUniversityofLouvainMedicalSchoolatBrussels,
Belgium. He has received various honors, such as Roger de Spoelberch award for
neurosciences (Switzerland) in 2010, FRM Fondation Guillaumat-Piel award
(France) in 2013, and the Elsie Widdowson Lecture at the Neonatal Society,
London, UK in 2017. He has been invited as a speaker to various prestigious
conferences. He has published his research/review articles in many international
journalsofgreatrepute.
SreekalaS.Nampoothiri iscurrentlyapostdoctoralresearcheratINSERM1172,
Development and plasticity of the neuroendocrine brain, Lille Neuroscience &
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