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PREFACE
The field of blood–brain barrier (BBB) pharmacology is a relatively new
area. We owe our start to the seminal work of Reese and Karnovsky
in 1967, whom answered an ongoing controversy, first observed by Paul
Ehrlichin1885,thattheBBBliesprincipallyattheendotheliumofcerebral
capillaryendothelialcells.Soonafterin1969,BrightmanandReeseshowed
keyultrastructuralevidenceofproteintightjunctionsthatfunctiontoblock
paracellular delivery of almost all solutes to the brain primarily due to high
transendothelial cell resistance. In 2002, leaders at the National Institute of
NeurologicalDisordersandStrokeformedaStrokeProgressReviewGroup
(SPRG),whichrecognizedtheurgencytodeterminetheroleoftheBBBin
stroke. This SPRG identified the priority to “better define the molecular
influences and cell-signaling mechanisms that characterize the interaction
betweencirculatingbloodelementsandthebloodvesselwall,theextracel-
lular matrix, glia and neurons (together, the neurovascular unit)....”
(NVU).TheBBBandNVUremainthemostsignificantchallengetocentral
nervous system (CNS) drug development from the past century. This fact
drives the passion of our students and colleagues. We understand that pro-
gress in preventing, diagnosing, or treating diseases of the CNS depends
upon understanding the BBB and NVU. It is often stated, “if we cannot
get the drug into the brain we cannot treat a disease of the brain.”
Presented in this timely volume are three sections of seminal contribu-
tions from outstanding, internationally acclaimed experts describing (1)
BBB/NVU protein, ion, and receptor-mediated transporters that can be
pharmacologically targeted to improve/modulate CNS drug delivery; (2)
world-class experts’focuson specifictargeting ofCNSdisorders associated
with stroke, inflammation, ischemia, cancer, human African trypanosomi-
asis sleeping sickness, and two exciting chapters by established experts
describingrecentadvancesinengineeringproteins,peptides,andantibodies
totreatCNSdisorders;and(3)aspecialinnovativesectiononthechallenges
oftreating complexcomorbiditiessuchashyperglycemia/diabetes/hemor-
rhagic transformation/stroke; aging/metabolic syndrome/ischemic stroke;
and drug abuse-induced CNS disorders.
Iwishtothankeachoneofmyvaluedcolleaguesformakingthisvolume
possible. What links each of these authors together is a strong allegiance to
theirchosenfieldthatisinteractive,collegialandfocusedonexcellence.In
xi
xii Preface
short,wearea“tightgroup”offriendsaswell.AsBBB/NVUinvestigators
wehaveauniqueperspective,andresponsibility,toaddressacriticalprior-
ity; that after a century of developing and testing CNS therapeutics,
pharmaceutical and biotech companies remain frustrated at the enormity
ofproblemsassociatedwithdeliveringdrugstotheCNS.Itismyhopethat
thisvolumeisasourceofinspiration,drugdevelopmentstrategy,andideas
thatresultinimprovedCNSdrugdevelopmentanddelivery.Ifthechapters
in this volume attain these goals and aid patient outcome, it is a success.
THOMAS P. DAVIS
Department of Pharmacology,
College of Medicine, University of Arizona,
Tucson, Arizona, USA
CONTRIBUTORS
ThomasAbbruscato
DepartmentofPharmaceuticalSciences,SchoolofPharmacy,TexasTechUniversityHealth
SciencesCenter,Amarillo,Texas,USA
TamimaAshraf
DepartmentofPharmaceuticalSciences,LeslieDanFacultyofPharmacy,Universityof
Toronto,Toronto,Ontario,Canada
WilliamA.Banks
GeriatricResearchEducationalandClinicalCenter,VeteransAffairsPugetSoundHealth
CareSystem,andDepartmentofMedicine,DivisionofGerontologyandGeriatric
Medicine,UniversityofWashington,Seattle,Washington,USA
DavidJ.Begley
King’sCollegeLondon,InstituteofPharmaceuticalScience,London,UnitedKingdom
ReinaBendayan
DepartmentofPharmaceuticalSciences,LeslieDanFacultyofPharmacy,Universityof
Toronto,Toronto,Ontario,Canada
AlianaY.Culp
DepartmentofNeurology,OregonHealthandScienceUniversity,Portland,Oregon,USA
ThomasP.Davis
DepartmentofPharmacology,CollegeofMedicine,UniversityofArizona,Tucson,
Arizona,USA
NancyD.Doolittle
DepartmentofNeurology,OregonHealthandScienceUniversity,Portland,Oregon,USA
RichardD.Egleton
DepartmentofPharmacology,PhysiologyandToxicology,JoanC.EdwardsSchoolof
Medicine,MarshallUniversity,Huntington,WestVirginia,USA
XiangFan
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA
GrahamK.Farrington
BiogenIdecInc.,12CambridgeCenter,Cambridge,Massachusetts,USA
MehmetFidanboylu
King’sCollegeLondon,InstituteofPharmaceuticalSciences,London,UnitedKingdom
ArsalanS.Haqqani
HumanHealthTherapeuticsPortfolio,NationalResearchCouncilofCanada,Ottawa,
Ontario,Canada
xiii
xiv Contributors
Ken-ichiHosoya
DepartmentofPharmaceutics,GraduateSchoolofPharmaceuticalSciences,Universityof
Toyama,Toyama,Japan
JasonD.Huber
The Center for Neuroscience, School of Medicine, and Department of Basic
Pharmaceutical Sciences, West Virginia University, School of Pharmacy, Morgantown,
West Virginia, USA
YinghuaJiang
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA,andDepartmentofNeurosurgery,TheFirstAffiliatedHospital,
ChongqingMedicalUniversity,Chongqing,PRChina
N.JoanAbbott
King’sCollegeLondon,InstituteofPharmaceuticalScience,London,UnitedKingdom
AmyKao
DepartmentofPharmaceuticalSciences,LeslieDanFacultyofPharmacy,Universityof
Toronto,Toronto,Ontario,Canada
KristinKemmerich
HumanHealthTherapeuticsPortfolio,NationalResearchCouncilofCanada,Ottawa,
Ontario,Canada
EngH.Lo
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA
AricF.Logsdon
The Center for Neuroscience, School of Medicine, and Department of Basic
Pharmaceutical Sciences, West Virginia University, School of Pharmacy, Morgantown,
West Virginia, USA
BrandonP.Lucke-Wold
DepartmentofNeurosurgery,andTheCenterforNeuroscience,WestVirginiaUniversity,
SchoolofMedicine,Morgantown,WestVirginia,USA
DavidS.Miller
LaboratoryofToxicologyandPharmacology,NationalInstituteofEnvironmentalHealth
Sciences,NationalInstitutesofHealth,ResearchTrianglePark,NorthCarolina,USA
LeslieL.Muldoon
DepartmentofNeurology,andDepartmentofCellandDevelopmentalBiology,Oregon
HealthandScienceUniversity,Portland,Oregon,USA
EdwardA.Neuwelt
DepartmentofNeurology;DepartmentofNeurosurgery,OregonHealthandScience
University,andOfficeofResearchandDevelopment,DepartmentofVeteransAffairs
MedicalCenter,Portland,Oregon,USA
Contributors xv
MarthaE.O’Donnell
DepartmentofPhysiologyandMembraneBiology,SchoolofMedicine,Universityof
California,Davis,California,USA
JaneE.Preston
King’sCollegeLondon,InstituteofPharmaceuticalScience,London,UnitedKingdom
PatrickT.Ronaldson
DepartmentofPharmacology,UniversityofArizonaCollegeofMedicine,Tucson,Arizona,
USA
CharlesL.Rosen
DepartmentofNeurosurgery,andTheCenterforNeuroscience,WestVirginiaUniversity,
SchoolofMedicine,Morgantown,WestVirginia,USA
ThereseS.Salameh
GeriatricResearchEducationalandClinicalCenter,VeteransAffairsPugetSoundHealth
CareSystem,andDepartmentofMedicine,DivisionofGerontologyandGeriatric
Medicine,UniversityofWashington,Seattle,Washington,USA
LucySanchez-Covarubias
DepartmentofPharmacology,CollegeofMedicine,UniversityofArizona,Tucson,
Arizona,USA
LisaSanderson
King’sCollegeLondon,InstituteofPharmaceuticalSciences,London,UnitedKingdom
KarinE.Sandoval
PharmaceuticalSciences,SchoolofPharmacy,SouthernIllinoisUniversity,Edwardsville,
Illinois,USA
GayathriN.Sekhar
King’sCollegeLondon,InstituteofPharmaceuticalSciences,London,UnitedKingdom
DanicaStanimirovic
HumanHealthTherapeuticsPortfolio,NationalResearchCouncilofCanada,Ottawa,
Ontario,Canada
XiaochuanSun
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA,andDepartmentofNeurosurgery,TheFirstAffiliatedHospital,
ChongqingMedicalUniversity,Chongqing,PRChina
MasanoriTachikawa
DivisionofMembraneTransportandDrugTargeting,GraduateSchoolofPharmaceutical
Sciences,TohokuUniversity,Sendai,Japan
TetsuyaTerasaki
DivisionofMembraneTransportandDrugTargeting,GraduateSchoolofPharmaceutical
Sciences,TohokuUniversity,Sendai,Japan
SarahA.Thomas
King’sCollegeLondon,InstituteofPharmaceuticalSciences,London,UnitedKingdom
xvi Contributors
BrandonJ.Thompson
DepartmentofPhysiology,UniversityofArizonaCollegeofMedicine,Tucson,Arizona,
USA
MargaretE.Tome
DepartmentofPharmacology,CollegeofMedicine,UniversityofArizona,Tucson,
Arizona,USA
RyanC.Turner
DepartmentofNeurosurgery,andTheCenterforNeuroscience,WestVirginiaUniversity,
SchoolofMedicine,Morgantown,WestVirginia,USA
XiaoyingWang
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA
ChristopherP.Watson
King’sCollegeLondon,InstituteofPharmaceuticalSciences,London,UnitedKingdom
KenA.Witt
PharmaceuticalSciences,SchoolofPharmacy,SouthernIllinoisUniversity,Edwardsville,
Illinois,USA
ShuanglinXiang
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA,andKeyLaboratoryofProteinChemistryandDevelopmentalBiology
ofStateEducationMinistryofChina,CollegeofLifeSciences,HunanNormalUniversity,
Changsha,Hunan,PRChina
ZhanyangYu
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA
JingYuan
NeuroprotectionResearchLaboratory,DepartmentofNeurologyandRadiology,
MassachusettsGeneralHospital,NeuroscienceProgram,HarvardMedicalSchool,Boston,
Massachusetts,USA,andKeyLaboratoryofProteinChemistryandDevelopmentalBiology
ofStateEducationMinistryofChina,CollegeofLifeSciences,HunanNormalUniversity,
Changsha,Hunan,PRChina
CHAPTER ONE
ABC Transporter Regulation
–
by Signaling at the Blood Brain
Barrier: Relevance
to Pharmacology
David S. Miller1
LaboratoryofToxicologyandPharmacology,NationalInstituteofEnvironmentalHealthSciences,National
InstitutesofHealth,ResearchTrianglePark,NorthCarolina,USA
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. Introduction 2
2. ABCTransportersattheBlood–BrainBarrier 4
3. ABCTransporterRegulation 7
3.1 Regulationofexpression 8
3.2 SignalsthatregulateABCtransporteractivity 12
4. Conclusion 20
ConflictofInterest 20
Acknowledgments 20
References 21
Abstract
BraincapillaryendothelialcellsexpressmultipleATP-bindingcassettetransportproteins
ontheluminal,blood-facing,plasmamembrane.Therethesetransportersfunctionas
ATP-driven efflux pumps for xenobiotics and endogenous metabolites, providing an
importantelementofthebarrier.Whenthetransporterslimitneurotoxicantentryinto
thecentralnervoussystem(CNS),theyareneuroprotective;whentheylimittherapeutic
drugentry,theyareobstaclestodrugdeliverytotreatCNSdiseases.Certainly,changes
inthetransporterexpressionandtransportactivitycanhaveaprofoundeffectonCNS
pharmacotherapy,withincreasedtransportactivityreducingdrugaccesstothebrain
andviceversa.Here,Ireviewthesignalsthataltertransporterexpressionandtransport
functionwithanemphasisonP-glycoprotein,MRP2,andbreastcancerresistancepro-
tein(ABCG2)(BCRP),theeffluxtransportersforwhichwehavethemostdetailedpicture
of regulation. Recent work shows that transporter protein expression can be
upregulatedinresponsetoinflammatoryandoxidativestress,therapeuticdrugs,diet,
andpersistentenvironmentalpollutants;asaconsequence,drugdeliverytothebrainis
reduced. For many of these stimuli, the transcription factor, nuclear factor kappa-
light-chain-enhancer of activated B cells (NF-κB), appears to be involved. However,
AdvancesinPharmacology,Volume71 2014PublishedbyElsevierInc. 1
ISSN1054-3589
http://dx.doi.org/10.1016/bs.apha.2014.06.008
2 DavidS.Miller
NF-κBactivationandnucleartranslocationisofteninitiatedbyupstreamsignaling.In
contrast,basaltransportactivityofP-glycoproteinandBCRPcanbereducedthrough
complexsignalingpathways.Targetingsuchsignalsprovidesopportunitiestorapidly
and reversibly increase brain accumulation of drugs that are transporter substrates.
The extent to which such signaling-based strategies can be utilized in the clinic
remainstobeseen.
ABBREVIATIONS
ABC ATP-bindingcassette
AEDs antiepilepticdrugs
AhR arylhydrocarbonreceptor
Akt proteinkinaseB
BCRP breastcancerresistanceprotein(ABCG2)
CAR constitutiveandrostanereceptor
CNS centralnervoussystem
COX-2 cyclooxygenase-2
E2 17-β-estradiol
EP-1 prostaglandinE2receptor
ER estrogenreceptor
ET-1 endothelin-1
GR glucocorticoidreceptor
GSK-3β glycogensynthasekinase3beta
iNOS induciblenitricoxidesynthase
MRP multidrugresistance-associatedprotein(ABCCsubfamily)
NF-κB nuclearfactorkappa-light-chain-enhancerofactivatedBcells
NMDA N-methyl-D-aspartate
Nrf2 nuclearfactor(erythroid-derived2)-like2
PI3-K phosphatidylinositide3-kinase
PKCβ1 proteinkinaseCisoformβ1
PTEN phosphataseandtensinhomolog
PXR pregnaneXreceptor
S1P sphingosine-1-phosphate
S1PR1 sphingosine-1-phosphatereceptor1
TNF-α tumornecrosisfactor-α
VDR vitaminDreceptor
VEGF vascularendothelialgrowthfactor
1. INTRODUCTION
Biologicalsignalingreferstothetransferofinformationwithinorgan-
isms,tissues,andcellsandoverthedimensionsofspaceandtime.Inessence,
this flow of information allows the various parts of multicellular organisms
SignalingattheBlood–BrainBarrier 3
andcellstocommunicatewitheachotherandbeawareofalterationsintheir
extracellular and intracellular microenvironment so that they can respond
appropriately and preserve homeostasis. In general, cells sense changes in
theirexternalenvironmentasalteredlevelsofnutrients,toxicants,stressors,
and signaling molecules that might be receptor ligands or hormones. Cells
then change the form of the message and respond by altered cellular func-
tion, e.g., altered pattern of gene expression, activation or inhibition of
metabolism, release of additional signals. On the one hand, cell signaling
isapartofacomplexsystemofcommunicationthatgovernsbasiccell,tissue,
and organismal activities and coordinates actions and responses. On the
other hand, aberrant signaling is the mechanistic basis for many diseases,
including cancer and diabetes.
Thetraditionalconceptofbiologicalsignalinghasinvokeddiscretepath-
ways.However,wehavelongknownthatthesepathwaysintersect,thatthe
intersectionsarenumerousandthattheconnectedpathwayscanformcom-
plexsignalingnetworks.Ithasbecomeclearthatafullunderstandingofcell
function and regulation requires knowledge of the major signaling path-
ways,theunderlyingstructureofsignalingnetworks,theemergentfeatures
ofthenetworks,andthewaysbywhichchangesinnetworkstructureaffect
thetransmissionandflowofinformationoverspaceandtime.Whetherwe
are considering genetic or metabolic networks, the existence of complex
network structures within cells has important implications. First, network
structure indicates that multiple paths are available for signals to flow from
pointAtopointB(Janes&Lauffenberger,2013).Thisimpliesthatthepath
taken and the integrated response can be context-dependent, i.e., deter-
minedbywhatelsemaybehappeningwithinthecellortissue.Forexample,
such complexity has been shown to be the basis for interaction between
growth factor and proinflammatory signaling (Janes & Lauffenberger,
2013). Second, complex multicomponent signaling pathways provide
opportunities for feedback, signal amplification, and interactions involving
multiple signals and signaling pathways. Third, added complexity comes
from the fact that signaling networks have an intrinsic spatial component,
since signals often must cross multiple cellular domains, e.g., plasma mem-
brane, cytoplasm, and nucleus.
Cellularsignalingnetworkscomeintwoflavors:geneticandmetabolic.
Genetic networks are characterized by a structure that is focused on gene
expressionandthusleadstoalterationsinthemRNAand/orproteinexpres-
sionofkeycomponents;theseinturnaffectcellfunction(Boucher&Jenna,
2013).Becauseofthetimerequiredfortranscription/translation,responses
