The Blood Brain Barrier (BBB)

169 Pages·2014·3.326 MB·English

by  Gert Fricker, Melanie Ott, Anne Mahringer (eds.)

Topics in Medicinal Chemistry 10
Gert Fricker
Melanie Ott
Anne Mahringer Editors
The Blood
Brain
Barrier (BBB)
10
Topics in Medicinal Chemistry
EditorialBoard:
P.R.Bernstein,RoseValley,USA
A.Buschauer,Regensburg,Germany
G.I.Georg,Minneapolis,USA
J.A.Lowe,Stonington,USA
U.Stilz,Malov,Denmark
C.T.Supuran,SestoFiorentino(Firenze),Italy
A.K.Saxena,Lucknow,India
Aims and Scope
Drugresearchrequiresinterdisciplinaryteam-workattheinterfacebetweenchemis-
try,biologyandmedicine.Therefore,thenewtopic-relatedseriesTopicsinMedicinal
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of diseases, identification and validation of (emerging) drug targets, structural
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Gert Fricker Melanie Ott Anne Mahringer
l l
Editors
The Blood Brain Barrier
(BBB)
With contributions by
D. Belletti (cid:1) R. Chhabra (cid:1) R. van Doorn (cid:1) D. Ferna´ndez-
Lo´pez (cid:1) F. Forni (cid:1) G. Fricker (cid:1) A.M. Grabrucker (cid:1)
(cid:1) (cid:1) (cid:1)
M. Hammarlund-Udenaes A. Mahringer S. Meairs
(cid:1) (cid:1) (cid:1) (cid:1) (cid:1)
D.S. Miller M.R. Mizee M. Ott A. Prat B. Ruozi
(cid:1) (cid:1) (cid:1)
G. Tosi M.A. Vandelli Z.S. Vexler H.E. de Vries
Editors
GertFricker MelanieOtt
Institutfu¨rPharmazieundMolekulare AnneMahringer
Biotechnologie Dept.forPharmaceuticalTechnologyand
Universita¨tHeidelberg Pharmacology
Heidelberg InstituteofPharmacyandMolecular
Baden-Wu¨rttemberg Biotechnology
Germany
Heidelberg
Germany
ISSN1862-2461 ISSN1862-247X(electronic)
ISBN978-3-662-43786-5 ISBN978-3-662-43787-2(eBook)
DOI10.1007/978-3-662-43787-2
SpringerHeidelbergNewYorkDordrechtLondon
LibraryofCongressControlNumber:2014947829
#Springer-VerlagBerlinHeidelberg2014
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Preface
Since its discovery by Paul Ehrlich in the late nineteenthcentury, the blood–brain
barrier has been the object of intensive research. It is formed by brain capillary
endothelialcellsandrepresentsadynamicinterfacethatseparatesthebrain,themost
criticalorganinourbody,fromthebloodcirculation.Itprotectsthecentralnervous
system(CNS)frompotentiallyharmfulxenobioticsandmetabolites,whilesimulta-
neously regulating transport of essential molecules and maintaining a stable envi-
ronment within the brain. Together with pericytes, astrocytes and neurons, the
capillaryendothelialcellsformtheso-calledneurovascularunit,whichisregulated
by extremely complex signaling cascades. Unfortunately, the blood–brain barrier
alsopreventsmosttherapeuticagentsfromreachingtheirtargetinthebrain,whichis
whyeffectivetreatmentofCNSdiseasessuchasAlzheimer´sdisease,Parkinson’s
Disease, Depression, Epilepsy or brain tumors, including brain metastases from
peripheraltumors,remainstobeoneofthebigchallengesinmodernmedicine.
This volume of “Topics in Medicinal Chemistry” is a compilation of the latest
research concerning new developments in the blood–brain barrier field. Seven
internationallyacknowledgedresearchgroupshavecontributedchapters,detailing
their findings in this exciting and challenging area of biomedical research. Their
workscoverabroadrangeoftopicsincludinggeneralstructureandfunctionofthe
blood–brainbarrier,modestostudytheblood–brainbarrierinvivo,activetransport
systems,drugdeliveryacrossthebarrierbycolloidalcarriersorultrasoundaswell
as alterations of the barrier at various disease states. From these chapters the
complexity of the blood–brain barrier becomes apparent and they also illustrate
which enormous efforts still lie ahead of us before we obtain a complete under-
standingofthisfascinatingarea.
Ithasbeenagreatpleasureforustoactaseditorsforthisvolumeandwethank
allauthorswhocontributed.Inaddition,wehopethatthevolumemightstimulate
others to enter this research area and help to clarify the manifold unresolved
questions.
Heidelberg,Germany GertFricker
April2014 MelanieOtt
AnneMahringer
v
.
Contents
TheBlood–BrainBarrier:AnIntroductiontoItsStructure
andFunction .................................................................... 1
AnneMahringer,MelanieOtt,andGertFricker
InVivoApproachestoAssessingtheBlood–BrainBarrier ................ 21
MargaretaHammarlund-Udenaes
ABCTransportersattheBlood–BrainBarrier ............................. 49
DavidS.Miller
NanoparticlesasBlood–BrainBarrierPermeableCNSTargeted
DrugDeliverySystems ........................................................ 71
AndreasM.Grabrucker,ReshamChhabra,DanielaBelletti,FlavioForni,
MariaAngelaVandelli,BarbaraRuozi,andGiovanniTosi
Blood–BrainBarrierandStroke ............................................. 91
DavidFerna´ndez-Lo´pezandZinaidaS.Vexler
InflammationattheBlood–BrainBarrierinMultipleSclerosis ......... 117
MarkR.Mizee,RubenvanDoorn,AlexandrePrat,andHelgaE.deVries
DrugDeliveryAcrosstheBlood–BrainBarrierwithFocused
UltrasoundandMicrobubbles .............................................. 143
StephenMeairs
Index .......................................................................... 159
vii
TopMedChem(2014)10:1–20
DOI:10.1007/7355_2013_20
©Springer-VerlagBerlinHeidelberg2013
Publishedonline:13December2013
The Blood–Brain Barrier: An Introduction to
Its Structure and Function
AnneMahringer,MelanieOtt,andGertFricker
Abstract Theblood-brainbarrier(BBB)formedbythebrainsmicrovascularsystem
isimpermeableformosttherapeuticallyusedcompoundsandovercomingthisbarrier
remains to be one of the big challenges in modern medicine. It is composed of
highly specialized endothelial cells, which are surrounded by pericytes and a basal
membrane.Togetherwithnearbyastrocytesandneuronstheyconstitutetheso-called
neurovascular unit, which restricts substance transfer from blood to brain and vice
versa and maintains the cerebral ion homeostasis. Chapters of this book describe the
discovery of the BBB, its evolutionary development as well as the cellular and
molecularmechanisms,whichunderlayitsstructureandfunctioninhealthanddisease.
The organization of tight junctional complexes or specific transport processes at the
BBBwillbeaddressedaswellasmethodstoinvestigateBBBfunctioninvitroandin
vivo.Changesinthebarrierfunctionunderseveraldiseasesconditionssuchasstroke
or inflammation will be discussed as well as approaches to overcome the barrier by
colloidalcarriersorultrasound.
Keywords Blood–brainbarrier,Neurovascularunit,Morphology,Transporter
Contents
1 TheBBB:AHistoricalPerspective.......................................................... 2
2 EvolutionaryDevelopmentofaBBB....................................................... 5
3 AnatomicPrinciplesoftheBBB............................................................. 5
4 Pericytes...................................................................................... 7
5 Astrocyte:EndotheliumInteractions........................................................ 8
A.Mahringer(*),M.OttandG.Fricker
InstituteofPharmacyandMolecularBiotechnology,Ruprecht-KarlsUniversity,ImNeuenheimer
Feld366,69120Heidelberg,Germany
e-mail:[email protected];[email protected];[email protected]
2 A.Mahringeretal.
6 Neurons...................................................................................... 8
7 BasalMembrane............................................................................ 9
8 JunctionalComplexesattheBBB.......................................................... 9
9 TransportProteinsattheBBB.............................................................. 12
10 CytoticProcessesattheBBB............................................................... 14
11 Outlook...................................................................................... 15
References........................................................................................ 16
The brain is the most critical organ in our body, which requires a very well-
balancedionhomeostasis.Itisextremelysensitivetoalargevarietyofchemicals,
whichincludepotentiallytoxicmetabolitesorconstituentsofourdailyfoodintake
without being toxic to other parts of the body. Therefore, it is obvious that the
centralnervoussystem(CNS)needsspecialprotection,whichissetupbythebrain
capillaries, the so called blood–brain barrier (BBB). This microvessel network
operates as a dynamic regulator of ion balance, a mediator of nutrient transport,
and an impediment to harmful molecules. This barrier also represents a major
obstacletothedevelopmentofCNSdrugs.Approximately98%ofsmallmolecule
and all large molecule drugs, e.g., recombinant peptides or anti-sense-agents are
normallyexcludedfromthebrain[1,2].Hence,theunderstandingofthemorpho-
logyoftheBBBaswellasthemolecularandcellularmechanismsthatdetermineits
functionisaninevitableprerequisiteforsuccessfuldrugdeliverytothebrain.Here,
wereviewtheBBBfromahistoricalperspectiveanddiscussthecurrentknowledge
aboutthecomponentsofthatbarrierandtheirintegratedfunction.
1 The BBB: A Historical Perspective
Thefirstexperimentsindicatingtheexistenceofthebarrierwereperformedin1885
by the German immunologist Paul Ehrlich. He observed that a peripherally
administered dye stained animal organs but failed to color brain tissue [3]. The
initial interpretation of this finding was based on different binding affinities [4].
Subsequent pharmacological studies by Bield and Kraus [5] and Lewandowsky
provokedtheexistenceofabarrieratthelevelofcerebralvessels(1900),especially
whenLewandowskywasstudyingthelimitedpermeationofpotassiumferrocyanate
into the brain. This barrier was named “blood–brain barrier” by Goldmann [6].
Goldmann, a student of Ehrlich, also performed staining experiments with dogs
andrabbitswherehedemonstratedaclear,exclusivestainingofthechoroidplexus
after injection of water soluble dyes into the peripheral circulation, whereas the
surrounding brain tissue and cerebrospinal fluid (CSF) remained colorless [7], thus
confirming observations of other scientists in the years before [5, 8–10]. He also
found that after sub-arachnoidal injection the brain was stained except the choroid
plexusandconcludedthattheplexusepitheliumwastheverybarrierpreventingthe
transfer of dye into the brain [6]. However, the Russian physiologist Lina Stern
observedthatsometestcompoundscouldbefoundselectivelyinthebrainandinthe