血脑屏障(英文版)-课件

Structureandfunctionoftheblood–brainbarrierNeurobiologyofDisease

2017.9.20ABSTRACTNeuralsignallingrequiresahighlycontrolledmicroenvironmentCellsatthreekeyinterfacesformbarriers

BBBmajorsiteofblood–CNSexchangeblood–CSFbarrierthearachnoidbarrier

thephysicalbarriertheendothelialtightjunctions

thetransportbarriermembranetransportersandvesicularmechanisms.

astrocyticglialcellsendfeetTheassociatedcellspericytes

microglia

TheembryonicdevelopmentoftheBBB,andchangesinpathologyAnyprogrammefordrugdiscoveryordelivery,totargetoravoidtheCNS,needstoconsiderthespecialfeaturesoftheBBB.

1.Introduction

2.BBBtightjunctions

3.TransportacrosstheBBB

4.Developmentoftheblood–brain

5.Blood–brainbarrierinpathology

6.Blood–brainbarrierregulation

1.Introduction

1.1Signallinginthecentralnervoussystem

chemicalNeuronsCommunicationelectricalsignalslocalioni

Barrierlayersplayamajorroleinthisregulation

1.2

CNSbarriers

microvessels

thebloodcerebrospinalfluidbarrier

theavasculararachnoidepithelium

thelargestinterfaceforblood–brainexchangethesealbetweentheextracellularfluidsofthecentralnervoussystemandthatoftherestofthebody

theepithelialcellsofthechoroidplexus1.3.FunctionsofCNSbarriers

1.3.1Ionregulation

TheBBBprovideacombinationofspecificionchannelsandtransporters

keepstheioniccompositionoptimalforsynapticsignallingfunctionCa2+

Mg2+andpHareactivelyregulatedattheBBBandBCSFB

1.3.2Neurotransmitters

BBBhelpstokeepthecentralandperipheraltransmitterpoolsseparateandcommunicatewitheachother.

Glutamatereleasedinanuncontrolledmannerstrokeconsiderableandpermanentneurischemicotoxic/neuroexcitatorydamage

1.3.3Macromolecules

preventsmacromoleculesfromenteringthebrainNeuroproteceive

Plasmaproteinsdamagingtonervoustissueleadtoapoptosis

ahigherconcentrationinCSFthaninplasmamaybeaprotectivemeasureagainstmicro-leakspreventallowplasmacomponentstoseepintothebrain1.3.4Neurotoxins

TheBBBshieldstheCNSfromneurotoxicsubstances

*endogenousmetabolites

*Proteins

*xenobioticsingestedinthedietorfrom

theenvironment

1.3.5Brainnutrition

TheBBBhaslowpassivepermeabilitySpecifictransportsystemsthereforeareexpressedintheBBBtoensureanadequatesupplyofthesesubstances

essentialwatersolublenutrientsmetabolites2.BBBtightjunctionstightjunctions(akeyfeatureoftheBBB)

reducepermeationofpolarsolutesthroughparacellulardiffusionalpathwaysThejunctionalcomplexesadherensjunctions(AJs)TJsAjsholdingthecellstogethergivingthetissuestructuralsupportdisruptionbarrier

afurthercomplexofproteins(occludinandclaudins)andjunctionaladhesionmolecules(JAMs)disruptionThetightjunctionsTJs

InEAEandGBMselectiveofclaudin-3

lossofBBBintegritypermeabilityareassociatedwithinflammatoryeventsattheBBBlackclaudin-5aseverelycompromisedandleakyblood–brainbarrierdieshortlyafterbirthTJsisnotsolelyrelatedtotheexpressionandpresenceofclaudinsandoccludin,butisalsoinfluencedbythewaytheseproteinsareorganizedandinteract

Thetightjunctionsareresponsibleforthesevererestrictionoftheparacellulardiffusionalpathwaybetweentheendothelialcellstoionsandotherpolarsolutes,andeffectivelyblockpenetrationofmacromolecules

Inductionandmaintenanceofblood–brainbarrierpropertiesastrocytesTightjunctioncanbeinduced

barrierinductioninvolvesmultipleagentsandcelltypesinductionbypericytes,neuronsandcellsofmonocytelineagehasalsobeendescribed

3.TransportacrosstheBBB

3.1PassivepartitioningintobrainAwiderangeoflipid-solublemoleculescandiffusethoughtheBBBandenterthebrainpassively.

FactorsrestricttheentryofcompoundsintotheCNS

*polarsurfacearea(PSA)

*rotatablebondsinthemoleculeandamolecularweightinexcessof450Da

*Ahighaffinityofbindingtoplasmaproteinswithalowoff-rateThesefactorsarenotalwaysanabsoluteindication

Thesefactorsarenotalwaysanabsoluteindication3.2SolutecarriersintheBBB

ThebarrierisolatesthebrainfrommanyessentialpolarnutrientstheBBBendotheliummustcontainanumberofspecificsolutecarriertosupplytheCNSwiththesesubstances.

MostpolarmoleculescannotdiffusethroughcellmembranesexpressSLCsinthecellmembrane

3.3ATP-bindingcassettetransporters

alargenumberofsolutesanddrugshaveamuchlowerCNSentryratethanmightbeexpectedfromtheirlogDincreasingthelipidsolubilityofadrugtomakeitmorebrainpenetrantmaysometimesbecounter-productiveincreasethelikelihoodofthemoleculebecomingasubstrateforABCeffluxtransporters

ThemajorfunctionoftheABCtransportersintheBBB

pumpsconsumingATPtransportingadiverserangeoflipid-solublecompoundsremovingfromthebrainpotentiallyneurotoxicendogenousorxenobioticmoleculeneuroprotectiveanddetoxifyingfunction

3.4BBBtransportofmacromoleculesspecificandsomenon-specifictranscytotic

mechanismstransportlargemoleculesandcomplexesacrosstheBBB.

Thesevesicularmechanismsreceptor-mediatedtranscytosis(RMT)adsorptive-mediatedtranscytosis(AMT).

RMTreceptorsandtheirboundligandclustercaveolusInternalisedDissociationoftheligand/receptorpresumablyoccursduringcellulartransitorduringtheexocytoticevent

AMTrequiresanexcesspositivechargeinteractionwithcellsurfacebindingsitesinducesendocytosisandsubsequenttranscytosis

3.5CellmovementacrosstheBBB

**Cellsfromthebone-marrowderivedmonocytelineageenterthebrainduringembryonicdevelopmentandbecomeresidentimmunologically-competentmicroglia

**IninflammationandpathologicalstatesPerivascularmacrophagesandmicrogliaactivatedthetightjunctionsopenedcytokinesandotheragents,andmononuclearcellsenter

4.Developmentoftheblood–brainbarrier

TheBBBdevelops(fetallifeandiswellformedbybirth)Inthemouseidentifiabletightjunctionsarepresent(E11E17)ionregulationmaycontinuetomatureandonlybecomefullyexpressedandfunctionalintheperi-orpost-natalperiodWnt/beta-cateninsignallingcontrolsdevelopmentof

theblood–brainbarrier

Thehighelectricalresistance,characteristicoftheblood–brainbarrierexhibitedintheBBBofratsbyE21

aneffectivebarriertothemovementofions

TightjunctionformationappearstobeaveryearlyfeatureofBBBdevelopmentandbeinitiatedbysignalsfromneuronsandprogenitorcellsratherthanfromdifferentiatedgliainthefirstinstance.